Feasibility and efficacy of 223Ra-dichloride (223Ra) to treat bone metastases in patients (pts) with castration resistant prostate cancer (mCRPC)

Aim: To share the Tuscany single-centre experience about the employing of the novel therapeutic radiopharmaceutical 223Ra in the treatment planning of mCRPC pts

Deltamethrin Resistance Mechanisms in Aedes aegypti Populations from Three French Overseas Territories Worldwide

BACKGROUND:Aedes aegypti is a cosmopolite mosquito, vector of arboviruses. The worldwide studies of its insecticide resistance have demonstrated a strong loss of susceptibility to pyrethroids, the major class of insecticide used for vector control. French overseas territories such as French Guiana (South America), Guadeloupe islands (Lesser Antilles) as well as New Caledonia (Pacific Ocean), have encountered such resistance. METHODOLOGY/PRINCIPAL FINDINGS:We initiated a research program on the pyrethroid resistance in French Guiana, Guadeloupe and New Caledonia. Aedes aegypti populations were tested for their deltamethrin resistance level then screened by an improved microarray developed to specifically study metabolic resistance mechanisms. Cytochrome P450 genes were implicated in conferring resistance. CYP6BB2, CYP6M11, CYP6N12, CYP9J9, CYP9J10 and CCE3 genes were upregulated in the resistant populations and were common to other populations at a regional scale. The implication of these genes in resistance phenomenon is therefore strongly suggested. Other genes from detoxification pathways were also differentially regulated. Screening for target site mutations on the voltage-gated sodium channel gene demonstrated the presence of I1016 and C1534. CONCLUSION /SIGNIFICANCE:This study highlighted the presence of a common set of differentially up-regulated detoxifying genes, mainly cytochrome P450 genes in all three populations. GUA and GUY populations shared a higher number of those genes compared to CAL. Two kdr mutations well known to be associated to pyrethroid resistance were also detected in those two populations but not in CAL. Different selective pressures and genetic backgrounds can explain such differences. These results are also compared with those obtained from other parts of the world and are discussed in the context of integrative research on vector competence

Control of Visceral Leishmaniasis in Latin America—A Systematic Review

Visceral leishmaniasis is a vector-borne disease characterized by fever, spleen and liver enlargement, and low blood cell counts. In the Americas VL is zoonotic, with domestic dogs as main animal reservoirs, and is caused by the intracellular parasite Leishmania infantum (syn. Leishmania chagasi). Humans acquire the infection through the bite of an infected sand fly. The disease is potentially lethal if untreated. VL is reported from Mexico to Argentina, with recent trends showing a rapid spread in Brazil. Control measures directed against the canine reservoir and insect vectors have been unsuccessful, and early detection and treatment of human cases remains as the most important strategy to reduce case fatality. Well-designed studies evaluating diagnosis, treatment, and prevention/control interventions are scarce. The available scientific evidence reasonably supports the use of rapid diagnostic tests for the diagnosis of human disease. Properly designed randomized controlled trials following good clinical practices are needed to inform drug policy. Routine control strategies against the canine reservoirs and insect vectors are based on weak and conflicting evidence, and vector control strategies and vaccine development should constitute research priorities

Novel radiopharmaceuticals for therapy

In the era of personalizedmedicine, "target radionuclide therapy" (TRT) is designed to damage only the cancerous cells while sparing unnecessary damage to the adjacent healthy cells/tissues. Unlike conventional external beam radiation therapy, TRT is intended to cause less or no collateral damage to normal tissues, as it aims at achieving targeted drug delivery either to a clinically diagnosed cancer not amenable to surgery or to metastatic tumor cells and tumor cell clusters, thus providing systemic therapy of cancer. Currently there are hundreds of new pathwaytargeted anticancer agents undergoing phase II and phase III clinical trials. TRT is just one type within the domain of "targeted therapies." In addition to the effective targeted radiopharmaceuticals already well validated for routine clinical use, newer radiolabeled agents are still in the phase of either preclinical or clinical validation. This chapter describes the main physical and radiochemical characteristics of radionuclides that have potential or have already been employed to label biologically reactive molecules for the development of novel radiopharmaceuticals for therapy. Some of these agents have entered advanced clinical trials in tumor-bearing patients. Results of these clinical trials cover a wide spectrum of potential clinical usefulness. The chapter is divided into two main parts depending on the type of particle emission (α- or β-associated or not with the emission of either γ- or β+-radiation). Within each domain, there is some exchange of experience and shift of focus in the various phases of development, depending on the modalities of ascertaining efficient tumor targeting according to the principles of theranostics. The example of a novel α-emitting radiopharmaceutical that has most recently achieved approval by regulatory agencies for clinical use ( 223 Ra-dichloride) is presented in detail as the paradigm for an agent that is showing a survival advantage besides the original target of pain palliation from bone metastases

Efficacy and safety of sunitinib therapy in FDG-PET-positive, iodine-refractory advanced thyroid cancer

no abstract availabl

Sentinel lymph node mapping in breast cancer: a critical reappraisal of the internal mammary chain issue

Although, like the axilla, the internal mammary nodes (IMNs) are a first-echelon nodal drainage site in breast cancer, the importance of their treatment has long been debated. Seminal randomized trials have failed to demonstrate a survival benefit from surgical IMN dissection, and several retrospective studies have shown that IMNs are rarely the first site of recurrence. However, the recent widespread adoption of sentinel lymph node (SLN) biopsy has stimulated a critical reappraisal of such early results. Furthermore, the higher proportion of screening-detected cancers, improved imaging and techniques (i.e., lymphoscintigraphy for radioguided SLN biopsy) make it possible to visualize lymphatic drainage to the IMNs. The virtually systematic application of adjuvant systemic and/or loco-regional radiotherapy encourages re-examination of the significance of IMN metastases. Moreover, randomized trials testing the value of postmastectomy irradiation and a meta-analysis of 78 randomized trials have provided high levels of evidence that local-regional tumor control is associated with long-term survival improvements. This benefit was limited to trials that used systemic chemotherapy, which was not routinely administered in the earlier studies. However, the contribution from IMN treatment is unclear. Lymphoscintigraphic studies have shown that a significant proportion of breast cancers have primary drainage to the IMNs, including approximately 30% of medial tumors and 15% of lateral tumors. In the few studies where IMN biopsy was performed, 20% of sentinel IMNs were metastatic. The risk of IMN involvement is higher in patients with medial tumors and positive axillary nodes. IMN metastasis has prognostic significance, as recognized by its inclusion in the American Joint Committee on Cancer staging criteria, and seems to have similar prognostic importance as axillary nodal involvement. Although routine IMN evaluation might be indicated, it has not been routinely performed, perhaps because IMN drainage with lymphoscintigraphy is more difficult to demonstrate than axillary drainage. This difference is due to technical reasons and not the absence of lymphatics to the IMN. Recent anatomical studies have confirmed a model of breast lymphatic drainage that comprises superficial, deep and perforating systems. The superficial system drains to the axilla, usually to a lymph node posterior to the pectoralis minor muscle. The deep system drains to the axilla and also anastomoses with the perforating system which drains to the IMNs. The perforating system does not connect with the superficial system. The prevalence of IMN drainage tends to reflect the method of lymphoscintigraphy, where peritumoral (deep lymphatic system) injections have a much higher likelihood of IMN drainage than subareolar or subdermal (superficial lymphatic system) injections. The fused SPECT/CT images represent a further technical solution to increase the identification of IMNs and consequently can significantly reduce the false negative rate of sentinel lymph node biopsy. Before mature results from current and future randomized trials assessing the benefit of IMN irradiation become available, lymphoscintigraphy and IMNs biopsy may be used to guide decisions regarding systemic and local-regional treatment. However, even in patients with visualized primary IMN drainage, the potential benefit of treatment should be balanced against the risk of added morbidity

Effects of bariatric surgery on brain glucose metabolism and cognitive function: insight from dynamic FDG PET/CT study

Aim/Introduction: We aimed to evaluate the impact of bariatric surgery (RYGB) on the brain glucose metabolism and the interplay between gut hormones/metabolomics, cerebral metabolic rate of glucose (CMRGlu) and cognitive function. Materials and Methods: Thirteen morbidly obese subjects with normal glucose tolerance (BMI 46±4.9 kg/m2; HbA1c 40.1±5.9 mmol/mol; age 42.4±9.8 years) planned for RYGB surgery were recruited. Theoral glucose tolerance test (OGTT) was performed, followed by 60 minutes FDG dynamic PET study.Continuous blood samples were drawn before and at 30, 60, 90, and 120 min for glucose, insulin, GLP, VIP, GIP and C-peptide measurements. The same venous blood samples were used for calculating radioactivity concentration in plasma. Fasting blood samples for metabolomics (leptin, brain derived neurotrophic factor, BDNF) were also collected and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as an index of insulin resistance. The influx constant (Ki) and MRGlu were then quantified using the two tissue compartment Patlak approach with an imaged-derived input function (PMOD). Subsequently, the parametric CMRGlu images were created and spatially normalized in MNI space. The paired t-test and Spearman rank correlation were applied to assess changes and associations of voxel-wise CMRGlu and metabolomics. All patients underwent a battery of neuropsychiatric tests (MMSE, MoCA, Token test, TMT, etc) to assess cognitive function in several domains, before and 6 months after RYGB. Results: Six months after RYGB a significant BMI reduction (p<0.001) was achieved. Post-OGTT GLP1 was increased (p<0.01) as well as GIP (p<0.01). The HOMA- IR dropped significantly 6m after RYGB (p=0.02). Either whole brain and region-selective CMRGlu decreased 6m after surgery (15.9±4.6 to 10.5±5.1 μmol/min/100ml; p<0.01). Voxel-wise paired analysis displayed clusters of decreased CMRGlu 6m after RYGB in the widespread brain regions. In addition, we found a significant positive relationship between CMRGlu and HOMA-IR. All patients at baseline presented MMSE and MoCA scores in the normal range. However, 6 months after RYGB, the cognitive domains examined showed a trend of global improvement. MMSE score increased statistically significantly (p 0.002) as well as MoCA score (p <0.005). Conclusion: After bariatric surgery, there are several modifications of multiple factors that play a role in the so-called “intestinal-brain cross-talk”, in CMRGluand in cognitive function. CMRGluof morbidly obese subjects is abnormally enhanced in response to insulin. Bariatric surgery seems to reverse this insulin-mediated signal dysfunction and could produce significant CNS effects decreasing brain glucose over-consumption and promoting potential neuroprotective effect

The precuneus-a witness for excessive aβ gathering in alzheimer's disease pathology

Evidence of cortical beta-amyloid (Aβ) load, assessed by Aβ positron emission tomography (Aβ-PET), is an established in vivo biomarker of Alzheimer's disease (AD)-related pathophysiology. Qualitative assessment of Aβ-PET provides binary information; meanwhile semiquantitative approaches require a parcellation of PET image either manually or by placement of atlas-based volumes of interest. We supposed that a whole-brain approach with voxel-by-voxel standardized uptake value ratio (SUVr) parametric images may better elucidate the spatial trajectories of Aβ burden along the continuum of AD. Methods: We recruited 32 subjects with a diagnosis of probable AD dementia (ADD, n = 20) and mild cognitive impairment due to AD (MCI-AD, n = 12) according to the NIA-AA 2011 criteria. We also enrolled a control group of 6 cognitively healthy individuals (HCs) with preserved cognitive functions and negative Aβ-PET scan. The PET images were spatially normalized using the AV45 PET template in the MNI brain space. Subsequently, parametric SUVr images were calculated using the whole cerebellum as a reference region. A voxel-wise analysis of covariance was used to compare (between groups) the Îβ distribution pattern considering age as a nuisance covariate. Results: Both ADD and MCI-AD subjects showed a widespread increase in radiotracer uptake when compared with HC participants (p < 0.001, uncorrected). After applying a multiple comparison correction (p < 0.05, corrected), a relative large cluster of increased [ 18 F]-flor-betapir uptake was observed in the precuneus in the ADD and MCI-AD groups compared to HCs. Voxel-wise regression analysis showed a significant positive linear association between the voxel-wise SUVr values and the disease duration. Conclusions: The voxel-wise semiquantitative analysis shows that the precuneus is a region with higher vulnerability to Aβ depositions when compared to other cortical regions in both MCI-AD and ADD subjects. We think that the precuneus is a promising PET-based outcome measure for clinical trials of drugs targeting brain Aβ. We found a positive association between the overall Aβ-PET SUVr and the disease duration suggesting that the region-specific slow saturation of Aβ deposition continuously takes place as the disease progresses