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Item Acute toxicity in comprehensive head and neck radiation for nasopharynx and paranasal sinus cancers: cohort comparison of 3D conformal proton therapy and intensity modulated radiation therapy.(BMC, 2016) McDonald, Mark W.; Liu, Yuan; Moore, Michael G.; Johnstone, Peter A. S.; Department of Otolaryngology--Head & Neck Surgery, IU School of MedicineBackground: To evaluate acute toxicity endpoints in a cohort of patients receiving head and neck radiation with proton therapy or intensity modulated radiation therapy (IMRT). Methods: Forty patients received comprehensive head and neck radiation including bilateral cervical nodal radiation, given with or without chemotherapy, for tumors of the nasopharynx, nasal cavity or paranasal sinuses, any T stage, N0-2. Fourteen received comprehensive treatment with proton therapy, and 26 were treated with IMRT, either comprehensively or matched to proton therapy delivered to the primary tumor site. Toxicity endpoints assessed included g-tube dependence at the completion of radiation and at 3 months after radiation, opioid pain medication requirement compared to pretreatment normalized as equivalent morphine dose (EMD) at completion of treatment, and at 1 and 3 months after radiation. Results: In a multivariable model including confounding variables of concurrent chemotherapy and involved nodal disease, comprehensive head and neck radiation therapy using proton therapy was associated with a lower opioid pain requirement at the completion of radiation and a lower rate of gastrostomy tube dependence by the completion of radiation therapy and at 3 months after radiation compared to IMRT. Proton therapy was associated with statistically significant lower mean doses to the oral cavity, esophagus, larynx, and parotid glands. In subgroup analysis of 32 patients receiving concurrent chemotherapy, there was a statistically significant correlation with a greater opioid pain medication requirement at the completion of radiation and both increasing mean dose to the oral cavity and to the esophagus. Conclusions: Proton therapy was associated with significantly reduced radiation dose to assessed non-target normal tissues and a reduced rate of gastrostomy tube dependence and opioid pain medication requirements. This warrants further evaluation in larger studies, ideally with patient-reported toxicity outcomes and quality of life endpoints.Item Anterolateral thigh osteomyocutaneous femur (ALTO) flap reconstruction for composite mandible and near total tongue defect utilizing a retrograde intramedullary femoral nail stabilization technique: Report of a first case(Elsevier, 2020-06-01) Novinger, Leah J.; Cannady, Steven B.; Wurtz, Lawrence D.; Sim, Michael W.; Moore, Michael G.; Mantravadi, Avinash V.; Shipchandler, Taha Z.; Otolaryngology – Head and Neck Surgery, School of MedicineThe anterior lateral thigh osteomyocutaneous free flap (ALTO) offers the advantage of reconstructing large bony and soft tissue defects. We report a novel approach for femur stabilization via retrograde intramedullary nail placement in a patient with a near total tongue and large mandibular defect who underwent ALTO reconstruction that saves operating room time and decreases risk of post-operative fracture.Item Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion through DNA-PK and Rac1 Signaling(American Association for Cancer Research, 2016-04-15) Romick-Rosendale, Lindsey E.; Hoskins, Elizabeth E.; Privette Vinnedge, Lisa M.; Foglesong, Grant D.; Brusadelli, Marion G.; Potter, S. Steven; Komurov, Kakajan; Brugmann, Samantha A.; Lambert, Paul F.; Kimple, Randall J.; Virts, Elizabeth L.; Hanenberg, Helmut; Gillison, Maura L.; Wells, Susanne I.; Pediatrics, School of MedicinePURPOSE: Head and neck squamous cell carcinoma (HNSCC) remains a devastating disease, and Fanconi anemia (FA) gene mutations and transcriptional repression are common. Invasive tumor behavior is associated with poor outcome, but relevant pathways triggering invasion are poorly understood. There is a significant need to improve our understanding of genetic pathways and molecular mechanisms driving advanced tumor phenotypes, to develop tailored therapies. Here we sought to investigate the phenotypic and molecular consequences of FA pathway loss in HNSCC cells. EXPERIMENTAL DESIGN: Using sporadic HNSCC cell lines with and without FA gene knockdown, we sought to characterize the phenotypic and molecular consequences of FA deficiency. FA pathway inactivation was confirmed by the detection of classic hallmarks of FA following exposure to DNA cross-linkers. Cells were subjected to RNA sequencing with qRT-PCR validation, followed by cellular adhesion and invasion assays in the presence and absence of DNA-dependent protein kinase (DNA-PK) and Rac1 inhibitors. RESULTS: We demonstrate that FA loss in HNSCC cells leads to cytoskeletal reorganization and invasive tumor cell behavior in the absence of proliferative gains. We further demonstrate that cellular invasion following FA loss is mediated, at least in part, through NHEJ-associated DNA-PK and downstream Rac1 GTPase activity. CONCLUSIONS: These findings demonstrate that FA loss stimulates HNSCC cell motility and invasion, and implicate a targetable DNA-PK/Rac1 signaling axis in advanced tumor phenotypes.Item Multicancer Early Detection Tests: A State-of-the-Art Review for Otolaryngologists(Wiley, 2024-10-26) Kennedy, Elena; Durm, Greg; Farlow, Janice L.; Otolaryngology -- Head and Neck Surgery, School of MedicineObjective: To provide a review of the science and applicability of current multi-cancer early detection (MCED) tests for otolaryngologists. Data sources: PubMed, clinicaltrials.gov, company websites. Review methods: Using PRISMA methodology, primary literature regarding MCED tests was queried from April 26 to May 12, 2024 using MCED search terms. Ongoing clinical trials incorporating MCED screens were identified via the National Institutes of Health clinicaltrials.gov website. Company websites for available or upcoming MCED tests were reviewed. Conclusion: Long-term robust data regarding the performance characteristics, effects on clinical outcomes, and cost-utility of MCED tests for head and neck cancer are currently lacking. Otolaryngologists should be aware of the implications of MCED tests as these assays become more widely used. Implications for practice: Although not FDA-approved or covered by insurances at the time of writing of this manuscript, MCED testing is rapidly gaining interest, and patients with positive tests are presenting to otolaryngologists for evaluation. While MCED technologies hold great promise for early detection of disease and potential reduction of morbidity and mortality, more study is needed about their utility for head and neck cancer and optimal diagnostic workflows.Item RAD51C – a new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC)(Elsevier, 2014-03) Scheckenbach, Kathrin; Baldus, Stephan E.; Balz, Vera; Freund, Marcel; Pakropa, Petra; Sproll, Christoph; Schäfer, Karl-Ludwig; Wagenmann, Martin; Schipper, Jörg; Hanenberg, Helmut; Pediatrics, School of MedicineINTRODUCTION: Head and neck squamous cell carcinomas (HNSSCs) are one of the leading causes of cancer-associated death worldwide. Although certain behavioral risk factors are well recognized as tumor promoting, there is very little known about the presence of predisposing germline mutations in HNSCC patients. METHODS: In this study, we analyzed 121 individuals with HNSCCs collected at our institution for germline alterations in the newly identified cancer susceptibility gene RAD51C. RESULTS: Sequencing of all exons and the adjacent introns revealed five distinct heterozygous sequence deviations in RAD51C in seven patients (5.8%). A female patient without any other risk factors carried a germline mutation that disrupted the canonical splice acceptor site of exon 5 (c.706-2A>G). CONCLUSIONS: As there are only a few publications in the literature identifying germline mutations in head and neck cancer patients, our results provide the first indication that paralogs of RAD51, recently described as mutated in breast and ovarian cancer patients, might also be candidates for genetic risk factors in sporadic squamous cell carcinomas of the head and neck.