Biomedical subjects

Peter Bernhardt

Publications and source records attributed to Peter Bernhardt.

36 records · Page 2Linked to original sources

PubMed2005

Patients at high risk with atrial fibrillation: a prospective and serial follow-up during 12 months with transesophageal echocardiography and cerebral magnetic resonance imaging.

OBJECTIVE: Patients with atrial fibrillation and echocardiographic risk factors have a relevant risk of cerebral embolism. However, there is little knowledge about the long-term fate and the rate of clinical silent cerebral embolism under continued oral anticoagulation. Our aims were to assess the prognosis of patients with atrial fibrillation and determine a high-risk group with an increased risk of cerebral embolism under oral anticoagulation. METHODS: A total of 173 consecutive patients with persistent or permanent atrial fibrillation and left atrial (LA) thrombi, dense spontaneous echocontrast, reduced LA appendage peak emptying velocities, or a combination of these were included in the study. In all, 169 patients with atrial fibrillation and without echocardiographic risk factors served as control patients. We performed serial and prospective transesophageal echocardiography, cranial magnetic resonance imaging, and clinical examinations during a period of 12 months. RESULTS: During the follow-up period 7 (4%) of the patients at high risk had cerebral embolism with neurologic deficits. A total of 4 (2%) patients died because of embolic events and 19 (11%) patients had silent embolism as documented on magnetic resonance imaging. In the control group, 10 (6%) patients had embolic events documented on magnetic resonance imaging; one was clinically apparent. Study patients with an event had more often previous thromboembolism (P < .0001). CONCLUSIONS: Patients with persistent or permanent atrial fibrillation and LA thrombi, dense spontaneous echocontrast, or reduced LA appendage peak emptying velocities have an explicitly increased risk of cerebral embolism (17%) despite oral anticoagulation. Previous thromboembolic event is another important predictor for an event.

Administration, Oral↗

PubMed2005

Differences in biodistribution between 99mTc-depreotide, 111In-DTPA-octreotide, and 177Lu-DOTA-Tyr3-octreotate in a small cell lung cancer animal model.

AIM: (177)Lu-DOTA-Tyr(3)-octreotate is a candidate radiopharmaceutical for the therapy of somatostatin receptor (sstr)-positive small cell lung cancer (SCLC). Scintigraphy of lung tumors is made with 2 alternative somatostatin analogs, (111)In-DTPA-octreotide or (99m)Tc-depreotide. The aim of this study was to compare the biodistribution of these 3 radiopharmaceuticals in SCLC xenografted to nude mice. METHODS: Nude mice, bearing tumors from the human SCLC cell line NCI-H69, were intravenously injected with 10 MBq (2.4 microg) (99m)Tc-depreotide and 2 MBq (0.5 microg) (111)In-DTPA-octreotide simultaneously. The activity concentration (%IA/g) was measured in tumor and normal tissue at 2, 4, and 24 hours postinjection (hpi). The results were compared with earlier published biodistribution data of 3 MBq (0.7 microg) (177)Lu-DOTA-Tyr(3)-octreotate in the same animal model. RESULTS: The activity concentration of (111)In-DTPAoctreotide in tumor was higher than the activity concentration of (99m)Tc-depreotide at 2-24 hpi, p < 0.05. The highest tumor uptake at 24 hpi was, however, found for (177)Lu-DOTA-Tyr(3)-octreotate. The activity concentration of (99m)Tc-depreotide was significantly higher in the heart, lungs, liver, the salivary glands, spleen, and bone marrow than for (111)In-DTPA-octreotide at 2-24 hpi. Saturation of the somatostatin receptors may have influenced the uptake in tumor and sstr-positive normal tissues. CONCLUSION: The low tumor-to-lung and tumor-to-liver activity concentration ratios for (99m)Tc-depreotide could result in a lower detection rate of SCLC with this compound versus (111)In-DTPA-octreotide. (177)Lu-DOTA-Tyr(3)-octreotate gave the highest tumor-activity concentration, and has, thus, the best properties for therapy.

Animals↗

PubMed2005

A novel photon radiation detector system for in vitro biokinetic measurements.

OBJECTIVE: This study evaluates a novel photon radiation detector system for in vitro biokinetic measurements. METHODS: A cell-culture well can be considered to consist of two different compartments: the cells and the medium. By placing the well on a lead-collimated scintillation (NaI(T1)) detector, changes in activity distribution between the compartments will result in changes in count rates owing to the efficiency ratio (ER) between the cells and the medium. The ER depends on differences in detection solid angles for the compartments and differences in attenuation of photons emitted from the compartments. Evaluation of the optimal measuring geometries for the detector system was done by Monte Carlo (MC) simulations. The detector system was tested in two different in vitro situations. RESULTS: The MC simulations showed that the most optimal detector system was obtained by using a lead-collimated well crystal. Both the MC simulations and the experiments have proven the usability of the system. CONCLUSIONS: The detector system was demonstrated to be of value for biokinetic studies. The cellular binding of radiolabeled substances can be determined with high precision, and real-time measurements can be performed on a cell culture without harvesting the cells.

Computer Simulation↗

PubMed2005

Myelotoxicity and RBE of 211At-conjugated monoclonal antibodies compared with 99mTc-conjugated monoclonal antibodies and 60Co irradiation in nude mice.

UNLABELLED: The rationale of this study was to determine the myelotoxicity in nude mice of the alpha-emitter 211At conjugated to monoclonal antibodies (mAbs) and to compare the effect with an electron emitter, (99m)Tc, and external irradiation from a 60Co source, for estimation of the relative biological effectiveness (RBE). METHODS: 211At and (99m)Tc were conjugated to the IgG1 mAbs MX35 and 88BV59. Nude female BALB/c mice, 8- to 12-wk old, were injected intraperitoneally or intravenously. The biodistribution was determined 3, 6, and 18 h after injection. The bone-to-blood and bone marrow-to-blood activity concentration ratios (BBLR and BMBLR, respectively) were determined for simultaneously injected 211At- and (99m)Tc-mAbs. Bone marrow samples were taken from the femur. For each mouse, the whole-body retention was measured as well as the blood activity by repeated blood samples from the tail vein (0), 1, 3, 6, 12, and 18 h after injection. External-beam irradiation from a 60Co source was also performed at 3 different dose levels. White blood cell (WBC) counts, red blood cell counts, platelet counts, and hemoglobin were determined for each mouse initially and on days 1, 4, 5, 7, 15, 22, and 27 after injection. The calculations of the absorbed dose to the bone marrow were based on the BBLR, BMBLR, the cumulated activities, and the absorbed fractions. The absorbed fractions, phi, for alpha-particles and electrons in the bone marrow were calculated using Monte Carlo simulations based on a bone marrow dosimetry model. RESULTS: The BMBLR was 0.58 +/- 0.06 and 0.56 +/- 0.06 for the 211At- and (99m)Tc-mAbs, respectively. No significant variation in BMBLR with time was found. The absorbed fractions for alpha-particles and electrons in the bone marrow were 0.88 and 0.75, respectively. The mean absorbed fractions of the photons from (99m)Tc were 0.033 and 0.52 for 140 and 18.3 keV, respectively. When different amounts of 211At- and (99m)Tc-mAbs (0.09-1.3 and 250-1,300 MBq, respectively) were administered intraperitoneally or intravenously, corresponding to absorbed doses to the bone marrow of 0.01-0.60 and 0.39-1.92 Gy, respectively, the WBC counts was suppressed by 1%-90% and 23%-89%, respectively. When external-beam irradiation with a 60Co source was performed to absorbed doses of 1.4, 1.9, and 2.4 Gy, the WBC counts was suppressed by 47%-90%. These results indicate a myelotoxic in vivo RBE of 3.4 +/- 0.6 for alpha-particles compared with (99m)Tc and 5.0 +/- 0.9 compared with 60Co irradiation. CONCLUSION: The effect on the WBC counts from bone marrow irradiation with 211At-mAbs indicates an in vivo RBE of 3.4 +/- 0.6 in comparison with (99m)Tc-mAbs. The RBE value compared with external irradiation is 5.0 +/- 0.9.

Animals↗

PubMed2004

Fate of left atrial thrombi in patients with atrial fibrillation determined by transesophageal echocardiography and cerebral magnetic resonance imaging.

Patients with atrial fibrillation (AF) and atrial thrombi have an increased risk for cerebral embolism. However, there is little knowledge about the long-term fate of atrial thrombi and the incidence of cerebral embolism in patients receiving continued oral anticoagulation. Forty-three consecutive patients with AF and atrial thrombi were enrolled in the study. Serial and prospective transesophageal echocardiographic studies, cranial magnetic resonance imaging (MRI), and clinical examinations were performed during a period of 12 months. Oral anticoagulation was continued or initiated in all patients. An international normalized ratio of 2.0 to 3.0 was regarded as effective. During follow-up, 56% of the thrombi disappeared (7 [16%] at 1 month, 18 [42%] at 3 months, 21 [49%] at 6 months, and 24 [56%] at 12 months). Patients with the disappearance of thrombi had significantly smaller thrombi compared with patients with persistent thrombi (1.5 +/- 0.8 cm in length and 0.8 +/- 0.5 cm in width vs 1.9 +/- 0.6 cm in length and 1.3 +/- 0.4 cm in width, p = 0.04), reduced echogenicity of thrombi (46% vs 89%, p <0.01), and smaller left atrial (LA) volume (83 +/- 27 vs 116 +/- 55 cm(3)). Seven patients (16%) had embolic lesions during follow-up MRI. Six of these patients (86%) had clinically apparent embolisms, and 1 died from stroke. The only independent predictors of cerebral embolism were an elevated peak emptying velocity of the LA appendage (p <0.01) and previous thromboembolic events (p = 0.02). Patients with AF and atrial thrombi have a large likelihood of cerebral embolism (16%) and/or death despite oral anticoagulation therapy. Thrombus size may predict thrombus resolution under continued anticoagulation.

Atrial Fibrillation↗

PubMed2004

Chromogranin A as a determinant of midgut carcinoid tumour volume.

Neuroendocrine (NE) tumours are characterized by their capacity to synthesize, store and release hormonal products. These substances are stored in neurosecretory vesicles together with chromogranin A (CgA). The concentration of plasma CgA in patients with NE tumours is thought to reflect the degree of NE differentiation, total tumour burden and effect of medical treatment. The aim of this study was to analyse the correlation between tumour weight and plasma CgA levels as well as the influence of treatment with a long-acting somatostatin analogue (octreotide) using nude mice with xenografted human ileal carcinoid tumours. There was a correlation between tumour weight and plasma CgA levels in all animals (p < 0.00001). In octreotide-treated mice, plasma CgA levels were significantly reduced versus untreated animals (p = 0.037). In conclusion, this study demonstrates that plasma CgA levels are closely correlated to tumour burden, and that plasma CgA is well suited for monitoring the clinical course and outcome of treatment in patients with NE tumours.

Animals↗

PubMed2004

Biodistribution data from 100 patients i.v. injected with 111In-DTPA-D-Phe1-octreotide.

The aim of this study was to obtain accurate data on the biodistribution of 111In-DTPA-D-Phe1-octreotide in tumour and normal tissues to facilitate dosimetric evaluations. Patients with carcinoid tumours, medullary thyroid carcinoma (MTC), differentiated thyroid tumours, endocrine pancreatic tumour (EPT), breast carcinoma, and various other tumour types were i.v. injected with 111In-DTPA-D-Phe-1-octreotide. Tumour and normal tissue samples were collected during surgery 1-35 days later, and the 111In activity concentration determined. Results showed large inter- and intra-individual variations. The 111In concentration was in general higher in carcinoids and some EPT (range 0.33-77% IA/kg) than in MTC and other tumours (0.017-7.8% IA/kg). Tumour-to-blood ratios (T/B) higher than 100 were found in most patients with carcinoids, EPT, renal carcinoma, and neuroendocrine carcinoma (max value 1500), while T/B was below 80 in most other tumours. Normal-tissue-to-blood ratios were in general < or = 10 but higher values were found in liver, kidneys, and spleen. The results presented are important for dosimetric calculations, when radiolabelled octreotide is used for diagnostic or therapeutic purposes.

Adolescent↗

PubMed2004

Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies.

Two prospective, randomized studies evaluated everolimus 1.5 vs. 3 mg/day with steroids and low-exposure cyclosporine (CsA) (C2 monitoring) in de novo renal transplant patients. Everolimus dosing was adjusted to maintain a minimum trough level of 3 ng/mL. Study 1 (A2306; n=237) had no induction therapy; in Study 2 (A2307; n=256) basiliximab was administered (Days 0 and 4). The primary endpoint was renal function at 6 months. CsA C2 target levels, initially 1200 ng/mL in Study 1 and 600 ng/mL in Study 2, were tapered over time post-transplant. Median creatinine levels in Study 1 were 133 and 132 micromol/L at 6 months in the 1.5 and 3 mg/day groups, respectively, and 130 micromol/L in both groups in Study 2. Biopsy-proven acute rejection (BPAR) occurred in 25.0% and 15.2% of patients in the 1.5 and 3 mg/day groups in Study 1, and 13.7% and 15.1% in Study 2. Incidence of BPAR was significantly higher in patients with an everolimus trough <3 ng/mL. There were no significant between-group differences in the composite endpoint of BPAR, graft loss or death, nor any significant between-group differences in adverse events in either study. Concentration-controlled everolimus with low-exposure CsA provided effective protection against rejection with good renal function.

Adult↗

PubMed2004

Modelling of metastatic cure after radionuclide therapy: influence of tumor distribution, cross-irradiation, and variable activity concentration.

The objective was to study the influence of tumor number and size, cross-irradiation from normal tissue, and of variable activity concentration on metastatic cure after radionuclide therapy. A model to calculate the metastatic cure probability (MCP) was developed, in which it was assumed that the tumor response was an exponential function of the absorbed dose. All calculations were performed for monoenergetic electron emitters with different energies (10-1000 keV). The influence of tumor size and number of tumors were investigated with different log uniform distributions; the basic tumor distribution consisted of tumors with 1, 10, ..., 10(11) cells. The influence of cross-irradiation was assessed by calculating MCP for various tumor-to-normal tissue activity concentration ratios (TNC). The influence of variable activity concentration between tumors was calculated by assuming that the activity concentration in tumors was an inverse power law function of tumor mass. The required activity concentration (C0.9) and absorbed dose (D0.9) to obtain MCP=0.9 was calculated in the different models. The C0.9 and D0.9 needed to obtain MCP were very high; more than 25 MBq/g and 80 Gy, respectively. The lowest C0.9 and D0.9 for equal activity concentration in the different tumor sizes were obtained for electron energies less than 80 keV. For higher energies the low absorbed energy fraction in small tumors will increase the required C0.9 and D0.9 markedly. Cross-irradiation from normal cells surrounding the tumor will cause sterilization of the smallest tumors and decrease the required C0.9 and D0.9 for higher electron energies. Assuming that the activity concentration decreased with increased tumor mass caused a marked increase in C0.9 and D0.9 in favor of higher electron energies. With the MCP model we demonstrated significant influence of the number of tumors, their size, TNC and variable activity concentration on MCP. The results are valuable when evaluating optimal choices for radionuclides for internal-emitter therapy.

Algorithms↗

PubMed2004

GOT1 xenografted to nude mice: a unique model for in vivo studies on SSTR-mediated radiation therapy of carcinoid tumors.

Malignant carcinoid tumors express high numbers of somatostatin receptors. Radiation therapy using labeled somatostatin analogs is a novel treatment modality for these tumors. We have analyzed the biokinetics and therapeutic effect of radiolabeled somatostatin analog on a human midgut carcinoid grafted to nude mice. A transplantable human midgut carcinoid (GOT1) was grafted to the back of nude mice. Tumor-bearing mice were injected with (111)In-DTPA-D-Phe(1)-octreotide, followed by measurement of (111)In activity concentration ratios in tumor tissues. Tumor-bearing mice were also injected with (177)Lu-DOTA-Tyr(3)-octreotate and followed for 7 days. The concentration of (111)In-DTPA-D-Phe(1)-octreotide in tumor tissues was very high 4 hours postinjection with 0.4-13% of injected activity per gram. Injection of 30-120 MBq (177)Lu-DOTA-Tyr(3)-octreotate reduced tumor volume to 7-14% of the original tumor volume 7 days postinjection. Microscopic analysis of treated tumors revealed widespread areas of tumor cell necrosis and fibrosis. It was found that grafted GOT1 cells to nude mice represent an authentic model for studying human midgut carcinoids. Radiolabeled somatostatin analogs have a high selectivity for tumor tissue and can induce tumor cell necrosis. Radiotherapy of carcinoid tumors with (177)Lu-DOTA-Tyr(3)-octreotate appears to be a promising treatment modality for either palliative treatment or completion therapy after attempted surgical cure.

Animals↗

PubMed2004

Importance of vesicle proteins in the diagnosis and treatment of neuroendocrine tumors.

We have analyzed the expression of synaptic vesicle proteins in human neuroendocrine tumors and the potential use of vesicle proteins in the diagnosis and treatment of neuroendocrine tumors. Biopsies from endocrine and nonendocrine tumors of the gastrointestinal tract, pancreas, and adrenals were examined by immunocytochemistry using antibodies against synaptic vesicle protein 2 (SV2), vesicular monoamine transporter 1 and 2 (VMAT1 and 2), and neuroendocrine secretory protein 55 (NESP55). SV2 was expressed in all endocrine tumors of the gastrointestinal tract and pancreas as well as in gastrointestinal stromal tumors (GISTs). None of the adenocarcinomas expressed SV2. VMAT1 and 2 were expressed in amine-producing tumors of the gastrointestinal tract (ECL cell and EC cell carcinoids) and in a small number of peptide-producing pancreatic endocrine tumors. NESP55 was expressed in neuroblastomas and adrenal pheochromocytomas as well as in a subgroup of pancreatic endocrine tumors. The importance of VMAT1 and 2 for the uptake of 123I-MIBG in tumor cells was demonstrated. It was concluded that neuroendocrine tumors express multiple synaptic vesicle proteins that are useful in the histopathological diagnosis and classification of tumors. Vesicle proteins may prove to be useful for targeting tumor therapy.

3-Iodobenzylguanidine↗

PubMed2004

Radiation therapy of small cell lung cancer with 177Lu-DOTA-Tyr3-octreotate in an animal model.

UNLABELLED: Small cell lung cancer (SCLC) is a tumor of neuroendocrine (NE) origin with very low survival rate. Somatostatin receptor scintigraphy using 111In-DTPA-octreotide (DTPA is diethylenetriaminepentaacetic acid) is a well-established method for the visualization of somatostatin receptor-expressing NE tumors. Recently, new combinations of radionuclides and somatostatin analogs have been investigated for therapeutic purposes. In this study, the somatostatin analog DOTA-Tyr3-octreotate (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid), labeled with the medium-energy electron emitter 177Lu (maximal electron energy = 498 keV, half-life = 6.6 d), was used for radiation therapy of human SCLC in an animal model. METHODS: Nude mice, bearing tumors from the human SCLC cell line NCI-H69, were injected intravenously with 177Lu-DOTA-Tyr3-octreotate. Groups of animals (n = 5 or 6) were injected with 45-, 60-, and 120-MBq fractions and two 45-MBq fractions 48 h apart. Furthermore, 1 control group was treated with unlabeled DOTA-Tyr3-octreotate and another control group was not treated. RESULTS: In both control groups, the tumor volumes were increased 2-fold in approximately 5 d. Treatment with 177Lu-DOTA-Tyr3-octreotate resulted in marked tumor regression with statistically significant tumor volume reduction after 1 wk (P < 0.001). The tumor growth delay time was dependent on the amount of injected activity for the groups with single injections, 26 d for 60 MBq and 40 d for 120 MBq. The best therapeutic effect was obtained in mice injected with 2 fractions of 45 MBq. The relative tumor volume after 1 mo was 0.004 +/- 0.004. CONCLUSION: Radiation therapy with 177Lu-DOTA-Tyr3-octreotate on SCLC-bearing mice was successful. Since the experiments were performed on a human SCLC cell line xenografted to nude mice, the results may be clinically relevant and treatment with 177Lu-DOTA-Tyr3-octreotate could be a treatment alternative in this tumor disease that normally has a dismal prognosis.

Animals↗

PubMed2003

Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients.

BACKGROUND: Everolimus, a novel proliferation inhibitor and immunosuppressive agent, may suppress cardiac-allograft vasculopathy. We conducted a randomized, double-blind, clinical trial comparing everolimus with azathioprine in recipients of a first heart transplant. METHODS: A total of 634 patients were randomly assigned to receive 1.5 mg of everolimus per day (209 patients), 3.0 mg of everolimus per day (211 patients), or 1.0 to 3.0 mg of azathioprine per kilogram of body weight per day (214 patients), in combination with cyclosporine, corticosteroids, and statins. The primary efficacy end point was a composite of death, graft loss or retransplantation, loss to follow-up, biopsy-proved acute rejection of grade 3A, or rejection with hemodynamic compromise. RESULTS: At six months, the percentage of patients who had reached the primary efficacy end point was significantly smaller in the group given 3.0 mg of everolimus (27.0 percent, P<0.001) and the group given 1.5 mg of everolimus (36.4 percent, P=0.03) than in the azathioprine group (46.7 percent). Intravascular ultrasonography showed that the average increase in maximal intimal thickness 12 months after transplantation was significantly smaller in the two everolimus groups than in the azathioprine group. The incidence of vasculopathy was also significantly lower in the 1.5-mg group (35.7 percent, P=0.045) and the 3.0-mg group (30.4 percent, P=0.01) than in the azathioprine group (52.8 percent). The rates of cytomegalovirus infection were significantly lower in the 1.5-mg group (7.7 percent, P<0.001) and the 3.0-mg group (7.6 percent, P<0.001) than in the azathioprine group (21.5 percent). Rates of bacterial infection were significantly higher in the 3.0-mg group than in the azathioprine group. Serum creatinine levels were also significantly higher in the two everolimus groups than in the azathioprine group. CONCLUSIONS: Everolimus was more efficacious than azathioprine in reducing the severity and incidence of cardiac-allograft vasculopathy, suggesting that everolimus therapy may alleviate this serious problem.

Adult↗

PubMed2003

Silent and apparent cerebral embolism after retrograde catheterisation of the aortic valve in valvular stenosis: a prospective, randomised study.

BACKGROUND: In most patients, severity of valvular aortic stenosis can be accurately assessed non-invasively by echocardiography. However, retrograde catheterisation of the aortic valve is often undertaken. This procedure has a potential risk of neurological complications, with an unknown incidence of clinically silent embolism. We aimed to establish the frequency of clinically apparent and silent cerebral embolism after this procedure. METHODS: We prospectively randomised 152 consecutive patients with valvular aortic stenosis at a German university hospital to receive either cardiac catheterisation with (n=101) or without (n=51) passage through the aortic valve. Patients underwent cranial MRI and neurological assessment within 48 h before and after the procedure to assess cerebral embolism. Controls were 32 patients without valvular aortic stenosis who underwent coronary angiography and laevocardiography. FINDINGS: 22 of 101 patients (22%) who underwent retrograde catheterisation of the aortic valve had focal diffusion-imaging abnormalities in a pattern consistent with acute cerebral embolic events after the procedure; three of these patients (3%) had clinically apparent neurological deficits. By contrast, none of the patients without passage of the valve, or any of the controls, had evidence of cerebral embolism as assessed by MRI. INTERPRETATION: Patients with valvular aortic stenosis who undergo retrograde catheterisation of the aortic valve have a substantial risk of clinically apparent cerebral embolism, and frequently have silent ischaemic brain lesions. Patients should be informed about these risks, and this procedure should be used only in patients with unclear echocardiographical findings when additional information is necessary for clinical management.

Aortic Valve↗

PubMed2003

Biodistribution of 111in-DTPA-D-Phe1-octreotide in tumor-bearing nude mice: influence of amount injected and route of administration.

In nude mice carrying the human carcionoid GOT1 different amounts of (111)In-DTPA-Phe(1)-octreotide and routes of administration were studied in relation to uptake in tumor and normal organs. The relative organ uptake varied with given amount; highest in tumor after 0.1 and 1 microg and lowest in muscle, heart and blood after 0.1 microg. The uptake decreased in lungs and spleen with higher amounts of (111)In-DTPA-Phe(1)-octreotide. In all organs studied the tumor-to-normal-tissue activity concentration ratio was maximal at 0.1 and 1 microg, but route of administration influenced the uptake only little.

Animals↗

PubMed2003

Biodistribution and dosimetry of 177Lu-labeled [DOTA0,Tyr3]octreotate in male nude mice with human small cell lung cancer.

UNLABELLED: In this study the biodistribution of a somatostatin analogue, (177)Lu-[DOTA(0),Tyr(3)]octreotate, was investigated in an animal model, as a possible therapeutic radiopharmaceutical. METHODS: (177)Lu-[DOTA(0),Tyr(3)]octreotate was injected i.v. into nude mice bearing somatostatin receptor-positive tumors of the human small cell lung cancer (SCLC) cell line NCI-H69. In addition, nontumor bearing mice were injected i.v. with (177)LuCl(3). The activity concentration in tumor and normal tissues was measured and dosimetric estimations for tumor tissue were made. RESULTS: The tumor had higher activity concentration of (177)Lu-[DOTA(0),Tyr(3)]octreotate compared to all measured normal tissues at all time points. The activity concentration in the tumor tissue was 3.7 %IA/g, 2.1 %IA/g, and 1.2 %IA/g after 24 h, 3 days and 7 days, respectively. The mean absorbed dose to a 1 g tumor was 0.3 Gy/MBq. The highest activity concentration of (177)LuCl(3) was observed in the bone marrow and increased with time. CONCLUSION: This study shows that (177)Lu-labeled [DOTA(0),Tyr(3)]octreotate has therapeutic potential for SCLC. The study also points out the importance of optimal labeling efficiency since the high bone marrow uptake of free lutetium ions can be controlled by a high peptide-bound fraction.

Algorithms↗

PubMed2003

The pollination of Trimenia moorei (Trimeniaceae): floral volatiles, insect/wind pollen vectors and stigmatic self-incompatibility in a basal angiosperm.

Trimenia moorei (Oliv.) Philipson is an andromonoecious liane with >0.40 of the total flower buds maturing as bisexual flowers. Male and bisexual flowers are strongly scented with pollen, anther sacs and receptacle scars testing positively for volatile emissions. Scent analyses detect over 20 components. The major fatty acid derivative is 8-heptadecene, and 2-phenylethanol dominates the benzenoids. While hover-flies in the genera Melangyna and Triglyphus contact the stigma with their probosces, the stigma secretes no free-flowing, edible fluids. Copious pollen is the only edible reward consumed by hover-flies (Syprhidae), sawflies (Pergidae) and bees in the families Apidae, Colletidae and Halictidae. All these insects carried pollen of T. moorei on their heads, legs and thoraces and female bees in the genera Apis, Exoneura, Leioproctus and Lasioglossum stored pollen on their hind legs. Pollen traps also indicate that pollen is shed directly into the air, permitting wind pollination. When bisexual flower buds are bagged (isolated from insect foragers) on the liane then subjected to a series of hand-pollination experiments after perianth segments open, the structural analyses of pollen-carpel interactions indicate that T. moorei has a trichome-rich dry-type stigma with an early-acting self-incompatibility (SI) system. Bicellular pollen grains deposited on stigmas belonging to the same plant germinate but fail to penetrate intercellular spaces, while grains deposited following cross-pollination reach the ovule within 24 h. Fluorescence analyses of 76 carpels collected at random from unbagged (open-pollinated) flowers on five plants indicates that at least 64% of carpels are cross-pollinated in situ. Trimenia moorei is the first species within the ANITA group, and second within reilictual-basal angiosperm lineages, to exhibit stigmatic SI in combination with dry-type stigma and bicellular pollen, a condition once considered to be atypical for angiosperms as a whole but now known to be present in numerous taxa.

Animals↗

PubMed2003

Model of metastatic growth valuable for radionuclide therapy.

The aim was to make a Monte Carlo simulation approach to estimate the distribution of tumor sizes and to study the curative potential of three candidate radionuclides for radionuclide therapy: the high-energy electron emitter 90Y, the medium-energy electron emitter 177Lu and the low-energy electron emitter 103mRh. A patient with hepatocellular carcinoma with recently published serial CT data on tumor growth in the liver was used. From these data the growth of the primary tumor, and the metastatis formation rate, were estimated. Assuming the same tumor growth of the primary and all metastases and the same metastatis formation rate from both primary and metastases the metastatic size distribution was simulated for various time points. Tumor cure of the metastatic size distribution was simulated for uniform activity distribution of three radionuclides; the high-energy electron emitter 90Y, the mean-energy electron emitter 177Lu and the low-energy electron emitter 103mRh. The simulation of a tumor cure was performed for various time points and tumor-to-normal tissue activity concentrations, TNC. It was demonstrated that it is important to start therapy as early as possible after diagnosis. It was of crucial importance to use an optimal radionuclide for therapy. These simulations demonstrated that 90Y was not suitable for systemic radionuclide therapy, due to the low absorbed fraction of the emitted electrons in small tumors (< 1 mg). If TNC was low 103mRh was slightly better than 177Lu. For high TNC values low-energy electron emitters, e.g., 103mRh was the best choice for tumor cure. However, the short half-life of 103mRh (56 min) might not be optimal for therapy. Therefore, other low-energy electron emitters, or alpha emitters, should be considered for systemic targeted therapy.

Apoptosis↗