Jesper Graff

Short-term Administration of Glucagon-like Peptide-2. Effects on Bone Mineral Density and Markers of Bone Turnover in Short-Bowel Patients with No Colon

Background: Glucagon-like peptide 2 (GLP-2) is a newly discovered intestinotrophic hormone. We have recently reported that a 5-week GLP-2 treatment improved the intestinal absorptive capacity of shortbowel patients with no colon. Additionally, GLP-2 treatment was associated with changes in body composition that included a significant increase in total body bone mass. This article describes the effect of GLP-2 on spinal and hip bone mineral density (BMD) and biochemical markers of bone turnover in these patients. Methods: In an open-labelled pilot study, eight short-bowel patients (3M, 5F; mean age 49 years) with small-bowel resection and no colon received 400 μg s.c. of GLP-2 twice daily for 5 weeks. Four received home parenteral nutrition (mean length of residual jejunum 83 cm) and 4 did not (mean length of ileum resected 106 cm). The outcome measures were the mean percent change from baseline in spinal and hip BMD measured by dual-energy X-ray absorptiometry, changes in four biochemical markers of bone-turnover, PTH, 25-hydroxy vitamin-D, and the intestinal absorption of calcium. Results: Mean ± s x (SEM) percent changes in spinal and hip BMD were 1.1 ± 0.4% ( P < 0.05) and 1.9 ± 0.8% ( P = 0.06), respectively. The intestinal calcium absorption increased by 2.7% ( P = 0.87). Serum ionized calcium increased in 5/8 patients with a concomitant decrease in serum PTH values. Three of the four markers of bone turnover decreased. Conclusion: A 5-week GLP-2 administration significantly increased spinal BMD in short-bowel patients with no colon. The mechanism by which GLP-2 affects bone metabolism remains unclear, but may be related to an increased mineralization of bone resulting from an improved intestinal calcium absorption.

PET/CT and Histopathologic Response to Preoperative Chemoradiation Therapy in Locally Advanced Rectal Cancer

PurposeThe objective of this study was to investigate the possibility of using positron emission tomography/computer tomography to predict the histopathologic response in locally advanced rectal cancer treated with preoperative chemoradiation.MethodsThe study included 30 patients with locally advanced rectal adenocarcinoma treated with a combination of radiotherapy and concurrent Uftoral® (uracil, tegafur) and leucovorine. All patients were evaluated by positron emission tomography/computer tomography scan seven weeks after end of chemoradiation, and the results were compared to histopathologic tumor regression as the “standard.” The pathologic response was quantified by tumor regression grade.ResultsPositron emission tomography/computer tomography correctly identified six of eight patients (specificity 75 percent) with complete pathologic response. However, the sensitivity of positron emission tomography/computer tomography was only 45 percent and the accuracy 53 percent. The positive and negative predictive values were 83 and 33 percent, respectively.ConclusionsWe conclude that positron emission tomography/computer tomography performed seven weeks after the end of chemoradiation is not able to predict the histopathologic response in locally advanced rectal cancer. There is an obvious need for other complementary methods especially with respect to the low sensitivity of positron emission tomography/computer tomography.

18F-FDG PET/CT as a Diagnostic Tool in Patients with Extracervical Carcinoma of Unknown Primary Site: A Literature Review

BACKGROUNDnCarcinoma of unknown primary (CUP) represents a heterogeneous group of metastatic malignancies for which no primary tumor site can be identified after extensive diagnostic workup. Failure to identify the primary site may negatively influence patient management. The aim of this review was to evaluate (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) as a diagnostic tool in patients with extracervical CUP.nnnMATERIALS AND METHODSnA comprehensive literature search was performed and four publications were identified (involving 152 patients) evaluating (18)F-FDG PET/CT in CUP patients with extracervical metastases. All studies were retrospective and heterogeneous in inclusion criteria, study design, and diagnostic workup prior to (18)F-FDG PET/CT.nnnRESULTSn(18)F-FDG PET/CT detected the primary tumor in 39.5% of patients with extracervical CUP. The lung was the most commonly detected primary tumor site (∼50%). The pooled estimates of sensitivity, specificity, and accuracy of (18)F-FDG PET/CT in the detection of the primary tumor site were 87%, 88%, and 87.5%, respectively.nnnCONCLUSIONSnThe present review of currently available data indicates that (18)F-FDG PET/CT might contribute to the identification of the primary tumor site in extracervical CUP. However, prospective studies with more uniform inclusion criteria are required to evaluate the exact value of this diagnostic tool.

Bile Acid Malabsorption or Disturbed Intestinal Permeability in Patients Treated with Enzyme Substitution for Exocrine Pancreatic Insufficiency Is Not Caused by Bacterial Overgrowth

Introduction In some patients with severe exocrine pancreatic insufficiency, enzyme replacement therapy will not lead to clinical improvement or reduction of steatorrhea. Therefore, other mechanisms separately or in interplay with reduced enzyme secretion might be responsible for malabsorption in these patients. Aims To evaluate the prevalence of bacterial overgrowth, bile acid absorption capacity, and intestinal permeability in a group of patients with well-characterized exocrine pancreatic insufficiency. Methodology Eleven men with severe exocrine pancreatic insufficiency, of whom 10 were receiving enzyme replacement therapy, were studied. The prevalence of bacterial overgrowth was evaluated by means of a hydrogen and methane breath test with glucose. Gamma camera scintigraphy after intake of 75Se-homocholic acid taurine (75Se-HCAT) was used to evaluate bile acid absorption capacity. Intestinal permeability was assessed from urine excretion of ingested 14C-mannitol and 99mTc–diethylenetriaminepentaacetic acid (99mTc-DTPA), and these data were compared with results for 10 age-matched healthy men. Results No patients had abnormal breath hydrogen or methane concentrations after glucose intake. Abdominal retention of 75Se-HCAT was reduced in three of the patients. The patients had lower urine excretion of 14C-mannitol than the control subjects, whereas no difference was revealed in urine excretion of 99mTc-DTPA. Conclusion Bile acid absorption and small intestinal permeability might be affected in patients with exocrine pancreatic insufficiency who receive treatment with enzyme supplementation. The prevalence of bacterial overgrowth seems to be low among these patients and does not explain the findings.

Paediatric doses—a critical appraisal of the EANM paediatric dosage card

In the May 2007 issue of the European Journal of Nuclear Medicine and Molecular Imaging, two very important papers concerning paediatric nuclear medicine were published: an editorial “PET/CT in paediatrics: it is time to increase its use” [1] and “The new EANM paediatric dosage card” [2]. In the excellent editorial by Isabel Roca and co-workers, it was recommended that the use of PET/CT for diagnostic purposes in children should be increased. We fully support this statement: based on our experience gained from performing approximately 100 PET scans per year in children, and the use of paediatric PET since 1991, it is our impression that the added value from PET/CT is even more pronounced in children than in adults [3]. The new dosage card suggested by the EANM Dosimetry and Paediatrics groups [2] represents a major step forward. It utilises much of the existing knowledge about the dosimetry for different radiopharmaceuticals to estimate the activity that can be given to children at different weights whilst maintaining the same effective dose as given to adults. We acknowledge the large uncertainty of all these calculated values. The ICRP [4, 5] accounts for neither the normal age-dependent biodistribution nor the diseasedependent differences among patients. Compared with the large effort that has been put into the calculation of the new weight-dependent doses, however, the suggested minimum values are still not based on sound scientific argument [2]. In the text they are described as “determined based upon considerations concerning the limitations of conventional gamma cameras and PET scanners in terms of image quality, as described by Jacobs et al.” [2, 6]. In reference [6], however, the considerations mainly consist of referring the problem to be “addressed by a working party ...”. With the newly recommended minimum doses for PET [2], examinations of neonatal patients will result in very high effective doses and thereby either entail considerable risk or simply be impossible to perform according to the recommendations owing to ethical considerations. We are, of course, not the first to point out that minimum values may not be necessary in all cases. Smith and Gordon [7], in their paper on radiopharmaceutical schedules in children, applied some theoretical scaling arguments. Børch et al. [8] showed, although for a special instrument, that in HMPAO brain imaging in neonates, linear scaling (4 MBq/kg) without a minimum may apply. Also for FDG, Ruotsalainen et al. [9] performed imaging and effective dose estimation in neonates with a fixed activity per weight down to 1.8 kg. It should also be noted that the EANM guidelines for Brain Imaging using [F]FDG (http://www. eanm.org) do apply a minimum limit, but of 10 MBq rather than the 70 MBq proposed in [2]. The images we present here (Figs. 1, 2) clearly show that PET images of sufficient quality can be obtained with an amount of activity that is considerably less than that suggested as the “minimum” in the new dosage card [2]. Why is that? In the paper by Jacobs et al. [6], ”image quality” is inferred solely from “count rate”. Given the influence of this choice on the recommendations, it is important to note that little reflection has been given to this subject. Below, we explain how, in our opinion, the authors are making a number of mistakes, and how these result in over-dosing (particularly in PET) of the smallest children, for whom the original aim of protection has the greatest importance. Eur J Nucl Med Mol Imaging (2007) 34:1713–1718 DOI 10.1007/s00259-007-0508-0

Effect of sildenafil on gastric emptying and postprandial frequency of antral contractions in healthy humans

Background: Sildenafil is known to block phosphodiesterase type 5, which degrades nitric oxide‐stimulated cyclic guanosine monophosphate, thereby relaxing smooth muscle cells in various organs. The effect of sildenafil on gastric motor function after a meal was investigated in healthy humans. Methods: Ten healthy male volunteers (21–28 years) participated in a placebo‐controlled, double‐blind, cross‐over study. In random order and on two separate days each volunteer ingested either 50u2005mg sildenafil (Viagra, Pfizer, New York, N.Y., USA) or placebo. A gamma camera technique was used to measure gastric emptying and postprandial frequency of antral contractions. Results: The area under the curve of gastric retention versus time of liquid or solid radiolabelled marker was not changed by sildenafil intake, nor was the postprandial frequency of antral contractions affected by sildenafil. Conclusion: A single dose of 50u2005mg sildenafil does not change gastric emptying or postprandial frequency of antral contractions in healthy volunteers.

Diagnosis of bile acid diarrhoea by fasting and postprandial measurements of fibroblast growth factor 19.

Background A deficiency in the ileal hormone fibroblast growth factor 19 (FGF19) has been described in patients with bile acid diarrhoea (BAD), but fasting FGF19 levels have insufficient diagnostic power. We assess whether single postprandial sampling of FGF19 has greater discriminative value than fasting FGF19 for detection of BAD and we evaluate the reproducibility of fasting FGF19. Materials and methods Twenty-six patients consecutively referred to 75Se homocholic acid retention test (SeHCAT) were included. Serum FGF19 was measured after an overnight fast and again 1u2009h postprandially and again in the fasting state 1 week later. Results Nine of 26 patients had SeHCAT less than 10% and fasting FGF19 was lower [median 62u2009pg/ml, interquartile range (IQR): 47–67] than in the 17 diarrhoea controls with SeHCAT at least 10% (median 103u2009pg/ml, IQR: 77–135, P=0.006). Postprandial FGF19 in BAD patients (61u2009pg/ml, IQR: 48–69) was similar to fasting values (P=0.59) and increased insignificantly in diarrhoea controls (137u2009pg/ml, IQR: 88–182; P=0.25). The difference in postprandial FGF19 between patients with BAD and diarrhoea controls was highly significant (P<0.001). Conclusion The difference in serum FGF19 between groups of patients with BAD and diarrhoea controls is amplified postprandially. Within each group, the difference between fasting and postprandial FGF19 was not statistically significant. Further investigations are warranted on stimulated FGF19 response to elucidate its role in BAD.

Parameter Estimation in Six Numeric Models of Transperitoneal Transport of Glucose

&NA; Six competing kinetic models of transperitoneal glucose transport were formulated and validated. The models were designed to elucidate the presence or absence of diffusive, nonlymphatic convective and lymphatic convective solute transport. The validation procedure included an assessment of theoretical and practical identifiability, goodness of fit, residual error analysis, and plausibility of parameter estimates. Experimental results were obtained from 21 patients without diabetes. The validation procedure demonstrated that the model that only included diffusion was superior to the other models. Theoretically, both nonlymphatic convective and lymphatic convective transports might exist. However, neither the ultrafiltration sieving coefficient nor the lymphatic flow rate were practically identifiable, probably because any amount of glucose transported by nonlymphatic convective and lymphatic convective transport mechanisms was negligible compared with the amount transported by diffusion. Based on these results, there appear to be problems measuring convective solute transport parameters when the solute transport is in the dialysate‐to‐blood direction while the fluid transport is in the blood‐to‐dialysate direction. ASAIO Journal 1994; 40:1005‐1011.

Whole body 18F-FDG PET/CT is superior to CT as first line diagnostic imaging in patients referred with serious non-specific symptoms or signs of cancer: a randomized prospective study of 200 patients

A fast-track pathway has been established in Denmark to investigate patients with serious nonspecific symptoms and signs of cancer (NSSC), who are not eligible to enter an organ-specific cancer program. The prevalence of cancer in this cohort is approximately 20%. The optimal screening strategy in patients with NSSC remains unknown. The aim of the study was to investigate whether 18F-FDG PET/CT was superior to CT as an initial imaging modality in patients with NSSC. In a randomized prospective trial, the imaging modalities were compared with regard to diagnostic performance. Methods: Two hundred patients were randomized 1:1 to whole-body 18F-FDG PET/CT or CT of the thorax and abdomen as the imaging modality. A tentative diagnosis was established after first-line imaging. The final referral diagnosis was adjudicated by the physician, when sufficient data were available. Results: One hundred ninety-seven patients were available for analysis because 3 patients withdrew consent before scanning. Thirty-nine (20%) patients were diagnosed with cancer, 10 (5%) with an infection, 15 (8%) with an autoimmune disease, and 76 (39%) with other diseases. In the remaining 57 patients (28%), no specific disease was found. 18F-FDG PET/CT had a higher specificity (96% vs. 85%; P = 0.028) and a higher accuracy (94% vs. 82%; P = 0.017) than CT. However, there were no statistically significant differences in sensitivity (83% vs. 70%) or negative predictive values (96% vs. 92%). No difference in days to final referral diagnosis according to randomization group could be shown (7.2 vs. 7.6 d). However, for the subgroups in which the imaging modality showed a suggestion of malignancy, there was a significant delay to final diagnosis in the CT group compared with the 18F-FDG PET/CT group (11.6 vs. 5.7 d; P = 0.02). Conclusion: Compared with CT, we found a higher diagnostic specificity and accuracy of 18F-FDG PET/CT for detecting cancer in patients with NSSC. 18F-FDG PET/CT should therefore be considered as first-line imaging in this group of patients.

Effects of the H2-receptor antagonist ranitidine on gastric motor function after a liquid meal in healthy humans

Objective. Studies on animals have shown that histamine may be involved in the regulation of gastrointestinal smooth muscle tone. However, the role of histamine in the regulation of human gastric motor function is not clear. This study examined the effect of ranitidine, an H2‐receptor antagonist, on gastric volume and gastric emptying after a liquid meal in healthy humans. Material and methods. Twelve healthy volunteers participated in a randomized crossover study with 50u2005mg ranitidine as a bolus intravenously versus no medication. Gastric volume at baseline was determined with single photon emission computed tomography (SPECT) after intravenous injection of 99mTc‐pertechnetate. After ingestion of a 600‐mL liquid meal radiolabelled with 111In‐diethylenetriaminepentaacetic acid, dual‐isotope technique with SPECT and planar imaging assessed gastric volume as well as gastric emptying. Results. Ranitidine did not change gastric volume before the meal, nor at 0u2005h or 1u2005h after it. Furthermore, ranitidine did not influence gastric retention of meal components after 0.5u2005h and 1u2005h. Conclusions. Intravenous bolus injection of 50u2005mg ranitidine does not modify gastric volume or gastric emptying after a 600u2005mL liquid meal in healthy humans.