Molecular imaging of the urokinase plasminogen activator receptor: opportunities beyond cancer.

The urokinase plasminogen activator receptor (uPAR) plays a multifaceted role in almost any process where migration of cells and tissue-remodeling is involved such as inflammation, but also in diseases as arthritis and cancer. Normally, uPAR is absent in healthy tissues. By its carefully orchestrated interaction with the protease urokinase plasminogen activator and its inhibitor (plasminogen activator inhibitor-1), uPAR localizes a cascade of proteolytic activities, enabling (patho)physiologic cell migration. Moreover, via the interaction with a broad range of cell membrane proteins, like vitronectin and various integrins, uPAR plays a significant, but not yet completely understood, role in differentiation and proliferation of cells, affecting also disease progression. The implications of these processes, either for diagnostics or therapeutics, have received much attention in oncology, but only limited beyond. Nonetheless, the role of uPAR in different diseases provides ample opportunity to exploit new applications for targeting. Especially in the fields of oncology, cardiology, rheumatology, neurology, and infectious diseases, uPAR-targeted molecular imaging could offer insights for new directions in diagnosis, surveillance, or treatment options.

Identifying Biomarkers in Lymph Node Metastases of Esophageal Adenocarcinoma for Tumor-Targeted Imaging.

INTRODUCTION: Tumor-targeted imaging is a promising technique for the detection of lymph node metastases (LNM) and primary tumors. It remains unclear which biomarker is the most suitable target to distinguish malignant from healthy tissue in esophageal adenocarcinoma (EAC). OBJECTIVE: We performed an immunohistochemistry study to identify viable tumor markers for tumor-targeted imaging of EAC. METHODS: We used samples from 72 patients with EAC to determine the immunohistochemical expression of ten potential tumor biomarkers for EAC (carbonic anhydrase IX [CA-IX], carcinoembryonic antigen [CEA], hepatic growth factor receptor, epidermal growth factor receptor, epithelial membrane antigen [EMA], epithelial cell adhesion molecule [EpCAM], human epidermal growth factor receptor 2 [HER-2], urokinase plasminogen activator receptor, vascular endothelial growth factor-A [VEGF-A], and VEGF receptor 2). Immunohistochemistry was performed on tissue microarrays of LNM (n = 48), primary EACs (n = 62), fibrotic tissues (n = 11), nonmalignant lymph nodes (n = 24), and normal esophageal and gastric tissues (n = 40). Tumor marker staining was scored on intensity and percentage of positive cells. RESULTS: EMA and EpCAM showed strong expression in LNM (> 95%) and primary EACs (> 95%). Significant expression was also observed for LNM and EAC using VEGF-A (85 and 92%), CEA (68 and 54%), and CA-IX (4 and 34%). The other tumor biomarkers showed expression of 0-15% for LNM and primary EAC. Except for VEGF-A, nonmalignant lymph node staining was scored as slight or absent. CONCLUSIONS: High expression rates and correlation between LNM in EAC combined with low expression rates in healthy lymph nodes and esophagus tissues were observed for EpCAM and CEA, meaning these are promising targets for tumor-targeted imaging approaches for lymph nodes in patients with EAC.

Prediction of GTV median dose differences eases Monte Carlo re-prescription in lung SBRT.

BACKGROUND AND PURPOSE: The use of Monte Carlo (MC) dose calculation algorithm for lung patients treated with stereotactic body radiotherapy (SBRT) can be challenging. Prescription in low density media and time-consuming optimization conducted CyberKnife centers to propose an equivalent path length (EPL)-to-MC re-prescription method based on GTV median dose. Unknown at the time of planning, GTV D50% practical application remains difficult. The current study aims at creating a re-prescription predictive model in order to limit conflicting dose value during EPL optimization. MATERIAL AND METHODS: 129 patients planned with EPL algorithm were recalculated with MC. Relative GTV_D50% discrepancies were assessed and influencing parameters identified using wrapper feature selection. Based on best descriptive parameters, predictive nomogram was built from multivariate linear regression. EPL-to-MC OARs near max-dose discrepancies were reported. RESULTS: The differences in GTV_D50% (median 10%, SD: 9%) between MC and EPL were significantly (p < .001) impacted by the lesion's surface-to-volume ratio and the average relative electronic density of the GTV and the GTV's 15 mm shell. Built upon those parameters, a nomogram (R2 = 0.79, SE = 4%) predicting the GTV_D50% discrepancies was created. Furthermore EPL-to-MC OAR dose tolerance limit showed a strong linear correlation with coefficient range [0.84-0.99]. CONCLUSION: Good prediction on the required re-prescription can be achieved prior planning using our nomogram. Based on strong linear correlation between EPL and MC for OARs near max-dose, further restriction on dose constraints during the EPL optimization can be warranted. This a priori knowledge eases the re-prescription process in limiting conflicting dose value.

Preclinical uPAR-targeted multimodal imaging of locoregional oral cancer.

OBJECTIVES: Establishing adequate resection margins and lymphatic mapping are crucial for the prognosis of oral cancer patients. Novel targeted imaging modalities are needed, enabling pre- and intraoperative detection of tumour cells, in combination with improved post-surgical examination by the pathologist. The urokinase-receptor (uPAR) is overexpressed in head and neck cancer, where it is associated with tumour progression and metastasis. MATERIAL AND METHODS: To determine suitability of uPAR for molecular imaging of oral cancer surgery, human head and neck tumours were sectioned and stained for uPAR to evaluate the expression pattern compared to normal mucosa. Furthermore, metastatic oral squamous carcinoma cell line OSC-19 was used for targeting uPAR in in vivo mouse models. Using anti-uPAR antibody ATN-658, equipped with a multimodal label, the in vivo specificity was investigated and the optimal dose and time-window were evaluated. RESULTS: All human oral cancer tissues expressed uPAR in epithelial and stromal cells. Hybrid ATN-658 clearly visualized tongue tumours in mice using either NIRF or SPECT imaging. Mean fluorescent TBRs over time were 4.3±0.7 with the specific tracer versus 1.7±0.1 with a control antibody. A significant difference in TBRs could be seen between 1nmol (150µg) and 0.34nmol (50µg) dose groups (n=4, p<0.05). Co-expression between BLI, GFP and the NIR fluorescent signals were seen in the tongue tumour, whereas human cytokeratin staining confirmed presence of malignant cells in the positive cervical lymph nodes. CONCLUSION: This study shows the applicability of an uPAR specific multimodal tracer in an oral cancer model, combining SPECT with intraoperative guidance.

Commissioning Monte Carlo algorithm for robotic radiosurgery using cylindrical 3D-array with variable density inserts.

INTRODUCTION: To commission the Monte Carlo (MC) algorithm based model of CyberKnife robotic stereotactic system (CK) and evaluate the feasibility of patient specific QA using the ArcCHECK cylindrical 3D-array (AC) with Multiplug inserts (MP). RESULTS: Four configurations were used for simple beam setup and two for patient QA, replacing water equivalent inserts by lung. For twelve collimators (5-60mm) in simple setup, mean (SD) differences between MC and RayTracing algorithm (RT) of the number of points failing the 3%/1mmgamma criteria were 1(1), 1(3), 1(2) and 1(2) for the four MP configurations. Tracking fiducials were placed within AC for patient QA. Single lung insert setup resulted in mean gamma-index 2%/2mm of 90.5% (range [74.3-95.9]) and 82.3% ([66.8-94.5]) for MC and RT respectively, while 93.5% ([86.8-98.2]) and 86.2% ([68.7-95.4]) in presence of largest inhomogeneities, showing significant differences (p<0.05). DISCUSSION: After evaluating the potential effects, 1.12g/cc PMMA and 0.09g/cc lung material assignment showed the best results. Overall, MC-based model showed superior results compared to RT for simple and patient specific testing, using a 2%/2mm criteria. Results are comparable with other reported commissionings for flattening filter free (FFF) delivery. Further improvement of MC calculation might be challenging as Multiplan has limited material library. CONCLUSIONS: The AC with Multiplug allowed for comprehensive commissioning of CyberKnife MC algorithm and is useful for patient specific QA for stereotactic body radiation therapy. MC calculation accuracy might be limited due to Multiplan's insufficient material library; still results are comparable with other reported commissioning measurements using FFF beams.

[I beg your pardon? I can be treated by another modality than surgery for my vestibular schwannoma]. / Ai-je bien entendu? Je peux me faire traiter autrement que par chirurgie pour mon schwannome de l'acoustique.

The history of the treatment of vestibular schwannoma (VS) clearly shows a shift from microsurgery towards radiotherapy as "standard therapy". The microsurgical approach obviously yields excellent tumour control, but is hampered by a high morbidity rate, especially at the level of cranial nerves. The literature reports a normal facial nerve function in only 60% of patients surgically treated for VS with a maximum diameter of 25 mm. Hearing preservation is only around 15% for tumours > 15 mm and around 50% for tumours less than 15 mm. Progress in techniques and computer sciences in the field of radiotherapy provides the opportunity to reach high levels of tumour control (92 - 98%), keeping cranial nerve morbidity on a very low level (< 2%). Hearing capacity and serviceable hearing can be maintained in about 70% of cases. Based on these results, one can assume that radiation therapy should be used upfront for those benign tumours.