Synthesis, radiolabeling, and pre-clinical evaluation of [44Sc]Sc-AAZTA conjugate PSMA inhibitor, a new tracer for high-efficiency imaging of prostate cancer.

PURPOSE: The aim of this work was to demonstrate the suitability of AAZTA conjugated to PSMA inhibitor (B28110) labeled with scandium-44 as a new PET tracer for diagnostic imaging of prostate cancer. BACKGROUND: Nowadays, scandium-44 has received significant attention as a potential radionuclide with favorable characteristics for PET applications. A polyaminopolycarboxylate heptadentate ligand based on a 1,4-diazepine scaffold (AAZTA) has been thoroughly studied as chelator for Gd3+ ions for MRI applications. The excellent results of the equilibrium, kinetic, and labeling studies led to a preliminary assessment of the in vitro and in vivo behavior of [44Sc][Sc-(AAZTA)]- and two derivatives, i.e., [44Sc][Sc (CNAAZTA-BSA)] and [44Sc][Sc (CNAAZTA-cRGDfK)]. RESULTS: B28110 was synthesized by hybrid approach, combining solid-phase peptide synthesis (SPPS) and solution chemistry to obtain high purity (97%) product with an overall yield of 9%. Subsequently, the radioactive labeling was performed with scandium-44 produced from natural calcium target in cyclotron, in good radiochemical yields (RCY) under mild condition (pH 4, 298 K). Stability study in human plasma showed good RCP% of [44Sc]Sc-B28110 up to 24 h (94.32%). In vivo PET/MRI imaging on LNCaP tumor-bearing mice showed high tracer accumulation in the tumor regions as early as 20 min post-injection. Ex vivo biodistribution studies confirmed that the accumulation of 44Sc-PSMA-617 was two-fold lower than that of the radiolabeled B28110 probes. CONCLUSIONS: This work demonstrated the suitability of B28110 for the complexation with scandium-44 at room temperature and the high performance of the resulting new tracer based on AAZTA chelator for the diagnosis of prostate cancer using PET.

The comparison of thrombocytosis and platelet-lymphocyte ratio as potential prognostic markers in colorectal cancer.

The aim of the present study was to analyse the preoperative platelet count and the platelet-lymphocyte ratio (PLR) in patients with colorectal cancer (CRC) of different stages and with hepatic metastasis of CRC (mCRC) and to compare these factors as potential prognostic markers. Clinicopathological data of 10 years were collected retrospectively from 336 patients with CRC and 118 patients with mCRC. Both in the CRC and the mCRC group overall survival (OS) was significantly worse in patients who had elevated platelet count (hazard ratio [HR] = 2.2, p < 0.001 and HR = 2.9, p = 0.018, respectively). Multivariate analysis indicated that elevated platelet count was an independent prognostic factor of CRC (HR = 1.7, p = 0.035) and mCRC (HR = 3.1, p = 0.017). Disease-free survival (DFS) was significantly worse in patients with elevated platelet count in the CRC group (HR = 2.0, p = 0.011). In the multivariate analysis the PLR was not a prognostic factor in either of the two cohorts (HR = 0.92, p < 0.001 and HR = 0.89, p = 0.789, respectively). The platelet count is a valuable prognostic marker for the survival in patients both with CRC and mCRC while the PLR is not prognostic in either group.

Bevacizumab treatment before resection of colorectal liver metastases: safety, recovery of liver function, pathologic assessment.

Patients with metastatic colorectal cancer receive chemotherapy prior liver resection more and more frequently. This preoperative treatment has many effects which have to be analysed, like the safety of liver resection, toxicity, tissue regeneration, radiological and pathological response and survival data. The aim of the study was to evaluate the safety of bevacizumab containing preoperative chemotherapy and functional recovery of the liver after resection for colorectal liver metastases (CLM) and to analyse radiological and pathological data. Data of three groups of 120 consecutive patients-(1) CTX + BV: cytotoxic chemotherapy + bevacizumab, (2) CTX: cytotoxic chemotherapy, (3) NC: no treatment before liver resection-were analysed. Postoperative liver function and complications were compared, clinical, radiological and pathological data were evaluated. Between 01.12.2006 and 31.12.2010 41 resections was performed after chemotherapy + bevacizumab (CTX + BV) and 27 resections was performed after preoperative chemotherapy without bevacizumab (CTX). There were 60 hepatic resections in this period without neoadjuvant treatment (NC). 8 patients had repeated resections. The postoperative complication rate was 40 % but there was no statistical difference between the groups (P = 0.72). Only the type of resection was associated with a significantly higher complication rate (p = 0.03). The subgroup of patients, who received irinotecan had a higher complication rate in the CTX group than in the BV + CTX group (55 % vs 41 %). Preoperative administration of bevacizumab was associated with higher peak postoperative AST, ALT levels but did not affect functional recovery of the liver. The RECIST system was not able to predict the outcome after chemotherapy in every patient and in many cases this system overestimated the effect of chemotherapy. On histopathological examination the presence of necrosis was not associated with chemotherapy or pathological response. Use of chemotherapy before hepatic resection of CLM was not associated with a significant increase in complication rates. The functional recovery of the liver was not affected by the preoperative administration of chemotherapy. The use of combined neoadjuvant chemotherapy is safe before hepatic resection.

Pancreatic pseudocyst propagating into retroperitoneum and mediastinum.

The extrahepatic pseudocysts of pancreatic origin sometimes propagate into mediastinum and retroperitoneum. A large pseudocyst of pancreatic origin propagating into the mediastinum up to the aortic arch is published. The surgical intervention has been urged by the dislocation of the heart, by the danger of autodigestion of the mediastinal aorta and by the danger of rupture. Attention is directed to the external drainage operation which is suitable for emptying of the pseudocyst not independently from the ripeness of pseudocyst wall and the characteristics of the pseudocyst content. Should the time short after the exacerbation and should the amylase content high in the cyst, the immediate result of external drainage better and reliable safe.

Lymphadenectomy in gastrointestinal surgery for malignancy.

In a randomised study 25 patients with gastrointestinal surgery combined with extended lymphadenectomy (three field lymphadenectomy in case of esophageal cancer, D2 lymphadenectomy in case of gastric cancer) has been compared to the same number of patients with limited lymphadenectomy (D1). The operation time and the need for blood transfusion has increased in the extended lymphadenectomy group. The complication rate was more than doubled in the extended lymphadenectomy group, due to fluid or lymph collection, lymphatic edema, and infection. The mapping and staging was superior in extended lymphadenectomy group, but increased morbidity and mortality has been found in this group. However the favourable effect of extended lymphadenectomy on survival needs further long-term studies and proofs.

Urinary excretion of endogenous ouabain-like substance is reduced in NaCl supplemented premature infants.

Ouabain or an isomer has been identified as endogenous ouabain-like substance (EOLS). The role of EOLS in the adaptation of premature infants to alterations of sodium balance was investigated by measuring urinary ouabain excretion serially in 9 low birth weight premature infants with (group S, mean birth weight 1,578 g, mean gestational age 30.4 weeks) and without (group NS, mean birth weight 1,537 g, mean gestational age 30.8 weeks) NaCl supplementation. The study was performed on the 7th day and weekly thereafter until the 5th week of life. NaCl supplementation was given in a dose of 3-5 and 1.5-2.5 mmol/kg/day at the postnatal ages of 8-21 and 22-35 days, respectively. Prior to NaCl supplementation, urinary ouabain excretion was similar in the two groups (146.2 +/- 16.8 pg/kg/h in group S versus 180.0 +/- 9.6 pg/kg/h in group NS) and remained at about the same level throughout the study when supplemental NaCl was provided. In infants of group NS, urinary ouabain excretion increased significantly by the 3rd week (p < 0.01) and no consistent change occurred later on. As a result, the differences in urinary ouabain excretion between the two groups proved to be significant during weeks 2-5 (p < 0.001). Essentially the same pattern of ouabain excretion was seen when it was expressed in terms of pg/mg creatinine. In infants receiving high sodium diet there was a significant positive correlation between urinary sodium and ouabain excretion. It is concluded that premature infants receiving low sodium intake have elevated EOLS excretion by the 3rd week of life. Although the relationship between ouabain and sodium excretion in supplemented premature infants suggests some physiological significance for sodium excretion, ouabain does not appear to be regulated by extracellular volume.

Comparison of 5-hydroxyindole-acetic acid and para-amino hippurate clearances in newborn rabbits.

Recent study indicates that endogenous 5-hydroxyindole-acetic acid (5-HIAA) clearance can be used as an alternative procedure to para-amino hippurate (PAH) clearance for the estimation of renal plasma flow in human patients. In view of the limitations of PAH clearance measurements in newborn infants we made an attempt to validate the technique of measuring renal blood flow with 5-HIAA quantitatively against PAH clearance. Thirty-four simultaneous determinations of PAH and 5-HIAA clearances were performed in 14 newborn rabbits. 5-HIAA concentrations in plasma and urine were measured by using HPLC coupled with electrochemical detection (Beckman). Renal blood flow was found to range between 0.60 and 6.90 ml/min/kg (mean: 3.39 ml/min/kg) for 5-HIAA and from 0.93 to 6.61 ml/min/kg (mean: 3.68 ml/min/kg) for PAH clearances. There was a significant positive correlation between the values obtained by the two techniques (r = 0.84, P < 0.001). When 5-HIAA clearance was analyzed as a function of plasma 5-HIAA level only a weak, but statistically significant correlation could be detected (r = 0.33, P < 0.05). Plasma 5-HIAA measurement alone, therefore, does not reflect renal blood flow in newborn rabbits. It is concluded that endogenous 5-HIAA clearance might serve as a reliable estimate of renal blood flow in the neonate under different physiologic and pathologic conditions.

[Memory clinic: a new special unit, basic principles and first experiences of its function]. / Memória klinika: új speciális profilú egység müködésének alapelvei és elsö tapasztalatai.

Memory Clinic is a special unit of the National Institute of Psychiatry and Neurology in Hungary since January, 1992. Authors describe the methods of clinical investigation and the frames of therapy. In the first year 315 patients were examined, that underlines the authority of establishing such a special centre. A high proportion of the patients were in their active working period (age average were 55 years in the outpatient, and 56 in hospitalized patients). In the etiologic spectrum the organic cerebral lesions were the most frequent, but were not the only reasons. Depression was a very frequently observed associated symptom. The function of the new unit has interdisciplinary characteristics: modern organic examinations joined with psychotherapy-oriented therapeutic regime. There seems to have a chance for collaboration with other establishing Memory Clinics in the world.

Influence of NaCl supplementation on vasopressin secretion and water excretion in premature infants.

The study was carried out to assess the possible involvement of excess AVP and free water retention in the development of late hyponatremia by comparing the postnatal course of plasma AVP and urinary excretion of AVP and sodium as well as creatinine, osmolar and free water clearances in premature infants with (group S) and without (group NS) NaCl supplementation. Plasma total protein and albumin concentrations were also determined. Group NS consisted of 8 infants with a birth weight of 1,150-1,730 g (mean: 1,440 g) and gestational age of 28-32 weeks (mean: 30.4 weeks). Group S included 8 infants with a mean birth weight of 1,390 g (range: 980-1,700 g) and a mean gestational age of 30.1 weeks (range: 27-32 weeks). Measurements were made on the 7th day and weekly thereafter until the 5th week of life. NaCl supplementation was given in a dose of 3-5 and 1.5-2.5 mmol/kg/day for 8-21 and 22-35 days, respectively. Infants receiving sodium supplements had significantly greater urinary sodium excretion (p < 0.01), retained more sodium (p < 0.01), maintained plasma sodium at normal levels and gained weight at slightly higher rates when compared with those on low sodium. Plasma AVP tended to be higher in group S but did not differ significantly from that in NS group. Urinary AVP excretion, however, either expressed in ng/day or ng/100 ml GFR, was significantly higher in group S, although the age-related increase could not be seen when correction was made for GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

[Exclusion of Sandhoff disease (Tay-Sachs 0 variant) by chorion biopsy]. / Sandhoff-betegség (Tay-Sachs 0 varians) kizárása chorionbiopszia segítségével.

Transcervical chorionic villus sampling with ultrasound guidance at the 11-th week of pregnancy was made at a woman with the history of one lethal case of Sandhoff disease. The total hexosaminidase and the hexosaminidase A were determined. At the 16-th week amniocentesis was performed and the characteristic enzymes were determined from the amniotic cell culture. The results of the examinations made possible to advise the patient to carry out the pregnancy. The examinations after delivery confirmed the newborn to be a carrier.

Effect of thyroxine administration on renal functions in newborn infants with perinatal asphyxia.

The study was undertaken to assess the influence of thyroxine given to improve respiratory adaptation in asphyxiated neonates on the recovery of compromised renal functions. Two groups of infants with perinatal asphyxia were selected for the study. Group I consisted of 8 infants treated conventionally, while Group II included 7 infants who in addition to standard therapy were administered 50 micrograms thyroxine at admission and repeated 24 hours later. Their respective mean gestational ages were 38.7 weeks (range: 34-42 weeks) and 37.4 weeks (range: 34-41 weeks). The studies were performed on days 1, 7 and 14 and the results compared to those obtained in 13 healthy neonates with the gestational age of 39.2 weeks (range: 38-41 weeks) (Group III). Asphyxiated neonates had significantly higher plasma uric acid, xanthine, hypoxanthine and creatinine levels (p < 0.05), while their GFR proved to be markedly reduced (p < 0.01) when compared to the values of healthy controls. Moreover, there was a significant elevation of urinary excretion of NAGA (p < 0.001), urine osmolality (p < 0.05), PENa, FECa, RFI (p < 0.05) in infants presenting with perinatal asphyxia. Renal tubular responsiveness to aldosterone measured as TTKG was also found to be depressed (p < 0.025). In response to thyroxine therapy renal functional recovery appeared to be accelerated as indicated by the lower plasma creatinine level, lower rate of fractional electrolyte and urinary NAGA excretion and improved reactivity to aldosterone on days 7 and/or 14 as compared to those obtained in neonates presenting with asphyxia but without thyroxine therapy. The results seem to suggest that thyroid hormones may have an important role in the recovery of renal functions in newborn infants suffering from perinatal asphyxia.

Decreased urinary excretion of dopamine and sodium in diabetic children with incipient nephropathy.

It has been suggested previously that a decrease in urinary dopamine output might be related to a decrease in the urinary sodium excretion in subjects with diabetic nephropathy suffering from type 2 diabetes. To investigate the renal dopamine status in children with type 1 (insulin-dependent) diabetes mellitus, we measured the 24-hour urinary excretion of dopamine, norepinephrine and sodium in 12 patients with incipient nephropathy (group A, 24-hour albumin excretion rate 70-200 micrograms/min), in 20 age matched patients with normal microalbuminuria (group B, AER less than 20 micrograms/min) and in 8 healthy controls (group C). The mean values for urinary excretion of dopamine and norepinephrine were significantly lower in group A compared to groups B and C (25.6 +/- 14.8 vs. 65.9 +/- 25.5 and 73.3 +/- 18.0 micrograms/day, p less than 0.001 and 11.8 +/- 4.6 vs. 25.1 +/- 12.1 and 28.4 +/- 8.9 micrograms/day, p less than 0.01, respectively). The mean value for the urinary excretion of sodium was also significantly lower in group A than in groups B and C (98.4 +/- 24.1 vs. 206.2 +/- 59.5 and 198.1 +/- 42.8 mEq/day, p less than 0.01). The 24-hour urinary excretion of dopamine correlated significantly with the sodium excretion (r = 0.65, p less than 0.001). Arterial blood pressure was elevated in group A compared to group C (p less than 0.01). Our results suggest that a decrease in endogenous dopamine could play a role in the low urinary sodium excretion thereby resulting in sodium retention which may in turn lead to the development of higher blood pressure in diabetic children with incipient nephropathy.

Disturbed brain purine metabolism results in a gross opening of the blood-brain barrier in newborn piglets following experimental pneumothorax.

Changes in the permeability of pial-arachnoideal microvessels [30-210 microns), of the blood-brain barrier (BBB), were intravitally studied by fluorescent microscopy and compared to the hypoxanthine (HX) level of cerebrospinal fluid (CSF) in newborn piglets (n = 24) using the open cranial window technique. Eight animals served as controls (Group 1), the others were studied in the course of bilateral experimental pneumothorax (BEP) using low (Na(+)-fluorescein, MW 376, Group 2) and large molecular weight (FITC dextran, MW 40,000, Group 3) fluorescent tracer molecules. Cisternal CSF was sampled from the animals: 8 piglets from Group 1, and 4-4 piglets from Groups 2 and 3 at different stages of pathological condition: (i) at the critical (C) stage (severe acidosis, bradycardia, arterial hypotension and hypoxaemia) and also (ii) at the recovery (R) stage (mild metabolic acidosis, tachycardia, arterial hypotension) and the HX concentration was determined with high-pressure liquid chromatography. In Group 1 neither low (n = 4) nor large (n = 4) molecular weight tracers penetrated BBB. In Group 2, however, the fluorescein dye passed BBB as a spotty leakage in animals at C stage (n = 8). Diffuse fluorescein penetration was seen at R stage, too (n = 4). In Group 3 no change in permeability was found at C stages (n = 8), but at R stage (n = 4), 2 h after the primary hypoxic insult, when the animals had recovered from cardiovascular and metabolic shock, the tracer passed locally the microvascular wall and appeared as leaky spots (number of leaky sites = 2.3 +/- 0.4/0.10 cm2, means +/- SE).(ABSTRACT TRUNCATED AT 250 WORDS)

[Concentration of C-reactive protein in neonatal pathology]. / C-reaktív protein koncentráció pathologiás újszülöttekben.

C-reactive protein concentration was measured in 56 preterm and 61 full term newborn infants with various pathology, at the postnatal age of 0-24 hrs and 1, 2, 3, 4 weeks. One third of all study babies had an increased (greater than 10 mg/l) CRP level measured within 24 hrs of birth. On the first day, CRP concentration in neonates with a pronounced perinatal asphyxia was as high as in those who suffered from perinatal infection. Further postnatal changes in CRP level need individual evaluation in every case, considering the diagnosis, clinical course and treatment. In connection with the results the clinical usefulness of CRP determinations in neonatal medicine is shortly discussed.

Connective tissue metabolism in children with chronic renal failure.

To assess the characteristics of connective tissue metabolism in chronic renal failure (CRF), urinary excretion of glycosaminoglycan (GAG) fractions and hydroxyproline (HYP) was determined in ten patients with CRF and in ten age-matched healthy children. CRF was found to be associated with elevated free HYP (19.9 +/- 6.1 vs 9.8 +/- 3.6 mumol/day, P less than 0.05) and depressed peptide HYP excretion (33.1 +/- 13.5 vs 225.2 +/- 17.7 mumol/day, P less than 0.01), a low rate of total GAG excretion (7.0 +/- 2.4 vs 16.1 +/- 1.9 mumol uronic acid/day, P less than 0.05) with low chondroitin 4 -sulphate + chondroitin 6 -sulphate (Ch-Ss) (14.0 +/- 9.9 vs 65.0 +/- 22.1%) and a high proportion of non-sulphated or under-sulphated fractions, i.e. hyaluronic acid + chondroitin + heparan sulphate (HA + Ch + HS) (75.3 +/- 11.4 vs 31.5 +/- 5.7%). Urinary 3-methyl-histidine (3-met-HIS) excretion and plasma essential free amino acids did not differ in the two groups. In response to haemodialysis no consistent change occurred in urinary excretion of 3-met-HIS, peptide-bound HYP, total GAG or percentage distribution of individual GAG fractions. After haemodialysis all plasma amino acids decreased significantly, and there was a significant increase in urinary excretion of free HYP (P less than 0.05). We conclude that the alterations in urinary excretion of total and individual GAGs observed in CRF may reflect disturbed connective tissue metabolism which does not appear to be accounted for by protein malnutrition or enhanced protein breakdown and remains uninfluenced by haemodialysis therapy.

Serum lipid and lipoprotein-cholesterol values in cord blood and on the sixth postnatal day in newborns of varying maturity.

Triglyceride, total cholesterol, phospholipid, HDL-cholesterol, VLDL-cholesterol and LDL-cholesterol concentrations were studied in 22 eutrophic, 16 true premature and 22 small-for-gestational age neonates in cord blood and on the 6th postnatal day. According to the findings the lipid-lipoprotein metabolism was influenced primarily by gestational age. Parallel with increasing gestational age, phospholipid and triglyceride concentrations rose whereas cholesterol values decreased. Postnatal changes of lipid-lipoprotein metabolism developed more slowly in premature than in mature newborns. The effects of intrauterine malnutrition manifested themselves mainly in differences of the triglyceride and phospholipid levels.

Effect of glucagon infusion on some plasma metabolites and hormones in obese children.

The metabolic and hormonal effects of glucagon infusion (6 micrograms/kg/h) for three hours were studied in obese children. Glucagon caused a sustained hyperglycaemia and hyperinsulinaemia and a lower than normal (non-obese) growth hormone response. Plasma triglycerides, cholesterol, glycerol and the majority of the free amino acids showed a significant decrease in comparison with the controls, while free fatty acids showed a moderate decrease. Glucagon administration revealed some hormonal and metabolic abnormalities of obesity. The effect of glucagon-induced insulin secretion and the action of pharmacologic doses of glucagon have, however, to be considered in the interpretation of the metabolic effect of glucagon.