PurposeUrokinase-like Plasminogen Activator Receptor (uPAR) is overexpressed in a variety of carcinoma types, and therefore represents an attractive imaging target. The aim of this study was to assess the feasibility of two uPAR-targeted probes for PET and fluorescence tumor imaging in a human xenograft tongue cancer model.Experimental design and resultsTumor growth of tongue cancer was monitored by bioluminescence imaging (BLI) and MRI. Either ICG-Glu-Glu-AE105 (fluorescent agent) or 64Cu-DOTA-AE105 (PET agent) was injected systemically, and fluorescence imaging or PET/CT imaging was performed. Tissue was collected for micro-fluorescence imaging and histology. A clear fluorescent signal was detected in the primary tumor with a mean in vivo tumor-to-background ratio of 2.5. Real-time fluorescence-guided tumor resection was possible, and sub-millimeter tumor deposits could be localized. Histological analysis showed co-localization of the fluorescent signal, uPAR expression and tumor deposits. In addition, the feasibility of uPAR-guided robotic cancer surgery was demonstrated. Also, uPAR-PET imaging showed a clear and localized signal in the tongue tumors.ConclusionsThis study demonstrated the feasibility of combining two uPAR-targeted probes in a preclinical head and neck cancer model. The PET modality provided preoperative non-invasive tumor imaging and the optical modality allowed for real-time fluorescence-guided tumor detection and resection. Clinical translation of this platform seems promising.

There is an increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the western world due to human papillomavirus (HPV). According to the Danish Head and Neck Cancer Group guidelines, the current recommended treatment of patients with OPSCC in Denmark is primary radiation therapy (RT) with or without concomitant chemotherapy. This is the first study in Scandinavia from a head and neck cancer centre that aims to demonstrate the feasibility of performing primary transoral robotic surgery (TORS) and concurrent neck dissection for patients with early stage OPSCC. Between September 2014 and January 2016, 30 consecutive patients with clinical T1-T2, N0-N1 OPSCC underwent primary TORS and concurrent neck dissection. The patients were offered postoperative adjuvant therapy according to pathological risk parameters: pT >2, T-site margin <2 mm, pN >1 or extracapsular extension (ECE). Concomitant chemotherapy was offered to patients with the presence of ECE or involved margins. Twenty-nine patients had negative margins on T-site after primary resection. Only one patient had a close margin of 1 mm. Unilateral neck dissection was performed in 21 patients while nine patients underwent bilateral neck dissection. Due to an upstaging following surgery, 13 patients were referred to adjuvant therapy. Four of these patients received RT and two patients received concomitant chemo-radiation (CCR) therapy. Seven patients declined the recommended adjuvant therapy one of whom later developed an N-site recurrence and received salvage surgery with postoperative RT. In summary, 43% of the patients were referred to adjuvant therapy following primary surgery which was mainly due to N-site stage migration and ECE. Primary TORS and concurrent neck dissection is a safe and feasible procedure that may be an alternative to primary RT and CCR in a selected group of patients with early stage OPSCC.

The primary tumour was identified by TORS in seven of the 13 patients (54%) at the lingual tonsils. Human papillomavirus DNA and p16 were positive in all identified primary tumour specimens and in the corresponding lymph node metastases.

No abstract

Functional and QoL outcomes were compared longitudinally in a cohort of patients treated for oropharyngeal squamous cell carcinoma (OPSCC) with primary transoral robotic surgery (TORS) or radiotherapy (RT). Forty‐four patients undergoing primary TORS (n = 31) or RT (n = 13) for any stage OPSCC were included. Only low‐stage disease was treated with TORS. Functional outcomes were: salivary flow rate, image‐based swallowing function, and a self‐reported 10‐point scale comparing current swallowing function to baseline (CvB scale). QoL was assessed with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ‐C30), Head & Neck Module (EORTC QLQ‐HN35), and MD Anderson Dysphagia Inventory (MDADI). Shoulder impairment was assessed with Neck Dissection Impairment Index (NDII) and Oxford Shoulder Score (OSS). In the RT group, salivary flow rates had significantly declined at 12‐month follow‐up, with the biggest declines in QoL subscale scores recorded in the RT group for dry mouth and sticky saliva. Swallowing function on imaging studies was overall good, with no severe dysphagia within 1 year although, both treatment groups showed significant deterioration relative to baseline at the 12‐month follow‐up with increased DIGEST scores and pharyngeal retention. Shoulder impairment was rare at 1 year in both groups. A comprehensive examination of this cohort treated for OPSCC showed overall good functional and QoL outcomes 1 year after treatment. However, persistent impairment was seen in both groups with regards to swallowing function. In the TORS group, at 12‐months follow‐up, the QoL questionnaires showed worse scores in only one subscale (sticky saliva).

With an optimized analgesia regime TORS for OPSCC can be performed with postoperative pain levels comparable to bilateral tonsillectomy in adults.

No abstract

Pancreatic cancer remains one of the deadliest cancers. The five-year survival rates have been reported as 3%. Radical surgical tumor resection is critical for improved outcome and the low survival rate for pancreatic cancer is due to lack of other effective treatments and here optical guided surgery could be a solution for better surgical outcome. In the present study, we targeted the urokinase plasminogen activator receptor (uPAR) with a peptide conjugated with the fluophore ICG (ICG-Glu-Glu-AE105) for optical imaging. In the first part of the study we aimed to validate ICG-Glu-Glu-AE105 for resection of the primary tumor and metastases in an orthotopic human xenograft pancreatic cancer model. In the second part of the study we aimed to investigate if fluorescent-guided imaging could locate additional metastases following conventional removal of metastasis under normal white light surgery.Our study showed that ICG-Glu-Glu-AE105 was an excellent probe for intraoperative optical imaging with a mean tumor-to-background ratio (TBR) for the primary tumor of 3.5 and a TBR for the metastases of 3.4. Further, a benefit using intraoperative fluorescent guidance yielded identification of an additional 14% metastases compared to using normal white light surgery. In 4 of 8 mice there were identified additional metastases with uPAR optical imaging compared to white light.In conclusion, the uPAR-targeted optical probe ICG-Glu-Glu-AE105 enables intraoperative optical cancer imaging, including robotic surgery, and may be a benefit during intended radical resection of disseminated pancreas cancer by finding more metastasis than with traditional white light surgery.