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Several pharmacological approaches are used for glioblastoma (GBM) treatment, each hinging on the triggering of different biochemical or functional processes; the development of specific and sensitive PET procedures for monitoring their efficacy proceeds with the identification of such new treatments. This paper presents an overview of the available “tumour biomarker”–“PET probe” pairs (i.e. the combination of a tumour target and a selective PET radiopharmaceutical) for monitoring the different treatments for GBM tested in human subjects. A bibliographic search for papers on PET imaging for assessing treatment response in GBM was performed in PubMed and Web of science databases using the following string: (PET or positron) and (glioblastoma) and (treatment) and (monitoring); papers dealing with studies in human subjects published over the last 10 years were reviewed. Further papers were extracted from the bibliography of the reviewed papers. In this review, we highlight through a detailed table that in spite of the current use in GBM patients of a large variety of PET radiopharmaceuticals, very few papers have specifically addressed the issue of the optimization and use of imaging biomarker–probe pairs for the assessment of treatment response in GBM. While new PET probes are being developed for assessing old and new GBM biomarkers, very few clinical trials have been performed to this end. Whereas it appears that the use of old and new PET radiopharmaceuticals can advance the non-invasive assessment of treatment response in GBM, the optimal match of biomarker–probe pairs although highly needed is still being sought in particular with the active development of new highly specific treatments characterized by novel antitumoral targeting strategies.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor survival. Cytoreduction in association with radiotherapy and temozolomide (TMZ) is the standard therapy, but response is heterogeneous and life expectancy is limited. The combined use of chemotherapeutic agents with drugs targeting cell metabolism is becoming an interesting therapeutic option for cancer treatment. Here, we found that metformin (MET) enhances TMZ effect on TMZ-sensitive cell line (U251) and overcomes TMZ-resistance in T98G GBM cell line. In particular, combined-treatment modulated apoptosis by increasing Bax/Bcl-2 ratio, and reduced Reactive Oxygen Species (ROS) production. We also observed that MET associated with TMZ was able to reduce the expression of glioma stem cells (GSC) marker CD90 particularly in T98G cells but not that of CD133. In vivo experiments showed that combined treatment with TMZ and MET significantly slowed down growth of TMZ-resistant tumors but did not affect overall survival of TMZ-sensitive tumor bearing mice. In conclusion, our results showed that metformin is able to enhance TMZ effect in TMZ-resistant cell line suggesting its potential use in TMZ refractory GBM patients. However, the lack of effect on a GBM malignancy marker like CD133 requires further evaluation since it might influence response duration.

INTRODUCTION: Gliomas represent the most common adult neoplasm of the primary central nervous system (CNS) characterized by wide necrotic areas, high invasiveness, resistance to therapy and poor prognosis. Glioma is indeed refractory to conventional treatment combining surgery, radiotherapy and chemiotherapy (mostly Temozolomide, TMZ). Hypoxia is considered a major driving force for glioma progression inducing chemio- and radio-resistance, and sustaining tumor angiogenesis and invasiveness as well as proliferation with the hypoxia-mediated increase of HIF-1α activity. The presented research is part of the INSERT (INtegrated SPECT/MRI for Enhanced Stratification in Radio-chemo Therapy) project, a new collaborative research project founded by the European Seventh Research Framework Program (FP7) aimed at the development of a multi-modality imaging tool for concurrent SPECT and MRI studies to provide improved personalized radio-chemo therapies for brain tumors. Within this frame, the aim of the work, described herein, has been the identification of non-invasive theranostic biomarkers, involved in the regulation of tumor growth, and for the early assessment of tumor response to therapeutics using in vivo imaging strategies in an orthotopic mouse model of glioma. METHODS: Murine model was obtained by stereotaxic injection of human glioma cells (U251-HRE expressing Luciferase reporter gene under the control of multiple copies of hypoxia responsive element). Mice were treated with TMZ 400 mg/kg o.s 21 days after cell injection. Tumor growth was monitored in vivo with MRI (7 Tesla Bruker scanner) and Optical imaging (BLI and FLI, IVIS SPECTRUM/CT instrument), before and after treatment (0, 2 and 7 days). Moreover, ex vivo preliminary uptake studies were performed by autoradiography with [99mTc]MIBI. For MRI examinations were used different sequences such as: EPI-DTI (Diffusion Tensor), Turbo Spin Echo T2, Rare T1 Map, Dynamic Contrast Enhancement (DCE) Dynamic Susceptibility Contrast (DSC) and T1 post-contrast. RESULTS: TMZ treatment, beyond the already published reduction of HIF-1 activity, induced a reduction of tumor volume reported both by MRI and autoradiography one week after treatment. Treatment efficacy induced also variation of MRI detectable phenomena, such as diffusion and contrast enhancement (DWI and DCE MRI sequences). [99mTc]MIBI uptake resulted significantly lowered after TMZ treatment allowing the identification of responsive tumors. These data correlate with those already obtained by BLI and FLI. CONCLUSIONS: This study suggests that, in the U251-HRE orthotopic murine model, the responsiveness to TMZ treatment induced a pattern of changes probably involved with HIF-1 activity. These changes can be monitored by multiparametric analysis, and will be assessed using the newly hybrid imaging system proposed by INSERT project, allowing the validation of the new theranostic biomarkers of early tumor response to treatment. ACKNOWLEDGMENT: This work was supported by the FP7 INSERT project (HEALTH-2012-INNOVATION-1, GA305311).

Background/Aims: Congenital hyperinsulinism of infancy is a rare disease that needs prompt treatment to avoid brain damage. There are currently no data regarding the clinical and molecular features of Italian patients. Methods: Thirty-three patients with HI and their parents were included. Consanguinity was reported in six patients. Half of patients were macrosomic at birth. None had raised 3-hydroxybutyrylcarnitine or hyperammonemia. Molecular analysis of ABCC8 and KCNJ11 genes was performed in all patients, and subjects with no mutation underwent analysis of HNF4A and GCK. GLUD1 and HADH genes were analyzed in a patient with leucine sensitivity. Results: Mutations in the ABCC8 and KCNJ11 genes were found in 45% of the patients (6 novel). No mutations in HNF4A, GLUD1 and GCK genes were found. Recessive mode of inheritance was found in 21% of patients. A single heterozygous mutation was identified in 24% of probands. 72% of the patients were responsive to medical treatment, and 44% of the 17 patients with no identified mutation achieved spontaneous remission. Nine children, unresponsive to medical therapy, underwent pancreatectomy. Conclusion: This is the first report on hyperinsulinism of infancy in Italy, confirming the complexity of the clinical forms and the heterogeneity of the genetic causes of the disease.

Treatment with antiretroviral agents (ARVs) during pregnancy is important to prevent mother-to-child transmission of the human immunodeficiency virus (HIV), but their use has been associated with low bone mineral density in adult patients. Currently, there are no data regarding the bone status of HIV-infected women who received ARV during pregnancy. The aim of this study was to evaluate cortical bone status at delivery in a group of HIV-infected women who received ARV during pregnancy and to monitor the changes occurring during the first year postpartum. We studied 33 HIV-infected and 116 HIV-uninfected healthy Caucasian women within 4 days from delivery. Follow-up measurements were performed at 4 and 12 months postpartum in 17 HIV-infected and 55 healthy women. Cortical bone status was evaluated by quantitative ultrasonography at the mid-tibia, and bone measurements were expressed as the speed of sound (SOS). HIV-infected women after delivery had a median SOS of 3,985 (3,567–4,242) m/s, while the median SOS of healthy women was 4,025 (3,643–4,250) m/s. The difference was not significant (t = 0.39, P = 0.69). No significant differences were observed between ARV-exposed and control subjects at 4 and 12 months. Our data suggest that ARV during pregnancy and the first year after delivery does not affect negatively cortical bone status.