Measurable Serum Estradiol and Estrone in Women 36-56 Years During Adjuvant Treatment With Aromatase Inhibitors for a Hormone Receptor-Positive Breast Cancer. Case Studies and Cross-sectional Study Using an Ultra-sensitive LC-MS/MS-Method.

BACKGROUND AND PURPOSE: Ovarian function recovery (OFR) during adjuvant use of an aromatase inhibitor (AI) negatively impacts breast cancer outcome. We measured serum FSH and estrogen levels in consecutive AI-users with an uncertain menopausal status during follow-up and report associated risk factors of OFR METHODS: A retrospective cross sectional observational monocentric study including breast cancer patients in follow-up using an adjuvant AI, age 36 to 56 years, with at least one serum estradiol (E2) and estrone (E1) measurement between 2013 and 2020. Estrogens were quantified using a sensitive liquid chromatography-tandem mass spectrometry method (LC-MS/MS). Women on LHRH agonist were included while those with a bilateral oophorectomy or ovarian irradiation were not. We aimed to identify risk factors of OFR considering age, body mass index (BMI), previous chemotherapy and duration of AI use. Univariable analysis was used to evaluate risk factors of OFR. RESULTS: E2/E1 levels were assessed in 207 patients with a median age of 50 years (range 36-56). 17 of 159 on AI (10.7%) and 3 of 48 on AI + LHRH (6.3%) had OFR. Seven out of 17 patients (41,2%) with OFR in the AI only group and 2 out of 3 patients (66,7%) in the AI+LHRH agonist group were in amenorrhea. Age <50 y and adjuvant chemotherapy were statistically significantly different between the OFR group and the group with postmenopausal estrogen levels. CONCLUSION: Breast cancer patients aged 36 to56 years need to be monitored closely during adjuvant treatment with aromatase inhibitors: to confirm menopausal status, to evaluate compliance and to ensure ovarian activity remains adequately suppressed. Estrone might be a better marker then estradiol to detect ovarian reactivation.

Free Testosterone Reflects Metabolic as well as Ovarian Disturbances in Subfertile Oligomenorrheic Women.

BACKGROUND: Diagnosing polycystic ovary syndrome (PCOS) is based on ovulatory dysfunction, ovarian ultrasound data, and androgen excess. Total testosterone is frequently used to identify androgen excess, but testosterone is mainly bound to sex hormone-binding globulin (SHBG) and albumin. Only 1-2% of nonprotein-bound testosterone (so-called free testosterone) is biologically active and responsible for androgen action. Moreover, automated immunoassays which are frequently used for female testosterone measurements are inaccurate. OBJECTIVE: To assess the clinical usefulness of liquid chromatography-tandem mass spectrometry measured testosterone and calculated free testosterone in subfertile women attending a fertility clinic with oligomenorrhea and suspected PCOS. METHODS: Hormonal and metabolic parameters were evaluated, and ovarian ultrasound was performed. Total testosterone was measured by liquid chromatography-tandem mass spectrometry. Free testosterone was calculated from total testosterone and SHBG. RESULTS: Sixty-six women were included in the study. Total testosterone was associated with ovarian volume and antral follicle count but not with metabolic parameters. However, SHBG and calculated free testosterone were associated with both ovarian ultrasound and metabolic parameters, such as BMI and insulin resistance. CONCLUSIONS: Assessing SHBG and free testosterone is important in evaluating androgen excess in subfertile women with ovulatory dysfunction and suspected PCOS, as it reflects both ovarian and metabolic disturbances.

Identification of progastrin in gastrinomas, antrum, and duodenum by a novel radioimmunoassay.

Recent studies on the gene sequence encoding the human pyloric antral hormone, gastrin, indicate a precursor of 101 residues. We have now raised antibodies to a synthetic analogue corresponding to (Tyr)-human progastrin COOH-terminal pentapeptide. The antibodies could be used in radioimmunoassay to measure this peptide, but they did not react with corresponding fragments of procholecystokinin, porcine progastrin, or other human progastrin-derived peptides, notably heptadecapeptide gastrin (G17), and 34-residue gastrin (G34). Radioimmunoassay of human antral and duodenal extracts revealed a major peak of activity that corresponded to the native COOH-terminal fragment of progastrin, and occurred in approximately equimolar amounts with COOH-terminal G17 immunoreactivity. In addition, there was a minor peak of apparently higher molecular weight material. In some gastrinomas the latter material was the predominant immunoreactive form, and it occurred in higher molar concentrations than any other form of gastrin. Digestion of this material with trypsin liberated peptides that reacted with antibodies specific for the NH2-terminus of G34, and G17. On this basis the high molecular weight component was identified as a form of gastrin that extended from the COOH-terminus of the precursor to a point at least beyond the NH2-terminus of G34, and probably included the entire progastrin sequence. The results suggest differences in posttranslational processing pathways of progastrin in antrum, duodenum, and gastrinomas. They also indicate that the present experimental approach allows the identification of progastrin-like substances, which should open the way to studying the mechanisms of gastrin biosynthesis.

Metabolism of heptadecapeptide gastrin in humans studied by region-specific antisera.

The metabolism of synthetic human heptadecapeptide gastrin (G17) in vivo, and in serum in vitro, was studied by radioimmunoassay using region specific antisera, gel filtration, ion exchange chromatography, and high performance liquid chromatography. After infusion of G17 intravenously in normal human volunteers, COOH-terminal and NH2-terminal immunoreactive G17 fragments were generated. At a steady state, approximately 15% of COOH-terminal immunoreactivity was attributable to G14-like material and up to 25% of total NH2-terminal immunoreactivity was attributable to two NH2-terminal fragments; one had the chromatographic properties of 1-13 G17, and the other was less acidic and less hydrophobic. After stopping the infusion of G17, the latter fragments accounted for progressively greater proportions of total gastrin activity. When G17 was incubated in serum in vitro, there was time-dependent and temperature-dependent loss of immunoreactivity, and again COOH-terminal and NH2-terminal immunoreactive fragments were formed. Removal of the NH2-terminal pyroglutamic acid was probably the rate limiting step because synthetic 2-17 G17 was degraded more rapidly in serum (t1/2, 2-3 h) than G17 (t1/2, 3-5 h). EDTA blocked degradation at the COOH-terminus of both 2-17 G17 and G17 but cleavage at the NH2-terminus still occurred, giving rise to a G14-like peptide. The rate of conversion of G17 in serum was not enough to account for the production of fragments in vivo, and it is proposed that these are formed when G17 encounters enzymes on cell surfaces, perhaps during passage through the capillary circulation. The production of these fragments needs to be considered in interpreting studies of the identity, metabolism, and release of gastrin in health and disease.

The effect of paternal methyl-group donor intake on offspring DNA methylation and birth weight.

Most nutritional studies on the development of children focus on mother-infant interactions. Maternal nutrition is critically involved in the growth and development of the fetus, but what about the father? The aim is to investigate the effects of paternal methyl-group donor intake (methionine, folate, betaine, choline) on paternal and offspring global DNA (hydroxy)methylation, offspring IGF2 DMR DNA methylation, and birth weight. Questionnaires, 7-day estimated dietary records, whole blood samples, and anthropometric measurements from 74 fathers were obtained. A total of 51 cord blood samples were collected and birth weight was obtained. DNA methylation status was measured using liquid chromatography-tandem mass spectrometry (global DNA (hydroxy)methylation) and pyrosequencing (IGF2 DMR methylation). Paternal betaine intake was positively associated with paternal global DNA hydroxymethylation (0.028% per 100 mg betaine increase, 95% CI: 0.003, 0.053, P=0.03) and cord blood global DNA methylation (0.679% per 100 mg betaine increase, 95% CI: 0.057, 1.302, P=0.03). Paternal methionine intake was positively associated with CpG1 (0.336% per 100 mg methionine increase, 95% CI: 0.103, 0.569, P=0.006), and mean CpG (0.201% per 100 mg methionine increase, 95% CI: 0.001, 0.402, P=0.049) methylation of the IGF2 DMR in cord blood. Further, a negative association between birth weight/birth weight-for-gestational age z-score and paternal betaine/methionine intake was found. In addition, a positive association between choline and birth weight/birth weight-for-gestational age z-score was also observed. Our data indicate a potential impact of paternal methyl-group donor intake on paternal global DNA hydroxymethylation, offspring global and IGF2 DMR DNA methylation, and prenatal growth.

Degradation of human gastrin and CCK by endopeptidase 24.11: differential behaviour of the sulphated and unsulphated peptides.

The degradation of human sulphated heptadecapeptide gastrin (G17s) by human endopeptidase 24.11 was studied in vitro. The products of degradation were characterized by HPLC, region-specific gastrin radioimmunoassay and amino acid analysis. The enzyme cleaved G17s at four sites, Trp4-Leu5, Ala11-Tyr12, Gly13-Trp14 and Asp16-Phe17. The patterns of fragments produced when sulphated and unsulphated G17s are hydrolysed by endopeptidase 24.11 indicate that the enzyme cleaves both substrates at the same four bonds. However, the sulphated G17 was 3-times less rapidly degraded than the unsulphated G17 (G17ns). In contrast, the rate of cleavage of the octapeptide cholecystokinin (CCK8) was faster when the peptide was sulphated. The kinetic data of endopeptidase 24.11 indicated similar Km values for sulphated or unsulphated gastrin and CCK; sulphated CCK8 exhibited a 2-fold higher kcat/Km value compared to unsulphated CCK8, whereas G17s exhibited a 2-fold lower kcat/Km value compared to G17ns. The results indicate that the presence of a sulphate group causes a marked reduction in the rate of hydrolysis of gastrin by endopeptidase 24.11, whereas sulphation enhances cholecystokinin degradation by the same enzyme. They also suggest that endopeptidase 24.11 may be responsible for the difference in metabolism of sulphated and unsulphated G17, previously observed in human circulation.

Impaired gastric emptying in diabetic patients with cardiac autonomic neuropathy.

The aim of our study was to measure the gastric emptying rate for a solid meal in diabetic patients who had no gastrointestinal complaints with (group 1, n = 12) or without (group 2, n = 10) cardiac autonomic neuropathy and in normal controls comparable in age and sex (group 3, n = 10). Gastric emptying rate was assessed with a sequential scintiscanning method. The percentages of the initial isotope activity remaining in the stomach at different times (20, 40, 60, 80, 100, and 120 min) after the ingestion of a Tc-99m-labeled test meal and the emptying half-time were calculated. Cardiac autonomic neuropathy was determined by the beat-to-beat variations in heart rate during deep breathing. A significant reduction of the gastric emptying rate was observed in group 1. Indeed, at 80, 100, and 120 min the percentage of residual isotope activity was 73 +/- 4, 60 +/- 6, and 50 +/- 6% (mean +/- SE), respectively, in group 1 versus 61 +/- 3 (P less than .05), 45 +/- 4 (P less than .05), and 32 +/- 4% (P less than .02) in group 2. In group 3, residual isotope activity was 57 +/- 4 (P less than .05 vs. group 1), 41 +/- 4 (P less than .05), and 29 +/- 4% (P less than .02), respectively. Emptying half-time was also longer in group 1 (121 +/- 9 min) than in group 2 (95 +/- 6 min, P less than .05) or group 3 (90 +/- 4 min, P less than .02).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of molecular responses based on BCR-ABL1% (IS) results from an in-house TaqMan-based qPCR versus Xpert(®) assay in CML patients on tyrosine kinase inhibitor therapy.

OBJECTIVES: Tyrosine kinase inhibitors (TKIs) have drastically changed the prospects for chronic myeloid leukemia (CML) patients. The European LeukemiaNet (ELN) recommends molecular monitoring of BCR-ABL1 mRNA levels at distinct time points to define an optimal response, warning, or failure of treatment. METHODS: Sixty-four follow-up peripheral blood samples from CML patients on TKI were tested by two methods. Molecular responses based on BCR-ABL1% (IS) from an Xpert(®) BCR-ABL1 Monitor assay were compared with TaqMan-based qPCR. RESULTS: Seven samples showed 'molecularly undetectable leukaemia' by both methods (11%). In-house qPCR showed 57 BCR-ABL1+ samples; 45/57 samples (79%) were concordant for 'major molecular response' (MMR, n = 32) and 'no MMR' (n = 13) by both assays, whereas nine were BCR-ABL1 negative by Xpert(®). Identical molecular responses (i.e. 'optimal') were defined in 41 samples. Discordances seen in patients < 10 months on TKI (n = 2) had no impact on clinical management, whereas for patients >12 months on TKI, a different molecular response was defined ('warning' versus 'optimal'). Thirteen samples had 'no MMR' by both methods. 10/13 showed identical intervals (>10%(IS), 1-10%(IS) or 0·1-1%(IS)), corresponding to seven 'failures' and three 'warnings'. Discordant intervals were seen in 3/13 samples (all defined as 'failures'). Deep molecular responses (MR(4·0) or MR(5·0)) with detectable BCR-ABL1 showed some fluctuations between both methods, nevertheless, all had 'optimal' responses. 'Molecularly undetectable leukaemia' was observed more frequently by Xpert(®) (n = 16) as by our in-house assay (n = 7). DISCUSSION: Based on current ELN recommendations, Xpert(®) BCR-ABL1 assay defines identical molecular responses as TaqMan-based qPCR BCR-ABL1% (IS) data in 98% (63/64) of samples.

Evaluation of the Sebia Minicap Flex Piercing capillary electrophoresis for hemoglobinopathy testing.

INTRODUCTION: Capillary zone electrophoresis (CZE) at alkaline pH is one of the techniques used for hemoglobinopathy screening. In this study, an evaluation of the performance of a lower throughput CZE instrument, the Sebia Minicap Flex Piercing system, for this purpose is reported for the first time. METHODS: The analytical performance of the Sebia Minicap Flex Piercing system was evaluated. Furthermore, a method comparison between the Sebia Minicap Flex Piercing and two HPLC methods, that is, the Bio-Rad Variant Classic(™) and the Bio-Rad D-10(™) systems was performed by measuring samples with and without clinically relevant hemoglobin disorders. RESULTS: The analytical performance was acceptable for the determination of HbA, HbA2, HbS, and HbF, with an imprecision ≤2.0%. Method comparison showed a linear correlation for HbA2, HbF, and HbS measurements. Clinical concordance was acceptable when comparing CZE and HPLC. CONCLUSIONS: Lower throughput CZE using the Sebia Minicap Flex Piercing can be used for precise and accurate first line screening and follow-up of hemoglobinopathies.

Isolation and characterization of the intact gastrin precursor from a gastrinoma.

Antibodies to the extreme C-terminal region of human progastrin have been used to monitor the isolation of high-Mr immunoreactive material in a gastrinoma extract. Microsequence analysis of the product revealed amino acid residues in the first 18 positions corresponding to those predicted from the cDNA sequence for preprogastrin starting at position 22; the sequence and immunochemical data together allow the identification of this material as intact progastrin. Implications for gastrin biosynthesis are discussed.

Clinical evaluation of Tc-99m-diethyl-IDA in hepatobiliary disorders.

N,alpha(2,6-diethylacetanilide)-iminodiacetic acid is a new Tc-99m-labeled radiopharmaceutical primarily excreted through the biliary tract. Its high concentration in the bile allows the imaging of the biliary tree and the gallbladder. Scintigraphic studies were performed in 20 normal subjects and 42 patients suffering from various hepatobiliary disturbances. In normal subjects, the early liver uptake was followed by the accumulation of the tracer in the intrahepatic bile ducts and the gallbladder before its discharge into the duodenum. In cases of hepatocellar damage, the hepatic accumulation of the tracer was clearly depressed. Any acute or subacute disorder of the gallbladder was clearly demonstrated by Tc-99m-diethyl-IDA. In cases of asymptomatic cholelithiasis, we observed delayed visualization of the gallbladder associated with its decreased accumulation of the tracer. The intrahepatic bile ducts were distended in cases of incomplete obstruction of the hepatobiliary ducts, whereas they were never visualized when there was severe hepatocellular damage or complete obstruction of the biliary tree.

Somatostatin receptor imaging with indium-111-pentetreotide in gastroenteropancreatic neuroendocrine tumors: safety, efficacy and impact on patient management.

UNLABELLED: Indium-111-pentetreotide, a radiolabeled somatostatin analog, has been proposed for imaging tumors bearing somatostatin receptors. This study evaluates the safety, efficacy and impact on patient management of this scintigraphic agent in patients with gastroenteropancreatic (GEP) neuroendocrine tumors. METHODS: We studied 47 consecutive patients with a proven or clinically suspected GEP neuroendocrine tumor who were imaged 4 and 24 hr after injection of 111In-pentetreotide. The patients were monitored for adverse reactions and changes in vital signs or clinical chemistry over 24 hr. The scintigraphic findings were compared with results from conventional imaging methods. The patients were followed over a minimal 6-mo period during which further localization procedures were performed to confirm or refute the additional tumor sites found at scintigraphy. RESULTS: No adverse reactions or clinically relevant changes in clinical chemistry were noted after injection of the radiopharmaceutical. The final diagnosis of a GEP neuroendocrine tumor was retained in 38 patients. Somatostatin receptor-positive lesions were found in 33 of these patients, whereas conventional methods were positive in 31 patients. Of the 54 sites seen by conventional procedures, 50 sites were also detected scintigraphically. CONCLUSION: Indium-111-pentetreotide is a safe, sensitive imaging agent in the detection of GEP neuroendocrine tumor sites. Indium-111-pentetreotide also provides information on the somatostatin receptor status of the tumor and may therefore aid in therapeutic decisions.

Indium-111-pentetreotide uptake in endocrine tumors and lymphoma.

UNLABELLED: The biodistribution of 111In-pentetreotide was assessed in patients with gastroenteropancreatic (GEP) neuroendocrine tumors or lymphoma and in control patients and analyzed as a function of scanning time, presence or absence of tumor uptake, tumor type and previous octreotide treatment. METHODS: Patients underwent imaging 4 and 24 hr after injection of approximately 200 MBq 111In-pentetreotide. The frequency of organ visualization was assessed on planar views. Total organ and tumor uptake (% injected dose [ID]) was determined using the geometric mean method and regional tissue uptake (% ID/100 ml) by semiquantitative SPECT. RESULTS: Liver, spleen, kidneys and urinary bladder were visualized in all patients. Thyroid, bowel and pituitary were more often visualized at 24 hr than at 4 hr. Activity in the gallbladder, breast, ureters and ascites was only occasionally observed. Total liver, spleen and thyroid uptake was stable over time, whereas kidney activity decreased slightly. At 24 hr, regional uptake was threefold lower in the liver than in the spleen or kidneys and was similar in the three groups. In patients with long-term octreotide therapy, a positive correlation was found between the duration of octreotide therapy and liver or spleen uptake. Total and regional tumor uptake showed high intraindividual and interindividual variations. Total tumor activity was stable over 24 hr in patients with GEP and decreased in those with lymphoma. The mean regional tumor uptake was 10-fold lower in patients with lymphoma than in those with GEP. Cold octreotide injected 24 hr after tracer administration did not result in any displacement of organ and tumor activity. CONCLUSION: Organ uptake seems not to be influenced by the presence of 111In-pentetreotide-positive lesions or by tumor type. Tumor uptake is highly variable among patients and clearly lower in patients with lymphoma than in those with GEP. The widespread of uptake values in tumors indicates that radiotherapy using radiolabeled somatostatin analogs may not be applicable to all patients with 111In-pentetreotide-positive tumors.

Tc-99m-diethyl-IDA imaging: clinical evaluation in jaundiced patients.

Hepatobiliary imaging with Tc-99m-N,alpha-(2,6-diethylacetanilide)-iminodiacetic acid (Tc-diethyl-IDA) was performed in 91 jaundiced patients with documented hepatobiliary damage and serum total bilirubin up to 35 mg/dl. There were 56 patients with obstructive jaundice and 35 with hepatocellular disease. Correct discrimination between hepatocellular and obstructive jaundice was possible with an overall accuracy of 90%. Agreement with the final clinical diagnosis was obtained in 97% of patients with hepatocellular disease, and in 86% of patients with obstructive jaundice. The reliability of the test was inversely related to the serum bilirubin concentration. The incidence of true-positive scans dropped from 93% for bilirubin levels below 10 mg/dl to 83% for bilirubin between 10 and 20 mg/dl. Above 20 mg/dl, the demonstration of a mechanical obstruction was possible in only one out of the four patients with obstructive jaundice. The high predictive values of the test illustrate that Tc-diethyl-IDA imaging constitutes a reliable method to demonstrate an obstructive cause for the jaundice as long as the bilirubin level remains below 20 mg/dl.

Quantification of Helicobacter pylori infection in gastritis and ulcer disease using a simple and rapid carbon-14-urea breath test.

Gastric urease was studied isotopically in 230 patients with biopsy-proven normal mucosa or chronic gastritis, including 59 patients with ulcer disease. Carbon-14-urea was given in 25 ml of water without substrate carrier or nutrient-dense meal, and breath samples were collected over a 60-min period. The amount of 14CO2 excreted at 10 min was independent of the rate of gastric emptying and was not quantitatively influenced by the buccal urease activity. The 10-min 14CO2 values discriminated well between Helicobacter pylori positive and negative patients (94% sensitivity, 89% specificity) and correlated with the number of organisms assessed by histology. The test was a good predictor of chronic gastritis (95% sensitivity and 96% specificity), and a quantitative relationship was observed between 14CO2 values and the severity and activity of the gastritis. In H. pylori positive patients, breath 14CO2 was found to be similar in patients with and without ulcer disease, suggesting that the number of bacteria is not a determining factor for the onset of ulceration.

Brain tumor imaging with PET and 2-[carbon-11]thymidine.

METHODS: To assess the potential of thymidine for imaging brain tumors, 20 patients with untreated (n = 14) and recurrent (n = 6) supratentorial intracranial tumors were studied with PET by using 2-[11C]thymidine (Tdr), and the results were compared with [18F]fluorodeoxyglucose (FDG) PET data. RESULTS: Blood analysis consistently revealed a rapid clearance of the intact Tdr together with the appearance of CO2/HCO3- that, with time, accounted for approximately 70% of the total blood activity. As soon as 10 min after tracer injection, brain images showed a low and homogeneous Tdr distribution over the normal brain structures (cortex-to-blood ratio approximately 1). Visual and quantitative analysis revealed increased Tdr uptake (tumor-to-cortex ratio > or = 1.2) in 11 of 14 untreated tumors and in 5 of 6 recurrent tumors. No correlation was found between Tdr uptake and tumor grade. In 12 of the 14 untreated tumors, FDG uptake was low (tumor-to-cortex ratio: 0.83 +/- 0.79), but a FDG hot spot was visualized in 8 of 10 high-grade and in none of the 4 low-grade tumors. FDG uptake was consistently low in recurrent tumors (tumor-to-cortex ratio: 0.49 +/- 0.19), and PET-FDG was negative in 3 of the 6 cases. CONCLUSION: These data indicate the feasibility of brain tumor imaging with Tdr and suggest the potential clinical usefulness of the method in the detection of tumor recurrences. The specificity of the method remains, however, to be investigated.

Antibodies to the N-terminus of human Gastrin-34 react with material in rat and ferret brain.

Antibodies specific for the N-terminus of human big gastrin, or NT G34, reveal in immunohistochemistry extensive systems of nerve cell bodies and fibres in the rat and ferret brain. However, when the same antibodies were used in radioimmunoassay of rat and ferret brain tissue extracts they failed to reveal immunoreactive material. At least one of the antibodies used for radioimmunoassay could be shown to react with NT G34 in rat pyloric antral extracts. Antibodies specific for other peptides derived from progastrin failed to reveal the systems demonstrated with the N-terminal G34 antibodies. It is concluded that expression of the gastrin gene is unlikely to account for the present observations. Instead we suggest that a novel peptide with low affinity for NT G34 specific antibodies is found in rat and ferret central neurones.

Atriopeptin III degradation by endopeptidase 24.11: the Cys-Phe bond is not the preferential cleavage site.

Incubation of rANP(5-28)--also called atriopeptin III (AP III)--with purified endopeptidase 24.11 led preferentially to the production of Phe-Arg-Tyr, while other products of minor importance were detected. One of these was identified as rANP(5-25) (atriopeptin I) (AP I). This hydrolysis pattern of endopeptidase 24.11 towards AP III differs from the known favored site of cleavage at the Cys7-Phe8 bond of rANP(1-28). Moreover, by comparison with rANP(1-28), the degradation rate of AP III was slower. These data suggest that N-terminal peptide truncation results in conformational and/or charge modifications leading to a different positioning of the peptide in the endopeptidase 24.11 active site. In most hypothalamic nuclei of the rat brain known to contain AP III and endopeptidase 24.11, the preferential Ser25-Phe26 bond hydrolysis, although supposed to be responsible for a reduced degradation rate, might represent an effective enzymatic pathway of catabolism for AP III.

Intragastric distribution of a standardized meal in health and functional dyspepsia: correlation with specific symptoms.

In functional dyspepsia, abnormal intragastric distribution of a test meal has been identified but has never been correlated to any symptom pattern. The aim of this study was to compare the intragastric distribution of a meal between functional dyspepsia patients and controls, and to correlate distribution with symptom patterns, using scintigraphic gastric emptying studies. In forty patients with functional dyspepsia and 29 healthy volunteers, scintigraphic planar images were obtained immediately after ingestion of a mixed radiolabelled test meal and every 20 min for 2 h. The images of the stomach were divided into proximal and distal compartments. The mean intragastric distribution was similar in patients and controls. Over the whole test, 18 (45%) and 20 (50%) patients had a distal redistribution of the solid and liquid phase of the meal, respectively, while proximal retention of these phases was found in 13 (33%) and 9 (23%) patients. Early satiety was associated with early distal redistribution of the liquid phase and fullness was associated with late proximal retention. This study shows similar intragastric distribution of a test meal in health and functional dyspepsia. Within the patient group, an association between abnormal intragastric distribution patterns and symptom profiles was found, which might be related to different pathophysiological mechanisms.

The role of radioactive somatostatin and its analogues in the control of tumor growth.

Peptide receptor scintigraphy with the radioactive somatostatin analogue [111In-DTPA-D-Phe1]octreotide is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumors. With this technique primary tumors and metastases of neuroendocrine cancers as well as of many other cancer types can be localized. This technique is currently used to assess the possibility of peptide receptor radionuclide therapy with repeated administration of high doses of [111In-DTPA-D-Phe1]octreotide. 111In emits Auger and conversion electrons, having a tissue penetration of 0.02-10 microns and 200-500 microns, respectively. Thirty end-stage patients with mostly neuroendocrine progressing tumors were treated with [111In-DTPA-D-Phe1]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase-I trial. There were no major clinical side effects after up to 2 years of treatment, except that in a few patients a transient decline in platelet counts and lymphocyte subsets occurred. Promising beneficial effects on clinical symptoms, hormone production, and tumor proliferation were found. Of the 21 patients who received a cumulative dose of more than 20 GBq, eight showed stabilization of disease and six others a reduction in tumor size. There is a tendency towards better results in patients whose tumors have a higher accumulation of the radioligand. Peptide receptor radionuclide therapy is also feasible with 111In as the radionuclide. Theoretically, depending on the homogeneity of distribution of tumor cells expressing peptide receptors and the size of the tumor, beta-emitting radionuclides, e.g., 90Y, labeled to DOTA-chelated peptides may be more effective than 111In for peptide receptor radionuclide therapy. The first peptide receptor radionuclide therapy trials with [90Y-DOTA-Tyr3]octreotide started recently.