Peptide receptor radionuclide therapy with (90)Y-DOTATATE/(90)Y-DOTATOC in patients with progressive metastatic neuroendocrine tumours: assessment of response, survival and toxicity.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is an established treatment for patients with metastatic neuroendocrine tumours (NETs), although which factors are associated with an improved overall survival (OS) remains unclear. The primary aim of this study is to determine to what extent a radiological response to (90)Y-DOTATOC/(90)Y-DOTATATE PRRT is associated with an improved OS. The association of biochemical and clinical response to OS were assessed as secondary outcome measures. METHODS: A retrospective analysis was conducted on 57 patients: radiological response was classified using RECIST criteria, biochemical response was classified using WHO criteria and clinical response was assessed subjectively. Responses were recorded as positive response (PR), stable disease (SD) or progressive disease (PD), and survival analysed. RESULTS: Radiological response was achieved in 71.5% (24.5% PR, 47% SD) and was associated with a greater OS (51 and 56 months, respectively), compared with PD (18 months). A biochemical or clinical response post PRRT were not associated with a statistically significant improvement in OS. However, when combined with radiological response a survival benefit was observed according to the number of outcomes (radiological, biochemical, clinical), in which a response was observed. Mild haematological toxicity was common, renal toxicity was rare. CONCLUSION: In patients with progressive metastatic NETs receiving (90)Y-DOTATOC/(90)Y-DOTATATE PRRT, a radiological response with either a PR or a SD post therapy confers a significant OS benefit.

Renal tubular peptide catabolism in chronic vascular rejection.

Chronic vascular rejection (CR) is the commonest cause of renal transplant loss, with few clues to etiology, but proteinuria is a common feature. In diseased native kidneys, proteinuria and progression to failure are linked. We proposed a pathogenic role for this excess protein at a tubular level in kidney diseases of dissimilar origin. We demonstrated in both nephrotic patients with normal function and in those with failing kidneys increased renal tubular catabolism and turnover rates of a peptide marker, Aprotinin (Apr), linked to increased ammonia excretion and tubular injury. These potentially injurious processes were suppressed by reducing proteinuria with Lisinopril. Do similar mechanisms of renal injury and such a linkage also occur in proteinuric transplanted patients with CR, and if so, is Lisinopril then of beneficial value? We now examine these aspects in 11 patients with moderate/severe renal impairment (51CrEDTA clearance 26.2+/-3.3 mL/min/1.73 m2), proteinuria (6.1+/-1.5 g/24 h) and biopsy proven CR. Lisinopril (10-40 mg) was given daily for 2 months in 7 patients. Four others were given oral sodium bicarbonate (Na HCO3) for 2 months before adding Lisinopril. Renal tubular catabolism of intravenous 99mTc-Apr (Apr* 0.5 mg, 80MBq), was measured before and after Lisinopril by gamma-ray renal imaging and urinary radioactivity of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Total 24 h urinary N-acetyl-beta-glucoaminidase (NAG) and ammonia excretion in fresh timed urine collections were also measured every two weeks from two months before treatment. After Lisinopril proteinuria fell significantly (from 7.8+/-2.2 to 3.4+/-1.9 g/24 h, p<0.05). This was associated with a reduction in metabolism of Apr* over 26 h (from 0.5+/-0.05 to 0.3+/-0.005% dose/h, p < 0.02), and in fractional degradation (from 0.04+/-0.009 to 0.02+/-0.005/h, p<0.01). Urinary ammonia fell, but surprisingly not significantly and this was explained by the increased clinical acidosis after Lisinopril, (plasma bicarbonate fell from 19.1+/-0.7 to 17.4+/-0.8 mmol/L, p < 0.01), an original observation. Total urinary NAG did fall significantly from a median of 2108 (range 1044-3816) to 1008 (76-2147) micromol/L, p < 0.05. There was no significant change in blood pressure or in measurements of glomerular hemodynamics. In the 4 patients who were given Na HCO3 before adding Lisinopril, both acidosis (and hyperkalemia) were reversed and neither recurred after adding Lisinopril. These observations in proteinuric transplanted patients after Lisinopril treatment have not been previously described.

Gastroesophageal reflux in patients fed by percutaneous endoscopic gastrostomy (PEG): detection by a simple scintigraphic method.

OBJECTIVES: Gastroesophageal scintigraphy has been described as a sensitive and accurate way to detect and quantitate gastroesophageal reflux (GER). Our objectives here were to evaluate the usefulness of a modified scintigraphic technique in the detection of GER and lung aspiration in patients fed by percutaneous endoscopic gastrostomy (PEG), and to assess the incidence of GER after insertion of PEG. Further, we sought to examine whether or not the underlying cause of dysphagia plays any significant part in the causation of GER. METHODS: Twenty-two patients, 13 with neurological dysphagia and nine with mechanical dysphagia, were studied. Each patient received 25 MBq of Tc-99m-tin colloid in orange juice followed by 300 ml of normal saline through the PEG tube. Dynamic and static images were taken immediately and at 4 h over esophagus, stomach, and lungs. RESULTS: Twelve patients (10 with neurological dysphagia) had GER and one had aspiration into the lungs. In all but one patient GER occurred in the immediate postprandial period. CONCLUSIONS: Scintigraphy is useful in assessing GER in PEG-fed patients. We also note that GER is a major problem in patients with PEG, especially in those with neurological dysphagia.

Tubular peptide hypermetabolism and urinary ammonia in chronic renal failure in man: a maladaptive response?

Excessive renal tubular peptide uptake and degradation reflecting hypercatabolism may be a maladaptive response in chronic renal failure (CRF). It may also offer an explanation for the increased ammoniagenesis, per surviving nephron, observed in CRF but as yet unexplained. Neither has been explored in man. We have shown in patients with normal renal function and heavy (>5.0 g/24 h) proteinuria that tubular catabolism of a technetium-labelled peptide marker, aprotinin, and urinary ammonia were increased compared to others with less proteinuria. We now measure tubular kinetics of aprotinin and urinary ammonia in 16 CRF patients with variable proteinuria. Metabolism and turnover of aprotinin and ammonia excretion were increased, corrected for glomerular filtration rate, to levels found in patients with normal function and heavy proteinuria.

Proximal renal tubular peptide catabolism, ammonia excretion and tubular injury in patients with proteinuria: before and after lisinopril.

1. Progression to renal failure may be linked to the degree of proteinuria through tubulo-interstitial mechanisms. However, there are no data in man on the kinetics of proximal renal tubular protein catabolism or markers of tubular injury before and after lisinopril. We developed a method to allow such studies, and found increased tubular catabolism of 99mTc-labelled aprotinin (Trasylol) in patients with nephrotic range proteinuria which was associated with increased ammonia excretion. 2. In this study, 10 patients with mild renal impairment (51Cr-EDTA clearance 63.7 +/- 8.3 ml.min-1.1.73 m-2) and heavy proteinuria (8.2 +/- 2.3 g/ 24 h) were given lisinopril (10-20 mg) for 6 weeks. Renal tubular catabolism of intravenous aprotinin was measured before and after lisinopril by renal imaging and urinary excretion of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Fresh timed urine collections were also analysed for ammonia excretion every fortnight from 6 weeks before treatment. Total urinary N-acetyl-beta-D-glucosaminidase and the more tubulo-specific N-acetyl-beta-D-glucosaminidase 'A2' isoenzyme were also measured. 3. After lisinopril proteinuria fell significantly as expected (from 9.5 +/- 1.6 to 4.5 +/- 1.0 g/24 h, P < 0.01). This was associated with a reduction in metabolism over 26 h (from 1.7 +/- 0.1 to 1.2 +/- 0.1% dose/h, P < 0.01) and in fractional degradation of aprotinin (from 0.08 +/- 0.02 to 0.04 +/- 0.007/h, P < 0.04). Ammonia excretion also fell significantly (from 1.2 +/- 0.1 to 0.6 +/- 0.1 mmol/h, P < 0.0001), as did both total urinary N-acetyl-beta-D-glucosaminidase (P < 0.0001) and the N-acetyl-beta-D-glucosaminidase 'A2' isoenzyme (P < 0.015). These observations after lisinopril treatment have not been described previously. There was no significant change in blood pressure nor in glomerular haemodynamics.

Oral sodium bicarbonate reduces proximal renal tubular peptide catabolism, ammoniogenesis, and tubular damage in renal patients.

Oral sodium bicarbonate (NaHCO3) is widely used to treat acidosis in patients with renal failure. However, no data are available in man on the effects on proximal renal tubular protein catabolism or markers of tubular injury. We have developed methods to allow such studies, and both increased tubular catabolism of 99mTc-labelled aprotinin (Apr*), as well as tubular damage were found in association with increased ammonia (NH3) excretion in patients with nephrotic range proteinuria. We now examine the effects of reducing renal ammoniogenesis, without altering proteinuria, using oral NaHCO3 in 11 patients with mild/moderate renal impairment and proteinuria. Renal tubular catabolism of Apr* was measured before and after NaHCO3 by renal imaging (Kidney uptake, K% of dose) and urinary excretion of free 99mTcO4- (metabolism, Met% of dose/h) over 26 h. Fractional degradation (Frac) was calculated from Met/K (/h). Fresh urine was also analyzed for NH3 excretion every fortnight from 6/52 before treatment. Total urinary N-acetyl-beta-D-glucose-aminidase (NAG) and the more tubulo-specific NAG "A2" were measured. 51CrEDTA clearance and 99mTc-MAG 3 TER were also assessed. After NaHCO3 Met over 26 h was significantly reduced (from 1.3 +/- 0.2% of dose/h to 0.9 +/- 0.1% dose/hr, p < 0.005), as was Frac of Apr* (from 0.06 +/- .006/h to 0.04 +/- 0.005/hr, p < 0.003). NH3 excretion also fell significantly (from 0.9 +/- 0.2 mmol/h to 0.2 +/- 0.05 mmol/h, p < 0.007), as did both total urinary NAG (from 169 mumol/24 h, 74-642 mumol/24 h to 79 mumol/ 24 h, 37-393 mumol/24 h, p < 0.01), and the NAG 'A2' isoenzyme (from 81.5 mumol/24 h, 20-472 mumol/24 h to 35.0 mumol/24 h, 6-388 mumol/24 h, p < 0.001). Proteinuria remained unaltered, and there was no change in blood pressure nor in glomerular haemodynamics. Oral NaHCO3 may thus pro-tect the proximal renal tubule and help delay renal disease progression.

Dissection of hepatic receptor-mediated endocytic pathways using self-generated gradients of iodixanol (Optiprep).

Iodixanol is a new, nonionic, iodinated density gradient medium which has an advantage over other similar media in that it rapidly forms self-generated gradients in vertical or near-vertical rotors. Endocytosis of 99mTc-labeled neogalactosyl albumin (99mTc-NGA), a synthetic ligand for the asialoglycoprotein receptor, was studied by administering the ligand as a short pulse to perfused rat livers operating under single-pass conditions. Intracellular processing was arrested at various times after the pulse and the resultant homogenate cleared of nuclei and heavy mitochondria by centrifugation at 3000 g for 10 min. After adjustment to 12.5% (w/v) iodixanol, the 3000 g supernatants were centrifuged at 350,000 g for 60 min to form the gradients in which early, clathrin-containing vesicles, low-density endosomes, and lysosomes were well-resolved. 99mTc-NGA bound to the sinusoidal membrane could be partially resolved from clathrin-containing vesicles by inclusion of 1 mM CaCl2 in the homogenization and gradient buffers. Two populations of early clathrin-containing vesicles could be resolved by rate-zonal centrifugation in preformed iodixanol gradients. Thus, iodixanol is an excellent density gradient medium for the rapid and efficient resolution of endosome compartments.

Radionuclide imaging of abomasal emptying in sheep.

A liquid radionuclide tracer was administered to nine sheep in order to visualise the abomasum with a gamma camera computer system. The aim was to develop a method of studying gastric emptying, with minimal surgical intervention. Oral administration of the tracer gave good images of the whole complex stomach, but quantifying abomasal emptying was not possible because of the superimposition of the stomach compartments. When the reticular groove reflex was stimulated with oral copper sulphate the radionuclide bypassed the reticulorumen, allowing quantitative analysis of abomasal activity. However, the repeatability of the reflex activation was low. Radionuclide administered directly into the abomasum produced good images of abomasal outflow and provided digital data which were analysed quantitatively. A wide range of emptying rates was observed, generally with a stepped pattern.

Transscleral flow of aqueous humor: an in vitro experiment.

BACKGROUND AND OBJECTIVE: The minimal scleral flap thickness to ensure transscleral flow following a trabeculectomy has never been determined. The present study was designed to determine, in vitro, the critical scleral flap thickness that allows transscleral flow. MATERIALS AND METHODS: The apparatus consisted of two horizontal glass chambers (A and B) connected to each other by a customized scleral disc holder. High-pressure chamber A (at 25 mm Hg) was filled with sodium pertechnetate (99mTc) labeled normal saline and low-pressure chamber B (at 5 mm Hg) with normal saline. Transscleral flow of labeled normal saline from high-pressure chamber A via varying thickness scleral discs to low-pressure chamber B was observed over 16 hours using a gamma camera. Computer analysis was performed on the obtained images. RESULTS: Transscleral flow of labeled saline was observed only with scleral discs 0.5 mm thick or less. CONCLUSIONS: If the findings hold true for the in vivo situation, aqueous humor may reach the subconjunctival space following trabeculectomy via the transscleral route, provided scleral flap thickness is less than 0.5 mm. In addition, normal uveoscleral aqueous outflow may occur across sclera less than 0.5 mm thick, e.g., posterior to extraocular muscle insertions.

A novel method of determining portal systemic shunting using biodegradable 99Tcm labelled albumin microspheres.

Portal systemic shunting (PSS) and portal pressure were measured in control rats and in animals with portal hypertension induced by partial portal vein ligation (PPVL). The portal pressure in rats with partial portal vein ligation (13.4 +/- 0.5 mm.Hg.) was significantly higher (p < 0.005) than in the control group (9.6 +/- 0.6 mm.Hg.). Portal systemic shunting measured by consecutive injections of radiolabelled methylene diphosphonate (MDP), a non-diffusable marker and albumin microspheres directly into the splenic pulp was significantly increased (P < 0.005) in the portal hypertensive animals (30.8 +/- 2.5%) compared to sham operated rats (2.6 +/- 1.5%). Similarly, in portal hypertensive rats portal systemic shunting measured by intrasplenic injections of radiolabelled cobalt microspheres (37.1 +/- 3.9%) was significantly greater (p < 0.005) than in control animals. There was a good correlation and agreement (r = 00.97) between the two methods of measuring portal systemic shunting. However because the (99)Tc(m)-albumin microspheres are biodegradable the method allows portal systemic shunting to be measured in man. Furthermore since the computer adjusts the baseline to zero after each determination of portal systemic shunting the methodology allows repeated measurements to be made.

Renal tubular protein degradation of radiolabelled aprotinin (Trasylol) in patients with chronic renal failure.

1. The new method developed to measure renal tubular degradation of small filtered proteins in patients with normal renal function, using radiolabelled aprotinin (Trasylol) (R. Rustom, J. S. Grime, P. Maltby, H. R. Stockdale, M. Critchley, J. M. Bone. Clin Sci 1992; 83, 289-94), was evaluated in patients with chronic renal failure. 2. Aprotinin was labelled with either 99mTc (40 MBq) or 131I (0.1 MBq), and injected intravenously in nine patients, with different renal pathologies. 51Cr-EDTA clearance (corrected for height and weight) was 40 +/- 5.4 (range 11.2-81) ml min-1 1.73 m-2. Activity in plasma and urine was measured over 24-48 h, and chromatography on Sephadex-G-25-M was used to separate labelled aprotinin from free 99mTcO4- or 131I-. Renal uptake was measured for 99mTc-labelled aprotinin only. 3. The volume of distribution was 20.2 +/- 2.3 litres. Chromatography showed all plasma activity as undegraded aprotinin, and urine activity only as the free labels (99mTcO4- or 131I-). 4. As in patients with normal renal function, activity in the kidney appeared promptly, with 5.7 +/- 2.5% of the dose detected even at 5 min. Activity rose rapidly to 9.4 +/- 1.6% of dose after 1.5 h, then more slowly to 15.0 +/- 0.5% of dose at 4.5 h, and even more slowly thereafter, reaching 24.1 +/- 2.8% of dose at 24 h. Extra-renal uptake was again insignificant, and both 99mTcO4- and 131I- appeared promptly in the urine, with similar and uniform rates of excretion over 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Observations on the early renal uptake and later tubular metabolism of radiolabelled aprotinin (Trasylol) in man: theoretical and practical considerations.

1. The novel method recently developed to measure renal tubular degradation of filtered proteins in man using radiolabelled aprotinin (Trasylol) has been modified to allow the fate and the significance of the renal catabolism of radiolabelled aprotinin to be determined beyond 24h. 2. Ten renal patients with normal kidney function and variable proteinuria each received two separate intravenous injections of radiolabelled aprotinin, 5.0 mg of 99mTc-labelled aprotinin (40MBq) and 0.5mg of 131I-labelled aprotinin (5MBq). Chromatography (Sephadex-G-25-M) was used to separate undegraded radiolabelled aprotinin from the free isotope in urine and plasma. Renal uptake from gamma-camera images (24h for 99mTc-labelled aprotinin and up to 96h for 131I-labelled aprotinin) and urinary activity (48 and 96h, respectively) were measured. 3. The renal handling of radiolabelled aprotinin was similar with the two isotopes. Chromatography showed that all plasma activity was undegraded radiolabelled aprotinin, and urine activity was only the free isotopic label. 4. Kidney uptake of 131I-labelled aprotinin was prompt, reaching a cumulative maximum of 37.1 +/- 3.0% of dose at 24h, but falling exponentially thereafter to 5.6 +/- 1.0% of dose at 96h. 5. The rate of excretion of the free label in urine, i.e. the metabolic rate of radiolabelled aprotinin, was relatively constant over the first 24h (1.6 +/- 0.09% of dose/h), but then fell in parallel with the diminishing activity over the kidney, i.e. to 1.0 +/- 0.1% of dose/h over 24-48h and to only 0.4 +/- 0.08% of dose/h over 72-96h.(ABSTRACT TRUNCATED AT 250 WORDS)

A new method to measure renal tubular degradation of small filtered proteins in man using radiolabelled aprotinin (Trasylol).

1. A method has been developed to measure the renal tubular degradation of small filtered proteins in man using radiolabelled aprotinin (Trasylol), a 6500 Da cationic polypeptide. 2. Aprotinin (0.5 or 5.0 mg) was labelled with either 99mTc (40 MBq) or 131I (1 MBq) and injected intravenously in 19 renal patients (10 with normal renal function and nine on haemodialysis). Activity in plasma and urine was measured over 48 h, and chromatography with Sephadex-G-25-M was used to separate labelled aprotinin from free 99mTcO4- or 131I-. Renal uptake was measured for 99mTc-labelled aprotinin only. 3. The volumes of distribution were similar in all patients: 18.2 +/- 0.4 litres in those with normal renal function and 20.2 +/- 0.1 litres in the others. Chromatography showed all plasma activity as undegraded aprotinin and urine activity only as the free labels (99mTcO4- or 131I-). 4. In patients with normal renal function, activity in the kidneys rose rapidly to 24.2 +/- 2.8% of dose after 90 min and to 42.2 +/- 3.4% of dose after 24 h. In the dialysis patients, activity over the kidneys was only 2.7 +/- 0.8% of dose at 24 h. Extra-renal uptake was insignificant in all patients with normal kidney function. 5. Both 99mTcO4- and 131I- appeared in the urine promptly after injection, and the rates of excretion of the two isotopes were similar, varying little over 24 h (1.8 +/- 0.04% of dose/h and 1.7 +/- 0.04% of dose/h for 99mTc and 131I, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of lysine infusion on the renal metabolism of aprotinin (Trasylol) in man.

1. Aprotinin (Trasylol) is a cationic 6500 Da polypeptide that inhibits proteolytic enzymes, and when labelled with 99mTc it is a reproducible marker for the renal tubular turnover of small filtered proteins in man. Lysine potently inhibits tubular peptide uptake, and may thus depress the uptake and metabolism of aprotinin. This was investigated in 14 glomerulonephritic patients with normal renal function and variable proteinuria and in one healthy subject. 2. 99mTc-labelled aprotinin was given intravenously alone, and again 3 days later, immediately after the intravenous administration of 3-6 g of lysine, followed by an infusion over 1 h of 0.3-1.9 g of lysine/kg in individual patients. Activity over kidneys and in urine was measured over 24 h and chromatography was used to separate the undegraded peptide from free isotope. 3. At the low dosage of lysine (< 0.8 g/kg) given to six patients, kidney activity (representing tubular uptake) was unchanged, but early urine samples contained some undegraded aprotinin. Urinary excretion of free isotope, representing tubular metabolism, fell from 1.6 +/- 0.2% of dose/h with no lysine to 0.9 +/- 0.1% of dose/h in the 24 h after lysine, suggesting suppression of tubular aprotinin degradation. Corrected fractional degradation was calculated from the mean urinary excretion of free isotope over a given interval, determined by chromatography, divided by the mean cumulative kidney counts over this same interval, and this also fell after lysine from 0.06 +/- 0.006 to 0.03 +/- 0.006 h-1 (P < 0.005) between 3.75 and 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiolabelled white blood cell imaging in arthritis. Is it a blood pool effect?

The aim of this study is to determine whether white blood cell imaging in inflammatory conditions is due to a blood pool effect as a result of an increased vascularity and vascular permeability, or whether cellular migration is the major contributing factor. It will be shown that white cell uptake is a specific phenomenon in the rheumatoid knee joint and not just a blood pool effect.

Differences in the intracellular processing of the radiolabel following the uptake of iodine-125- and technetium-99m-neogalactosyl albumin by the isolated perfused rat liver.

Neogalactosyl albumin (NGA) is a synthetic ligand to the asialoglycoprotein receptor (hepatic binding protein), which has been proposed as a useful receptor binding radiopharmaceutical for the noninvasive assessment of liver function. We have compared the uptake and intracellular processing of iodine-125- (125I) and technetium-99m- (99mTc) NGA following its administration as a 1-min pulse (147 pmol) to the isolated perfused rat liver. Approximately 40% of a pulse of either 125I- or 99mTc-NGA were taken up first pass by the liver. Of the 125I taken up by the liver, 82% was released after 15-20 min at the sinusoidal pole of the hepatocyte, predominantly as small molecular weight metabolites. A further 8% of the 125I-associated radioactivity was secreted as intact NGA into bile by the non-lysosomal (direct) pathway while 6% remained in the liver 1 hr after the pulse. In contrast, of the 99mTc taken up by the liver, only 4% reappeared in the perfusate while 40% was secreted into bile by the lysosomal (indirect) pathway and 55% remained in the liver 1 hr after the pulse. Since labeled metabolites of 99mTc-NGA do not appear in plasma, this permits kinetic modeling with 99mTc-NGA without correction for labeled metabolites. Thus, 99mTc-NGA is an excellent candidate as a receptor-binding radiopharmaceutical.

Induced hepatic arterial blockade by degradable starch microspheres in the rat.

Degradable starch microspheres (DSM, Spherex) have been shown to cause intermittent blockage of hepatic arterial flow and to increase the concentration of regionally injected cytotoxics. The Spherex monitoring system has been developed by Pharmacia, Sweden to establish the correct dose of DSM to optimize hepatic arterial blockade. Groups of normal rats received varying dosages of DSM and co-injected methylene diphosphonate (MDP) in order to reproduce the effect of reduction of passing fraction and marker flow rate as determined by the Spherex monitoring system. A flow reduction and significant decrease in passing fraction was achieved on injection of 4 mg of DSM via the hepatic artery.