Genome-Wide Identification and Validation of Gene Expression Biomarkers in the Diagnosis of Ovarian Serous Cystadenocarcinoma.

Ovarian cancer is the second most prevalent gynecologic malignancy, and ovarian serous cystadenocarcinoma (OSCA) is the most common and lethal subtype of ovarian cancer. Current screening methods have strong limits on early detection, and the majority of OSCA patients relapse. In this work, we developed and cross-validated a method for detecting gene expression biomarkers able to discriminate OSCA tissues from healthy ovarian tissues and other cancer types with high accuracy. A preliminary ranking-based approach was applied, resulting in a panel of 41 over-expressed genes in OSCA. The RNA quantity gene expression of the 41 selected genes was then cross-validated by using NanoString nCounter technology. Moreover, we showed that the RNA quantity of eight genes (ADGRG1, EPCAM, ESRP1, MAL2, MYH14, PRSS8, ST14 and WFDC2) discriminates each OSCA sample from each healthy sample in our data set with sensitivity of 100% and specificity of 100%. For the other three genes (MUC16, PAX8 and SOX17) in combination, their RNA quantity may distinguish OSCA from other 29 tumor types.

Novel Biological and Molecular Characterization in Radiopharmaceutical Preclinical Design.

In this study, the potential of a digital autoradiography system equipped with a super resolution screen has been evaluated to investigate the biodistribution of a 18F-PSMA inhibitor in a prostate cancer mouse model. Twelve double xenograft NOD/SCID mice (LNCAP and PC3 tumours) were divided into three groups according to post-injection time points of an 18F-PSMA inhibitor. Groups of 4 mice were used to evaluate the biodistribution of the radiopharmaceutical after 30-, 60- and 120-min post-injection. Data here reported demonstrated that the digital autoradiography system is suitable to analyse the biodistribution of an 18F-PSMA inhibitor in both whole small-animal bodies and in single organs. The exposure of both whole mouse bodies and organs on the super resolution screen surface allowed the radioactivity of the PSMA inhibitor distributed in the tissues to be detected and quantified. Data obtained by using a digital autoradiography system were in line with the values detected by the activity calibrator. In addition, the image obtained from the super resolution screen allowed a perfect overlap with the tumour images achieved under the optical microscope. In conclusion, biodistribution studies performed by the autoradiography system allow the microscopical modifications induced by therapeutic radiopharmaceuticals to be studied by comparing the molecular imaging and histopathological data at the sub-cellular level.

ESTIMATION OF THERMAL & EPITHERMAL NEUTRON FLUX AND GAMMA DOSE DISTRIBUTION IN A MEDICAL CYCLOTRON FACILITY FOR RADIATION PROTECTION PURPOSES USING GOLD FOILS AND GATE 9.

The aim of this study is to characterise the neutron flux generated directly behind targets used in medical cyclotrons. The characterisation process aims at determining the feasibility of using the generated neutrons for research purposes in neutron activation analysis. The study was performed by activating gold foils placed directly behind the cyclotron targets. The thermal and epithermal neutron flux were found to be 4.5E+05 ± 8.78E+04 neutrons cm-2 s-1 and 2.13E+06 ± 8.59E+04 neutrons cm-2 s-1, respectively. The flux value is the same order of magnitude listed in the manual produced by the cyclotron manufacturer. The results are encouraging and show high potential for using the cyclotron facility as a thermal neutron source for research purposes. However, it is important radiation protection procedures be followed to ensure the safety of researchers due to the high gamma dose rate measured directly behind the target at 2.46 Sv/h using an OSL chip during the beam on time.

Impact of 68Ga-DOTATOC PET/CT in comparison to 111In-Octreotide SPECT/CT in management of neuro-endocrine tumors: A case report.

RATIONALE: In the diagnostics of neuroendocrine tumors (NETs), scintigraphy and Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) with Indium-Octreotide occupy a prominent place.The introduction in clinical practice of Gallium-labelled somatostatin analogues (DOTA-TOC, DOTA-TATE, DOTA-NOC) for Positron Emission Tomography/Computed Tomography (PET/CT), significantly improved NETs diagnostics due to greater sensitivity and improved lesion detection in addition to better patient convenience and decreased radiation dose. PATIENT CONCERNS: We report a case of a patient who was diagnosed with a neuroendocrine tumor of the ileocecal valve. DIAGNOSES: Diagnosis was made by ultrasonography, CT, and colonoscopy. Hystology after surgery was G2 NET of ileo-cecal valve. Restaging was carried out by In-Octreotide SPECT/CT and, 1 month later, by Ga-DOTATOC PET/CT. F-FDG PET/C was also carried out. INTERVENTIONS: Ga-DOTATOC PET/CT showed larger disease that modified disease management from surgery to medical treatment. OUTCOMES: After an initial improvement in the patient clinical condition, the tumor caused a worsening with the appearance of ascites. LESSONS: Ga-DOTA-conjugate PET/CT is appropriate in low and intermediate NET (Ki67 index respectively ≤3% and 3%-20%) characterized by better survival and better response after Peptide Receptor Radionuclide Therapy.F-FDG is mostly useful in high grade (G3) of disease, so that Ga-DOTA-conjugate SUV and F-FDG SUV have an opposite trend in relation to the tumor grade. Ga-DOTATOC PET/CT changes, as in our case, therapeutic management in about 40% of cases.

Novel bisphosphonates with antiresorptive effect in bone mineralization and osteoclastogenesis.

Bisphosphonates such as zoledronic, alendronic and risedronic acids are a class of drugs clinically used to prevent bone density loss and osteoporosis. Novel P-C-P bisphosphonates were synthesized for targeting human farnesyl pyrophosphate synthase (hFPPS) and human geranylgeranyl pyrophosphate synthase (hGGPPS), key enzymes of the mevalonate pathway, and capable of anti-proliferative action on a number of cell lines (PC3, MG63, MC3T3, RAW 264.7, J774A.1, bone marrow cells and their co-colture with PC3) involved in bone homeostasis, bone formation and death. Among sixteen compounds, [1-hydroxy-2-(pyrimidin-2-ylamino)ethane-1,1-diyl]bis(phosphonic acid) (10) was effective in reducing PC3 and RAW 264.7 cell number in crystal-violet and cell-dehydrogenase activity assays at 100 µM concentration. 10 reduced differentiated osteoclasts number similarly with zoledronic acid in osteoclastogenesis assay. At nanomolar concentrations, 10 was more effective than zoledronic acid in inducing mineralization in MC3T3 and murine bone marrow cells. Further, 10 significantly inhibited the activity of hFPPS showing an IC50 of 0.31 µM and a remarkable hydroxyapatite binding of 90%. Docking calculations were performed identifying putative interactions between some representative novel bisphosphonates and both hFPPS and hGGPPS. Then, 10 was found to behave similarly or even better than zoledronic acid as a anti-resorptive agent.

A novel injectable formulation of 6-fluoro-l-DOPA imaging agent for diagnosis of neuroendocrine tumors and Parkinson's disease.

Two [19F]F-l-DOPA (F-DOPA) new ß-cyclodextrin (CD)-based dosage forms (FA and FB, respectively) have been studied and their physico-chemical and pharmacological features determined to overcome the administration site reactions showed by the currently used [18F]F-l-DOPA formulation (IASOdopa®) to perform PET-CT diagnosis in oncology (neuroendocrine tumors) and neurological (Parkinson's disease) field. Chemical stability of FA and FB was found to be longer than IASOdopa® by adding the thiol-antioxidant agent, L-Cysteine. 1H and 19F NMR investigations suggest the formation of an inclusion complex of F-DOPA with ß-CD. In vitro experiments on the effects of FA and FB on mouse skeletal muscle fibers and on the human neuroblastoma SH-SY5Y and embryonal kidney tsA201 cell lines viability showed that FA was the most performant formulation compared to F-DOPA solutions. In vivo tolerability tests of FA on adult male rat showed no significant effects on body weight and no change in their dried organs weight. In addition, their metabolic and physiological parameters were not affected. In conclusion, [18F]F-l-DOPA, formulated as FA, constitutes a promising dosage form for PET-CT diagnosis of both neuroendocrine tumors and Parkinson's disease.

Pharmaceutical development of novel lactate-based 6-fluoro-l-DOPA formulations.

6-[18F]fluoro-l-dihydroxyphenylalanine (18F-DOPA) is a diagnostic positron emission tomography (PET) agent, which has been used for decades in imaging the loss of dopaminergic neurons in Parkinson's disease, and more recently to detect, stage and restage neuroendocrine tumors (NETs) and to search for recurrence of viable glioma tissue. The commercially available 18F-DOPA PET radiopharmaceutical for diagnostic use in European Union countries, is formulated in an aqueous solution of acetic acid (1.05mg/mL) and has the disadvantages that, immediately before injection, the pH must be adjusted to 4.0-5.0 by the addition of a sterile solution of sodium bicarbonate (84mg/mL) causing a light and transient burning sensation at the injection site. To overcome these drawbacks, preformulation studies were accomplished to confirm that F-DOPA degradation was affected by pH. Hence, two formulations of F-DOPA, namely ND1 and ND2, were prepared maintaining the pH=5.0 using 1mM l-(+)-lactate buffer, excluding oxygen, and incorporating in the formula the chelating agent Na2EDTA (1mM). F-DOPA oxygen exposure, the presence of free metal cations in formulation and high pH values seem to promote F-DOPA degradation. The resulting formulations proved to guarantee the chemical stability of F-DOPA in solution at pH5.0, value also compatible with the direct infusion. In vitro cell viability tests on mouse skeletal muscle fibers, renal tsa201 and neuronal SH-SY5Y cell lines, and in vivo studies in rats reported elsewhere, showed cell tolerability to the new F-DOPA formulations providing the basis for their further in vivo evaluation.

Patient positioning in the proton radiotherapy era.

The main hindrance to the diffusion of proton therapy facilities is the high cost for gantry installations. An alternative technical option is provided by fixed-beam treatment rooms, where the patient is rotated and translated in space with a robotic arm solution to enable beam incidence from various angles. The technological efforts based on robotic applications made up to now for patient positioning in proton beam facilities are described here, highlighting their limitations and perspectives.