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In penile squamous cell carcinoma (pSCC), primary surgery aims to obtain oncologically safe margins while minimizing mutilation. Surgical guidance provided by receptor-specific tracers could potentially improve margin detection and reduce unnecessary excision of healthy tissue.Here, we present the first results of a prospective feasibility study for real-time intraoperative visualization of pSCC using a fluorescent mesenchymal-epithelial transition factor (c-MET) receptor targeting tracer (EMI-137). MethodsEMI-137 tracer performance was initially assessed ex vivo (N=10) via incubation of freshly excised pSCC in a solution containing EMI-137 (500 nM). The in vivo potential of c-MET targeting and intraoperative tumour visualization was assessed after intravenous administration of EMI-137 in five pSCC patients scheduled for surgical resection using a Cyanine-5 (Cy5) fluorescence camera.Fluorescence imaging results were related to standard pathological tumour evaluation and c-MET immunohistochemistry. Three of the five in vivo patients also underwent a sentinel node resection after local administration of the hybrid tracer indocyanine green (ICG)-99m Tcnanocolloid, which could be imaged using a near-infrared fluorescence camera. ResultsNo tracer-related adverse events were encountered. Both ex vivo and in vivo, EMI-137 enabled c-MET based tumour visualization in all patients. Histopathological analyses showed that all pSCC's expressed c-MET, with expression levels of ≥70% in 14/15 patients. Moreover, the highest c-MET 4 4 expression levels were seen on the outside rim of the tumours, and a visual correlation was found between c-MET expression and fluorescence signal intensity. No complications were encountered when combining primary tumour targeting with lymphatic mapping. As such, simultaneous use of Cy5 and ICG in the same patient proved to be feasible. ConclusionFluorescence imaging of c-MET receptor-expressing pSCC tumours after intravenous injection of EMI-137 was shown to be feasible and can be combined with fluorescence-based lymphatic mapping. This combination is unique and paves the way towards further development of this surgical guidance approach.

3 Background: Patients (Pts) with advanced squamous cell carcinoma of the penis (aPeCa) have a poor prognosis (21% 2-year overall survival from moment of diagnosis) and high morbidity, due to progressive locoregional disease. Pre-clinical studies show high rates of infiltrating immune cells and high PD-L1 expression, suggesting that immunotherapy may be beneficial for these patients. In the PERICLES study, we assess the activity of atezolizumab (atezo) in aPeCa pts, with or without radiotherapy (RT) to control locoregional lymph node disease. Methods: A single-centre phase 2 study with two treatment arms (non-randomized) was conducted in 32 histologically confirmed aPeCa pts with a WHO performance status of 0-1 (NCT03686332). Any previous treatment except for immunotherapy was allowed. Study treatment consisted of atezo 1200 mg every 3 weeks (all pts). Pts expected to benefit from RT for locoregional disease control (cohort A) additionally received 33 fractions of 1.5 Gy (locoregional affected lymph node regions and penile region) and 1.8 Gy (macroscopic tumor + margin) irradiation. Response was evaluated with 12-weekly CT scans of the abdomen and thorax using RECIST1.1. Toxicity was scored by NCI-CTCAE V4. The primary endpoint was 1-year progression free survival (PFS) for the full cohort. Results: From Oct 2018 to Aug 2021, 20 pts were included in cohort A (RT + atezo) and 12 pts in cohort B (only atezo). Median follow-up was 22 months (interquartile range (IQR) 4.3-14). Median age was 67 years (IQR 60-72) and all patients had stage IV aPeCa. Pts received no prior treatment (25%), or prior RT (34%), chemoradiation (22%), chemotherapy (6%) or surgery (69%). An immunotherapy or radiotherapy-related grade 3-4 AE was observed in 3/32 (9.4%) and 1/20 (5.0%) patients, respectively. There were no grade 5 treatment-related AEs. One-year PFS was 12% (95% confidence interval (CI) 4.0-33), which did not meet the primary objective. The response rate of RECIST1.1 evaluable pts was 30% (see table). In two patients with pulmonary metastases, a complete response was observed. Initial responses with early progression were seen in 5 pts. Median overall survival (OS) was 12 months (95% CI 5.4-19). Conclusions: Anti-tumor activity of atezo was observed in aPeCa, including complete and durable responses. The trial failed to meet its primary objective (PFS). Our results suggest that a subset of aPeCa pts has incomplete immunological activity and/or early resistance to atezo. Analysis of tumor tissue collected in this trial (including on-treatment biopsies) could suggest new therapeutic strategies to overcome resistance and improve clinical outcome to immunotherapy in aPeCa. Clinical trial information: NCT03686332. [Table: see text]

LC metrics based on the methods of Zhang et al. and Billeter et al. predicted mortality in trauma patients, and their prognostic value did not differ between patients with and without TBI. However, initial lactate value was equally prognostic as these LC metrics. Our findings suggest that a single initial lactate measurement may be a more clinically useful tool to predict mortality than the calculation of lactate clearance.