@article{meneses_gidcumb_marcus_gonzalez_lai_mishra_lascelles_nolan_2023, title={Acute radiotherapy-associated oral pain may promote tumor growth at distant sites}, volume={13}, ISSN={["2234-943X"]}, url={http://dx.doi.org/10.3389/fonc.2023.1029108}, DOI={10.3389/fonc.2023.1029108}, abstractNote={IntroductionPatients developing acute radiotherapy induced dermatitis or oral mucositis commonly experience pain. When severe, this radiotherapy-associated pain (RAP) can necessitate treatment breaks; unfortunately, in a variety of cancers, prolongation of the radiotherapy course has been associated with early cancer relapse and/or death. This is often attributed to accelerated repopulation, but it is unknown whether pain or pain signaling constituents might alter tumor behavior and hasten metastatic disease progression. We studied this by testing the hypothesis that severe acute RAP at one site can hasten tumor growth at a distant site.MethodsMice underwent single fraction tongue irradiation (27 Gy, or 0 Gy “sham” control) to induce severe glossitis. At the time of maximal oral RAP, one of three luciferase-transfected tumor cell lines were injected via tail vein (4T1, B16F10, MOC2; each paired to their syngeneic host: BALB/c or C57BL/6); tumor burden was assessed via in vivo transthoracic bioluminescence imaging and ex vivo pulmonary nodule quantification. Survival was compared using Kaplan-Meier statistics.ResultsTongue irradiation and resultant RAP promoted lung tumor growth of 4T1-Luc2 cells in BALB/c mice. This effect was not a result of off-target radiation, nor an artefact of environmental stress caused by standard (subthermoneutral) housing temperatures. RAP did not affect the growth of B16F10-Luc2 cells, however, C57BL/6 mice undergoing tail vein injection of MOC2-Luc2 cells at the time of maximal RAP experienced early lung tumor-attributable death. Lung tumor growth was normalized when RAP was reduced by treatment with resiniferatoxin (300 µg/kg, subcutaneously, once).DiscussionThis research points towards radiation-induced activation of capsaicin-responsive (TRPV1) neurons as the cause for accelerated growth of tumors at distant (unirradiated) sites.}, journal={FRONTIERS IN ONCOLOGY}, publisher={Frontiers Media SA}, author={Meneses, Constanza S. and Gidcumb, Emily M. and Marcus, Karen L. and Gonzalez, Yarines and Lai, Yen Hao and Mishra, Santosh K. and Lascelles, B. Duncan X. and Nolan, Michael W.}, year={2023}, month={May} } @article{nolan_berman_watson-skaggs_quinn_marcus_russell_yoshikawa_olby_gieger_2022, title={Stereotactic radiotherapy (10 Gy X 3) for canine nonlymphomatous intranasal tumors is associated with prolonged survival and minimal risk of severe radiotoxicity}, volume={260}, ISSN={["1943-569X"]}, DOI={10.2460/javma.22.03.0141}, abstractNote={Abstract OBJECTIVE To describe oncologic outcomes following administration of a uniform stereotactic radiotherapy protocol (SRT; 10 Gy X 3) for canine intranasal tumors and to identify whether any clinical or dosimetric factors were predictive of event-free or overall survival time (EFST or OST). ANIMALS 129 dogs. PROCEDURES In this single-institution retrospective study, the medical records database was searched for canine nonlymphomatous intranasal tumors treated with 10 Gy X 3 SRT between August 2013 and November 2020. Findings regarding adverse effects and outcomes were analyzed overall, for dogs grouped on the basis of life stage (mature adult, senior, or end of life), and for treatment-related or tumor-related variables to identify potential predictors of outcome. RESULTS After SRT, most dogs clinically improved with minimal acute radiotoxicity. The median EFST was 237 days; median OST was 542 days. Receipt of other tumor-directed therapies before or after SRT was associated with improved EFST in senior dogs (hazard ratio [HR], 0.416) and improved OST in mature adult (HR, 0.241) and senior dogs (HR, 0.348). In senior dogs, administration of higher near-minimum radiation doses was associated with improved EFST (HR, 0.686) and OST (HR, 0.743). In senior dogs, chondrosarcoma was associated with shorter OST (HR, 7.232), and in dogs at end of life, having a squamous cell or transitional carcinoma was associated with worse EFST (HR, 6.462). CLINICAL RELEVANCE This SRT protocol results in improved quality of life and prolonged OST for dogs of all life stages. Radiation protocol optimization or use of multimodal therapy may further improve outcomes. }, number={12}, journal={JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION}, author={Nolan, Michael W. and Berman, Alyssa R. and Watson-Skaggs, Maegan L. and Quinn, Claire N. and Marcus, Karen L. and Russell, Katharine and Yoshikawa, Hiroto and Olby, Natasha J. and Gieger, Tracy L.}, year={2022}, month={Sep}, pages={1496–1506} } @article{price_lai_marcus_robertson_lascelles_nolan_2020, title={Early radiation‐induced oral pain signaling responses are reduced with pentoxifylline treatment}, volume={62}, ISSN={1058-8183 1740-8261}, url={http://dx.doi.org/10.1111/vru.12943}, DOI={10.1111/vru.12943}, abstractNote={AbstractRadiation‐induced acute oral mucositis is associated with inflammation and pain. In other realms of pain research, nociceptors are known to be activated by inflammatory cytokines; for example, tumor necrosis factor alpha (TNF‐α) can activate transient receptor potential ion channels on sensory neurons. But there is an unclear relationship between inflammatory cytokines and molecular mediators of pain in radiation‐induced mucositis (RIM) and radiation‐associated pain (RAP). In this prospective, analytical, experimental pilot study, a common drug (pentoxifylline [PTX]) was used with the goal of inhibiting TNF‐α signaling in mice that underwent lingual irradiation to induce severe acute oral RIM/RAP. Body weight and glossitis scores were recorded daily. Eye wiping behaviors were assayed as a surrogate measure of oral discomfort (which is possible due to cross‐sensitization of the mandibular and ophthalmic branches of the trigeminal nerve). Quantitative real‐time reverse transcription polymerase chain reaction was performed on irradiated tongue tissue to measure changes in expression of TNF‐α, its receptor, nuclear factor kappa‐light‐chain‐enhancer of activated B cells, transient receptor potential vanilloid type 1 (TRPV1), and transient receptor potential vanilloid type 4 (TRPV4). Responsiveness of afferent sensory trigeminal neurons to TNF‐α, a TRPV1 agonist (capsaicin), and a partial TRPV4 agonist (histamine) was measured via calcium imaging. Although PTX treatment did not reduce glossitis severity or mitigate weight loss in mice with RIM/RAP, it did inhibit the upregulation of TNF‐α’s receptor that normally accompanies RIM, and it also reduced neuronal responsiveness to each of the aforementioned chemical stimuli. These results provide provisional evidence that inhibition of TNF‐α signaling with PTX treatment may serve as a useful tool for reducing pain in head and neck cancer patients.}, number={2}, journal={Veterinary Radiology & Ultrasound}, publisher={Wiley}, author={Price, Mikayla L. and Lai, Yen‐Hao (Erik) and Marcus, Karen L. and Robertson, James B. and Lascelles, B. Duncan X. and Nolan, Michael W.}, year={2020}, month={Dec}, pages={255–263} } @article{nolan_long_marcus_sarmadi_roback_fukuyama_baeumer_lascelles_2017, title={Nocifensive Behaviors in Mice with Radiation-Induced Oral Mucositis}, volume={187}, ISSN={["1938-5404"]}, url={https://dx.doi.org/10.1667/rr14669.1}, DOI={10.1667/rr14669.1}, abstractNote={Oral mucositis can result in significant dysphagia, and is the most common dose-limiting acute toxicity in head and neck cancer patients receiving chemoradiotherapy. There is a critical need to determine the cellular and molecular mechanisms that underlie radiotherapy-associated discomfort in patients with mucositis. The objective was to induce oral mucositis in mice, using a clinical linear accelerator, and to quantify resultant discomfort, and characterize peripheral sensitization. A clinical linear accelerator was used to deliver ionizing radiation to the oral cavity of mice. Mucositis severity scoring, and various behavioral assays were performed to quantify bouts of orofacial wiping and scratching, bite force, gnawing behavior and burrowing activity. Calcium imaging was performed on neurons of the trigeminal ganglia. Glossitis was induced with a single fraction of at least 27 Gy. Body weight decreased and subsequently returned to baseline, in concert with development and resolution of mucositis, which was worst at day 10 and 11 postirradiation, however was resolved within another 10 days. Neither bite force, nor gnawing behavior were measurably affected. However, burrowing activity was decreased, and both facial wiping and scratching were increased while mice had visible mucositis lesions. Sensory nerves of irradiated mice were more responsive to histamine, tumor necrosis factor alpha and capsaicin. Radiation-induced glossitis is associated with hyper-reactivity of sensory neurons in the trigeminal ganglia of mice, and is accompanied by several behaviors indicative of both itch and pain. These data validate an appropriate model for cancer treatment related discomfort in humans.}, number={3}, journal={RADIATION RESEARCH}, publisher={BioOne}, author={Nolan, Michael W. and Long, C. Tyler and Marcus, Karen L. and Sarmadi, Shayan and Roback, Donald M. and Fukuyama, Tomoki and Baeumer, Wolfgang and Lascelles, B. Duncan X.}, year={2017}, month={Mar}, pages={397–403} }