We conducted a comprehensive systematic review of the literature on volumetric parameters and a meta-analysis of the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with head and neck cancer (HNC). Methods: A systematic search of MEDLINE and EMBASE was performed using the key words PET, head and neck, and volume. Inclusion criteria were ¹⁸F-FDG PET used as an initial imaging tool; studies limited to HNC; patients who had not undergone surgery, chemotherapy, or radiotherapy before PET scans; and studies reporting survival data. Event-free survival and overall survival were considered markers of outcome. The impact of MTV or TLG on survival was measured by the effect size hazard ratio (HR). Data from each study were analyzed using Review Manager. Results: Thirteen studies comprising 1,180 patients were included in this study. The combined HR for adverse events was 3.06 (2.33–4.01, P < 0.00001) with MTV and 3.10 (2.27–4.24, P < 0.00001) with TLG, meaning that tumors with high volumetric parameters were associated with progression or recurrence. Regarding overall survival, the pooled HR was 3.51 (2.62–4.72, P < 0.00001) with MTV and 3.14 (2.24–4.40, P < 0.00001) with TLG. There was no evidence of significant statistical heterogeneity at an I² of 0%. Conclusion: MTV and TLG are prognostic predictors of outcome in patients with HNC. Despite clinically heterogeneous HNC and the various methods adopted between studies, we can confirm that patients with a high MTV or TLG have a higher risk of adverse events or death.

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non–small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFα to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy. Significance: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.

Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate adenocarcinoma (AdPC) cells and acts as a target for molecular imaging. However, some case reports indicate that PSMA-targeted imaging could be ineffectual for delineation of neuroendocrine (NE) prostate cancer (NEPC) lesions due to the suppression of the PSMA gene (FOLH1). These same reports suggest that targeting somatostatin receptor type 2 (SSTR2) could be an alternative diagnostic target for NEPC patients. This study evaluates the correlation between expression ofFOLH1, NEPC marker genes andSSTR2. We evaluated the transcript abundance forFOLH1andSSTR2genes as well as NE markers across 909 tumors. A significant suppression ofFOLH1in NEPC patient samples and AdPC samples with high expression of NE marker genes was observed. We also investigated protein alterations of PSMA and SSTR2 in an NE-induced cell line derived by hormone depletion and lineage plasticity by loss of p53. PSMA is suppressed following NE induction and cellular plasticity in p53-deficient NEPC model. The PSMA-suppressed cells have more colony formation ability and resistance to enzalutamide treatment. Conversely, SSTR2 was only elevated following hormone depletion. In 18 NEPC patient-derived xenograft (PDX) models we find a significant suppression ofFOLH1and amplification ofSSTR2expression. Due to the observedFOLH1-supressed signature of NEPC, this study cautions on the reliability of using PMSA as a target for molecular imaging of NEPC. The observed elevation ofSSTR2in NEPC supports the possible ability of SSTR2-targeted imaging for follow-up imaging of low PSMA patients and monitoring for NEPC development.

Arg-Gly-Asp (RGD) derivatives have been labeled with various radioisotopes for the imaging of angiogenesis in ischemic tissue, in which α_vβ₃ integrin plays an important role. In this study, cyclic Arg-Gly-Asp-d-Tyr-Lys [c(RGDyK)] was conjugated with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bz-NOTA) and then labeled with ⁶⁸Ga. The labeled RGD so produced was subjected to an in vitro binding assay and in vivo biodistribution and PET studies. Methods: A mixture of SCN-Bz-NOTA (660 nmol) and c(RGDyK) (600 nmol) in 0.1 M sodium carbonate buffer (pH 9.5) was allowed to react for 20 h at room temperature in the dark for thiourea bond formation. The conjugate obtained was purified by semipreparative high-performance liquid chromatography (HPLC). The purified c(RGDyK)–SCN-Bz-NOTA (NOTA-RGD) was then labeled with ⁶⁸Ga from a ⁶⁸Ge/⁶⁸Ga generator and purified by semipreparative HPLC. A competitive binding assay for c(RGDyK) and NOTA-RGD was performed with ¹²⁵I-c(RGDyK) as a radioligand and α_vβ₃ integrin–coated plates as a solid phase. ⁶⁸Ga-NOTA-RGD (0.222 MBq/100 μL) was injected, through a tail vein, into mice with hind limb ischemia and into mice bearing human colon cancer SNU-C4 xenografts. Biodistribution and imaging studies were performed at 1 and 2 h after injection. Results: The labeling of NOTA-RGD with ⁶⁸Ga was straightforward. The K_i values of c(RGDyK) and NOTA-RGD were 1.3 and 1.9 nM, respectively. In the biodistribution study, the mean ± SD uptake of ⁶⁸Ga-NOTA-RGD by ischemic muscles was 1.6 ± 0.2 percentage injected dose per gram (%ID/g); this uptake was significantly blocked by cold c(RGDyK) to 0.6 ± 0.3 %ID/g (P < 0.01). Tumor uptake was 5.1 ± 1.0 %ID/g, and the tumor-to-blood ratio was 10.3 ± 4.8. Small-animal PET revealed rapid excretion through the urine and high levels of tumor and kidney uptake. Conclusion: Stable ⁶⁸Ga-NOTA-RGD was obtained in a straightforward manner at a high yield and showed a high affinity for α_vβ₃ integrin, specific uptake by angiogenic muscles, a high level of uptake by tumors, and rapid renal excretion. ⁶⁸Ga-NOTA-RGD was found to be a promising radioligand for the imaging of angiogenesis.