Pancreatic neuroendocrine neoplasms.

Pancreatic neuroendocrine tumors originate from the diffuse neuroendocrine system in the pancreatic region. These tumors exhibit a rising incidence despite their rareness and due to their benign behavior a considerable prevalence. Pathogenesis of pancreatic neuroendocrine tumors is characterized by common pathways of hereditary and sporadic tumors. Pancreatic neuroendocrine tumors may secrete peptide hormones or biogenic amines in an autonomous fashion as functional active tumors. Pathological grading and staging by TNM systems has been established in recent years classifying well and moderately differentiated pancreatice neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Chromogranin A and less so pancreatic polypeptide are suitable tumor markers for pancreatic neuroendocrine tumors. Expression of receptors for somatostatin is the basis of treatment of pancreatic neuroendocrine tumors with somatostatin analogues as antisecretive and antiproliferative agents. In addition, somatostatin scintigraphy or PET/CT allows comprehensive diagnosis of pancreatic neuroendocrine tumors, which should be supported by (endoscopic and contrast enhanced) ultrasound, CT and MRI. Therapy of pancreatic neuroendocrine tumors consists of somatostatin analogues, chemotherapy, targeted therapy and peptide receptor radionuclide therapy. Two molecular substances hav been registered for pancreatic neuroendocrine tumors recently, sunitinib (Sutent®) and everolimus (Afinitor®). Predominant tumor load in the liver may be treated by local ablative therapy or liver transplantation. These treatment options have been included in guidelines of several professional societies and weighted for sequential therapy of patients with pancreatic neuroendocrine tumors according to effects and side effects.

Hexadecylphosphocholine inhibits inositol phosphate formation and protein kinase C activity.

Hexadecylphosphocholine (HePC) inhibits protein kinase C (PKC) from NIH3T3 cells in cell-free extracts with a 50% inhibitory concentration of about 7 microM. Inhibition is competitive with regard to phosphatidylserine with a Ki of 0.59 microM. In order to determine whether HePC affects PKC in intact cells, the bombesin or tetradecanoylphorbolacetate-induced, PKC-mediated activation of the Na+/H(+)-antiporter was determined. It is demonstrated that HePC causes a drastic inhibition of this enzyme indicating a similar sensitivity of PKC to HePC in intact cells compared to cell-free extracts. In addition to the effects on PKC, treatment of NIH3T3 cells with HePC depresses the bombesin-induced formation of inositol 1,4,5-trisphosphate and the concomitant mobilization of intracellular Ca2+. Dose-response curves for the inhibition of inositol 1,4,5-trisphosphate formation and Ca2+ mobilization reveal 50% inhibitory concentrations of 2 or 5 microM, respectively. Polyphosphorylated phosphoinositides accumulate in HePC-treated cells indicating that the depression of inositol 1,4,5-trisphosphate generation is not caused by an inhibition of phosphoinositide kinases. Addition of bombesin to HePC-treated cells in the presence of LiCl revealed no evidence for an accelerated rate of inositol 1,4,5-trisphosphate turnover by the phospholipid analogue. It is concluded that HePC inhibits phosphoinositidase C in intact cells. The data strongly suggest that the growth-inhibitory effect of HePC is at least in part explained by the interference with mitogenic signal transduction.

Long-chain polyunsaturated fatty acids in children with severe protein-energy malnutrition with and without human immunodeficiency virus-1 infection.

Fatty acids in plasma phospholipids were studied in 35 severely malnourished young children with a median age of 29 mo (range: 9-43 mo), who were either seronegative for human immunodeficiency virus-1 (HIV) (n = 16) or suffered from asymptomatic (stage P-1; n = 12) or symptomatic (stage P-2; n = 7) HIV disease. The malnourished children had significantly lower percentages (% by wt) of phospholipid arachidonic (20:4n-6, AA) and docosahexaenoic (22:6n-3, DHA) acids than 25 age-matched healthy control subjects (AA: 7.05% and 8.70% by wt; DHA: 0.92 and 2.61% by wt, P < 0.001). Body weights of malnourished children did not correlate with linoleic (18:2n-6) and alpha-linolenic (18:3n-3) acid values but were significantly and positively correlated with AA and DHA values (r = 0.40, P = 0.02 and r = 0.63, P < 0.0001, respectively). Plasma concentrations (mg/L) of total phospholipid fatty acids did not differ among seronegative, stage P-1, or stage P-2 patients. Percentage contributions of AA and eicosapentaenoic acid (20:5n-3, EPA) did not differ among those seronegative or in stages P-1 and P-2. In contrast, values of dihomo-gamma-linolenic acid (20:3n-6) were significantly (P < 0.05) lower in stage P-2 (2.38 mg/L) than in either seronegative (3.47 mg/L) or stage P-1 (3.66 mg/L) patients. We conclude that the severely malnourished children developed a depletion of both AA and DHA proportional to the degree of malnutrition.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective study of the association of serum neopterin, beta 2-microglobulin, and hepatitis B surface antigenemia with death in infants and children with HIV-1 disease.

A high percentage of HIV-1-infected infants and children in Romania are coinfected with hepatitis B virus. Little information is available on the impact of concurrent hepatitis B infection on the course of HIV-1 infection. We conducted a prospective cohort study over 1 year in a group of 68 HIV-1-infected infants and children to determine whether hepatitis B surface antigenemia, neopterin, and beta 2-microglobulin (B2M) predicted death. Among the 44 hepatitis B surface antigen-positive (HBsAg+) subjects at enrollment, 13 (30%) died during 1 year of follow-up. In comparison, two of 24 (8%) HBsAg-negative subjects died (RR = 7.7; p = 0.05). Higher initial serum concentrations of neopterin and B2M were negatively associated with survival. After stratifying by baseline clinical evidence of HIV-related disease, survival was negatively associated with HBsAg+ status (p = 0.04) in 33 children in stage P-2, adjusting for age, serum neopterin, and serum B2M levels. The results of this study suggest that serum neopterin is a marker for severity of clinical illness and that HBsAg+ status increases the mortality rate among children with clinical evidence of HIV infection.

Effect of monounsaturation of a branched fatty acid on organ selectivity.

UNLABELLED: 1-[11C]-3-R,S-methylheptadecanoic acid (BMHA) is a branched chain fatty acid analog that is transported into the myocardium. Due to incomplete metabolism, however, radiolabeled products are trapped within myocytes. Recently, we demonstrated that this compound is an excellent tracer to monitor fatty acid metabolism. METHOD: To evaluate the effect of mono-unsaturation on myocardial substrate utilization, we prepared 1-[11C]-3-R,S-methyl-trans--heptadec-7-enoic acid (t-7-BMHA) and measured its biodistribution in rats. In addition, preliminary PET studies were performed on dogs. RESULTS: Biodistribution studies demonstrated that myocardial-to-lung and myocardial-to-blood ratios for t-7-BMHA are higher than those for BMHA. Fifteen minutes after injection, heart-to-lung ratios were 5.23 compared to 2.92 and heart-to-liver ratios were 3.07 compared to 1.41 for t-7-BMHA and BMHA. By 30 min postinjection heart-to-lung ratios were 7.03 compared to 5.88 and heart-to-liver ratios were 4.43 compared to 1.09. The heart-to-blood ratio of t-7-BMHA was greater than 11:1. PET imaging with 1-[11C]-t-7-BMHA demonstrated high myocardial extraction, prolonged retention of radioactivity and excellent image quality. Accumulation of radioactivity in the myocardium reached a plateau within 10 min postinjection, with heart-to-blood ratios exceeding 20:1 and heart-to-lung ratios exceeding 10:1. Blood clearance of radioactivity was biphasic with half-times of 1.46 and 14.7 min, respectively. CONCLUSION: These data suggest that introduction of a trans-double bond in BMHA improves myocardial selectivity and results in a potentially superior imaging agent.

New approaches in nuclear medicine for early diagnosis of Alzheimer's disease.

Dementia, Alzheimer's disease (AD) being the most common cause of it, is a major and growing medical and social problem, particularly in the advanced age, with the highest rate in the population over 75 y. Recent sophisticated therapeutic measures require more sensitive diagnostic tests to recognize early stages of the disease. In this paper, the current neuronuclear imaging literature is reviewed with regard to early and differential diagnosis of dementia. Functional imaging with single photon emission computed tomography (SPECT) and positron emission tomography (PET) could provide the clinician with additional information complementary to morphological assessments, thus contributing to achieve a more adequate diagnosis, and also with information regarding prodromal stages of AD.

The use of electronic autoradiography in radiopharmacy.

The use of Microchannel Plate Analysers (Instant Imager, Canberra Packard), the so called Electronic Autoradiography, in Radiopharmacy is described. The system can be used for quality control of radiopharmaceuticals as well as for scientific research purposes. Quantitative analysis of 2-dimensional radioactive samples of all radionuclides used in Nuclear Medicine (especially 99mTc) can be performed in a very short time with little effort. Advantages and limitations for radiopharmaceutical work are described.

One year's clinical experience of 18F-FDG PET with a modified SPET camera using molecular coincidence detection.

High-quality positron emission tomographic (PET) cameras are expensive and, therefore, not available in many centres. To allow access to clinical 18F-fluorodeoxyglucose (18F-FDG) PET, we began working with an ADAC Vertex camera equipped with a molecular coincidence detection (MCD) module in February 1997. Here we give a preliminary assessment of the clinical utility of our approach. To date, 109 studies have been performed in MCD-mode using standardized protocols (99 oncology cases, 10 neurology cases). Twenty-eight cardiological and 15 other studies were performed using 511 keV collimators without attenuation correction. The average dose of 18F-FDG for MCD studies was 150 MBq, thus avoiding overloading the detectors; cardiac studies required 370 MBq. The results obtained were carefully compared with computed tomography, magnetic resonance imaging, myocardial perfusion scans, coronary angiography and conventional radiology. The results were compared on a patient basis, including histology, surgical notes, autopsy reports and follow-up data. Oncological studies were performed to assess malignancy in a particular lesion (n = 22), staging of cancer (n = 57) or to evaluate whether therapy had been successful or not (n = 20). Indications for conducting studies were categorized as appropriate (Ia) or adequate (Ib). For Ia category cases, the results were: true-positive = 31, true-negative = 12 and false-positive = 2. For Ib category cases, the corresponding figures were: true-positive = 18, true-negative = 10, false-positive = 3 and false-negative = 1. False-positive studies were a result of inflammatory disease or artefacts. Six cases with temporal lobe epilepsy were correctly identified. In cardiac studies, we also found a good correlation with clinical parameters (i.e. hibernating myocardium or scarred tissue). Altogether, this cost-effective set-up allows nuclear medicine institutions to obtain valuable data in clinical practice with a system used both for single photon emission tomography and PET.

Association between neopterin and beta-2-microglobulin levels and HIV status in Romanian orphanage children.

Serologic markers of immune activation, neopterin and beta-2-microglobulin (B2M), have been shown to predict progressive human immunodeficiency virus type 1 (HIV-1) disease based on cohort studies in adults. Both parameters appear also to be valuable in distinguishing HIV-1 infants with progressive disease from asymptomatic infants and HIV-1 seronegative infants. In a cross-sectional study we examined the utility of neopterin and B2M testing in 135 infants of an orphanage in Romania, 69 of the infants (51%) were found to be HIV-1 antibody seropositive; 95% of the 135 infants were either hepatitis B virus (HBV) antigen or antibody seropositive. In the HIV-1 seronegative infants B2M was higher in those with HBV antigenaemia. Serum neopterin and B2M concentrations were higher in HIV-1 seropositive than in seronegative infants (p = 7 x 10(-12) and 1 x 10(-6)). Children with CDC stage P2 had only slightly higher neopterin and B2M values as compared to stage P1 (P = 0.04 and 0.08). Our study indicates that measurement of neopterin and B2M is useful to monitor HIV-1 infection, particularly in areas where laboratory facilities are limited. Both parameters continue to be associated with HIV-1 infection even when there is a high background rate of other infections.

The GOSTT concept and hybrid mixed/virtual/augmented reality environment radioguided surgery.

The popularity gained by the sentinel lymph node (SLN) procedure in the last two decades did increase the interest of the surgical disciplines for other applications of radioguided surgery. An example is the gamma-probe guided localization of occult or difficult to locate neoplastic lesions. Such guidance can be achieved by intralesional delivery (ultrasound, stereotaxis or CT) of a radiolabelled agent that remains accumulated at the site of the injection. Another possibility rested on the use of systemic administration of a tumour-seeking radiopharmaceutical with favourable tumour accumulation and retention. On the other hand, new intraoperative imaging devices for radioguided surgery in complex anatomical areas became available. All this a few years ago led to the delineation of the concept Guided intraOperative Scintigraphic Tumour Targeting (GOSTT) to include the whole spectrum of basic and advanced nuclear medicine procedures required for providing a roadmap that would optimise surgery. The introduction of allied signatures using, e.g. hybrid tracers for simultaneous detection of the radioactive and fluorescent signals did amply the GOSTT concept. It was now possible to combine perioperative nuclear medicine imaging with the superior resolution of additional optical guidance in the operating room. This hybrid approach is currently in progress and probably will become an important model to follow in the coming years. A cornerstone in the GOSTT concept is constituted by diagnostic imaging technologies like SPECT/CT. SPECT/CT was introduced halfway the past decade and was immediately incorporated into the SLN procedure. Important reasons attributing to the success of SPECT/CT were its combination with lymphoscintigraphy, and the ability to display SLNs in an anatomical environment. This latter aspect has significantly been improved in the new generation of SPECT/CT cameras and provides the base for the novel mixed reality protocols of image-guided surgery. In these protocols the generated virtual SPECT/CT elements are visually superimposed in the body of the patient in the operating room to directly facilitate, by means of visualization on screen or using head-mounted devices, the localization of radioactive and/or fluorescent targets by minimal invasive approaches in areas of complex anatomy. All these technological advances will play an increasing role in the future extension and the clinical impact of the GOSTT concept.

Vandetanib therapy in medullary thyroid cancer.

The U.S. Food and Drug Administration (FDA) approved vandetanib in April 2011 for the treatment of unresectable, locally advanced or metastatic medullary thyroid cancer (MTC). In Europe it was approved in March 2012, but only for the treatment of aggressive and symptomatic MTC. This small molecule is a tyrosine kinase inhibitor of several growth factors involved in cellular proliferation and angiogenesis, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptors 2 and 3 (VEGFR-2, VEGFR-3). In addition, vandetanib is an inhibitor of the RET (rearranged during transfection) gene, a proto-oncogene often mutated in familial MTC. Since MTC is a rare disease, for which no previous medical therapies are approved, vandetanib is the first drug shown to be effective in a large phase III trial treating patients with metastatic or locally advanced MTC. Common adverse events are diarrhea, nausea, hypertension, headache and QT prolongation that are manageable and are commonly outweighed by the benefits of vandetanib in terms of delaying disease progression and inducing tumor response.

Fluorine-18 radiopharmaceuticals beyond [18F]FDG for use in oncology and neurosciences.

Positron emission tomography (PET) is a rapidly expanding clinical modality worldwide thanks to the availability of compact medical cyclotrons and automated chemistry for the production of radiopharmaceuticals. There is an armamentarium of fluorine-18 ((18)F) tracers that can be used for PET studies in the fields of oncology and neurosciences. However, most of the (18)F-tracers other than 2-deoxy-2-[18F]fluoro-D-glucose (FDG) are in less than optimum human use and there is considerable scope to bring potentially useful (18)F-tracers to clinical investigation stage. The International Atomic Energy Agency (IAEA) convened a consultants' group meeting to review the current status of (18)F-based radiotracers and to suggest means for accelerating their use for diagnostic applications. The consultants reviewed the developments including the synthetic approaches for the preparation of (18)F-tracers for oncology and neurosciences. A selection of three groups of (18)F-tracers that are useful either in oncology or in neurosciences was done based on well-defined criteria such as application, lack of toxicity, availability of precursors and ease of synthesis. Based on the recommendations of the consultants' group meeting, IAEA started a coordinated research project on "Development of (18)F radiopharmaceuticals (beyond [(18)F]FDG) for use in oncology and neurosciences" in which 14 countries are participating in a 3-year collaborative program. The outcomes of the coordinated research project are expected to catalyze the wider application of several more (18)F-radiopharmaceuticals beyond FDG for diagnostic applications in oncology and neurosciences.

Impact of instrumentation on DaTSCAN imaging: how feasible is the concept of cross-systems correction factor?

AIM: The aim of this investigation was to study the impact of applying different camera emission computed tomography (ECT) systems on semi-quantitative analysis of the novel dopamine transporter (DaT) radioligand [123I]-ioflupane (DaTSCAN) and whether applying a system-dependent correction factor is feasible to allow a migration of a ''normal'' reference data set between systems. METHODS: Two triple-head systems, PrismXP-3000 equipped with high resolution Fan-Beam (PRISM) and Irix (Philips Medical Systems, Europe) equipped with high resolution parallel whole collimators (IRIX), were compared in phantom and patient studies. Acquisition and quantification parameters were standardized. The anthropometric striatal calibration phantom (RSD Inc., CA, USA) at rising striatum: background ratios between 2-11 was studied. Fifty-one consecutive patients (25 females, age 64.5+/-11.9 years, and 26 males, age 60.6+/-12.7 years) were randomized to both cameras for acquisition time typically beginning 3.5 to 4.5 h after i.v. injection of 123I-Joflupane at 2.06+/-0.47 MBq/kg. Striatal uptake of the radioligand was categorized as normal or abnormal, and abnormal images were further subdivided into 3 severity levels. Striatum: cerebellum ratio (SCr) was determined by applying a fixed circular or rectangular striatal and fuzzy cerebellar regions. The effect of introducing scatter compensation (Sc) on quantification and on SCr was investigated. RESULTS: The regression coefficient (Rc) of SCr computed for both systems was close to identity (IRIX=0.999x (PRISM)+0.48 and 1.01x(PRISM)+0.86 for right and left striatum). Rc of SCr values in the phantom studies was closer to identity when Sc was added (IRIX=0.982x [PRISM]+0.724 with Sc vs 1.22x[PRISM]-0.32 without Sc). SCr values were higher for IRIX by 5-10%. Including Sc increased the percent recovery and the linear dynamic range for both systems; however, fan beam recovery decreased at low SCr values. The delineation of the striatal boundaries improved after applying Sc. Identifying the cerebellar region was easier with PRISM owing to significantly higher count statistics. Both systems performed equally well with respect to image quality. Visual scoring by 2 observers correlated significantly on the k-test (K: 0.883, T: 10, P<0.0001). CONCLUSION: A simple linear correction is applicable to ''normal'' reference data set to migrate from one system to another; however, data acquisition and quantification parameters need to be standardized. Higher recovery values are dependent on system resolution. The spatial distribution and image quality of DaTSCAN on different high-resolution systems applying standardized acquisition and reconstruction protocols is less operator dependent and does not affect visual rating of striatal DaT loss.

[Effects of health and medical undertreatment on the clinical status and social behavior of infants and small children in a Romanian orphanage]. / Auswirkungen von hygienischer und medizinischer Unterversorgung auf den klinischen Zustand und das soziale Verhalten bei Säuglingen und Kleinkindern in einem rumänischen Kinderheim.

The homage of 135 abandoned children in the city of Resita, south west Rumania, has been checked by a medical team from the University of Innsbruck for social, clinical and hyginical situation. The local government had applied for such an investigation. Most of the infections and other diseases are based on a dramatically bad hygienical situation. 52% of checked sera were HIV positiv by RIA and Western Blot, moreover 60% Hepatitis B antigen positiv. We assume a high rate of horizontal transmission of the HIV virus. One of the main clinical symptoms was maternal-deprivation syndrome, with an incidence of 80%. Consequences in personal policy of the homage as well as medical strategies have to follow.

Correlation of ribonucleic acid polymerase chain reaction, acid dissociated p24 antigen, and neopterin with progression of disease. A retrospective, longitudinal study of vertically acquired human immunodeficiency virus type 1 infection in children.

OBJECTIVE: We investigated the relationship between cell-free viral load, neopterin, age-adjusted CD4+ cell concentration, and clinical events in 49 children with vertically acquired human immunodeficiency virus type 1 infection. STUDY DESIGN: Viral load was measured by quantitating viral ribonucleic acid in serum by polymerase chain reaction and measurement of immune complex dissociated p24 antigen in serum and plasma. Children were followed for an average of 2 1/2 years, with an average of 6 samples per child. Medical records were reviewed for weight, CD4+ cell count and clinical events. RESULTS: High virus copy number in serum was predictive of a decrease in weight-for-age zscore during the subsequent 6 months. High viral load, low CD4+ cell count, and high neopterin level were correlated with encephalopathy. High viral load correlated with opportunistic infections. All of these relationships held regardless of treatment status, although viral load decreased significantly after treatment was begun. CONCLUSIONS: Measurements of viral load were useful prognostic indicators for poor weight gain. Elevated serum virus levels and neopterin values and low CD4+ cell counts were all associated with encephalopathy.