Varvara Valotassiou

Molecular nanomedicine towards cancer: 111In‐labeled nanoparticles

Nanomedicine is the medical application of materials, devices, or systems in the nanometer scale and is currently undergoing explosive development. Molecular imaging of cancer using nanosized materials comprises an important part in diagnosis, therapy, and drug discovery in medical nanosciences. Radiopharmaceuticals are a key tool of molecular imaging in the field of nuclear medicine. The in vivo administration of radiolabeled nanoparticles (NPs) can provide an accurate biodistribution profile of the nanoformulations, as well as visualization of their route in vivo. Surface modifications of NPs with antibodies, peptides, or other small molecules that bind to tumor cell receptors have resulted in the development of sensitive and specific targeted imaging and diagnostic modalities for in vitro and in vivo applications. Radiometals are the most favorable of all radionuclides for labeling applications and they have the most suitable properties for single-photon emission computed tomography imaging. Indium-111((111)In), specifically, is a readily available gamma-emitting radiometal, which is widely used in clinical practice for diagnosis and/or therapy. Herein, we will overview the latest evolvement on (111)In-labeled nanoparticles for biodistribution assessment and/or imaging evaluation of nanocarriers, as well as therapy in cancer.

Imaging in situ breast carcinoma (with or without an invasive component) with technetium-99m pentavalent dimercaptosuccinic acid and technetium-99m 2-methoxy isobutyl isonitrile scintimammography.

IntroductionThe aim of the study was to retrospectively define specific features of the technetium-99m pentavalent dimercaptosuccinic acid (99mTc-(V)DMSA) and technetium-99m 2-methoxy isobutyl isonitrile (99mTc-Sestamibi [99mTc-MIBI]) distribution in ductal breast carcinoma in situ and lobular breast carcinoma in situ (DCIS/LCIS), in relation to mammographic, histological and immunohistochemical parameters.Materials and methodsOne hundred and two patients with suspicious palpation or mammographic findings were submitted preoperatively to scintimammography (a total of 72 patients with 99mTc-(V)DMSA and a total of 75 patients with 99mTc-Sestamibi, 45 patients receiving both radiotracers). Images were acquired at 10 min and 60 min, and were evaluated for a pattern of diffuse radiotracer accumulation. The tumor-to-background ratios were correlated (T-pair test) with mammographic, histological and immunohistochemical characteristics.ResultsHistology confirmed malignancy in 46/102 patients: 20/46 patients had DCIS/LCIS, with or without coexistent invasive lesions, and 26/46 patients had isolated invasive carcinomas. Diffuse 99mTc-(V)DMSA accumulation was noticed in 18/19 cases and 99mTc-Sestamibi in 6/13 DCIS/LCIS cases. Epithelial hyperplasia demonstrated a similar accumulation pattern. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value for each tracer were calculated. Solely for 99mTc-(V)DMSA, the tumor-to-background ratio was significantly higher at 60 min than at 10 min and the diffuse uptake was significantly associated with suspicious microcalcifications, with the cell proliferation index ≥ 40% and with c-erbB-2 ≥ 10%.Conclusion99mTc-(V)DMSA showed high sensitivity and 99mTc-Sestamibi showed high specificity in detecting in situ breast carcinoma (99mTc-(V)DMSA especially in cases with increased cell proliferation), and these radiotracers could provide clinicians with preoperative information not always obtainable by mammography.

Radiolabeling approaches of nanoparticles with 99m Tc

Nanomedicine applications have recently gathered great attention in terms of their revolutionary properties and multivalency. Nanoparticles (NPs) have proven useful owing to their size, surface and kinetics advantages, as well as their ability to be functionalized with targeting, imaging and therapeutic moieties. Nuclear medicine is actively involved in nano-research innovative breakthrough efforts in multiple applications, through the radiolabeling of NP structures. There are several ways that NP-radiolabeling can be approached depending on the radionuclide that is used and the NP type. The radiolabeling of NPs with the most widely and easily available radiometal, which is (99m) Tc, is the focus of this review.

Long-term prognostic value of heart-rate recovery after treadmill testing in patients with diabetes mellitus

BACKGROUND Heart-rate recovery (HRR) is considered to be an independent predictor of cardiac and all-cause mortality. We examined the long-term prognostic value of HRR in patients suffering from diabetes mellitus. METHODS In this study, we included 258 consecutive patients. Patients whose HRR value or myocardial perfusion imaging could have been influenced by factors other than myocardial ischaemia, were excluded. The value of HRR was defined as the decrease in the heart-rate from peak exercise to 1 min after the termination of the exercise. All patients underwent SPECT myocardial perfusion imaging combined with exercise testing. Cardiovascular death and non-fatal myocardial infarction were considered as hard cardiac events, while late revascularization procedures as soft events. Cox proportional-hazard models were applied to evaluate the association between HRR and the investigated outcome. RESULTS During the follow-up period (30.8+/-6.9 months), hard cardiac events occurred in 21 (8%) patients (15 with abnormal HRR value, p<0.001), while 35 (14%) patients underwent revascularization (31 with abnormal HRR value, p<0.001). Considering it as a continuous variable, HRR was a strong predictor for both hard cardiac (coefficient=-0.41, SE=0.052, p<0.001) and soft cardiac events (coefficient=-0.63, SE=0.058, p<0.001). After adjustments were made for potential confounders, including scintigraphic variables, abnormal HRR remained an independent predictor for hard and soft cardiac events (p<0.001). CONCLUSION Our results suggest that among patients with diabetes, a decreased HRR is a significant independent predictor of hard and soft cardiac events.

Increased fetuin A levels in Helicobacter pylori infection: a missing link between H. pylori and insulin resistance?

To the Editor: Helicobacter pylori infection has been associated with diverse biological processes, including inflammation, metabolism, oncogenic transformation [1, 2]. In view of its effect on metabolic variables, H. pylori has been linked with both dyslipidaemia and insulin resistance (IR) [1, 2]. Among the various factors capable of inducing IR, the upregulation of α2-Heremans Schmid glycoprotein, also known as human fetuin A, has been linked with impaired insulin sensitivity, glucose metabolism and, subsequently, the onset of diabetes mellitus [3, 4]. Interestingly, certain pathogens have been shown to induce an increase in the level of fetuin A or fetuin A-like molecules such as Mycobacterium bovis in cattle and severe acute respiratory syndrome-coronavirus (SARSCoV) in humans [5]. Based on these data, we performed a study to investigate whether the H. pylori-induced IR is mediated through an upregulation of fetuin A levels. Determination of circulating fetuin A (by ELISA; BioSource Europe, Nivelles, Belgium), fasting insulin (by ELISA; DRG Instruments, Marburg, Germany) and glucose levels (hexokinase method, cat. no. OSR6521; Olympus Life Science Research Europa, Hamburg, Germany) was performed for 105 non-diabetic individuals (Table 1) undergoing oesophagogastroduodenoscopy owing to dyspeptic complaints. According to the results of a Campylobacter-like organism test and histology, study participants were classified into H. pylori-positive (Hp, n=72) and negative (Hp, n=33) groups matched for age, sex, BMI and smoking. For IR, the HOMA-IR (www.hepcnomads. co.uk/HOMACalc.htm, accessed 11 November 2010) was used. Details of lipoprotein, triacylglycerol and C-reactive protein (CRP) levels were also available from routine examinations. None of the participants was receiving any medication and none had any factor that could affect H. pylori diagnosis, fetuin A levels or glucose metabolism (family history of diabetes mellitus, obesity, proton pump inhibitor use, liver, kidney, systemic disorders, polycystic ovary disease). The study had been approved by the Ethics Committee of the University of Thessaly Medical School. Informed consent was obtained from all individuals prior to inclusion in the study. A. C. Manolakis : E. K. Tiaka :A. N. Kapsoritakis : F. Tsiopoulos : S. P. Potamianos (*) Department of Gastroenterology, University of Thessaly, School of Medicine, Mezourlo, 41110 Larissa, Greece e-mail: spotam@med.uth.gr

Ghrelin New Insights into Female Reproductive System–Associated Disorders and Pregnancy

Ghrelin is considered the endogenous ligand of growth hormone secretagogue receptor type 1a, and its modulatory actions have been demonstrated in a large array of endocrine and nonendocrine functions. According to recent studies, ghrelin seems to act at different levels of the reproductive system, exerting predominantly inhibitory effects on mammalian reproduction. It has been shown to influence the reproductive system by regulating hormone secretion from the brain and by acting directly on the gonads to affect tissue development and steroidogenesis. Thus, the endocrine network, which integrates energy balance and fertility, might involve ghrelin. Furthermore, ghrelin levels and actions have been assessed in various female reproductive system disorders. The findings could lead to a better understanding of the pathogenesis of these disorders and, possibly, to more beneficial therapeutic strategies.Ghrelin is considered the endogenous ligand of growth hormone secretagogue receptor type 1a, and its modulatory actions have been demonstrated in a large array of endocrine and nonendocrine functions. According to recent studies, ghrelin seems to act at different levels of the reproductive system, exerting predominantly inhibitory effects on mammalian reproduction. It has been shown to influence the reproductive system by regulating hormone secretion from the brain and by acting directly on the gonads to affect tissue development and steroidogenesis. Thus, the endocrine network, which integrates energy balance and fertility, might involve ghrelin. Furthermore, ghrelin levels and actions have been assessed in various female reproductive system disorders. The findings could lead to a better understanding of the pathogenesis of these disorders and, possibly, to more beneficial therapeutic strategies.

The Emerging Roles of Adiponectin in Female Reproductive System-Associated Disorders and Pregnancy

Adiponectin, the most abundant adipose-released cytokine, has an important role in metabolism, primarily through reducing insulin resistance. Reproductive functions are known to be influenced by energy balance and adiponectin may be involved in the underlying mechanisms connecting reproduction and metabolism. Interestingly, adiponectin has been shown to exert actions in the female reproductive system, including the hypothalamic–pituitary–ovarian axis and the endometrium. The peripheral effects of this adipocytokine are mediated mainly via 2 receptors, AdipoR1 and AdipoR2. The expression of these receptors has been reported in the brain, ovaries, endometrium, and the placenta. Thus, adiponectin may influence fertility and pregnancy. Furthermore, adiponectin concentrations and effects have been assessed in some pregnancy-associated disorders and gynecological conditions. The findings may lead to the use of adiponectin or its receptors as therapeutic targets in novel treatment strategies of these disorders.

Current and potential roles of ghrelin in clinical practice

Ghrelin is a novel GH-releasing peptide, which has been identified as an endogenous ligand for GH-secretagogue receptor. Ghrelin is mainly secreted by the stomach and plays a critical role in a variety of physiological processes including endocrine, metabolic, cardiovascular, immunological, and other actions. Ghrelin stimulates food intake via hypothalamic neurons and causes a positive energy balance and body weight gain by decreasing fat utilization and promoting adiposity. Given the multiple effects of ghrelin, its potential clinical applications have been evaluated in various conditions. Preliminary trials have shown that it may prove valuable in the management of diseaseinduced cachexia. Ghrelin may improve the wasting syndrome through GH-dependent or GH-independent effects. Moreover, ghrelin may play a role in the management of disorders of gut motility and obesity. Finally, other potential clinical applications of ghrelin include the treatment of patients with diabetes mellitus, infections, rheumatological diseases or GH deficiency and the diagnosis of this hormonal disorder.

SPECT and PET Imaging of Meningiomas

Meningiomas arise from the meningothelial cells of the arachnoid membranes. They are the most common primary intracranial neoplasms and represent about 20% of all intracranial tumors. They are usually diagnosed after the third decade of life and they are more frequent in women than in men. According to the World Health Organization (WHO) criteria, meningiomas can be classified into grade I meningiomas, which are benign, grade II (atypical) and grade III (anaplastic) meningiomas, which have a much more aggressive clinical behaviour. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are routinely used in the diagnostic workup of patients with meningiomas. Molecular Nuclear Medicine Imaging with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) could provide complementary information to CT and MRI. Various SPECT and PET tracers may provide information about cellular processes and biological characteristics of meningiomas. Therefore, SPECT and PET imaging could be used for the preoperative noninvasive diagnosis and differential diagnosis of meningiomas, prediction of tumor grade and tumor recurrence, response to treatment, target volume delineation for radiation therapy planning, and distinction between residual or recurrent tumour from scar tissue.

Alzheimers Disease: SPECT and PET Tracers for Beta-Amyloid Imaging

The definite diagnosis of Alzheimers disease (AD) is based on the detection of beta amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) - which are the pathological hallmarks of the disease- in the postmortem brains. Although regional Cerebral Blood Flow (rCBF) and Cerebral Glucose Metabolism (CGM) abnormalities have already been studied in AD patients with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), the development of specific imaging agents for direct mapping of Aβ plaques in the living brain, is a great challenge. Aβ probes could significantly contribute to the early diagnosis of AD, the elucidation of the underlying neuropathological processes and the evaluation of anti-amyloid therapies which are currently under investigation. The development of SPECT and PET tracers for Aβ imaging represents an active area in radiopharmaceutical design. A substantial number of potential Aβ imaging radioligands have been designed and used in-vitro. They are either monoclonal antibodies to Aβ and radiolabeled Aβ peptides, or derivatives of histopathological stains such as Congo red (CR), chrysamine-G (CG) and Thioflavin T (TT). Though, only few of them, that display high binding affinity to Aβ as well as sufficient brain penetration, have been used primarily in in-vivo studies and to a smaller degree on human subjects. Since Aβ plaques are not homogenous and contain multiple binding sites that can accommodate structurally diverse compounds, they offer flexibility in designing various different probes, as potential amyloid imaging agents.