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Purpose: Metastatic breast cancer is the second leading cause of cancer-related death in women. The 5-year survival rate for metastatic breast cancer has remained near 26.9 % for over a decade. The recruitment of hematopoietic stem cells with high expression of the vascular endothelial growth factor receptor 1 (VEGFR-1) has been implicated in early stages of metastasis formation. We propose the use of an 18F-labeled single-chain version of VEGF121, re-engineered to be selective for VEGFR-1 (scVR1), as a positron emission tomography (PET) imaging agent to non-invasively image early-stage metastases.Procedures: scVR1 was 18F-labeled via a biorthogonal click reaction between site-specifically trans-cyclooctene functionalized scVR1 and an Al18F labeled tetrazine-NODA (1,4,7-triazacyclononane-1,4-diiacetic acid). The [18F]AlF-NODA-scVR1 was purified using a PD10 column and subsequently analyzed on HPLC to determine radiochemical purity. Animal experiments were performed in 6-8-week-old female BALB/c mice bearing orthotopic primary 4T1 breast tumors or 4T1 metastatic lesions. The [18F]AlF-NODA-scVR1 tracer was administered via tail vein injection; PET imaging and ex vivo analysis was performed 2 h post-injection.Results: The [18F]AlF-NODA-scVR1 was prepared with a 98.2 ± 1.5 % radiochemical purity and an apparent molar activity of 7.5 ± 1.2 GBq/μmol. The specific binding of scVR1 to VEGFR-1 was confirmed via bead-based assay. The ex vivo biodistribution showed tumor uptake of 3.5 ± 0.5 % ID/g and was readily observable in PET images. Metastasis formation was detected with [18F]AlF-NODA-scVR1 tracer showing colocalization with bioluminescent imaging as well as ex vivo autoradiography and immunofluorescent staining of VEGFR-1.Conclusions: The diagnostic capabilities of the [18F]AlF-NODA-scVR1 PET tracer was confirmed in both orthotopic and metastatic murine cancer models. These results support the potential use of [18F]AlF-NODA-scVR1 as a PET tracer that could image metastases, providing clinicians with an additional tool to assess a patient's need for adjuvant therapies. [ABSTRACT FROM AUTHOR]

Introduction: Surgical resection is the standard of care for Oral Squamous Cell Carcinoma (OSCC) and the surgeon's ability to secure negative resection margins is associated with a reduced risk of local recurrence and improved survival rates.(1) Optimal functional outcomes are dependent on the balance between adequate surgical resection for complete removal of cancer and preservation of normal tissue to preserve essential functions such as swallowing, speaking, and breathing. Currently, histopathologic examination of the surgical resection specimen is the gold standard for margin assessment, yet it is time consuming and does not allow the surgeon intraoperative modification of the resection. Intraoperative frozen section is widely used but has significant limitations.(2) There is therefore a need for novel intraoperative imaging tools that can rapidly assess margin status by comprehensive examination of the excised surgical specimen in the operating room. Objective: Our team has explored the applications of PARPi-FL for molecular imaging of several cancers including OSCC.(3) PARPi-FL is a small molecule that targets poly-ADP ribose polymerase 1 (PARP1), an enzyme involved in DNA damage. We hypothesize that PARPi-FL is able to differentiate tumor cells from adjoining benign tissue in surgical specimens of OSCC and therefore, would be a rapid and reliable method of intra-operative margin assessment during surgery. In this pilot study, our aim was to analyze the fluorescence signal of PARPi-FL in tumor versus marginal normal tissue after topical application in OSCC specimens immediately after surgical resection. Methods: Previously untreated patients undergoing definitive surgery as their primary therapy for OSCC were eligible for the study (IRB 20-422). Immediately after surgical resection, the fresh surgical specimen (tumor and surrounding tissue) was submerged en bloc in 100mL of a solution containing 1,000nM of PARPi-FL in 30% PEG/PBS. Mucosal margins were imaged using a Quest Spectrum imaging device with an endoscopic camera and a PARPi-FL optimized LED-filter system, testing three different exposure times (30ms, 60ms, and 80ms). The specimen was then sectioned by the study pathologist per standard of care, and the sectioned specimen was imaged again after submersion in PARPi-FL to study depth of infiltration. Biopsies of the transition between margins and tumor were performed to compare the fluorescence imaging results with the standard H&E, and PARP1 expression on immunohistochemistry (IHC), and fluorescence imaging. All fluorescent images were analyzed in ImageJ by quantifying the average radiant efficiency of the PARPi-FL signal in regions of interest placed in tumor and normal tissue. For the statistical analysis, a GEE model was used to determine the association between uptake values and tissue, exposure time, and section (surface vs depth). Results: In the preliminary analysis of 8 patients of this ongoing study we observed a tumor mucosa fluorescence in average 2.85 times higher than in normal, adjusting for section and exposure time (p<0.001). Analyzing the IHC and H&E slides on tumor sections, we could confirm higher levels of PARP1 expression in the tumor areas, aligning with the higher fluorescent signals observed on the QUEST images (Figure 1). A major advantage of our method is that we were able to study wide areas of interest on the ex vivo specimens, including the evident malignant tissue and transition to normal tissue. Conclusion: PARPi-FL based ex vivo molecular imaging of surgically resected specimens holds promise for rapid and comprehensive intraoperative assessment of surgical margins in OSCC. [ABSTRACT FROM AUTHOR]

Background: Segmental mandibulectomy impairs health‐related quality of life (QoL), by altering speech, mastication, swallowing, and facial aesthetics. Fibula free flap (FFF) used for mandible reconstruction is known to improve outcomes; however, minimal information exists in the literature regarding patient‐reported outcomes. We aim to assess how current studies evaluate patient perception following segmental mandibulectomy and FFF mandible reconstruction. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines, a search was conducted for publications involving FFF mandible reconstruction from 2005 to 2017 using PubMed, Cochrane, EMBASE, Web of Science, and PsychInfo. Results: Of 2212 articles identified initially, only 7 studies were deemed suitable. Six studies used the University of Washington Quality of Life questionnaire, 3 Oral Health Impact Profile, and 1 used European Organization for Research and Treatment of Cancer Head and Neck (EORTC‐H&N35). Conclusions: There is a paucity of information in published reports on QoL outcomes following mandible reconstruction with FFF. In the era of patient‐centered health care, observations warrant attention from researchers for physician‐assessed patient‐reported measures to factor in QoL expectation during surgical decision‐making about the choice of reconstruction. [ABSTRACT FROM AUTHOR]

Surgeries and trauma result in traumatic and iatrogenic nerve damage that can result in a debilitating condition that approximately affects 189 million individuals worldwide. The risk of nerve injury during oncologic surgery is increased due to tumors displacing normal nerve location, blood turbidity, and past surgical procedures, which complicate even an experienced surgeon's ability to precisely locate vital nerves. Unfortunately, there is a glaring absence of contrast agents to assist surgeons in safeguarding vital nerves. To address this unmet clinical need, we leveraged the abundant expression of the voltage-gated sodium channel 1.7 (Na V 1.7) as an intraoperative marker to access peripheral nerves in vivo , and visualized nerves for surgical guidance using a fluorescently-tagged version of a potent Na V 1.7-targeted peptide, Tsp1a, derived from a Peruvian tarantula. We characterized the expression of Na V 1.7 in sensory and motor peripheral nerves across mouse, primate, and human specimens and demonstrated universal expression. We synthesized and characterized a total of 10 fluorescently labeled Tsp1a-peptide conjugates to delineate nerves. We tested the ability of these peptide-conjugates to specifically accumulate in mouse nerves with a high signal-to-noise ratio in vivo . Using the best-performing candidate, Tsp1a-IR800, we performed thyroidectomies in non-human primates and demonstrated successful demarcation of the recurrent laryngeal and vagus nerves, which are commonly subjected to irreversible damage. The ability of Tsp1a to enhance nerve contrast during surgery provides opportunities to minimize nerve damage and revolutionize standards of care across various surgical specialties., Competing Interests: Competing Interests T.R. and J.S.L are shareholders of Summit Biomedical Imaging, LLC. T.R. is a paid consultant for Theragnostics, Inc. T.R. is now an employee of and a shareholder of Evergreen Theragnostics. All other authors have no conflict to declare. This arrangement has been reviewed and approved by MSK in accordance with its conflict-of-interest policies. P.D.S.M., J.G, J.S.L., T.R., Y.J., and G.F.K. are co-inventors on a US patent describing the Tsp1a peptide.