Inhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlates with a block in translation of mRNA encoding hypoxia-inducible factor (HIF1A), and is rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5' untranslated region. VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. Our findings provide preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting.

In patients with SX, the microcirculatory response to cold, reflecting the endothelium function, is normal and unaltered by intravenous L-arginine. This suggests preserved microcirculatory endothelial function. However, a markedly attenuated hyperemic flow and flow reserve after DIP suggest a dysfunction of the adenosine-mediated endothelium-independent vasodilatation at the microcirculatory level in these patients.

68 Ga-satoreotide trizoxetan is a novel somatostatin receptor antagonist associated with high sensitivity and reproducibility in neuroendocrine tumour (NET) detection and localisation.However, the optimal peptide mass and radioactivity ranges for 68 Ga-satoreotide trizoxetan have not yet been established. We therefore aimed to determine its optimal dosing regimen in patients with metastatic gastroenteropancreatic NETs in a prospective, randomised, 2×3 factorial, multicentre, phase II study.Methods: Patients received 68 Ga-satoreotide trizoxetan at a peptide mass of 5-20 µg on day 1 of the study and of 30-45 µg on day 16-22, at one of three gallium-68 radioactivity ranges . Whole-body PET/CT imaging was performed 50-70 minutes after each injection. The primary endpoint was the detection rate of NET lesions imaged by 68 Gasatoreotide trizoxetan relative to contrast-enhanced CT (CECT) (for each of the six peptide mass/radioactivity range combinations).Results: Twenty-four patients were evaluated in the per-protocol analysis. The median number of lesions detected by 68 Ga-satoreotide trizoxetan PET/CT or PET only was at least twice as high as the number of lesions detected by CECT across the six studied peptide mass dose/radioactivity range combinations. There were no differences between the two peptide mass ranges and between the three radioactivity ranges in the number of identified lesions. However, a trend towards a lower 3 relative lesion count was noted in the liver for the 40-80 MBq range. No relationship was observed between the radioactivity range per patient's body weight (MBq/kg) and the number of lesions detected by 68 Ga-satoreotide trizoxetan. Median diagnostic sensitivity of 68 Ga-satoreotide trizoxetan PET/CT, based on the number of lesions per patient, ranged from 85% to 87% across the different peptide mass and radioactivity ranges. Almost all reported adverse events were mild and self-limiting. Conclusion:A radioactivity of 100-200 MBq with a peptide mass up to 50 μg were confirmed as the optimal dosing regimen for 68 Ga-satoreotide trizoxetan to be used in future phase III studies.

Preclinical models predict that blockade of the coinhibitory molecule cytotoxic T lymphocyte-associated antigen 4 (CTLA4) on lymphocytes results in the release of a cell cycle inhibitory checkpoint, allowing lymphocyte proliferation, tumor targeting, and regression. However, there is a paucity of data demonstrating that lymphocyte proliferation does occur in humans treated with CTLA4-blocking antibodies. Methods: We tested the role of whole-body molecular imaging in patients with advanced melanoma receiving the CTLA4-blocking antibody tremelimumab, allowing the analysis of changes in glucose metabolism using the PET probe 18 F-FDG and cell replication with the PET probe 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT). Results: PET/CT scans obtained at a median of 2 mo after initial dosing did not demonstrate significant changes in lesion size or 18 F-FDG or 18 F-FLT uptake when focusing on metastatic lesions. Similarly, there was no difference in 18 F-FDG uptake in the non-melanoma-involved spleen. However, there were significant increases in standardized uptake values for 18 F-FLT in the spleen using post-and pretremelimumab treatment scans. Conclusion: Molecular imaging with the PET probe 18 F-FLT allows mapping and noninvasive imaging of cell proliferation in secondary lymphoid organs after CTLA4 blockade in patients with metastatic melanoma. The cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a coinhibitory activation-induced surface receptor on T cells that functions as a major negative regulator of anti-self-immune responses. It provides a dominant negative signaling to T cells on binding to the costimulatory molecules CD80 (B7.1) and CD86 (B7.2) expressed on the surface of antigen-presenting cells (1). Most naïve T cells do not express surface CTLA4 because of its binding to AP50, a subunit of the clathrin adaptor AP-2 protein (2). Once a T cell is activated through its T-cell receptor, downstream T-cell receptor signaling through Src kinases results in tyrosine phosphorylation of CTLA4 and the uncoupling of CTLA4 from AP50, allowing its surface expression, which peaks at 48 h after activation. Cell surface CTLA4 has 100-1,000 times higher affinity for the costimulatory molecules expressed by antigen-presenting cells, thereby efficiently competing with the positive costimulatory receptor CD28 (1). The engagement of CTLA4 by costimulatory molecules results in decreased T-cell receptor signaling, interleukin 2 transcription (3), and cell cycle arrest at the G1 stage, with the final result of inducing T-cell anergy (4,5). A clear example of the critical role of CTLA4 on tolerance is the striking phenotype of CTLA4 knock-out mice, which develop rapid T-cell proliferation and autoimmune infiltration of multiple organs shortly after birth (6,7).Monoclonal antibodies blocking CTLA4 induce regression of immunogenic tumors in mice (8) and are being pursued as a treatment approach for patients with cancer. Two fully human antibodies with CTLA4-blocking activity-ipilimumab and tremelimumab-are in clinical develo...

ObjectiveTo determine whether the use of [18F]2-fluoro-2-deoxyglucose positron emission tomography (FDG PET) in addition to computed axial tomography (CT) is helpful in managing recurrent colorectal cancer (CRC). Summary Background DataThere is no consensus on a management algorithm for CRC. However, when recurrence is suspected, CT is generally used for further evaluation and staging of disease. MethodsThe authors used decision trees based on theoretical models to assess the cost-effectiveness of a CT ϩ FDG PET strategy for the diagnosis and management of recurrent CRC compared with a CT-alone strategy. These theoretical models focus on patients with hepatic recurrence who are potentially curable through surgical hepatic resection. The population entering the decision trees consisted of patients with CRC who had undergone surgical resection of their primary CRC and who were suspected of having recurrence based on elevated levels of carcinoembryonic antigen. ResultsThe CT ϩ FDG PET strategy was found to be cost-effective for managing patients with elevated carcinoembryonic antigen levels who were candidates for hepatic resection. The CT ϩ FDG PET strategy was higher in mean cost by $429 per patient but resulted in an increase in the mean life expectancy of 9.527 days per patient. ConclusionsThese results show, through rigorous decision tree analysis, the potential cost-effectiveness of FDG PET in the management of recurrent CRC. The decision trees can be used to model various features of the management of recurrent CRC, including the cost-effectiveness of other newly emerging technologies.In the United States, the number of new cases of colorectal cancer (CRC) was estimated at 129,400 in 1999.