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Biomedical subjects

M Peck-Radosavljevic

Publications and source records attributed to M Peck-Radosavljevic.

33 records · Page 2Linked to original sources
PubMed1999

Intestinal tuberculosis presenting as fever of unknown origin in a heart transplant patient.

Patients undergoing transplantation have an increased risk of developing infections such as tuberculosis, Pneumocystis carinii pneumonia, Candida infections or cytomegalovirus infections because of their immunosuppressive therapy with cyclosporin A, azathioprine and steroids. Mycobacterial infection is well recognized as a complication in the immunocompromised host but diagnosis and therapy are very difficult.

Antitubercular Agents↗
PubMed1999

Thrombopoietic cytokines and reversal of thrombocytopenia after liver transplantation.

OBJECTIVES: Thrombopoietin (TPO), the key regulator of platelet production, is mainly produced by the liver and reduced expression of TPO could cause thrombocytopenia in liver cirrhosis. Reversal of thrombocytopenia by orthotopic liver transplantation seems to be mediated through an increase in TPO plasma levels after transplantation, but other cytokines with thrombopoietic activity could augment the actions of TPO on post transplant platelet recovery. DESIGN: Measurement of thrombopoietic cytokines before and for 14 days post liver transplantation in a cohort of thrombocytopenic liver transplant patients. METHODS: TPO, interleukin-3 (IL-3), IL-6, and IL-11 plasma levels as well as peripheral platelet count were analysed in thrombocytopenic patients with liver disease undergoing orthotopic liver transplantation (17 patients) and followed for 14 days after the intervention. RESULTS: Before liver transplantation, TPO plasma levels were undetectable and IL-3, IL-6, and IL-11 levels were normal. Sixteen out of 17 patients showed a significant rise of TPO levels within 2 days after transplantation, with a peak between days 4 and 6, while IL-3 and IL-6 levels did not show a significant rise. IL-11 levels remained normal. Platelet counts were significantly higher than pretransplantation levels by day 14 post transplantation. CONCLUSION: Restitution of normal TPO production by liver replacement seems to be of key importance for reversal of thrombocytopenia in liver disease. The early acting thrombopoietic factor IL-3 and the late acting factors IL-6 and IL-11 do not play a major role for recovery of peripheral platelet count after orthotopic liver transplantation.

Analysis of Variance↗
PubMed1999

Histological findings after routine biopsy at the gastro-oesophageal junction.

OBJECTIVE: Endoscopy with biopsy is an important diagnostic procedure in patients with gastro-oesophageal reflux disease. However, it is still unclear whether histological findings such as intestinal metaplasia, squamous epithelial hyperplasia, and carditis should have an impact on patient management, and whether routine biopsies at the gastro-oesophageal junction should be taken. DESIGN: Patients undergoing routine gastroscopy for various indications were biopsied twice just below, directly at, and right above the gastro-oesophageal junction. METHODS: Clinical symptoms, endoscopic oesophagitis, and histopathologies such as carditis, reflux disease, and intestinal metaplasia were determined and graded. RESULTS: Epithelial hyperplasia suggestive of reflux disease (63%), chronic carditis (94%), active carditis (40%), foveolar hyperplasia (75%), and intestinal metaplasia (14%) were frequently observed. For patients with a normal appearing Z-line, there was a weak correlation of intestinal metaplasia at the cardia with intestinal metaplasia in the stomach (Spearman's R = 0.2, P = 0.008), but no correlation with either chronic or active carditis, or with epithelial hyperplasia in the oesophagus. There was no correlation between H. pylori status or symptoms of reflux disease with epithelial hyperplasia. The severity of chronic and active carditis was closely correlated with H. pylori status (R = 0.37, P < 0.00001). The median time for gastroscopy in 30 control patients was 4.6 min, while endoscopy with additional biopsies at the gastro-oesophageal junction took a median of 8 min (U-test, P < 0.00001). CONCLUSIONS: Intestinal metaplasia at the gastro-oesophageal junction was encountered too frequently to warrant regular follow-up in a surveillance programme. Correlation of epithelial hyperplasia with symptoms of reflux disease is poor. We propose that routine biopsy at the gastro-oesophageal junction is not warranted until an impact on patient management can be demonstrated.

Adolescent↗
PubMed1999

DOTA-lanreotide: a novel somatostatin analog for tumor diagnosis and therapy.

Long acting somatostatin-14 (SST) analogs are used clinically to inhibit tumor growth and proliferation of various tumor types via binding to specific receptors (R). We have developed a 111In-/90Y-labeled SST analog, DOTA-(D)betaNal1-lanreotide (DOTALAN), for tumor diagnosis and therapy. 111In-/90Y-DOTALAN bound with high affinity (dissociation constant, Kd, 1-12 nM) to a number of primary human tumors (n = 31) such as intestinal adenocarcinoma (n = 17; 150-4000 fmol/mg protein) or breast cancer (n = 4; 250-9000 fmol/mg protein). 111In-/90Y-DOTALAN exhibited a similar high binding affinity (Kd, 1-15 nM) for the human breast cancer cell lines T47D and ZR75-1, the prostate cancer cell lines PC3 and DU145, the colonic adenocarcinoma cell line HT29, the pancreatic adenocarcinoma cell line PANC1, and the melanoma cell line 518A2. When expressed in COS7 cells, 111In-DOTALAN bound with high affinity to hsst2 (Kd, 4.3 nM), hsst3 (Kd, 5.1 nM), hsst4 (Kd, 3.8 nM), and hsst5 (Kd, 10 nM) and with lower affinity to hsst1 (Kd, approximately 200 nM). The rank order of displacement of [125I]Tyr11-SST binding to hsst1 was: SST (IC50, 0.5 nM) >> DOTALAN (IC50, 154 nM) > lanreotide (LAN) approximate to Tyr3-octreotide (TOCT) approximate to DOTA-Tyr3-octreotide (DOTATOCT) approximate to DOTA-vapreotide (DOTAVAP; IC50, >1000 nM); that to hsst2 was: DOTATOCT approximate to TOCT approximate to DOTALAN approximate to SST approximately LAN approximate to DOTAVAP (IC50, 1.4 nM); that to hsst3 was: SST (IC50, 1.2 nM) > DOTALAN = LAN (IC50, 15 nM) approximate to TOCT (IC50, 20 nM) approximate to DOTAVAP (IC50, 28 nM) > DOTATOCT (IC50, 73 nM); that to hsst4 was: SST (IC50, 1.8 nM) approximate to DOTALAN (IC50, 2.5 nM) > LAN (IC50, 22 nM) >> DOTATOCT approximate to DOTAVAP approximate to TOCT (IC50, >500 nM); and that to hsst5 was: DOTALAN (IC50, 0.45 nM) > SST (IC50, 0.9 nM) > TOCT (IC50, 1.5 nM) > DOTAVAP (IC50, 5.4 nM) >> LAN (IC50, 21 nM) > DOTATOCT (IC50 260 nM). In Sprague Dawley rats (n = 10), 90Y-DOTALAN was rapidly cleared from the circulation and concentrated in hsst-positive tissues such as pancreas or pituitary. Taken together, our results indicate that 111In-/90Y-DOTALAN binds to a broad range of primary human tumors and tumor cell lines, probably via binding to hsst2-5. We conclude that this radiolabeled peptide can be used for hsst-mediated diagnosis (111In-DOTALAN) as well as systemic radiotherapy (90Y-DOTALAN) of human tumors.

Adenocarcinoma↗
PubMed1998

Somatostatin receptor subtype specificity and in vivo binding of a novel tumor tracer, 99mTc-P829.

Recent data suggest that somatostatin receptors (SSTRs) are expressed on various tumor cells. High-level expression of SSTR on the tumor cell surface provides the basis for the successful clinical use of radiolabeled ligands for the in vivo localization of tumor sites. We have characterized the in vitro binding properties of the novel SSTR ligand 99mTc-P829 using primary human tumors (carcinoids, breast cancers, intestinal adenocarcinomas, pheochromocytomas, small cell and non-small cell lung cancer, and melanomas; n = 28), various tumor cell lines, and COS7 cells transfected with the human SSTR (hSSTR) subtypes 1, 2, 3, 4, and 5. 99mTc-P829 bound to primary tumor cells and tumor cell lines with high affinity and high capacity. The dissociation constants (Kd) ranged between 1 and 20 nM. 99mTc-P829 also bound with high affinity to the transfected hSSTR2 (Kd, 2.5 nM), hSSTR5 (Kd, 2 nM), and hSSTR3 (Kd, 1.5 nM). Binding of 99mTc-P829 to hSSTR3 was found to be displaceable by unlabeled P829/([ReO]-P829), SST-14, and vasoactive intestinal peptide (VIP; IC50, 2 nM) and, less effectively, by Tyr3-octreotide (IC50, 20 nM). In contrast, the binding of 99mTc-P829 to hSSTR2 and hSSTR5 could be displaced by P829/([ReO]-P829) and Tyr3-octreotide but not by VIP. 99mTc-P829 scintigraphy revealed in vivo binding to primary or metastatic tumor sites in seven of eight patients with breast cancer and six of six patients with melanoma. In summary, our data show that 99mTc-P829 binds with high affinity to many different types of primary and cloned tumor cells. Furthermore, our data identify hSSTR2, the VIP acceptor hSSTR3, and hSSTR5 as the respective target receptors. Because these receptors are frequently expressed at high levels on primary tumor cells, 99mTc-P829 appears to be a promising novel peptide tracer for tumor imaging.

Animals↗
PubMed1998

Blunted thrombopoietin response to interferon alfa-induced thrombocytopenia during treatment for hepatitis C.

Thrombocytopenia is common in advanced-stage liver disease and is partly caused by inadequate thrombopoietin (TPO) production in the failing liver. Treatment of chronic hepatitis C with interferon alfa (IFN-) often induces thrombocytopenia, sometimes even leading to discontinuation of treatment. TPO regulation in response to IFN--induced thrombocytopenia was studied in patients with chronic hepatitis C with and without cirrhosis (Child A). An in vitro culture system with HepG2 cells was used to demonstrate any direct effects of IFN- on TPO mRNA expression, TPO synthesis, or TPO secretion from liver cells. Thrombocyte count was lower (U test: P < .05) in patients with hepatitis C cirrhosis compared with patients with chronic hepatitis C without cirrhosis before IFN therapy, and decreased in both patient groups (Wilcoxon matched-pairs test: P < . 05) on IFN therapy, the median decrease in both groups being comparable (noncirrhotic patients, 35%; cirrhotic patients, 32%; U test: P = .57). TPO levels rose in noncirrhotic patients (Wilcoxon matched-pairs test: P < .05), but not in patients with cirrhosis (noncirrhotic patients' median increase: 43% vs. cirrhotic patients' median decrease: 5%; U test: P < .001). Even in patients without cirrhosis, the increase in TPO levels was relatively small for the decrease in platelet count. No effect of IFN- could be demonstrated on TPO mRNA expression in vitro, but TPO secretion from liver cells was significantly reduced. Lower platelet counts but similar TPO levels in patients with chronic hepatitis C and cirrhosis compared with noncirrhotic patients and a moderate increase in TPO levels in noncirrhotic patients with a missing increase in cirrhotic patients during IFN--induced thrombocytopenia provide further evidence for an impairment of TPO production in patients with cirrhosis and during IFN therapy. Recombinant human TPO could be of value in patients developing severe thrombocytopenia under IFN- therapy.

Adult↗
PubMed1998

Preoperative TNM-classification is a better prognostic indicator for recurrence of hepatocellular carcinoma after liver transplantation than albumin mRNA in peripheral blood. Liver Transplant Oncology Group.

BACKGROUND/AIM: Survival after orthotopic liver transplantation for hepatocellular carcinoma is limited by a high rate of tumor recurrence. A polymerase chain reaction assay based on the detection of albumin mRNA expression in peripheral blood for detection of hematogenous micrometastasis of hepatocellular carcinoma has been described, which may help to select candidates for orthotopic liver transplantation. METHODS: The prognostic value of a highly sensitive nested reverse transcription-polymerase chain reaction assay was evaluated in comparison with the TNM-classification of the International Union against Cancer in a population of liver transplant candidates. RESULTS: Eighty patients with liver disease and 42 control patients were evaluated. Six of 21 patients with hepatocellular carcinoma and 11 of 59 patients with other diseases of the liver were positive for albumin reverse transcription-polymerase chain reaction, making this assay an indicator of ongoing liver damage without absolute specificity for hepatocellular carcinoma. Twelve patients with hepatoma were followed after liver transplantation and seven of those patients had a tumor recurrence within 12 months. Six of these patients with recurrence had International Union against Cancer stage IV A tumors preoperatively, while only one of them was positive for albumin reverse transcription-polymerase chain reaction before transplantation. Only one patient with a stage I to III tumor had a recurrence within 12 months. CONCLUSIONS: Detection of albumin mRNA in peripheral blood by reverse transcription-polymerase chain reaction seems to be an unreliable marker for assessing hematogenous spread of hepatocellular carcinoma. With International Union against Cancer stage IV A being a much better predictor of tumor recurrence, the practical value of albumin mRNA reverse transcription-polymerase chain reaction for patient selection in liver transplant candidates seems to be very limited.

Adult↗
PubMed1998

Direct evidence for an increase in thrombopoiesis after liver transplantation.

BACKGROUND: In advanced liver cirrhosis, thrombocytopenia results from 'hypersplenism' due to increased platelet sequestration and platelet 'pooling' in the enlarged spleen and/or from reduced platelet production in the bone marrow. We sought to differentiate between these two mechanisms by studying thrombopoiesis before and after orthotopic liver transplantation by the determination of reticulated platelets, direct indicators for the thrombopoietic activity in the bone marrow. METHODS: Reticulated platelets, peripheral platelet counts, mean platelet volumes and platelet-reactive antibodies were determined in 15 patients suffering from advanced liver cirrhosis before and during an observation period of 14 days after orthotopic liver transplantation (OLT). Thrombopoietin levels of ten patients were determined before transplantation and consecutively for 14 days after surgery. RESULTS: All patients except one were thrombocytopenic before transplantation (median count 94 x 10(9) L-1, range 69-114 x 10(9) L-1). Although levels of reticulated platelets rose 2 days after surgery from baseline values of 1.0% (range 0.2-1.6%) to peak values of 4.6% (range 1.7-17.9%, P < 0.05) on day 6, platelet counts declined during the first 5 days after transplantation. When peripheral platelet counts increased to the normal range (median day 11, range day 8-33), reticulated platelets were again at pretransplant levels. Thrombopoietin levels before OLT were within the normal range (< 85 pg mL-1). On day 5 post surgery, a maximum increase of 5.8-fold (range 2.2- to 28-fold) over baseline values was observed. Mean platelet volume did not show any significant deviation from the baseline values and platelet antibodies could not be detected during the observation period. CONCLUSION: Our findings provide direct evidence for an increase in de novo platelet production after orthotopic liver transplantation. As the elevation of reticulated platelets precedes platelet recovery, it could serve as an early indicator to predict thrombopoiesis as a result of reconstituted liver function.

Adult↗
PubMed1998

Transjugular intrahepatic portosystemic shunt and cardiac arrhythmias.

The approach to the liver for a transjugular intrahepatic porto-systemic shunt (TIPS) is through the venous system. Because catheter and guidewire system traverses the heart, cardiac arrhythmias may be expected during the procedure. We have prospectively investigated the incidence of such dysrhythmias during TIPS implantation. Twelve consecutive patients, 4 women and 8 men aged 26 to 75 years (mean, 58 +/- 13 years), were studied. Before and on the day of TIPS implantation, a 24-hour Holter recording was performed. Transjugular intrahepatic portosystemic shunt implantation was performed under local anesthesia (lidocaine) and sedoanalgesia (midazolam and fentanyl). None of the patients had concomitant cardiac disease or electrolyte disturbances. In all patients except one, TIPS implantation was successful without any technical complications. A mean of 43 +/- 5.3 hours of Holter recording was performed before and after TIPS implantation. All recordings obtained during this control period were considered inconspicuous. The mean heart rate was significantly higher during the implantation procedure of 136 +/- 37 minutes' duration (83 +/- 20 beats per minute vs 70 +/- 19 beats per minute; p < 0.01). Nine of the 12 patients experienced episodes of nonsustained supraventricular tachycardias, and one patient had two sustained supraventricular tachycardias. Frequent episodes of nonsustained ventricular tachycardias developed in 75% of the patients. It seems clear that TIPS implantation is frequently associated with supraventricular and ventricular tachyarrhythmias even in patients with apparently good cardiac condition at the beginning of the procedure. Thus close cardiac monitoring with resuscitation equipment immediately available throughout the procedure is mandatory.

Adult↗
PubMed1998

Location of a VIPoma by iodine-123-vasoactive intestinal peptide scintigraphy.

A major problem in patients with small endocrine tumors is the difficulty in localizing the primary tumor site. Many endocrine tumors possess larger amounts of high affinity vasoactive intestinal peptide (VIP) binding sites compared with normal tissue or blood cells. We used radiolabeled VIP to localize the tumor site in a patient with Verner-Morrison syndrome (VMS). Under octreotide therapy, the VIP levels had declined in this patient, but a tumor site could not be detected by conventional techniques or by radiolabeled octreotide. However, using 123I-VIP, the tumor was detectable in the pancreatic tail. Surgical resection of the tumor was followed by complete remission of the VMS. Expression of VIP binding sites in the tumor was confirmed by a radioreceptor assay and showed cross-competition between VIP and octreotide. The identity of the VIP binding site in the tumor was analyzed by Northern blotting and revealed the expression of somatostatin receptor subtype 3, which binds both somatostatin-14 and VIP with higher affinity than octreotide. Iodine-123-VIP scintigraphy would be an effective tracer to identity the tumor site in VMS patients.

Adult↗
PubMed1997

Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver?

BACKGROUND/AIMS: Thrombocytopenia secondary to cirrhosis of the liver and portal hypertension is a well-known complication of advanced stage liver disease, but theories about the underlying pathogenetic mechanisms, mostly centering on splenic sequestration and destruction of platelets, have failed to solve the problem so far. METHODS: Peripheral platelet count and thrombopoietin levels in human plasma were measured in 28 patients with cirrhosis of the liver. Seven of those patients underwent orthotopic liver transplantation and five patients portal decompression by transjugular intrahepatic portosystemic shunt. Thrombopoietin plasma levels were followed for 14 days after the interventions. RESULTS: No measurable thrombopoietin was detectable in the plasma of 28 thrombocytopenic patients with cirrhosis of the liver, in contrast to thrombocytopenic patients without liver disease. Seven of these patients with cirrhosis underwent orthotopic liver transplantation, resulting in a rise of thrombopoietin levels within 2 days after transplantation. The rise in platelet number followed with a mean lag of 6 days, and shortly thereafter, thrombopoietin levels returned to levels below the limit of detection. Five patients with thrombocytopenia, who underwent only decompression of portal hypertension, showed no rise in either thrombopoietin levels or platelet count. CONCLUSIONS: Thrombocytopenia associated with liver disease may at least in part be attributable to inadequate thrombopoietin production in the failing liver.

Humans↗
PubMed1997

Prevalence of hepatitis G virus in patients with hepatocellular carcinoma.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are known to be associated with hepatocellular carcinoma (HCC). In this study, we investigated the prevalence of the newly described hepatitis G virus (HGV) in patients with HCC. The sera of 85 patients (66 male, 19 female, 61 +/- 11 years) with HCC were studied for the presence of HGV RNA by reverse transcriptase-polymerase chain reaction. Seventeen (20%) of 85 patients with HCC, 10 (16%) of 61 patients with chronic hepatitis B without HCC and 14 (20%) of 68 patients with chronic hepatitis C without HCC were infected with HGV, a significantly higher proportion when compared with two (2%) of 85 healthy controls (P < 0.01). When grouped according to the underlying cause of liver disease, HCC patients with HBV infection (33%), HCV infection (21%), alcoholic liver disease (17%), or cryptogenic cirrhosis (15%) had similar serum levels of HGV RNA. Four of the 17 (24%) HGV-positive patients with HCC were coinfected with HBV and six (35%) with HCV; thus, 59% of HGV-positive patients with HCC were coinfected with other hepatotropic viruses. Seven (41%) HGV-positive patients were infected with HGV only. Patients with HGV infection were more likely to have a history of blood transfusion than patients without HGV infection (P = 0.024). Hence, the prevalence of HGV is significantly higher in patients with HCC in comparison with the healthy population.

Carcinoma, Hepatocellular↗
PubMed1997

Angiotensin-converting enzyme inhibition in cirrhotic patients--pharmacokinetics of ramipril.

In an open trial, the pharmacokinetics of the angiotensin converting enzyme inhibitor ramipril and its active metabolite ramiprilat were studied in 12 patients with liver cirrhosis. After a single oral dose of 5 mg ramipril plasma levels of the parent compound reached peak concentrations of 48.6 +/- 39.8 ng/ml after 0.7 +/- 0.5 h and declined rapidly to 0.7 +/- 1.2 ng/ml after 8 h. Plasma levels of ramiprilat reached peak concentrations of 3.8 +/- 2.9 ng/ml after 3.0 +/- 2.2 h, thereafter declined slowly and could be detected up to 240 h. The total recovery of ramipril and metabolites in urine within 96 h was on average 46.0 +/- 10.9% of the administered dose. Major fractions were due to diketopiperazines and glucuronides of ramipril and ramiprilat. The overall ACE inhibition was still 92.0 +/- 8.6%. In conclusion, patients with liver cirrhosis had enough capacity to metabolize and excrete the parent compound ramipril, but had not enough capacity to form ramiprilat, although enough ramiprilat was formed for sufficient ACE inhibition of about 90%. This indicates that titration of the dose should start with 5 mg or even lower doses in patients with markedly impaired liver function.

Administration, Oral↗
PubMed1996

In vitro and in vivo studies of three radiolabelled somatostatin analogues: 123I-octreotide (OCT), 123I-Tyr-3-OCT and 111In-DTPA-D-Phe-1-OCT.

Scintigraphy with long-acting somatostatin (SST) analogues may be useful for the localization of tumours expressing receptors (R) for SST. In this study we have analysed the in vitro and in vivo binding properties of three SST analogues, 123I-octreotide (OCT), 123I-Tyr-3-OCT and 111In-DTPA-d-Phe-1-OCT. In vitro binding studies performed with a variety of primary tumours (n=48) as well as with several tumour cell lines (A431, HT29, PANC1, COLO320, HMC1, KU812) indicated significant in vitro binding of these three radiolabelled SST analogues to two subpopulations of SSTR, high (Kd 0.2-2.0 nM) and low (Kd 5-15 nM) affinity ones. The number of SSTR on tumour cells was at least a 1000-fold higher as compared with normal peripheral blood cells. Comparative scintigraphic studies using 123I-OCT and/or 123I-Tyr-3-OCT and/or 111In-DTPA-d-Phe-1-OCT were performed in 21 patients with histologically verified intestinal carcinoid tumours. Corresponding scintigraphic results were obtained in 18 of 21 patients investigated with two different SSTR ligands, either 123I-OCT/123I-Tyr-3-OCT (four of five), 123I-OCT/111In-DTPA-d-Phe-1-OCT (eight of nine), or 123I-Tyr-3-OCT/111In-DTPA-d-Phe-1-OCT (six of seven). We conclude that various tumours express high amounts of SSTR which are recognized by three radiolabelled SST analogues: 123I-OCT, 123I-Tyr-3-OCT and 111In-DTPA-d-Phe-1-OCT. Differences between these SST analogues in their in vitro binding and/or in vivo scanning properties are observed in a minority of patients. Thus, the labelling of OCT with iodine may be an alternative approach for those nuclear medicine departments for which 111In-DTPA-d-Phe-1-OCT is not easily available, or is too expensive.

Adolescent↗