Search

Developing a noninvasive imaging method to detect immune system activation with a high temporal resolution is key to improving inflammatory bowel disease (IBD) management. In this study, granzyme B (GZMB), typically released from cytotoxic T and natural killer cells, was targeted using PET with 68 Ga-NOTA-GZP (where GZP is β-Ala-Gly-Gly-Ile-Glu-Phe-Asp-CHO) to detect early intestinal inflammation in murine models of colitis. Methods: Bioinformatic analysis was used to assess the potential of GZMB as a biomarker for detecting IBD and predicting response to treatment. Human active and quiescent Crohn disease and ulcerative colitis tissues were stained for GZMB. We used IL-10 -/- mice treated with dextran sulfate sodium (DSS) as an IBD model, wild-type C57BL/6J mice as a control, and anti-tumor necrosis factor as therapy. We used a murine GZMB-binding peptide conjugated to a NOTA chelator (NOTA-GZP) labeled with 68 Ga as the PET tracer. PET imaging was conducted at 1, 3, and 4 wk after colitis induction to evaluate temporal changes. Results: Bioinformatic analysis showed that GZMB gene expression is significantly upregulated in human ulcerative colitis and Crohn disease compared with the noninflamed bowel by 2.98-fold and 1.92-fold, respectively; its expression is lower by 2.16-fold in treatment responders than in nonresponders. Immunofluorescence staining of human tissues demonstrated a significantly higher GZMB in patients with active than with quiescent IBD ( P = 0.032). 68 Ga-NOTA-GZP PET imaging showed significantly increased bowel uptake in IL-10 -/- mice with DSS-induced colitis compared with vehicle-treated IL-10 -/- mice (SUV mean , 0.75 vs. 0.24; P < 0.001) and both vehicle- and DSS-treated wild-type mice (SUV mean , 0.26 and 0.37; P < 0.001). In the IL-10 -/- DSS-induced colitis model, the bowel PET probe uptake decreased in response to treatment with tumor necrosis factor-α (SUV mean , 0.32; P < 0.001). There was a 4-fold increase in colonic uptake of 68 Ga-NOTA-GZP in the colitis model compared with the control 1 wk after colitis induction. The uptake gradually decreased to approximately 2-fold by 4 wk after IBD induction; however, the inflamed bowel uptake remained significantly higher than control at all time points (week 4 SUV mean , 0.23 vs. 0.08; P = 0.001). Conclusion: GZMB is a promising biomarker to detect active IBD and predict response to treatment. This study provides compelling evidence to translate GZMB PET for imaging IBD activity in clinical settings., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Position emission tomography (PET) is widely used in clinics and research due to its quantitative merits and high sensitivity, but suffers from low signal-to-noise ratio (SNR). Recently convolutional neural networks (CNNs) have been widely used to improve PET image quality. Though successful and efficient in local feature extraction, CNN cannot capture long-range dependencies well due to its limited receptive field. Global multi-head self-attention (MSA) is a popular approach to capture long-range information. However, the calculation of global MSA for 3D images has high computational costs. In this work, we proposed an efficient spatial and channel-wise encoder-decoder transformer, Spach Transformer, that can leverage spatial and channel information based on local and global MSAs. Experiments based on datasets of different PET tracers, i.e., 18F-FDG, 18F-ACBC, 18F-DCFPyL, and 68Ga-DOTATATE, were conducted to evaluate the proposed framework. Quantitative results show that the proposed Spach Transformer framework outperforms state-of-the-art deep learning architectures.

Background: Acute interstitial nephritis is an immune-related adverse event that can occur in patients receiving immune checkpoint inhibitor therapy. Differentiating checkpoint inhibitor-associated acute interstitial nephritis from other causes of acute kidney injury in patients with cancer is challenging and can lead to diagnostic delays and/or unwarranted immunosuppression. In this case report, we assess the use of 18 F-flourodeoxyglucose positron-emission tomography imaging as an alternative diagnostic modality in the evaluation of potential acute interstitial nephritis., Case Presentation: A 55-year-old woman with metastatic vulvar melanoma underwent treatment with two cycles of ipilimumab plus nivolumab, followed by seven cycles of nivolumab combined with radiation therapy. During her treatment, she developed non-oliguric acute kidney injury to a creatinine of 4.5 mg/dL from a baseline of 0.5 mg/dL. A clinical diagnosis of acute interstitial nephritis was made, and steroids were initiated, with rapid improvement of her acute kidney injury. Retrospectively, four positron-emission tomography scans obtained for cancer staging purposes were reviewed. We found a markedly increased 18 F-flourodeoxyglucose uptake in the renal cortex at the time acute interstitial nephritis was diagnosed compared to baseline. In three cases of acute kidney injury due to alternative causes there was no increase in 18 F-flourodeoxyglucose uptake from baseline., Conclusions: To our knowledge, this is the first report describing increased 18 F-flourodeoxyglucose uptake in the renal cortex in a patient with checkpoint inhibitor-associated acute interstitial nephritis. Our findings suggest that 18 F-flourodeoxyglucose positron-emission tomography may be a valuable test for diagnosing immune-mediated nephritis, particularly in patients where timely kidney biopsy is not feasible.

Purpose: Response criteria of glioblastoma after chemoradiation do not account for metabolic changes that occur after treatment. The purpose of this study is to evaluate the utility of positron emission tomography (PET) imaging with C11 methionine (MET) (MET-PET) for detecting changes that occur after chemoradiation therapy and the value of molecular biomarkers for predicting the magnitude of metabolic response., Methods and Materials: Patients with newly diagnosed glioblastoma undergoing standard chemoradiation treatment were enrolled in this prospective imaging study, with MET-PET scan performed within 3 days after surgical resection and again at 4 weeks after completion of chemoradiation. Near contemporaneous contrast-enhanced magnetic resonance imaging was performed within 2 weeks of each MET-PET scan. MET-PET imaging was analyzed for maximum standardized uptake value (SUV), SUVmean, and SUVvolume on a multimodality workstation., Results: A total of 18 patients underwent baseline postoperative MET-PET imaging, 14 of whom underwent postchemoradiation MET-PET imaging. Among those who showed residual MET-avid disease on immediate postoperative MET-PET scans and underwent postchemoradiation MET-PET imaging (n = 10), mean ΔSUVmax was -40% (range -100% to 0%), mean ΔSUVmean was -35% (range -100% to 0%), and mean ΔSUV volume was -64% (range -100% to 0%). The Δtumor/brain reference was -40% (range -100% to 0%) using SUVmax and -35% (range -100% to 0%) using SUVmean. In contrast, none of the T2-weighted images on contrast-enhanced magnetic resonance imaging showed a >25% reduction in abnormal T2/fluid-attenuated inversion recovery signal on visual assessment. ΔSUVmax, ΔSUVmean, and ΔSUVvolume correlated with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status (P = .01), but not with epidermal growth factor receptor or c-MET amplification status. All patients were IDH-1 wildtype., Conclusions: MET-PET scanning shows a significant decrease in metabolic signal at 1 month after chemoradiation compared with the immediate postoperative period, even when T2/fluid-attenuated inversion recovery changed little. MGMT promoter methylation status further predicts differential metabolic responses. MET-PET may be a useful tool for delineation of radiation targets and assessment of response., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Reporter gene systems can serve as therapy targets. However, the therapeutic use of reporters has been limited by the challenges of transgene delivery to a majority of cancer cells. This study specifically assesses the efficacy of targeting human somatostatin receptor subtype 2 (hSSTR2) with peptide receptor radionuclide therapy (PRRT) when a small subpopulation of cells bears the transgene. Methods: The hSSTR2 transgene was delivered to A549 and Panc-1tumors using the lentiviral vector, LV-hSSTR2-IRES-GFP or murine mesenchymal stem cells (mMSC)s using a retroviral vector. SSTR2 expression was assessed using Western blot and correlated to GFP fluorescence and 68 Ga-DOTATOC uptake. Wild type (WT), transduced (TD), and mixed population A549 or Panc-1 xenografts were implanted in nude mice. Separate groups with A549 WT and Panc-1 WT tumors received intratumoral injection of SSTR2-expressing mMSCs. Tumor-bearing mice were treated with 90 Y-DOTATOC or saline and evaluated with 68 Ga-DOTATOC PET before and after treatment. Results: Cell studies showed a strong correlation between 68 Ga-DOTATOC uptake and SSTR2 expression in A549 (p < 0.004) and Panc-1 cells (p < 0.01). 68 Ga-DOTATOC PET SUVmean was 8- and 5-fold higher in TD compared to WT A549 and Panc-1 tumors, respectively (p < 0.001). After 90 Y-DOTATOC treatment, 100% TD and mixed population TD xenografts showed growth cessation while the WT xenografts did not. A549 WT and Panc-1 WT tumors with SSTR2-expressing mMSCs treated with 90 Y-DOTATOC showed significantly lower tumor volumes compared to controls (p < 0.05). 68 Ga-DOTATOC PET SUVmean of treated TD tumors monotonically declined and was significantly lower than that of non-treated xenografts. Conclusions: We showed that SSTR2 delivery to a small population of cells in tumor in conjunction with PRRT is effective in tumor growth cessation. The availability of various transgene delivery methods for hSSTR2 and radiotherpaeutic somatostatin analogs highlights the direct translational potential of this paradigm in the treatment of various cancers., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Unlabelled: Inhibitors of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway hold promise for the treatment of breast cancer, but resistance to these treatments can arise via feedback loops that increase surface expression of the receptor tyrosine kinases (RTK) epidermal growth factor receptor 1 (EGFR) and human epidermal growth factor receptor 3 (HER3), leading to persistent growth pathway signaling. We developed PET probes that provide a method of imaging this response in vivo, determining which tumors may use this escape pathway while avoiding the need for repeated biopsies., Methods: Anti-EGFR-F(ab')2 and anti-HER3-F(ab')2 were generated from monoclonal antibodies by enzymatic digestion, conjugated to DOTA, and labeled with (64)Cu. A panel of breast cancer cell lines was treated with increasing concentrations of the AKT inhibitor GDC-0068 or the PI3K inhibitor GDC-0941. Pre- and posttreatment expression of EGFR and HER3 was compared using Western blot and correlated to probe accumulation with binding studies. Nude mice xenografts of HCC-70 or MDA-MB-468 were treated with either AKT inhibitor or PI3K inhibitor and imaged with either EGFR or HER3 PET probe., Results: Changes in HER3 and EGFR PET probe accumulation correlate to RTK expression change as assessed by Western blot (R(2) of 0.85-0.98). EGFR PET probe PET/CT imaging of HCC70 tumors shows an SUV of 0.32 ± 0.03 for vehicle-, 0.50 ± 0.01 for GDC-0941-, and 0.62 ± 0.01 for GDC-0068-treated tumors, respectively (P < 0.01 for both comparisons to vehicle). HER3 PET probe PET/CT imaging of MDAMB468 tumors shows an SUV of 0.35 ± 0.02 for vehicle- and 0.73 ± 0.05 for GDC-0068-treated tumors (P < 0.01)., Conclusion: Our imaging studies, using PET probes specific to EGFR and HER3, show that changes in RTK expression indicative of resistance to PI3K and AKT inhibitors can be seen within days of therapy initiation and are of sufficient magnitude as to allow reliable clinical interpretation. Noninvasive PET monitoring of these RTK feedback loops should help to rapidly assess resistance to PI3K and AKT inhibitors and guide selection of an appropriate combinatorial therapeutic regimen on an individual patient basis., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Colorectal cancer is a serious complication associated with inflammatory bowel disease, often indistinguishable by screening with conventional FDG PET probes. We have developed an alternative EGFR-targeted PET imaging probe that may be used to overcome this difficulty, and successfully assessed its utility for neoplastic lesion detection in preclinical models. Cetuximab F(ab')2 fragments were enzymatically generated, purified, and DOTA-conjugated. Radiolabeling was performed with (67)Ga for cell based studies and (64)Cu for in vivo imaging. Competitive binding studies were performed on CT26 cells to assess affinity (KD) and receptors per cell (Bmax). In vivo imaging using the EGFR targeted PET probe and (18)F FDG was performed on CT26 tumor bearing mice in both control and dextran sodium sulfate (DSS) induced colitis settings. Spontaneous adenomas in genetically engineered mouse (GEM) models of colon cancer were additionally imaged. The EGFR imaging agent was generated with high purity (> 98%), with a labeling efficiency of 60 ± 5% and ≥99% radiochemical purity. The KD was 6.6 ± 0.7 nM and the Bmax for CT26 cells was 3.3 ± 0.1 × 10(6) receptors/cell. Target to background ratios (TBR) for CT26 tumors compared to colonic uptake demonstrated high values for both (18)F-FDG (3.95 ± 0.13) and the developed (64)Cu-DOTA-cetuximab-F(ab')2 probe (4.42 ± 0.11) in control mice. The TBR for the EGFR targeted probe remained high (3.78 ± 0.06) in the setting of colitis, while for (18)F FDG, this was markedly reduced (1.54 ± 0.08). Assessment of the EGFR targeted probe in the GEM models demonstrated a correlation between radiotracer uptake in spontaneous colonic lesions and the EGFR staining level ex vivo. A clinically translatable PET imaging probe was successfully developed to assess EGFR. The imaging agent can detect colonic tumors with a high TBR for detection of in situ lesions in the setting of colitis, and opens the possibility for a new approach for screening high-risk patients.

Esophageal cancer is the third most common malignancy of the alimentary tract. The incidence of esophageal cancer has steadily increased over the past three decades. Almost all therapeutic modalities for esophageal cancer are associated with a considerable mortality and morbidity. Consequently, there has been growing concern regarding effective management of esophageal cancer. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is playing an increasing role in the management of esophageal cancer, offering potential advantages in the accuracy of disease assessment at a number of decision points in the management pathway. This review evaluates the critical role of FDG-PET in (i) diagnosis, (ii) preoperative staging, (iii) monitoring of response to neoadjuvant therapy, (iv) assessment of recurrence and (v) prediction of prognosis of esophageal cancer. We have also compared diagnostic performance of FDG-PET and other current technologies such as computed tomography scan and endoscopic ultrasonography based on available evidence.