Lindsay Scott Moore, MD

All Publications

• Comparing the Outcomes of Osteocutaneous Radial Forearm and Fibula Free Flaps in the Reconstruction of Mandibular Osteoradionecrosis. Microsurgery Al Afif, A., Peña-Garcia, A., Thomas, C. M., Kain, J. J., Grayson, J. W., Tipirneni, K. E., Moore, L. S., Jeyarajan, H., Sweeny, L., Clemons, L., Rosenthal, E. L., Greene, B. J. 2024; 44 (7): e31243

  Abstract

  This study compares the outcomes of osteocutaneous radial forearm free flap (OC-RFFF) and fibula free flap (FFF) reconstruction of mandibular osteoradionecrosis (ORN).Retrospective review of patients undergoing OC-RFFF/FFF reconstruction for mandible ORN between 2005 and 2020 at a tertiary center. Patient characteristics, postoperative complications, and functional outcomes were evaluated using chi-squared and logistic regression analysis.Fifty-six patients were included (OC-RFFF: 38; FFF: 18). Significantly more OC-RFFF patients had lateral mandible defects (94% vs. 61%, p = 0.0014). There were significantly more patients with exposed intraoral bone in the OC-RFFF group (23% vs. 0% p = 0.02), but no significant differences in hardware complications or flap failure. Donor site partial skin graft loss was more common in the FFF group (22% vs. 2.6%, p = 0.016), but no other significant differences in donor site morbidity were seen. Bivariable analysis showed no impact of flap type, tobacco/alcohol use, diabetes, or hypothyroidism on postoperative complications. Sixty percent of OC-RFFF, and 67% of FFF, patients resumed an oral diet after surgery. Oral diet was not impacted by flap type (OR = 0.769, 95% CI = 0.201-2.706, p = 0.688).The OC-RFFF is an acceptable option in the reconstruction of ORN involving the lateral mandible, though there is increased risk of bone exposure. These findings can help guide surgeon selection of microvascular free flap donor sites and appropriate patient counseling.

  View details for DOI 10.1002/micr.31243

  View details for PubMedID 39415549

• Predicting outcomes in head and neck surgery with modified frailty index and surgical apgar scores. Oral oncology Al Afif, A., Rosen, P., Gardella, J., Norwood, T. G., Abbas, A., Moore, L. S., Grayson, J. W., Day, K. E., Prince, A. C., Greene, B. J., Carroll, W. R., Bae, S. 2024; 159: 107045

  Abstract

  To compare the efficacy of the Modified Frailty Index and Modified Surgical Apgar scores in predicting postoperative outcomes in head and neck cancer patients.We retrospectively reviewed patients who underwent major head and neck surgery between 2012 and 2015. Modified Surgical Apgar, and Frailty Index, scores were calculated on 723 patients. The primary outcome was 30-day complication and/or mortality.The mean Modified Frailty Index was 0.11 ± 0.12, and mean Modified Surgical Apgar score was 6.15 ± 1.67. Both scores were significantly associated with 30-day complication (P<0.05). The Modified Surgical Apgar score was superior to the Modified Frailty Index in predicting complications (Area Under the Curve (AUC) = 0.76; 95 % Confidence Interval (CI), 0.722-0.793; and AUC=0.59; 95 % CI, 0.548-0.633, respectively). Concurrent use of both scoring systems (AUC=0.77) was not superior to individual use. An increase in the mFI from 0.27 to 0.36 was associated with an increase in the risk of complication postoperatively (Odds Ratio (OR) = 3.67; 95 % CI, 1.30-10.34, P=.014). A reduction in the mSAS from 7 to 6 increased the risk of complication following surgery (OR=2.64; 95 % CI, 1.45-4.80; P=.002).Both scores are useful in risk stratifying head and neck cancer patients. The Modified Surgical Apgar score was superior at predicting complications; concurrent use of both scores added minimal benefit.

  View details for DOI 10.1016/j.oraloncology.2024.107045

  View details for PubMedID 39332273

• Interim Phase II Results Using Panitumumab-IRDye800CW during Transoral Robotic Surgery in Patients with Oropharyngeal Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Stone, L. D., Kasten, B. B., Rao, S., Gonzalez, M. L., Stevens, T. M., Lin, D., Carroll, W., Greene, B., Moore, L. S., Fuson, A., James, S., Hartman, Y. E., McCammon, S., Panuganti, B., Nabell, L. M., Li, Y., Li, M., Bailey, L., Rosenthal, E. L., Jeyarajan, H., Thomas, C. M., Warram, J. M. 2024; 30 (18): 4016-4028

  Abstract

  The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has continually increased during the past several decades. Using transoral robotic surgery (TORS) significantly improves functional outcomes relative to open surgery for OPSCC. However, TORS limits tactile feedback, which is often the most important element of cancer surgery. Fluorescence-guided surgery (FGS) strategies to aid surgeon assessment of malignancy for resection are in various phases of clinical research but exhibit the greatest potential impact for improving patient care when the surgeon receives limited tactile feedback, such as during TORS. Here, we assessed the feasibility of intraoperative fluorescence imaging using panitumumab-IRDye800CW (PAN800) during TORS in patients with OPSCC.Twelve consecutive patients with OPSCC were enrolled as part of a nonrandomized, prospective, phase II FGS clinical trial using PAN800. TORS was performed with an integrated robot camera for surgeon assessment of fluorescence. Intraoperative and ex vivo fluorescence signals in tumors and normal tissue were quantified and correlated with histopathology.Intraoperative robot fluorescence views delineated OPSCC from normal tissue throughout the TORS procedure (10.7 mean tumor-to-background ratio), including in tumors with low expression of the molecular target. Tumor-specific fluorescence was consistent with surgeon-defined tumor borders requiring resection. Intraoperative robot fluorescence imaging revealed an OPSCC fragment initially overlooked during TORS based on brightfield views, further substantiating the clinical benefit of this FGS approach.The results from this patient with OPSCC cohort support further clinical assessment of FGS during TORS to aid resection of solid tumors.

  View details for DOI 10.1158/1078-0432.CCR-24-0940

  View details for PubMedID 39012279

  View details for PubMedCentralID PMC11398989

• Single-cell transcriptomic atlas reveals increased regeneration in diseased human inner ear balance organs. Nature communications Wang, T., Ling, A. H., Billings, S. E., Hosseini, D. K., Vaisbuch, Y., Kim, G. S., Atkinson, P. J., Sayyid, Z. N., Aaron, K. A., Wagh, D., Pham, N., Scheibinger, M., Zhou, R., Ishiyama, A., Moore, L. S., Maria, P. S., Blevins, N. H., Jackler, R. K., Alyono, J. C., Kveton, J., Navaratnam, D., Heller, S., Lopez, I. A., Grillet, N., Jan, T. A., Cheng, A. G. 2024; 15 (1): 4833

  Abstract

  Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.

  View details for DOI 10.1038/s41467-024-48491-y

  View details for PubMedID 38844821

• Salvage Microsurgery Following Failed Primary Radiosurgery in Sporadic Vestibular Schwannoma. JAMA otolaryngology-- head & neck surgery Marinelli, J. P., Herberg, H. A., Moore, L. S., Yancey, K. L., Kay-Rivest, E., Casale, G. G., Durham, A., Khandalavala, K. R., Lund-Johansen, M., Kosaraju, N., Lohse, C. M., Patel, N. S., Gurgel, R. K., Babu, S. C., Golfinos, J. G., Roland, J. T., Hunter, J. B., Kutz, J. W., Santa Maria, P. L., Link, M. J., Tveiten, Ø. V., Carlson, M. L. 2024

  Abstract

  Management of sporadic vestibular schwannoma with radiosurgery is becoming increasingly common globally; however, limited data currently characterize patient outcomes in the setting of microsurgical salvage for radiosurgical failure.To describe the clinical outcomes of salvage microsurgery following failed primary stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) among patients with sporadic vestibular schwannoma.This was a cohort study of adults (≥18 years old) with sporadic vestibular schwannoma who underwent salvage microsurgery following failed primary SRS/FSRT in 7 vestibular schwannoma treatment centers across the US and Norway. Data collection was performed between July 2022 and January 2023, with data analysis performed between January and July 2023.Salvage microsurgical tumor resection.Composite outcome of undergoing less than gross total resection (GTR) or experiencing long-term facial paresis.Among 126 patients, the median (IQR) age at time of salvage microsurgery was 62 (53-70) years, 69 (55%) were female, and 113 of 117 (97%) had tumors that extended into the cerebellopontine angle at time of salvage. Of 125 patients, 96 (76%) underwent primary gamma knife SRS, while 24 (19%) underwent linear accelerator-based SRS; the remaining patients underwent FSRT using other modalities. Postoperative cerebrospinal fluid leak was seen in 15 of 126 patients (12%), hydrocephalus in 8 (6%), symptomatic stroke in 7 (6%), and meningitis in 2 (2%). Each 1-mm increase in cerebellopontine angle tumor size was associated with a 13% increased likelihood of foregoing GTR (64 of 102 patients [63%]) or long-term postoperative House-Brackmann grade higher than I (48 of 102 patients [47%]) (odds ratio, 1.13; 95% CI, 1.04-1.23). Following salvage microsurgery, tumor growth-free survival rates at 1, 3, and 5 years were 97% (95% CI, 94%-100%), 93% (95% CI, 87%-99%), and 91% (95% CI, 84%-98%), respectively.In this cohort study, more than half of patients who received salvage microsurgery following primary SRS/FSRT underwent less than GTR or experienced some degree of facial paresis long term. These data suggest that the cumulative risk of developing facial paresis following primary SRS/FSRT by the end of the patient's journey with treatment approximates 2.5% to 7.5% when using published primary SRS/FSRT long-term tumor control rates.

  View details for DOI 10.1001/jamaoto.2023.4474

  View details for PubMedID 38358763

  View details for PubMedCentralID PMC10870221

• Sporadic vestibular schwannoma in a pediatric population: a case series. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery Kosaraju, N., Moore, L. S., Mulders, J. Y., Blevins, N. H. 2023

  Abstract

  PURPOSE: To describe the characteristics, management, and outcomes of pediatric patients with sporadic vestibular schwannoma (sVS).METHODS: This was a case series at a tertiary care center. Patients were identified through a research repository and chart review. Interventions were microsurgery, stereotactic radiosurgery (SRS), and observation. Outcome measures were tumor control, facial nerve function, and hearing.RESULTS: Eight patients over 2006-2022 fulfilled inclusion criteria (unilateral VS without genetic or clinical evidence of neurofibromatosis type 2 (NF2); age≤21) with a mean age of 17years (14-20). Average greatest tumor length in the internal auditory canal was 9.7mm (4.0-16.1). Average greatest tumor dimension (4/8 tumors) in the cerebellopontine angle was 19.1mm (11.3-26.8). Primary treatment was microsurgery in five (62.5%) patients, observation in two (25%), and SRS in one (12.5%). Four (80%) surgical patients had gross total resections, and one (20%) had regrowth post-near total resection and underwent SRS. One observed patient and the primary SRS patient have remained radiographically stable for 3.5 and 7years, respectively. The other observed patient required surgery for tumor growth after 12months of observation. Two surgical patients had poor facial nerve outcomes. All post-procedural patients developed anacusis. Mean follow-up was 3years (0.5-7).CONCLUSIONS: We describe one of the largest reported cohorts of pediatric sVS in the USA. Diligent exclusion of NF2 is critical. Given the high likelihood of eventually requiring intervention and known adverse effects of SRS, microsurgery remains the preferred treatment. However, observation can be considered in select situations.

  View details for DOI 10.1007/s00381-023-06184-9

  View details for PubMedID 37889276

• Promoting Surgeon-Scientists in Otolaryngology-Head and Neck Surgery-From Bench to Bedside. JAMA otolaryngology-- head & neck surgery Kosaraju, N., Keating, D. P., Kim, G. S., Moore, L. S., Stankovic, K. M. 2023

  Abstract

  Surgeon-scientists (defined as principal investigators [PIs] with a Doctor of Medicine [MD] degree or a combined MD and Doctor of Philosophy [PhD] degree) in otolaryngology-head and neck surgery (OHNS) are imperative for achieving clinical translation in the OHNS field.To (1) raise awareness about the current state of surgeon-scientists in OHNS, (2) contextualize the landscape of surgeon-scientists in OHNS by comparing it to those of neurosurgery and ophthalmology, and (3) identify strategies for attracting and retaining surgeon-scientists in OHNS.Research funding data from fiscal years 2015 to 2021 among surgeon-scientists in OHNS, neurosurgery, and ophthalmology were obtained from the National Institutes of Health (NIH) Research Portfolio Online Reporting Tools Expenditures and Results and the US Department of Defense (DOD) Congressionally Directed Medical Research Programs awards database. The Association of American Medical Colleges provided the total number of active physicians in each specialty per year and the number and percentage of residents with an MD-PhD degree in each specialty per year. Cohen d was used to express the standardized value of the magnitude of the mean difference between compared groups.From 2015 to 2021, on average, there were 9566 active physicians in OHNS, 5559.8 in neurosurgery, and 18908.8 in ophthalmology. In OHNS, a greater number of NIH K (research career development) grants were held by surgeon-scientists than by PIs with a PhD degree (21.4 vs 5.1; mean difference, 16.3; 95% CI, 14.3-18.3; Cohen d = 9.6), whereas most NIH R (research) and U (cooperative agreement) grants (144.1 vs 81.6; mean difference, 62.6; 95% CI, 46.3-78.9; Cohen d = 4.5) and DOD grants (9.9 vs 4.1; mean difference, 5.7; 95% CI, 1.0-10.4; Cohen d = 1.4) were held by PIs with a PhD degree. In a comparison of OHNS to neurosurgery and ophthalmology, after the number of R and U grants was scaled by the number of physicians in each field, neurosurgery had a much greater number of grants per surgeon than OHNS (0.02 vs 0.01; mean difference, 0.01; 95% CI, 0.01-0.02; Cohen d = 4.2). Additionally, neurosurgeons received a much larger R and U grant amount per physician than otolaryngologists ($10 630.20 vs $4511.80; mean difference, $6118.40; 95% CI, $2625.90-$9610.80; Cohen d = 2.0). For the R and U grant metrics, there were no meaningful differences between OHNS and ophthalmology.Results of this database study showed that from 2015 to 2021, the number of governmental grants held by surgeon-scientists in OHNS increased, but there is room for improvement given the metrics of neurosurgeons, a population smaller than otolaryngologists. Possible strategies include intramural research grants, surgeon-scientist training programs, and partnerships between specialty societies and NIH administering institutes and centers.

  View details for DOI 10.1001/jamaoto.2023.3353

  View details for PubMedID 37856105

• The Future of Vestibular Schwannoma Management. Otolaryngologic clinics of North America Moore, L. S., Stankovic, K. M. 2023

  Abstract

  The future of the management of both sporadic and neurofibromatosis type 2-asscoiated vestibular schwannomas (VSs) will be shaped by cutting-edge technologic and biomedical advances to enable personalized, precision medicine. This scoping review envisions the future by highlighting the most promising developments published, ongoing, planned, or potential that are relevant for VS, including integrated omics approaches, artificial intelligence algorithms, biomarkers, liquid biopsy of the inner ear, digital medicine, inner ear endomicroscopy, targeted molecular imaging, patient-specific stem cell-derived models, ultra-high dose rate radiotherapy, optical imaging-guided microsurgery, high-throughput development of targeted therapeutics, novel immunotherapeutic strategies, tumor vaccines, and gene therapy.

  View details for DOI 10.1016/j.otc.2023.02.018

  View details for PubMedID 37019772

• Mortui vivos docent: a modern revival of temporal bone plug harvests. Frontiers in neuroscience Sagi, V., Kosaraju, N., Moore, L. S., Mulders, J. Y., Solyali, M., Ma, X., Regula, D. P., Hooper, J. E., Stankovic, K. M. 2023; 17: 1242831

  Abstract

  Human temporal bones (HTBs) are invaluable resources for the study of otologic disorders and for evaluating novel treatment approaches. Given the high costs and technical expertise required to collect and process HTBs, there has been a decline in the number of otopathology laboratories. Our objective is to encourage ongoing study of HTBs by outlining the necessary steps to establish a pipeline for collection and processing of HTBs. In this methods manuscript, we: (1) provide the design of a temporal bone plug sawblade that can be used to collect specimens from autopsy donors; (2) establish that decalcification time can be dramatically reduced from 9 to 3months if ethylenediaminetetraacetic acid is combined with microwave tissue processing and periodic bone trimming; (3) show that serial sections of relatively-rapidly decalcified HTBs can be successfully immunostained for key inner ear proteins; (4) demonstrate how to drill down a HTB to the otic capsule within a few hours so that subsequent decalcification time can be further reduced to only weeks. We include photographs and videos to facilitate rapid dissemination of the developed methods. Collected HTBs can be used for many purposes, including, but not limited to device testing, imaging studies, education, histopathology, and molecular studies. As new technology develops, it is imperative to continue studying HTBs to further our understanding of the cellular and molecular underpinnings of otologic disorders.

  View details for DOI 10.3389/fnins.2023.1242831

  View details for PubMedID 37886674

• Moving to a more restrictive transfusion protocol: Outcomes in head and neck free flap surgery. American journal of otolaryngology Skoog, H., Chisolm, P., Altonji, S. J., Moore, L., Carroll, W. R., Richman, J., Greene, B., Grayson, J. W. 2022; 43 (1): 103268

  Abstract

  To determine if a more restrictive transfusion protocol results in increased rates of adverse flap outcomes in patients undergoing free tissue transfer.Mixed retrospective and prospective cohort study. Patients who underwent surgery before the protocol change were collected retrospectively. Patients who underwent surgery after the protocol change were collected prospectively.Of the 460 patients who underwent free tissue transfer, 116 patients in the pre-change cohort (N = 211) underwent transfusion (54.98%) and 78 in the post-change cohort(N = 249) (31.33%) (p < 0.001). The mean number of units transfused was 1.55 + 2.00 in the pre-change cohort, and 0.78 + 1.51 in the post-change cohort (p < 0.001). When separated temporally, the pre-change cohort received significantly more blood transfusions than the post-change cohort in the operating room (33.65% vs 18.07%) (p < 0.01), within 72 h of surgery (35.55% vs 15.66%) (p < 0.001), and after 72 h after surgery to discharge (16.59% vs 8.03%) (p = 0.018017). The rate of flap failure was 6.70% in the pre-change cohort, and 5.31% in the post-change cohort (p = 0.67). In a logistic regression model controlling for potential confounders, transfusion protocol was not significantly associated with flap failure (OR = 1.1080, 95% CI: 0.48-2.54). There were no significant differences between cohorts for medical morbidity, ICU transfer, or death.Our data support the conclusion that patients undergoing free tissue transfer to the head and neck can be transfused following the same protocols as other patients, without increasing the rate of flap failure or other morbidities.3 (mixed retrospective, prospective cohort study).

  View details for DOI 10.1016/j.amjoto.2021.103268

  View details for PubMedID 34695698

• Above and Beyond: Periorbital Suspension for Endoscopic Access to Difficult Frontal Sinus Pathology. The Laryngoscope Tilak, A., Purvis, J., Peña-Garcia, A., Moore, L., Cho, D. Y., Grayson, J. W., Woodworth, B. A. 2022; 132 (3): 538-544

  Abstract

  The periorbital suspension (PS) is an advanced adjunctive technique performed during endoscopic approaches to frontal sinus pathology that would be too far lateral or superior to address using traditional endoscopic transnasal approaches. The objectives of this study are to characterize the utility of this technique for frontal sinus pathology, determine anatomic limitations, and assess clinical outcomes following surgical treatment.Prospective case series.Patient data including demographics, etiology, technique, complications, and clinical follow-up were collected. Preoperative computed tomography scans were reviewed for maximum lateral and superior extent of pathology, supraorbital recess height, anterio-posterior (AP) diameter of the frontal sinus, interorbital distance, and orbital-first olfactory neuron distance.The PS approach was used in 30 surgeries (29 patients) for cerebrospinal fluid leaks (n = 5), benign tumors (n = 17), malignant tumors (n = 5), allergic fungal sinusitis (n = 2), and mucocele (n = 1) between 2018 and 2020. Approaches included 15 Draf IIB and 15 Draf III frontal sinusotomies. All pathology was surgically accessible using the PS approach and there were no intraoperative or postoperative complications. Postoperative follow-up was 11.7 ± 7.6 months. Mean recorded measurements (in mm) were as follows: maximum lateral extent -15.0 ± 7.7, superior extent 21.2 ± 7.7 in surgical plane and 20.9 ± 9.8 in the vertical plane, supraorbital recess height -2.6 ± 1.9, AP frontal sinus diameter -13.2 ± 4.7, interorbital distance -29.8 ± 5.4, and orbital-olfactory neuron distance -14.8 ± 2.9.The PS technique can be safely and successfully utilized to provide endoscopic endonasal access to lateral and superior frontal sinus pathology.4 Laryngoscope, 132:538-544, 2022.

  View details for DOI 10.1002/lary.29797

  View details for PubMedID 34338319

• Predicting Schwannoma Growth in a Tumor Model Using Targeted Imaging. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology Morrison, D. R., Sorace, A. G., Hamilton, E., Moore, L. S., Houson, H. A., Udayakumar, N., Ovaitt, A., Warram, J. M., Walsh, E. M. 2021; 42 (5): e615-e623

  Abstract

  Vestibular schwannoma (VS) is a common pathology encountered in neurotology clinics. Many patients are observed with a "wait and scan" approach. Previous efforts to determine radiographic indicators of future growth have been unsuccessful. Using a mouse subcutaneous tumor model, we seek to determine if fluorescent imaging with directed immunotargets could be used to predict schwannoma growth rate.Anti-VEGFR2 and anti-Her2/Neu monoclonal antibodies were covalently linked to a near-infrared probe (IRDye800). Immunodeficient mice underwent subcutaneous injections with a rat-derived schwann (R3) cell line. When tumor growth was evident, either Anti-VEGFR2-IRDye800, anti-Her2/Neu-IRDye800, or Immunoglobulin G (IgG) Isotype-IRDye800 (control) were injected via tail vein. The mice were serially imaged in a closed field near-IR device. Fluorescent data were analyzed for tumor signal and correlated with tumor sie and growth rate. Heterogeneity of fluorescent tumor signal was also assessed.In both anti-VEGFR2 and anti-Her2/Neu groups, there were strong correlations between day 1 mean tumor fluorescence and eventual maximum tumor volume (p = 0.002, 0.001; r2 = 0.92, 0.86). There was also strong correlation with maximum tumor signal on day 1 and maximum tumor volume (p = 0.003, 0.008; r2 = 0.90, 0.91). There was no such correlation in the control group (p = 0.99, 0.75; r2 = 0.0002, 0.028).Given the potential morbidity in VS intervention, observation is an appropriate approach for patients with slow-growing or stagnant tumors. We seek to identify immunotargets in a murine model that show promise in predicting schwannoma growth with advanced imaging techniques. Both Her2/Neu and VEGFR2 correlated strongly wth tumor size and growth rates and are promising targets that merit further investigation.

  View details for DOI 10.1097/MAO.0000000000003063

  View details for PubMedID 33661237

  View details for PubMedCentralID PMC9762121

• Perioperative Pain Management Following Otologic Surgery. Otolaryngologic clinics of North America Morrison, D. R., Moore, L. S., Walsh, E. M. 2020; 53 (5): 803-810

  Abstract

  Otologic surgery involves a broad range of procedures. In general, postoperative pain from most otologic surgeries can be managed with little to no opioids, and surgeons should make a concerted effort to minimize narcotic prescriptions in the midst of the opioid crisis. Many procedures, including transcanal surgeries and even postauricular surgeries, may performed with local anesthetic in selected patients. Multimodal pain regimens, local anesthesia, and alternative approaches have shown promise in minimizing narcotic use, and should be considered. Preoperative counseling to appropriately manage expectations and goals is imperative for patient satisfaction and safety.

  View details for DOI 10.1016/j.otc.2020.05.009

  View details for PubMedID 32682533

• Comparison of Panitumumab-IRDye800CW and 5-Aminolevulinic Acid to Provide Optical Contrast in a Model of Glioblastoma Multiforme. Molecular cancer therapeutics Warram, J. M., Napier, T. S., Udayakumar, N., Jani, A. H., Hartman, Y. E., Houson, H. A., Moore, L., Amm, H. M., van den Berg, N. S., Sorace, A. G. 2020

  Abstract

  Maximal safe resection of malignant tissue is associated with improved progression-free survival and better response to radiation and chemotherapy for glioblastoma (GBM) patients. 5-aminolevulinic acid (5-ALA) is the current FDA-approved standard for intraoperative brain tumor visualization. Unfortunately, autofluorescence in diffuse areas and high fluorescence in dense tissues significantly limit discrimination at tumor margins. The present study is the first to compare 5-ALA to an investigational new drug, panitumumab-IRDye800CW, in the same animal model. A patient-derived GBM xenograft model was established in 16 nude mice, which later received injections of 5-ALA, panitumumab-IRDye800CW, IRDye800CW, 5-ALA and IRDye800CW, or 5-ALA and panitumumab-IRDye800CW. Brains were prepared for multi-instrument fluorescence imaging, immunohistochemistry, and quantitative analysis of tumor-to-background ratio (TBR) and tumor margin accuracy. Statistical analysis was compared with Wilcoxon rank-sum or paired t-test. Panitumumab-IRDye800CW had a 30% higher comprehensive TBR compared to 5-ALA (p = 0.0079). Standard deviations for core and margin regions of interest in 5-ALA-treated tissues were significantly higher than those found in panitumumab-IRDye800CW-treated tissues (p = 0.0240 and p = 0.0284, respectively). Panitumumab-IRDye800CW specificities for tumor core and margin were over 10% higher than those of 5-ALA. Higher area under the curve for panitumumab-IRDye800CW indicated strong capability to discriminate between normal and malignant brain tissue when compared to 5-ALA. This work demonstrates that panitumumab-IRDye800CW shows potential as a targeting agent for fluorescent intraoperative detection of GBM. Improved margin definition and surgical resection using panitumumab-IRDye800 has the potential to improve surgical outcomes and survival in GBM patients compared to 5-ALA.

  View details for DOI 10.1158/1535-7163.MCT-19-0819

  View details for PubMedID 32606015

• Fluorescently Labeled Cetuximab-IRDye800 for Guided Surgical Excision of Ameloblastoma: A Proof of Principle Study. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons Morlandt, A. B., Moore, L. S., Johnson, A. O., Smith, C. M., Stevens, T. M., Warram, J. M., MacDougall, M. n., Rosenthal, E. L., Amm, H. M. 2020

  Abstract

  Fluorescently labeled epidermal growth factor receptor (EGFR) antibodies have successfully identified microscopic tumors in multiple in vivo models of human cancers with limited toxicity. The present study sought to demonstrate the ability of fluorescently labeled anti-EGFR, cetuximab-IRDye800, to localize to ameloblastoma (AB) tumor cells in vitro and in vivo.EGFR expression in AB cells was confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry. Primary AB cells were labeled in vitro with cetuximab-IRDye800 or nonspecific IgG-IRDye800. An in vivo patient-derived xenograft (PDX) model of AB was developed. The tumor tissue from 3 patients was implanted subcutaneously into immunocompromised mice. The mice received an intravenous injection of cetuximab-IRDye800 or IgG-IRDye800 and underwent imaging to detect infrared fluorescence using a Pearl imaging system (LI-COR Biosciences, Lincoln, NE). After resection of the overlying skin, the tumor/background ratios (TBRs) were calculated and statistically analyzed using a paired t test.EGFR expression was seen in all AB samples. Tumor-specific labeling was achieved, as evidenced by a positive fluorescence signal from cetuximab-IRDye800 binding to AB cells, with little staining seen in the negative controls treated with IgG-IRDye800. In the animal PDX model, imaging revealed that the TBRs produced by cetuximab were significantly greater than those produced by IgG on days 7 to 14 for AB-20 tumors. After skin flap removal to simulate a preresection state, the TBRs increased with cetuximab and were significantly greater than the TBRs with the IgG control for PDX tumors derived from the 3 patients with AB. The excised tissues were embedded in paraffin and examined to confirm the presence of tumor.Fluorescently labeled anti-EGFR demonstrated specificity for AB cells and PDX tumors. The present study is the first report of tumor-specific, antibody-based imaging of odontogenic tumors, of which AB is one of the most clinically aggressive. We expect this technology will ultimately assist surgeons treating AB by helping to accurately assess the tumor margins during surgery, leading to improved long-term local tumor control and less surgical morbidity.

  View details for DOI 10.1016/j.joms.2020.05.022

  View details for PubMedID 32554066

• Angiosarcoma of the Temporal Bone: Case Report and Review of the Literature. World neurosurgery Bernstock, J. D., Shafaat, O., Hardigan, A., Fox, B. M., Moore, L. S., Chagoya, G., Elsayed, G., Gessler, F., Ilyas, A., Yamashita, D., McGrew, B., Fisher, W. S., Hackney, J., Sotoudeh, H. 2019; 130: 351-357

  Abstract

  Angiosarcomas are rare malignant tumors of endothelial origin. Nearly one half of all angiosarcomas occur in the head and neck. Temporal bone angiosarcomas are extremely uncommon. We present a case of temporal bone angiosarcoma and a review of the relevant data.We present the case of a 20-year-old man with a painful right postauricular mass after a closed head injury. Radiologic studies demonstrated a large right osteolytic and heterogeneously enhancing mass. The patient underwent right transpetrosal craniectomy for resection. Histologic studies confirmed high-grade sarcoma. Immunohistochemical staining demonstrated a uniformly positive ERG endothelial marker, CD31 staining with cytoplasmic and membranous patterns of immunopositivity, positive nuclear staining for FLI-1, positive cytoplasmic and membranous staining for CD99 and STAT6, and negative smooth muscle actin stains in the neoplastic cells. Ki-67 staining showed ∼94% positivity in the neoplastic cell nuclei. Postoperative follow-up imaging studies demonstrated evidence of metastatic right cervical lymphadenopathy.Angiosarcoma of the temporal bone is extremely uncommon. In the present case report, we explored a relationship between trauma and angiosarcoma of the temporal bone. We reviewed the reported data regarding the pathogenesis, diagnosis, treatment, radiologic findings, and histologic characteristics of angiosarcoma of the temporal bone.

  View details for DOI 10.1016/j.wneu.2019.07.107

  View details for PubMedID 31330332

• Adjuvant anti-angiogenic therapy enhances chemotherapeutic uptake in a murine model of head and neck cancer(*) JOURNAL OF DRUG TARGETING Prince, A. C., Patel, N. G., Moore, L. S., McGee, A. S., Ahn, J. C., Willey, C. D., Carroll, W. R., Rosenthal, E. L., Warram, J. M. 2019; 27 (2): 193–200

  View details for DOI 10.1080/1061186X.2018.1497040

  View details for Web of Science ID 000455930900007

• Submucosal gland mucus strand velocity is decreased in chronic rhinosinusitis. International forum of allergy & rhinology Tipirneni, K. E., Zhang, S., Cho, D. Y., Grayson, J., Skinner, D. F., Mackey, C., Moore, L., Cole, D., Banks, C. G., Woodworth, B. A. 2018; 8 (4): 509-512

  Abstract

  Chronic rhinosinusitis (CRS) may be initiated by innately impaired host defense mechanisms that predispose the upper airways to infection. Recent evidence suggests tethering of submucosal gland mucus strands represents an inciting event within cystic fibrosis (CF) airways, occurring prior to onset of chronic infection. Submucosal gland hypertrophy and defective mucociliary clearance (MCC) are present in actively inflamed sinuses, but mucus strand velocity may also be affected as a secondary event, further contributing to chronic disease. The objective of this study is to assess whether mucus strand velocity is decreased in patients with CRS.Mucosal explants from patients with and without CRS were submerged in Ringer's solution mixed with fluorescent nanospheres. Methacholine was then added, and videos demonstrating strand growth and detachment were generated from a time-lapse of Z-stack images using a multiphoton confocal microscope. Dynamic mucus strands were identified and individual velocities quantified with the MTrackJ plug-in of ImageJ.Fifteen patients met criteria for ex vivo analysis of mucus strand velocities (CRS, n = 9 vs controls, n = 6). Mucus strands were recorded (pixels/second) streaming from the submucosal gland openings. Average mucus strand velocities were significantly decreased in patients with CRS (1.53 ± 0.67 vs controls, 4.86 ± 1.68 pixels/second; p < 0.001).This study is the first to report evidence of abnormal mucus strand velocity from submucosal glands in diseased sinonasal mucosa. Future pharmacologic studies targeting this critical component of MCC are warranted.

  View details for DOI 10.1002/alr.22065

  View details for PubMedID 29319936

  View details for PubMedCentralID PMC6520985

• Adjuvant Anti-angiogenic Therapy Enhances Chemotherapeutic Uptake in a Murine Model of Head and Neck Cancer. Journal of drug targeting Prince, A. C., Patel, N. G., Moore, L. S., McGee, A. S., Ahn, J. C., Willey, C. D., Carroll, W. R., Rosenthal, E. L., Warram, J. M. 2018: 1–25

  Abstract

  Intratumoral metabolic demands result in excessive angiogenic cytokine release leading to unorganized vasculature. Resultant fluid dynamics oppose blood flow and drug penetration due to a marked increase in interstitial fluid hydrostatic pressure. It is hypothesized that anti-angiogenic therapy may function to "prune" vasculature and lead to improved chemotherapeutic penetration. Subcutaneous, OSC19 tumor bearing mice (n = 5/dose/agent) were administered varying doses of an anti-mouse VEGFR2 (DC101) or an anti-mouse VEGFR3 (31C1) -3d, -1d, 0d, +1d, and +3d prior to 200μg of cetuximab fluorescently labeled with IRDye800CW. Fluorescence imaging of tumors was performed 10d post cetuximab-IRDye800CW dose to monitor therapeutic uptake. Co-administration of dual anti-angiogenic agents at 50%-50%, 75%-25%, and 25%-75% using optimal dose and time (-1d 10mg/kg anti-VEGFR2 and -1d 40mg/kg anti-VEGFR3) was also evaluated. In order to establish vessel normalization, NG2 (pericyte marker) and CD31 (endothelial cells) ratios were assessed during immunohistochemical staining of tumor sections. Twenty-mg/kg anti-VEGFR3 + 5mg/kg anti-VEGFR2 significantly (p < 0.0005) reduced tumor size (-73%) compared to control (59%). The 20mg/kg anti-VEGFR3 + 5mg/kg anti-VEGFR2 and 30mg/kg anti-VEGFR3 + 2.5mg/kg anti-VEGFR2 significantly (p < 0.0004) improved percent-injected cetuximab-IRDye800CW dose/gram tumor tissue compared to other groups. Adjuvant, dual anti-angiogenic therapy targeting VEGFR2 and VEGFR3 significantly enhances tumor chemotherapeutic uptake compared to control.

  View details for PubMedID 29972342

• Evaluation of optical imaging agents in a fluorescence-guided surgical model of head and neck cancer. Surgical oncology Prince, A. C., Moore, L. S., Tipirneni, K. E., Ramesh, T. n., Limdi, M. A., Bevans, S. L., Walsh, E. M., Greene, B. n., Rosenthal, E. L., Warram, J. M. 2018; 27 (2): 225–30

  Abstract

  Tumor proliferation often occurs from pathologic receptor upregulation. These receptors provide unique targets for near-infrared (NIR) probes that have fluorescence-guided surgery (FGS) applications. We demonstrate the use of three smart-targeted probes in a model of head and neck squamous cell carcinoma.A dose escalation study was performed using IntegriSense750, ProSense750EX, and ProSense750FAST in mice (n = 5) bearing luciferase-positive SCC-1 flank xenograft tumors. Whole body fluorescence imaging was performed serially after intravenous injection using commercially available open-field (LUNA, Novadaq, Canada) and closed-field NIR systems (Pearl, LI-COR, Lincoln, NE). An ex vivo, whole-body biodistribution was conducted. Lastly, FGS was performed with IntegriSense750 to demonstrate orthotopic and metastatic disease localization.Disease fluorescence delineation was assessed by tumor-to-background fluorescence ratios (TBR). Peak TBR values were 3.3 for 1 nmol ProSense750EX, 5.5 for 6 nmol ProSense750FAST, and 10.8 for 4 nmol IntegriSense750 at 5.5, 3, and 4 d post administration, respectively. Agent utility is unique: ProSense750FAST provides sufficient contrast quickly (TBR: 1.5, 3 h) while IntegriSense750 produces strong (TBR: 10.8) contrast with extended administration-to-resection time (96 h). IntegriSense750 correctly identified all diseased nodes in situ during exploratory surgeries. Ex vivo, whole-body biodistribution was assessed by tumor-to-tissue fluorescence ratios (TTR). Agents provided sufficient fluorescence contrast to discriminate disease from background, TTR>1. IntegriSense750 was most robust in neural tissue (TTR: 64) while ProSense750EX was superior localizing disease against lung tissue (TBR: 13).All three agents appear effective for FGS.

  View details for PubMedID 29937175

• Laser-Assisted Indocyanine Green Dye Angiography for Postoperative Fistulas After Salvage Laryngectomy. JAMA otolaryngology-- head & neck surgery Partington, E. J., Moore, L. S., Kahmke, R., Warram, J. M., Carroll, W., Rosenthal, E. L., Greene, B. J. 2017

  Abstract

  Pharyngocutaneous fistula formation is an unfortunate complication after salvage laryngectomy for head and neck cancer that is difficult to anticipate and related to a variety of factors, including the viability of native pharyngeal mucosa.To examine whether noninvasive angiography with indocyanine green (ICG) dye can be used to evaluate native pharyngeal vascularity to anticipate pharyngocutaneous fistula development.This cohort study included 37 patients enrolled from June 1, 2013, to June 1, 2016, and follow-up was for at least 1 month postoperatively. The study was performed at the University of Alabama at Birmingham, a tertiary care center. Included patients were those undergoing salvage total laryngectomy who were previously treated with chemoradiotherapy or radiotherapy alone.The ICG dye was injected intraoperatively, and laser-assisted vascular imaging was used to evaluate the native pharyngeal mucosa after the ablative procedure. The center of the native pharyngeal mucosa was used as the reference to compare with the peripheral mucosa, and the lowest mean ICG dye percentage of mucosal perfusion was recorded for each patient.The primary outcome was the formation of a postoperative fistula, which was assessed by clinical and radiographic assessment to test the hypothesis formulated before data collection.A total of 37 patients were included (mean [SD] age, 62.3 [8.5] years; 32 [87%] male and 5 [14%] female); 20 had a history of chemoradiotherapy, and 17 had history of radiotherapy alone. Thirty-four patients (92%) had free flap reconstruction, and 3 had primary closure (8%). Ten patients (27%) developed a postoperative fistula. No significant difference was found in fistula rate between patients who underwent neck dissection and those who did not and patients previously treated with chemoradiotherapy and those treated with radiotherapy alone. A receiver operator characteristic curve was generated to determine the diagnostic performance of the lowest mean ICG dye percentage of mucosal perfusion determined by fluorescence imaging, which was found to be a threshold value of 26%. The area under the curve was 0.85 (95% CI, 0.73-0.97), which was significantly greater than the chance diagonal. The overall mean lowest ICG dye percentage of mucosal perfusion was 31.3%. The mean lowest ICG dye percentage of mucosal perfusion was 22.0% in the fistula group vs 34.9% in the nonfistula group (absolute difference, 12.9%; 95% CI, 5.1%-21.7%).Patients who developed postoperative fistulas had lower mucosal perfusion as detected by ICG dye angiography when compared with patients who did not develop fistulas.

  View details for DOI 10.1001/jamaoto.2017.0187

  View details for PubMedID 28520896

• Sensitivity and Specificity of Cetuximab-IRDye800CW to Identify Regional Metastatic Disease in Head and Neck Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Rosenthal, E., Moore, L., Tipirneni, K., de Boer, E., Stevens, T. M., Hartman, Y. E., Carroll, W. R., Zinn, K. R., Warram, J. M. 2017

  Abstract

  Purpose: Comprehensive cervical lymphadenectomy can be associated with significant morbidity and poor quality of life. This study evaluated the sensitivity and specificity of cetuximab-IRDye800CW to identify metastatic disease in patients with head and neck cancer.Experimental Design: Consenting patients scheduled for curative resection were enrolled in a clinical trial to evaluate the safety and specificity of cetuximab-IRDye800CW. Patients (n = 12) received escalating doses of the study drug. Where indicated, cervical lymphadenectomy accompanied primary tumor resection, which occurred 3 to 7 days following intravenous infusion of cetuximab-IRDye800CW. All 471 dissected lymph nodes were imaged with a closed-field, near-infrared imaging device during gross processing of the fresh specimens. Intraoperative imaging of exposed neck levels was performed with an open-field fluorescence imaging device. Blinded assessments of the fluorescence data were compared to histopathology to calculate sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV).Results: Of the 35 nodes diagnosed pathologically positive, 34 were correctly identified with fluorescence imaging, yielding a sensitivity of 97.2%. Of the 435 pathologically negative nodes, 401 were correctly assessed using fluorescence imaging, yielding a specificity of 92.7%. The NPV was determined to be 99.7%, and the PPV was 50.7%. When 37 fluorescently false-positive nodes were sectioned deeper (1 mm) into their respective blocks, metastatic cancer was found in 8.1% of the recut nodal specimens, which altered staging in two of those cases.Conclusions: Fluorescence imaging of lymph nodes after systemic cetuximab-IRDye800CW administration demonstrated high sensitivity and was capable of identifying additional positive nodes on deep sectioning. Clin Cancer Res; 1-9. ©2017 AACR.

  View details for DOI 10.1158/1078-0432.CCR-16-2968

  View details for PubMedID 28446503

• Fluorescence Imaging for Cancer Screening and Surveillance. Molecular imaging and biology Tipirneni, K. E., Rosenthal, E. L., Moore, L. S., Haskins, A. D., Udayakumar, N., Jani, A. H., Carroll, W. R., Morlandt, A. B., Bogyo, M., Rao, J., Warram, J. M. 2017

  Abstract

  The advent of fluorescence imaging (FI) for cancer cell detection in the field of oncology is promising for both cancer screening and surgical resection. Particularly, FI in cancer screening and surveillance is actively being evaluated in many new clinical trials with over 30 listed on Clinical Trials.gov . While surgical resection forms the foundation of many oncologic treatments, early detection is the cornerstone for improving outcomes and reducing cancer-related morbidity and mortality. The applications of FI are twofold as it can be applied to high-risk patients in addition to those undergoing active surveillance. This technology has the promise of highlighting lesions not readily detected by conventional imaging or physical examination, allowing disease detection at an earlier stage of development. Additionally, there is a persistent need for innovative, cost-effective imaging modalities to ameliorate healthcare disparities and the global burden of cancer worldwide. In this review, we outline the current utility of FI for screening and detection in a range of cancer types.

  View details for DOI 10.1007/s11307-017-1050-5

  View details for PubMedID 28155079

• Characterizing the Utility and Limitations of Repurposing an Open-Field Optical Imaging Device for Fluorescence-Guided Surgery in Head and Neck Cancer Patients JOURNAL OF NUCLEAR MEDICINE Moore, L. S., Rosenthal, E. L., Chung, T. K., de Boer, E., Patel, N., Prince, A. C., Korb, M. L., Walsh, E. M., Young, E. S., Stevens, T. M., Withrow, K. P., Morlandt, A. B., Richman, J. S., Carroll, W. R., Zinn, K. R., Warram, J. M. 2017; 58 (2): 246-251

  Abstract

  The purpose of this study was to assess the potential of U.S. Food and Drug Administration-cleared devices designed for indocyanine green-based perfusion imaging to identify cancer-specific bioconjugates with overlapping excitation and emission wavelengths. Recent clinical trials have demonstrated potential for fluorescence-guided surgery, but the time and cost of the approval process may impede clinical translation. To expedite this translation, we explored the feasibility of repurposing existing optical imaging devices for fluorescence-guided surgery.Consenting patients (n = 15) scheduled for curative resection were enrolled in a clinical trial evaluating the safety and specificity of cetuximab-IRDye800 (NCT01987375). Open-field fluorescence imaging was performed preoperatively and during the surgical resection. Fluorescence intensity was quantified using integrated instrument software, and the tumor-to-background ratio characterized fluorescence contrast.In the preoperative clinic, the open-field device demonstrated potential to guide preoperative mapping of tumor borders, optimize the day of surgery, and identify occult lesions. Intraoperatively, the device demonstrated robust potential to guide surgical resections, as all peak tumor-to-background ratios were greater than 2 (range, 2.2-14.1). Postresection wound bed fluorescence was significantly less than preresection tumor fluorescence (P < 0.001). The repurposed device also successfully identified positive margins.The open-field imaging device was successfully repurposed to distinguish cancer from normal tissue in the preoperative clinic and throughout surgical resection. This study illuminated the potential for existing open-field optical imaging devices with overlapping excitation and emission spectra to be used for fluorescence-guided surgery.

  View details for DOI 10.2967/jnumed.115.171413

  View details for Web of Science ID 000393360100017

  View details for PubMedID 27587708

  View details for PubMedCentralID PMC5288741

• Effects of Neoadjuvant Chemotherapy and Radiotherapy on Flap Perfusion in a Novel Mouse Model Using Standard Clinical Assessment and Near-Infrared Fluorescence Angiography Moore , L., Ramesh , T., Patel , N., Tipirneni , K., Warram , J., Richter , J., Walsh , E., Aaron , G., Morlandt , A., Hughley , B., Rosenthal , E. Arch Otolaryngol Rhinol. 2017 038-042

  Abstract

  DOI: http://doi.org/10.17352/2455-1759.000042

• Oncologic Procedures Amenable to Fluorescence-guided Surgery. Annals of surgery Tipirneni, K. E., Warram, J. M., Moore, L. S., Prince, A. C., de Boer, E., Jani, A. H., Wapnir, I. L., Liao, J. C., Bouvet, M., Behnke, N. K., Hawn, M. T., Poultsides, G. A., Vahrmeijer, A. L., Carroll, W. R., Zinn, K. R., Rosenthal, E. 2016

  Abstract

  Although fluorescence imaging is being applied to a wide range of cancers, it remains unclear which disease populations will benefit greatest. Therefore, we review the potential of this technology to improve outcomes in surgical oncology with attention to the various surgical procedures while exploring trial endpoints that may be optimal for each tumor type.For many tumors, primary treatment is surgical resection with negative margins, which corresponds to improved survival and a reduction in subsequent adjuvant therapies. Despite unfavorable effect on patient outcomes, margin positivity rate has not changed significantly over the years. Thus, patients often experience high rates of re-excision, radical resections, and overtreatment. However, fluorescence-guided surgery (FGS) has brought forth new light by allowing detection of subclinical disease not readily visible with the naked eye.We performed a systematic review of clinicatrials.gov using search terms "fluorescence," "image-guided surgery," and "near-infrared imaging" to identify trials utilizing FGS for those received on or before May 2016.fluorescence surgery for tumor debulking, wide local excision, whole-organ resection, and peritoneal metastases.fluorescence in situ hybridization, fluorescence imaging for lymph node mapping, nonmalignant lesions, nonsurgical purposes, or image guidance without fluorescence.Initial search produced 844 entries, which was narrowed down to 68 trials. Review of literature and clinical trials identified 3 primary resection methods for utilizing FGS: (1) debulking, (2) wide local excision, and (3) whole organ excision.The use of FGS as a surgical guide enhancement has the potential to improve survival and quality of life outcomes for patients. And, as the number of clinical trials rise each year, it is apparent that FGS has great potential for a broad range of clinical applications.

  View details for DOI 10.1097/SLA.0000000000002127

  View details for PubMedID 28045715

• Effects of an Unlabeled Loading Dose on Tumor-Specific Uptake of a Fluorescently Labeled Antibody for Optical Surgical Navigation. Molecular imaging and biology Moore, L. S., Rosenthal, E. L., de Boer, E., Prince, A. C., Patel, N., Richman, J. M., Morlandt, A. B., Carroll, W. R., Zinn, K. R., Warram, J. M. 2016: -?

  Abstract

  Intraoperative optical imaging to guide surgeons during oncologic resections offers a unique and promising solution to the ambiguity of cancer margins to tactile and visual assessment that results in devastatingly high rates of positive margins. Sequestering of labeled antibodies by normal tissues with high expression of the antibody target, or "antigen sinks", diminishes the efficacy of these probes to provide contrast between the tumor and background tissues by decreasing the amount of circulating probe available for uptake by the tumor and by increasing the fluorescence of non-tumor tissues. We hypothesized that administering a dose of unlabeled antibody prior to infusion of the near-infrared (NIR) fluorescently labeled antibody would improve tumor-specific uptake and contrast of the fluorescently labeled probe by occupying extra-tumoral binding sites, thereby increasing the amount of labeled probe available for uptake by the tumor.In this study, we explore this concept by testing two different "pre-load" doses of unlabeled cetuximab (the standard 10-mg test dose, and a larger, experimental 100-mg test dose) in six patients receiving cetuximab conjugated to the fluorescent dye IRDye800CW (cetuximab-IRDye800CW) in a clinical trial, and compared the amount of fluorescent antibody in tumor and background tissues, as well as the tumor-specific contrast of each.The patients receiving the larger preload (100 mg) of unlabeled cetuximab demonstrated significantly higher concentrations (9.5 vs. 0.1 μg) and a longer half-life (30.3 vs. 20.6 days) of the labeled cetuximab in plasma, as well as significantly greater tumor fluorescence (32.3 vs. 9.3 relative fluorescence units) and tumor to background ratios (TBRs) (5.5 vs. 1.7).Administering a preload of unlabeled antibody prior to infusion of the fluorescently labeled drug may be a simple and effective way to improve the performance of antibody-based probes to guide surgical resection of solid malignancies.

  View details for PubMedID 27830425

• Antiangiogenic antibody improves melanoma detection by fluorescently labeled therapeutic antibodies. Laryngoscope Sweeny, L., Prince, A., Patel, N., Moore, L. S., Rosenthal, E. L., Hughley, B. B., Warram, J. M. 2016

  Abstract

  Evaluate if vascular normalization with an antiangiogenic monoclonal antibody improves detection of melanoma using fluorescently labeled antibody-based imaging.Preclinical.Panitumumab and control IgG were covalently linked to a near-infrared fluorescent probe (IRDye800CW). Immunodeficient mice with ear xenografts of melanoma cell lines (A375 and SKMEL5) were systemically injected (200 μg, tail vein) with either IgG-IRDye800CW, panitumumab-IRDye800CW, or a combination (bevacizumab [5mg/kg], administered 72 hours prepanitumumab-IRDye800CW) (n = 5). Primary tumors were imaged with open-field (LUNA, Novadaq, Toronto, Ontario, Canada) and closed-field (Pearl, LI-COR Biosciences, Lincoln, NB) imaging devices. Postresection, the concentration of labeled antibody within the tumor (μg/g) was calculated using normalized standards.The mean fluorescence within the melanoma tumors was greater for the combination group compared to panitumumab alone for both cell lines (P < 0.001). The tumor-to-background ratio (TBR) for the A375 tumors was greater for the combination (3.4-7.1) compared to the panitumumab alone (3.2-5.0) (P = 0.04). The TBR for SKMEL5 tumors was greater for the combination (2.4-6.0) compared to the panitumumab alone (2.2-3.9) (P = 0.02). Within A375 tumors, the concentration was lower for panitumumab (0.51 μg/g) compared to combination group (0.68 μg/g) (P = 0.036). Within SKMEL5 tumors, the concentration was lower for panitumumab (0.0.17 μg/g) compared to combination group (0.35 μg/g) (P = 0.048). Residual tumor (1.0-0.2 mg) could be differentiated from background in both panitumumab and combination groups. For both cell lines, panitumumab and combination groups had greater mean fluorescence of the tumor compared to control IgG.The addition of antiangiogenic therapy improves uptake of fluorescently labeled monoclonal antibodies within melanoma tumors. Clinical translation could improve detection of melanoma intraoperatively, reducing positive margins and sparing normal tissue.NA Laryngoscope, 126:E387-E395, 2016.

  View details for DOI 10.1002/lary.26215

  View details for PubMedID 27576611

  View details for PubMedCentralID PMC5121084

• Photoimmunotherapy of residual disease after incomplete surgical resection in head and neck cancer models CANCER MEDICINE Moore, L. S., de Boer, E., Warram, J. M., Tucker, M. D., Carroll, W. R., Korb, M. L., Brandwein-Gensler, M. S., van Dam, G. M., Rosenthal, E. L. 2016; 5 (7): 1526-1534

  Abstract

  Antibody-based photodynamic therapy, or photoimmunotherapy (PIT), is a novel, targeted cancer therapy, which can serve as both a diagnostic and a therapeutic agent. The primary objective of this study was to evaluate the capacity of panitumumab-IRDye700DX (Pan-IR700) to eliminate microscopic tumor remnants in the postsurgical setting, which was accomplished using novel in vitro and in vivo models of residual disease after incomplete resection. Additionally, PIT was evaluated in fresh human-derived cancer tissue. To determine a threshold for cellular regrowth after PIT, an in vitro assay was performed using a range of cells representing microscopic disease quantities. Long-term growth inhibition was induced after treatment of 5 × 10(3) and 1 × 10(4) cells at 6 J. A novel in vivo mouse model of subtotal tumor resection was used to assess the effectiveness of Pan-IR700 mediated PIT to eliminate residual disease and inhibit recurrence in the post-surgical wound bed. Mice receiving surgical treatment plus adjuvant PIT showed a threefold and fourfold reduction in tumor regrowth at 30 days post PIT in the 50% and 90% subtotal resection groups, respectively (as measured by bioluminescence imaging), demonstrating a significant (P < 0.001) reduction in tumor regrowth. To determine the translatability of epidermal growth factor receptor (EGFR)-targeted PIT, SCCHN human tissues (n = 12) were treated with Pan-IR700. A significant reduction (P < 0.001) in ATP levels was observed after treatment with Pan-IR700 and 100 J cm(-2) (48% ± 5%) and 150 J cm(-2) (49% ± 7%) when compared to baseline. Targeting EGFR with Pan-IR700 has robust potential to provide a tumor-specific mechanism for eliminating residual disease in the surgical setting, thereby increasing therapeutic efficacy, prolonging progression-free survival, and decreasing morbidity.

  View details for DOI 10.1002/cam4.752

  View details for Web of Science ID 000380048900019

  View details for PubMedID 27167827

  View details for PubMedCentralID PMC4867660

• Fluorescence imaging to localize head and neck squamous cell carcinoma for enhanced pathological assessment. The journal of pathology. Clinical research Warram, J. M., de Boer, E., van Dam, G. M., Moore, L. S., Bevans, S. L., Walsh, E. M., Young, E. S., Carroll, W. R., Stevens, T. M., Rosenthal, E. L. 2016; 2 (2): 104-112

  Abstract

  Accurately identifying close or positive margins in real-time permits re-excision during surgical procedures. Intraoperative assessment of margins via gross examination and frozen section is a widely used tool to assist the surgeon in achieving complete resection. While this methodology permits diagnosis of freshly resected tissue, the process is fraught with misinterpretation and sampling errors. During fluorescence-guided surgery, an exogenous fluorescent agent specific for the target disease is imaged in order to navigate the surgical excision. As this technique quickly advances into the clinic, we hypothesize that the disease-specific fluorescence inherently contained within the resected tissues can be used to guide histopathological assessment. To evaluate the feasibility of fluorescence-guided pathology, we evaluated head and neck squamous cell carcinoma tumour specimens and margins resected from animals and patients after systemic injection of cetuximab-IRDye800CW. In a preclinical model of luciferase-positive tumour resection using bioluminescence as the gold standard, fluorescence assessment determined by closed-field fluorescence imaging of fresh resected margins accurately predicted the presence of disease in 33/39 positive margins yielding an overall sensitivity of 85%, specificity of 95%, positive predictive value (PPV) of 94%, and a negative predictive value (NPV) of 87%, which was superior to both surgical assessment (54%, 61%, 57%, and 58%) and pathological assessment (49%, 95%, 91%, and 66%), respectively. When the power of the technique was evaluated using human-derived tumour tissues, as little as 0.5mg (1mm(3)) of tumour tissue was identified (tumour-to-background-ratio:5.2). When the sensitivity/specificity of fluorescence-guided pathology was determined using traditional histological assessment as the gold standard in human tissues obtained during fluorescence-guided surgery, the technique was highly accurate with a sensitivity of 91%, specificity of 85%, PPV of 81%, and NPV of 93% for 90 human-derived samples. This approach can be used as a companion to the pathologist, eliminating confounding factors while impacting surgical intervention and patient management.

  View details for DOI 10.1002/cjp2.40

  View details for PubMedID 27499920

  View details for PubMedCentralID PMC4907060

• On the horizon: Optical imaging for cutaneous squamous cell carcinoma HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK de Boer, E., Moore, L. S., Warram, J. M., Huang, C. C., Brandwein-Gensler, M. S., van Dam, G. M., Rosenthal, E. L., Schmalbach, C. E. 2016; 38: E2204-E2213

  Abstract

  Surgical resection with negative margins remains the standard of care for high-risk cutaneous squamous cell carcinoma (SCC). However, surgical management is often limited by poor intraoperative tumor visualization and inability to detect occult nodal metastasis. The inability to intraoperatively detect microscopic disease can lead to additional surgery, tumor recurrence, and decreased survival.A comprehensive literature review was conducted to identify studies incorporating optical imaging technology in the management of cutaneous SCC (January 1, 2000-December 1, 2014).Several innovative optical imaging techniques, Raman spectroscopy, confocal microscopy, and fluorescence imaging, have been developed for intraoperative surgical guidance. Fifty-seven studies review the ability of these techniques to improve cutaneous SCC localization at the gross and microscopic level.Significant advances have been achieved with real-time optical imaging strategies for intraoperative cutaneous SCC margin assessment and tumor detection. Optical imaging holds promise in improving the percentage of negative surgical margins and in the early detection of micrometastatic disease. © 2015 Wiley Periodicals, Inc. Head Neck, 2015.

  View details for DOI 10.1002/hed.24079

  View details for Web of Science ID 000375116400288

  View details for PubMedID 25899874

• Standardized model for predicting flap failure using Indocyanine Green Dye Zimmermann, T. M., Moore, L. S., Warram, J. M., Greene, B. J., Nakhmani, A., Korb, M. L., Rosenthal, E. L., Pogue, B. W., Gioux, S. SPIE-INT SOC OPTICAL ENGINEERING. 2016

  View details for DOI 10.1117/12.2213194

  View details for Web of Science ID 000379313700025

• Intraoperative Fluorescence Angiography for Head and Neck Reconstruction Kahmke , R., Moore , L., Rosenthal , E., Greene , B. Curr Otorhinolaryngol Rep. 2016 194-200
• Near-infrared (NIR) fluorescence imaging of head and neck squamous cell carcinoma for fluorescence-guided surgery Moore, L., Warram, J. M., de Boer, E., Carroll, W. R., Morlandt, A., Withrow, K. P., Rosenthal, E. L., Pogue, B. W., Gioux, S. SPIE-INT SOC OPTICAL ENGINEERING. 2016

  View details for DOI 10.1117/12.2214002.4848635747001

  View details for Web of Science ID 000379313700027

• A ratiometric threshold for determining presence of cancer during fluorescence-guided surgery JOURNAL OF SURGICAL ONCOLOGY Warram, J. M., de Boer, E., Moore, L. S., Schmalbach, C. E., Withrow, K. P., Carroll, W. R., Richman, J. S., Morlandt, A. B., Brandwein-Gensler, M., Rosenthal, E. L. 2015; 112 (1): 2-8

  Abstract

  Fluorescence-guided imaging to assist in identification of malignant margins has the potential to dramatically improve oncologic surgery. However, a standardized method for quantitative assessment of disease-specific fluorescence has not been investigated. Introduced here is a ratiometric threshold derived from mean fluorescent tissue intensity that can be used to semi-quantitatively delineate tumor from normal tissue.Open-field and a closed-field imaging devices were used to quantify fluorescence in punch biopsy tissues sampled from primary tumors collected during a phase 1 trial evaluating the safety of cetuximab-IRDye800 in patients (n = 11) undergoing surgical intervention for head and neck cancer. Fluorescence ratios were calculated using mean fluorescence intensity (MFI) from punch biopsy normalized by MFI of patient-matched tissues. Ratios were compared to pathological assessment and a ratiometric threshold was established to predict presence of cancer.During open-field imaging using an intraoperative device, the threshold for muscle normalized tumor fluorescence was found to be 2.7, which produced a sensitivity of 90.5% and specificity of 78.6% for delineating disease tissue. The skin-normalized threshold generated greater sensitivity (92.9%) and specificity (81.0%).Successful implementation of a semi-quantitative threshold can provide a scientific methodology for delineating disease from normal tissue during fluorescence-guided resection of cancer.

  View details for DOI 10.1002/jso.23946

  View details for Web of Science ID 000358296100002

  View details for PubMedID 26074273

  View details for PubMedCentralID PMC4510011

• In Vivo Fluorescence Immunohistochemistry: Localization of Fluorescently Labeled Cetuximab in Squamous Cell Carcinomas SCIENTIFIC REPORTS de Boer, E., Warram, J. M., Tucker, M. D., Hartman, Y. E., Moore, L. S., de Jong, J. S., Chung, T. K., Korb, M. L., Zinn, K. R., van Dam, G. M., Rosenthal, E. L., Brandwein-Gensler, M. S. 2015; 5

  Abstract

  Anti-EGFR (epidermal growth factor receptor) antibody based treatment strategies have been successfully implemented in head and neck squamous cell carcinoma (HNSCC). Unfortunately, predicting an accurate and reliable therapeutic response remains a challenge on a per-patient basis. Although significant efforts have been invested in understanding EGFR-mediated changes in cell signaling related to treatment efficacy, the delivery and histological localization in (peri-)tumoral compartments of antibody-based therapeutics in human tumors is poorly understood nor ever made visible. In this first in-human study of a systemically administered near-infrared (NIR) fluorescently labeled therapeutic antibody, cetuximab-IRDye800CW (2.5 mg/m(2), 25 mg/m(2), and 62.5 mg/m(2)), we show that by optical molecular imaging (i.e. denominated as In vivo Fluorescence Immunohistochemistry) we were able to evaluate localization of fluorescently labeled cetuximab. Clearly, optical molecular imaging with fluorescently labeled antibodies correlating morphological (peri-)tumoral characteristics to levels of antibody delivery, may improve treatment paradigms based on understanding true tumoral antibody delivery.

  View details for DOI 10.1038/srep10169

  View details for Web of Science ID 000357041200001

  View details for PubMedID 26120042

• Kinase activation of ClC-3 accelerates cytoplasmic condensation during mitotic cell rounding. American journal of physiology. Cell physiology Cuddapah, V. A., Habela, C. W., Watkins, S., Moore, L. S., Barclay, T. C., Sontheimer, H. 2012; 302 (3): C527-38

  Abstract

  "Mitotic cell rounding" describes the rounding of mammalian cells before dividing into two daughter cells. This shape change requires coordinated cytoskeletal contraction and changes in osmotic pressure. While considerable research has been devoted to understanding mechanisms underlying cytoskeletal contraction, little is known about how osmotic gradients are involved in cell division. Here we describe cytoplasmic condensation preceding cell division, termed "premitotic condensation" (PMC), which involves cells extruding osmotically active Cl(-) via ClC-3, a voltage-gated channel/transporter. This leads to a decrease in cytoplasmic volume during mitotic cell rounding and cell division. Using a combination of time-lapse microscopy and biophysical measurements, we demonstrate that PMC involves the activation of ClC-3 by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in human glioma cells. Knockdown of endogenous ClC-3 protein expression eliminated CaMKII-dependent Cl(-) currents in dividing cells and impeded PMC. Thus, kinase-dependent changes in Cl(-) conductance contribute to an outward osmotic pressure in dividing cells, which facilitates cytoplasmic condensation preceding cell division.

  View details for DOI 10.1152/ajpcell.00248.2011

  View details for PubMedID 22049206

  View details for PubMedCentralID PMC3287156