Early differences in dynamic uptake of 68Ga-PSMA-11 in primary prostate cancer: A test-retest study.

INTRODUCTION: Dynamic PET/CT allows visualization of pharmacokinetics over the time, in contrast to static whole body PET/CT. The objective of this study was to assess 68Ga-PSMA-11 uptake in pathological lesions and benign tissue, within 30 minutes after injection in primary prostate cancer (PCa) patients in test-retest setting. MATERIALS AND METHODS: Five patients, with biopsy proven PCa, were scanned dynamically in list mode for 30 minutes on a digital PET/CT-scanner directly after an intravenous bolus injection of 100 MBq 68Ga-PSMA-11. Approximately 45 minutes after injection a static whole body scan was acquired, followed by a one bed position scan of the pelvic region. The scans were repeated approximately four weeks later, without any intervention in between. Semi-quantitative assessment was performed using regions-of-interest in the prostate tumor, bladder, gluteal muscle and iliac artery. Time-activity curves were extracted from the counts in these regions and the intra-patient variability between both scans was assessed. RESULTS: The uptake of the iliac artery and gluteal muscle reached a plateau after 5 and 3 minutes, respectively. The population fell apart in two groups with respect to tumor uptake: in some patients the tumor uptake reached a plateau after 5 minutes, whereas in other patients the uptake kept increasing, which correlated with larger tumor volumes on PET/CT scan. Median intra-patient variation between both scans was 12.2% for artery, 9.7% for tumor, 32.7% for the bladder and 14.1% for the gluteal muscle. CONCLUSION: Dynamic 68Ga-PSMA-11 PET/CT scans, with a time interval of four weeks, are reproducible with a 10% variation in uptake in the primary prostate tumor. An uptake plateau was reached for the iliac artery and gluteal muscle within 5 minutes post-injection. A larger tumor volume seems to be related to continued tumor uptake. This information might be relevant for both response monitoring and PSMA-based radionuclide therapies.

Cystic fibrosis: terminology and diagnostic algorithms.

There is great heterogeneity in the clinical manifestations of cystic fibrosis (CF). Some patients may have all the classical manifestations of CF from infancy and have a relatively poor prognosis, while others have much milder or even atypical disease manifestations and still carry mutations on each of the CFTR genes. It is important to distinguish between these categories of patients. The European Diagnostic Working Group proposes the following terminology. Patients are diagnosed with classic or typical CF if they have one or more phenotypic characteristics and a sweat chloride concentration of >60 mmol/l. The vast majority of CF patients fall into this category. Usually one established mutation causing CF can be identified on each CFTR gene. Patients with classic CF can have exocrine pancreatic insufficiency or pancreatic sufficiency. The disease can have a severe course with rapid progression of symptoms or a milder course with very little deterioration over time. Patients with non-classic or atypical CF have a CF phenotype in at least one organ system and a normal (<30 mmol/l) or borderline (30-60 mmol/l) sweat chloride level. In these patients confirmation of the diagnosis of CF requires detection of one disease causing mutation on each CFTR gene or direct quantification of CFTR dysfunction by nasal potential difference measurement. Non-classic CF includes patients with multiorgan or single organ involvement. Most of these patients have exocrine pancreatic sufficiency and milder lung disease. Algorithms for a structured diagnostic process are proposed.

Nutrition in patients with cystic fibrosis: a European Consensus.

This document is the result of an European Consensus conference which took place in Artimino, Tuscany, Italy, in March 2001 involving 33 experts on nutrition in patients with cystic fibrosis, organised by the European Cystic Fibrosis Society, and sponsored by Axcan-Scandipharm, Baxter, Dr Falk Pharma, Fresenius, Nutricia, SHS International, Solvay Pharmaceuticals (major sponsor). The purpose of the conference was to develop a consensus document on nutrition in patients with cystic fibrosis based on current evidence.

Directing portal flow is essential for graft survival in auxiliary partial heterotopic liver transplantation in the dog.

BACKGROUND/PURPOSE: Auxiliary liver transplantation is an attractive alternative for orthotopic liver transplantation in patients with certain inborn errors of metabolism of the liver in which complete resection of the liver is unnecessary or even contraindicated. Because in these diseases portal hypertension is mostly absent, finding a balance in portal blood distribution between native liver and graft is complicated. The objective of this study was to investigate requirements for long-term (180 days) graft survival in auxiliary partial heterotopic liver transplantation (APHLT) in a dog model. METHODS: A metabolic defect was corrected in 26 dalmation dogs with a 60% beagle heterotopic auxiliary liver graft. Four groups of different portal inflow were studied. In the ligation group the portal vein to the host liver was ligated. In the split-flow group graft and host liver received separate portal inflow. In the banding group the distribution of the portal flow was regulated with an adjustable strapband and in the free-flow group the portal blood was allowed to flow randomly to host or graft liver. RESULTS: Metabolic correction increased in all groups after transplantation from 0.19 +/- 0.02 to 0.70 +/- 0.05 (P< .0001) but remained significantly better in the ligation and split-flow groups (graft survival, 135 +/- 27 and 144 +/- 31 days). In the banding group metabolic correction decreased significantly after 70 days, and although the grafts kept some function for 155 +/- 14 days, in 4 of 6 dogs portal thrombosis was found. In the free-flow group, competition for the portal blood led to reduced correction within 12 days and total loss of function in 96 +/- 14 days. Graft function also was assessed with technetium (Tc) 99m dimethyl-iminodiacetic acid uptake. A good linear association between HIDA uptake and metabolic correction was observed (r = 0.74; P < .0005). Grafts that contributed more than 15% to the total uptake of HIDA showed biochemical correction. This indicates a critical graft mass of about 15% to 20% of the hepatocyte volume to correct this metabolic defect. CONCLUSION: Auxiliary partial heterotopic liver transplantation can be a valuable alternative treatment for inborn errors of hepatic metabolism if the native liver and the graft receive separate portal blood inflow.

Blocking of alpha 1 beta 1 integrin strongly improves survival of hepatocytes in allogeneic transplantation.

The survival rate of hepatocytes after allogeneic hepatocyte transplatation (HTX) is low, possibly because of formation of intravascular hepatocyte aggregates. The aim of this study was to determine the role of integrins in intravascular aggregation and intraparenchymal survival of transplanted hepatocytes in a fully allogeneic rat model. First, the expression profile of various integrins was determined on both isolated hepatocytes in vitro and on hepatocyte aggregates in recipient livers after intraportal transplantation of allogeneic hepatocytes. Next, the role of these integrins in hepatocyte aggregation was determined in an in vitro attachment assay on liver sections with function-blocking anti-integrin monoclonal antibodies (mAb). The results showed that anti-alpha 1 beta 1 integrin mAb significantly block hepatocyte attachment to vessel walls and liver parenchyma in vitro. Subsequently, the effect of preincubation of hepatocytes with anti-integrin mAb on their intravascular aggregation and on intraparenchymal survival was studied in an allogeneic HTX model. Preincubation with anti-leukocyte function-associated antigen-1 alpha or anti-beta 2 mAb significantly intravascular hepatocyte aggregation, and anti-leukocyte function-associated antigen-1 alpha mAb enhanced intraparenchymal survival. Preincubation with anti-alpha 1 or anti-beta 1 mAb did not inhibit aggregation but significantly improved survival from 2% to up to 45% at Day 2 after transplantation (p < 0.001). In conclusion, our results suggest that the blocking of alpha 1 beta 1 integrin significantly improves survival of allotransplanted hepatocytes.

Clinical use of acid steatocrit.

Malabsorption of fat is an important gastrointestinal cause of malnutrition and growth retardation in childhood. The gold standard for the evaluation of fat malabsorption is the faecal fat balance method. The acid steatocrit method has recently been introduced as a simple method to evaluate faecal fat. The present study was aimed at evaluating the acid steatocrit in clinical practice. Faecal fat excretion and acid steatocrit results were determined in 42 children, half with and half without fat malabsorption. Acid steatocrit results correlated significantly with both faecal fat excretion (p < 0.01) and faecal fat concentration (p < 0.001). Sensitivity and specificity of the acid steatocrit for the diagnosis of malabsorption were 90% and 100%, respectively. We consider the acid steatocrit method useful for the screening and monitoring of patients with steatorrhoea.

Low-dose versus high-dose ursodeoxycholic acid in cystic fibrosis-related cholestatic liver disease. Results of a randomized study with 1-year follow-up.

BACKGROUND: Ursodeoxycholic acid (UDCA) is beneficial in cholestasis related to cystic fibrosis (CF). High-dose treatment has been recommended to compensate for bile salt malabsorption. We compared the results of low-dose (10 mg/kg/day) and high-dose (20 mg/kg/day) UDCA treatment on liver biochemistry after 3 and 12 months' treatment. METHODS: Thirty CF patients (age > 5 years) with biochemical cholestasis and compensated liver disease were randomized for low-dose (n = 17) or high-dose (n = 13) UDCA. Baseline clinical variables were comparable. RESULTS: After 1 year one patient had died of liver failure (low dose), and three had dropped out because of pruritus (one in each group) or personal choice (low dose). In the high-dose group improvement in gamma-glutamyl transferase values was more pronounced after 3 months and 1 year (P < 0.004), and improvement of alanine aminotransferase was better after 1 yer (P < 0.02). Improvement of alkaline phosphatase and aspartate aminotransferase was comparable. Complete normalization of liver enzymes and bilirubin occurred more often in the high-dose group. CONCLUSION: High-dose UDCA induces a better response of liver biochemistry values than low-dose UDCA in CF patients with cholestatic liver disease.

Fecal polyamine concentration in children with and without nutrient malabsorption.

BACKGROUND: Fermentation products of malabsorbed nutrients are thought to be responsible for intestinal adaptation following small bowel resection in rats. It has been suggested that either short-chain fatty acids or polyamines (mainly putrescine and cadaverine) could be the fermentation products involved. There are no data available on fecal polyamine content in humans. The present study compared the fecal polyamine concentrations in children with and without malabsorption. METHODS: Sixteen (8 girls, 8 boys) malabsorption patients (cystic fibrosis: 13, short bowel syndrome: 2, biliary atresia: 1) with a mean age of 8 years were compared to 17 (9 girls, 8 boys) sick children without malabsorption (mean age 5.7 years). Three-day fecal collections were performed and analyzed for fat and polyamine concentrations. High-performance liquid chromatography (HPLC) was used for the measurement of polyamine concentrations. RESULTS: Mean and SEM for fecal fat excretion was 13.4 +/- 2.5 g/day and 1.5 +/- 0.3 g/day in the malabsorption and control group respectively. Median fecal cadaverine and putrescine concentrations were 3723 mumol.kg-1 feces and 4737 mumol.kg-1 feces for the malabsorption group and 114 mumol.kg-1 feces and 306 mumol.kg-1 feces for the control group (p < 0.007 and < 0.00001 respectively). No significant differences were found for fecal spermine and spermidine concentrations between the two groups. CONCLUSIONS: Children with malabsorption show very high fecal putrescine and cadaverine concentrations. Our results support the hypothesis that fecal polyamines could be important.

In vivo measurement of chloride and water secretion in the jejunum of cystic fibrosis patients.

In the present study, we have investigated the possible consequences of the chloride channel defect in the intestine of cystic fibrosis (CF) patients for electrolyte and water transport in the jejunum in vivo, using a multilumen, double occluding balloon catheter, and an Ag/AgCl intraluminal electrode. During a chloride-free perfusion, to optimize the sensitivity of our measurements, the transmural potential difference (PD) (lumen with reference to serosal side) was found to be significantly higher in the jejunum of CF patients (+8.0 +/- 2.1 mV; n = 5) than in healthy control subjects (-2.2 +/- 2.0 mV; n = 9). The chloride concentration measured in chloride-free jejunal perfusates of CF patients was significantly lower than in controls (10.9 +/- 2.3 and 41.4 +/- 8.2 mM, respectively). Possible differences in net chloride and water secretion did not reach statistical significance (chloride secretion controls: -2.1 +/- 0.9 mmol/10 cm/h; CF: -0.8 +/- 0.2 mmol/10 cm/h; water secretion controls: -0.8 +/- 2.5 mL/10 cm/h; CF: -11.7 +/- 8.9 mL/10 cm/h). In control subjects, intraluminally applied theophylline stimulated the secretion of water (delta 23.4 +/- 4.6 mL/10 cm/h) and chloride (delta 4.1 +/- 1.1 mmol/10 cm/h), but not in CF patients (respectively delta 3.6 +/- 3.3 mL/10 cm/h and delta 1.1 +/- 1.1 mmol/10 cm/h). In controls, theophylline caused a significant increase in lumen negativity (PD -10.2 +/- 2.6 mV), but no change could be seen in CF patient transmural PD. These observations provide in vivo evidence for a decreased chloride permeability in the jejunum in CF, resulting in a significant reduction in net electrolyte and water secretion in the presence, but not in the absence, of an intestinal secretagogue.

Correction of an inborn error of metabolism by intraportal hepatocyte transplantation in a dog model.

The aims of this study were (1) to assess portal hemodynamics during intraportal hepatocyte transplantation (HTX) in dogs, (2) to evaluate a new method for the detection of transplanted hepatocytes using 5-bromo-2'-deoxyuridine (BrdU) incorporation, and (3) to determine the metabolic effects of HTX on an inborn error of the purine metabolism in dalmatian dogs. HTX was performed by intraportal infusion of freshly isolated allogeneic beagle hepatocytes. Portal flow and pressure were monitored continuously during HTX. For the detection experiments, beagles received hepatocytes that had been exposed to BrdU during regeneration of the donor liver, induced by partial hepatectomy. For metabolic studies, dalmatian dogs were used as recipients. Repetitive HTX was performed. As judged by the portal hemodynamics, the number of hepatocytes that could be infused safely varied from 5 x 1O(8) to 8 x 1O(8) in beagles, to 1 x 10(9) in dalmatians. Transaminase levels showed a 5- to 6-fold increase (P=0.05) after HTX, but normalized within 3 weeks. BrdU-positive cells were identified in the recipient livers 2 weeks after HTX and 5-10% of the total amount of transplanted hepatocytes was retrieved. A significant (P=0.05) decrease in serum uric acid was demonstrated after repeated HTX in dalmatians. In conclusion, (1) intraportal HTX is feasible, but portal hypertension limits the maximum amount of hepatocytes that can be infused in one HTX; (2) BrdU labeling is an attractive method for the detection of transplanted hepatocytes in the recipient liver; and (3) after two consecutive hepatocyte transplantations, a temporary correction of the purine metabolism was accomplished in the dalmatian dog.

Current therapy for Crigler-Najjar syndrome type 1: report of a world registry.

This study represents a multicenter survey on the management of patients with Crigler-Najjar syndrome (CNS) type 1. The aim of the survey was to find guiding principles for physicians in the care of these patients. Fifty-seven patients were included. At the time of inclusion, 21 patients had received a liver transplant (37%). The average age at transplantation was 9.1 +/- 6.9 years (range, 1-23 years); the age of the patients who had not been transplanted at the time of inclusion was 6.9 +/- 6.0 years (range, 0-23 years). Brain damage had developed in 15 patients (26%). Five patients died, and 10 are alive with some degree of mental or physical handicap. In 2 patients, ages 22 and 23 years, early signs of bilirubin encephalopathy could be reversed, in 1 by prompt medical intervention followed by liver transplantation and in the other by prompt liver transplantation. Seven patients underwent transplantation with some degree of brain damage at the time of the surgery; 1 of these died after retransplantation, 2 improved neurologically, and 4 remained neurologically impaired. The age of 8 patients with and 13 without brain damage at or before transplantation was 14.3 +/- 5.9 and 5.9 +/- 5.4 years (P < .01), respectively. Therapy of CNS type 1 consists of phototherapy (12 h/d), followed by liver transplantation. Phototherapy, although initially very effective, is socially inconvenient and becomes less efficient in the older age group, thus also decreasing compliance. Currently, liver transplantation is the only effective therapy. This survey shows that, in a significant number of patients, liver transplantation is performed after some form of brain damage has already occurred. From this, one must conclude that liver transplantation should be performed at a young age, particularly in situations in which reliable administration of phototherapy cannot be guaranteed.

Present and future treatment modalities for gastrointestinal diseases in cystic fibrosis.

In recent years knowledge of the basic defect of CF has increased enormously. Many new drugs and treatment strategies are being introduced in the clinic. Nevertheless, there are a number of unsolved problems in the treatment of malabsorption and malnutrition. In spite of innovative technical and pharmacological improvement of pancreatic enzyme preparations maldigestion is still a problem. Better enzymes and coatings are needed. The integrated action of enzymatic digestion, intestinal motility and absorption is not under control. The role of malnutrition in the development of complications and in the outcome of the disease is still under discussion. The importance of a high energy intake is now generally accepted, but the question is how to achieve this. Tube feeding, endoscopic gastrostomy and the use of diets with a high energy content are becoming more popular. In CF the relationship between gastro-oesophageal reflux and lung complications is not well understood, but GER is frequently recognized. In the absence of CF GER is also associated with a number of pulmonary and upper airway diseases. The incidence of liver fibrosis and cholestatic liver disease is increasing with age. The problem is how to identify the patients at risk. The use of choleretic drugs has shown promising results in preliminary studies. Gene therapy in pancreatic and gastrointestinal pathology will be restricted to the liver. The biliary tract could be an interesting target, if patients at risk can be identified. In conclusion, new drugs and new strategies are necessary for the future implementation of the results of new insights in CF.

Determinants of mild clinical symptoms in cystic fibrosis patients. Residual chloride secretion measured in rectal biopsies in relation to the genotype.

Previous Ussing chamber measurements of secretagogue-provoked changes in short circuit current in rectal suction biopsies of cystic fibrosis (CF) patients showed that in a minority of patients chloride secretion in response to cholinergic agonists is reduced but not completely absent. To assess a possible relationship between this phenomenon and both the genotype and the phenotype, we performed Ussing chamber experiments on rectal suction biopsies of 51 CF patients. The CF mutation was identified in 89 out of 102 CF alleles. No apparent chloride secretion was found in 30 CF patients (group I). Low residual chloride secretion was found in 11 CF patients (group II), while a relatively high residual secretion appeared in 10 CF patients (group III). Pancreatic function was preserved more frequently in CF patients displaying residual secretion: 0% in group I, 27% in group II, and 60% in group III (P < 0.001). The age at diagnosis (mean +/- SEM) in group III (18.4 +/- 6.6) was significantly different from group I (1.2 +/- 0.4, P < 0.01) and group II (3.5 +/- 1.4, P = 0.05). Residual chloride secretion was found in some of the 28 dF508 homozygous patients (three in group II, and one in group III), disclosing that other factors than the CF gene defect itself affect the transepithelial chloride transport. The age at diagnosis correlates significantly with the magnitude of the secretory response, even within the dF508 homozygous patients (r = 0.4, P < 0.05). We conclude that residual chloride secretion in CF is the pathophysiological basis of preserved pancreatic function and delayed presentation of the disease, which is not exclusively determined by the CF genotype.

[Hepatitis B in children in 4 university centers in The Netherlands]. / Hepatitis B bij kinderen in vier universitaire centra in Nederland.

OBJECTIVE: To evaluate the prevalence and the natural course of hepatitis B infection in children. DESIGN: Retrospective longitudinal. SETTING: Four university pediatric centres. METHOD: To explore the possibility of starting a trial with interferon alpha, data of viral and biochemical tests and biopsies of children younger than 16 years were studied. RESULTS: In a period of 10 years (1980-1990) 145 patients, of whom 74% were not of original Dutch descent, were found positive for HBsAg. The data of 142 patients could be analysed. Seroconversion was seen in 27 patients and 42 were already anti-HBe positive at the time of presentation. Chronic hepatitis, representing the category which could benefit from interferon alpha treatment, was found in 24 patients. Severe complications of the hepatitis were found in 4% of the children, including hepatocellular carcinoma and cirrhosis. Follow-up was insufficient so the seroconversion rate could only be estimated at 12% for the first year following the diagnosis. CONCLUSION: As a result of this study the authors present a proposal for a therapeutic trial with interferon alpha. This is a national protocol under the auspices of the section for pediatric gastroenterology of the Nederlandse Vereniging voor Kindergeneeskunde (Netherlands Pediatric Association).

Bleeding as presenting symptom of cholestasis.

Four infants with conjugated hyperbilirubinemia who were brought for treatment primarily because of a hemorrhage are reported. Underlying disorders included extrahepatic biliary atresia, choledochal cysts, and alpha 1-antitrypsin deficiency. Prodromal signs of disturbed coagulation and diminished bile excretion were not recognized. The increased bleeding tendency was probably caused by vitamin K deficiency, resulting from a combination of cholestasis-induced fat malabsorption, absence of vitamin K supplementation after birth, and low vitamin K intake as a result of breast feeding.

Relationship between intestinal function and chloride secretion in patients with cystic fibrosis.

Cystic fibrosis (CF) is the most frequent inheritable disease with a lethal course. One of the major problems of the disease is malabsorption and malnutrition, due to pancreatic insufficiency which is already present at birth in more than 85% of the patients. Characteristically the mucoid secretion products of the epithelial tissues in lung, pancreas, liver and intestine have a high viscosity. The pathophysiology is characterized by obstruction of these organs with secondary damage and finally destruction. For a long period intestinal obstruction syndromes in CF were ascribed only to the pancreatic insufficiency. Malabsorption is not only caused by enzyme deficiency but is also related to transport processes to the surface of the enterocytes. This indicates that the intestinal disorders in CF are partly the result of mucoid plugging and not only of pancreatic insufficiency. Recently in vitro studies have shown a blockade of secretion through chloride channels in the mucosal membrane of CF tissues. In vivo measurements of chloride fluxes in the rectum showed a disturbed regulation in CF patients. The high viscosity of the mucus and plugging is directly related to the diminished chloride secretion. So it is postulated that the abnormal chloride secretion is responsible for the intestinal obstruction and partially also for the malabsorption.

Regulation of chloride transport in cultured normal and cystic fibrosis keratinocytes.

Cultured normal (N) cystic fibrosis (CF) keratinocytes were evaluated for their Cl(-)-transport properties by patch-clamp-, Ussing chamber- and isotopic efflux-measurements. Special attention was paid to a 32 pS outwardly rectifying Cl- channel which has been reported to be activated upon activation of cAMP-dependent pathways in N, but not in CF cells. This depolarization-induced Cl- channel was found with a similar incidence in N and CF apical keratinocyte membranes. However, activation of this channel in excised patches by protein kinase (PK)-A or PK-C was not successful in either N or CF keratinocytes. Forskolin was not able to activate Cl- channels in N and CF cell-attached patches. The Ca(2+)-ionophore A23187 activated in cell-attached patches a linear 17 pS Cl- channel in both N and CF cells. This channel inactivated upon excision. No relationship between the cell-attached 17 pS and the excised 32 pS channel could be demonstrated. Returning to the measurement of Cl- transport at the macroscopic level, we found that a drastic rise in intracellular cAMP induced by forskolin did in N as well as CF cells not result in a change in the short-circuit current (Isc) or the fractional efflux rates of 36Cl- and 125I-. In contrast, addition of A23187 resulted in an increase of the Isc and in the isotopic anion efflux rates in N and CF cells. We conclude that Cl(-)-transport in cultured human keratinocytes can be activated by Ca2+, but not by cAMP-dependent pathways.