Type I interferon signaling promotes radioresistance in head and neck cancer.

Despite the promise of concurrent radiotherapy (RT) and immunotherapy in head and neck cancer (HNC), multiple randomized trials of this combination have had disappointing results. To evaluate potential immunologic mechanisms of RT resistance, we compared pre-treatment HNCs that developed RT resistance to a matched cohort that achieved curative status. Gene set enrichment analysis demonstrated that a pre-treatment pro-immunogenic tumor microenvironment (TME), including type II interferon [interferon gamma (IFNγ)] and tumor necrosis factor alpha (TNFα) signaling, predicted cure while type I interferon [interferon alpha (IFNα)] enrichment was associated with an immunosuppressive TME found in tumors that went on to recur. We then used immune deconvolution of RNA sequencing datasets to evaluate immunologic cell subset enrichment. This identified M2 macrophage signaling associated with type I IFN pathway expression in RT-recurrent disease. To further dissect mechanism, we then evaluated differential gene expression between pre-treatment and RT-resistant HNCs from sampled from the same patients at the same anatomical location in the oral cavity. Here, recurrent samples exhibited upregulation of type I IFN-stimulated genes (ISGs) including members of the IFN-induced protein with tetratricopeptide repeats (IFIT) and IFN-induced transmembrane (IFITM) gene families. While several ISGs were upregulated in each recurrent cancer, IFIT2 was significantly upregulated in all recurrent tumors when compared with the matched pre-RT specimens. Based on these observations, we hypothesized sustained type I IFN signaling through ISGs, such as IFIT2, may suppress the intra-tumoral immune response thereby promoting radiation resistance.

Tumor-specific T cells in head and neck cancer have rescuable functionality and can be identified through single-cell co-culture.

BACKGROUND: Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a treatment-resistance disease with limited response to immunotherapy. While T cells in HNSCC are known to display phenotypic dysfunction, whether they retain rescuable functional capacity and tumor-killing capability remains unclear. METHODS: To investigate the functionality and tumor-specificity of tumor-infiltrating lymphocytes (TILs) across HNSCCs, malignant cell lines and TILs were derived from 31 HPV-negative HNSCCs at the time of standard surgical resection. T cell functional capacity was evaluated through ex vivo expansion, immunophenotyping, and IsoLight single-cell proteomics. Tumor-specificity was investigated through both bulk and single-cell tumor-TIL co-culture. RESULTS: TILs could be successfully generated from 24 patients (77%), including both previously untreated and radiation recurrent HNSCCs. We demonstrate that across HNSCCs, TILs express multiple exhaustion markers but maintain a predominantly effector memory phenotype. After ex vivo expansion, TILs retain immunogenic functionality even from radiation-resistant, exhausted, and T cell-depleted disease. We further demonstrate tumor-specificity of T cells across HNSCC patients through patient-matched malignant cell-T cell co-culture. Finally, we use optofluidic technology to establish an autologous single tumor cell-single T cell co-culture platform for HNSCC. Cells derived from three HNSCC patients underwent single-cell co-culture which enabled identification and visualization of individual tumor-killing TILs in real-time in all patients. CONCLUSIONS: These studies show that cancer-specific T cells exist across HNSCC patients with rescuable immunogenicity and can be identified on a single-cell level. These data lay the foundation for development of patient-specific T cell immunotherapies in HNSCC.

Comparison of da Vinci Single Port vs Si Systems for Transoral Robotic-Assisted Surgery: A Review With Technical Insights.

Importance: Transoral robot-assisted surgery (TORS) continues to have a major role in the treatment of oropharyngeal cancer. As new iterations of robotic technology are increasingly utilized, it is important to share learning experiences and clinical outcomes data, to optimize technical efficiency and clinical care. Observations: This was a retrospective review of a large academic institution's initial clinical use of the da Vinci Single Port (SP) compared with the da Vinci Si (Si) system. A total of 205 TORS cases were reviewed: 109 in the SP group (November 22, 2018, through September 30, 2020), and 96 in the Si group (January 1, 2016, through November 12, 2018). Both groups had comparable operative times, rates of postoperative pharyngeal hemorrhage, length of hospital stay, and duration of nasogastric feeding tube use. There was no difference in pathological characteristics, rates of positive margins, or indications for or time to initiation of adjuvant therapy between the groups. The collective experience of 6 faculty members-who have trained 139 TORS surgeons for the SP system rollout-was compiled to provide a summary of learning experiences and technical notes on safe and efficient operation of the SP system. Conclusions and Relevance: This Review found that the functional and oncologic outcomes were comparable between TORS cases performed with the Si and SP systems, and they had similar complication rates. Recognized advantages of the SP over the Si system include the availability of bipolar-energized instruments, a usable third surgical arm, and improved camera image quality.

Photoactivated HPPH-Liposomal therapy for the treatment of HPV-Negative head and neck cancer.

OBJECTIVES: Human Papillomavirus (HPV)-negative head and neck cancer (HNC) is an aggressive malignancy with a poor prognosis. To improve outcomes, we developed a novel liposomal targeting system embedded with 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a chlorin-based photosensitizer. Upon exposure to 660 nm light, HPPH phototriggering generates reactive oxygen species. The objective of this study was to evaluate biodistribution and test efficacy of HPPH-liposomal therapy in a patient-derived xenograft (PDX) model of chemoradioresistant HNC. MATERIALS AND METHODS: PDX models were developed from two surgically resected HNCs (P033 and P038) recurrent after chemoradiation. HPPH-liposomes were created including trace amounts of DiR (Ex/Em 785/830 nm), a near infrared lipid probe. Liposomes were injected via tail vein into PDX models. Biodistribution was assessed at serial timepoints in tumor and end-organs through in vivo DiR fluorescence. To evaluate efficacy, tumors were treated with a cw-diode 660 nm laser (90 mW/cm2, 5 min). This experimental arm was compared to appropriate controls, including HPPH-liposomes without laser or vehicle with laser alone. RESULTS: HPPH-liposomes delivered via tail vein exhibited selective tumor penetration, with a peak concentration at 4 h. No systemic toxicity was observed. Treatment with combined HPPH-liposomes and laser resulted in improved tumor control relative to either vehicle or laser alone. Histologically, this manifested as both increased cellular necrosis and decreased Ki-67 staining in the tumors treated with combined therapy. CONCLUSIONS: These data demonstrate tumor-specific anti-neoplastic efficacy of HPPH-liposomal treatment for HNC. Importantly, this platform can be leveraged in future studies for targeted delivery of immunotherapies which can be packaged within HPPH-liposomes.

Monitoring postoperative ambulation and sleep after head and neck surgery: Feasibility and utility study using wearable devices.

BACKGROUND: To evaluate use of wearable activity devices to monitor trends in ambulation and sleep after head and neck surgery. METHODS: Patients utilized Fitbit devices after surgery. Daily activity and sleep scores, step counts, and total sleep time (TST) were obtained. RESULTS: There were 30 patients within the final cohort. Trends in step counts after specific procedures were identified, and higher subjective activity level correlated with step counts (r = 0.25, 95% CI = 0.07-0.41). Among patients with complete step data (n = 24), POD1 steps ≥200 were associated with reduced length of stay (4.5 ± 1.7 days vs. 7.2 ± 4.0 days, 95% CI = 0.33-5.0). Mean TST was 5.4 ± 2.5 h, TST correlated with subjective sleep scores (r = 0.25, 95% CI = 0.03-0.044), and clinical events associated with sleep-wake transitions on Fitbit devices were identified. CONCLUSIONS: Wearable activity devices appear feasible for monitoring trends in postoperative ambulation and sleep. Use of these devices may facilitate postoperative recovery.

Osteocutaneous Radial Forearm Free Flap Fixed to a Prior Osteocutaneous Free Flap: Two Case Reports.

Reconstruction of mandibular defects is best accomplished by composite bony tissue. When the fibula is not available other sources must be used. Occasionaly tumor recurence will neccesitate a further resection and bony reconstruction. We report two cases in which osteocutaneous radial forearm free tissue transfer was used for secondary reconstructio after prior bony free flap reconstruction. Laryngoscope, 132:2177-2179, 2022.

Effect of Virtual Reality on Pain Management and Opioid Use Among Hospitalized Patients After Head and Neck Surgery: A Randomized Clinical Trial.

Importance: Optimal postoperative pain management is challenging. Virtual reality (VR) provides immersive, 3-dimensional experiences that may improve pain control and reduce reliance on pharmacologic pain management. Objective: To evaluate use of VR on postoperative pain management after head and neck surgery. Design, Setting, and Participants: This prospective, pilot randomized clinical trial was conducted at Oregon Health & Science University from July 2020 to October 2021 and included patients hospitalized after major head and neck surgery. Interventions: Similar 15-minute interactive gaming experiences (Angry Birds) using an Oculus Quest VR headset (VR intervention) or a handheld smartphone device (control). Main Outcomes and Measures: The primary outcome was postintervention pain reduction. Pain scores were obtained preintervention, immediately after intervention, and then hourly for 4 hours. Secondary outcomes included changes in opioid use, measured as milligram morphine equivalents (MMEs), and patient experiences with their intervention using 5-point Likert scales. Results: Of the 30 patients randomized for inclusion, the final population included 14 patients in the VR cohort and 15 patients in the control cohort; the majority of patients were male (26 of 29 [90%]), and the mean (SD) age was 58.3 (13.8) years. After outlier removal, there were clinically meaningful reductions in postintervention pain among patients in the VR group immediately after intervention (mean difference, -1.42; 95% CI, -2.15 to -0.70; d = 1.50), at 1 hour (mean difference, -0.86; 95% CI, -1.90 to 0.14; d = 0.67), 2 hours (mean difference, -1.07; 95% CI, -2.30 to 0.14; d = 0.69), and 3 hours (mean difference, -1.36; 95% CI, -2.80 to 0.13; d = 0.71) compared with patients in the control group. Patients in the VR group also demonstrated reductions in 4-hour postintervention opioid use compared with 4-hour preintervention opioid use (mean difference, -9.10 MME; 95% CI, -15.00 to -1.27 MME; d = 0.90) and 8-hour postintervention opioid use compared with 8-hour preintervention opioid use (mean difference, -14.00 MME; 95% CI, -25.60 to -2.40 MME; d = 0.94). There were no meaningful differences in subjective patient experiences with their respective interventions. Conclusions and Relevance: In this randomized clinical trial, VR reduced pain scores and opioid use compared with a control intervention. Virtual reality may be a useful adjunct for postoperative pain management after head and neck surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT04464304.

A phase 2 trial of a topical antiseptic bundle in head and neck cancer surgery: Effects on surgical site infection and the oral microbiome.

BACKGROUND: Head and neck cancer (HNC) surgery remains an important component of management but is associated with a high rate of surgical site infection (SSI). We aimed to assess the safety and efficacy of a topical mucosal antiseptic bundle in preventing SSI and evaluate microbial predictors of infection through a genomic sequencing approach. METHODS: This study was an open-label, single-arm, single-center, phase 2 trial of a topical mucosal antiseptic bundle in patients with HNC undergoing aerodigestive tract resection and reconstruction. Patients underwent topical preparation of the oral mucosa with povidone-iodine (PI) and chlorhexidine gluconate (CHG) pre- and intra-operatively followed by oral tetracycline ointment every 6 hours for 2 days post-operatively. The primary outcome was change in bacterial bioburden at the oral surgical site. Secondary outcomes included safety, SSI, and microbial predictors of infection. FINDINGS: Of 27 patients screened between January 8, 2021, and May 14, 2021, 26 were enrolled and 25 completed the study. There were no antiseptic-related adverse events. The topical mucosal antiseptic bundle significantly decreased oral bacterial colony-forming units from pre-operative levels (log10 mean difference 4·03, 95%CI 3·13-4·;92). There were three SSI (12%) within 30 days. In correlative genomic studies, a distinct set of amplicon sequence variants in the post-operative microbiome was associated with SSI. Further, despite no instance of post-operative orocervical fistula, metagenomic sequence mapping revealed the oral cavity as the origin of the infectious organism in two of the three SSI. INTERPRETATION: The bacterial strains which subsequently caused SSI were frequently identified in the pre-operative oral cavity. Accordingly, a topical antiseptic bundle decreased oral bacterial bioburden throughout the peri-operative period and was associated with a low rate of SSI, supporting further study of topical antisepsis in HNC surgery. FUNDING: Alliance Oncology.

Perioperative Topical Antisepsis and Surgical Site Infection in Patients Undergoing Upper Aerodigestive Tract Reconstruction.

Importance: Surgical site infections (SSIs) after vascularized reconstruction of the upper aerodigestive tract (UADT) are associated with considerable morbidity. The association between perioperative prophylaxis practices, particularly topical antisepsis, and SSIs remains uncertain. Objective: To assess the association between perioperative topical antisepsis and SSIs in patients undergoing vascularized reconstruction of the UADT. Design, Setting, and Participants: This cohort study included patients from 12 academic tertiary care centers over an 11-month period, from July 1, 2020, to June 1, 2021. Patients undergoing open surgical procedures requiring a communication between the UADT and cervical skin with a planned regional pedicled flap, free flap, or both were included. Patients with an active infection at the time of surgical procedure were excluded. Main Outcomes and Measures: The primary outcome measure was an SSI within 30 days of surgery. The association of demographic characteristics, perioperative antibiotic prophylaxis, surgical technique, and postoperative care with SSIs was assessed using univariable and multivariable analyses. The relative risk ratio and 95% CIs for developing SSI were calculated for each of the variables based on predetermined categories. Variables for which the relative risk 95% CI did not include the value of zero effect (relative risk = 1.00) were included in the multivariable model. Results: A total of 554 patients (median age, 64 years; range, 21-95 years; 367 men [66.2%]) were included. Cancer ablation was the most frequent reason for surgery (n = 480 [86.6%]). Overall, the SSI rate was 20.9% (n = 116), with most infections involving the head and neck surgical site only (91 [78.4%]). The median time to SSI diagnosis was 11 days (range, 1-28 days). Topical antisepsis mucosal preparation was performed preoperatively in 35.2% (195) and postoperatively in 52.2% (289) of cases. Ampicillin and sulbactam was the most common systemic antibiotic prophylaxis agent used (n = 367 [66.2%]), with 24 hours being the most common duration (n = 363 [65.5%]). On multivariable analysis, preoperative topical antisepsis mucosal preparation (odds ratio [OR], 0.49; 95% CI, 0.30-0.77) and systemic prophylaxis with piperacillin and tazobactam (OR, 0.42; 95% CI, 0.21-0.84) were associated with a decreased risk of a postoperative SSI. The use of an osseous vascularized flap was associated with an increased risk of postoperative SSI (OR, 1.76; 95% CI, 1.13-2.75). Conclusions and Relevance: Findings of this study suggest that preoperative topical antisepsis mucosal preparation was independently associated with a decreased risk of SSIs in a 12-center multi-institutional cohort. Further investigation of the association between individual perioperative practices and the incidence of postoperative SSIs is necessary to develop evidence-based protocols to reduce SSIs after UADT reconstruction.

Positive youth development: minority male participation in a sport-based afterschool program in an urban environment.

PURPOSE: As there is little research that investigates the experiences of minority boys participating in youth development programs (Fashola, 2003), the current research focused on a sport-based youth development program for early adolescent Black and Latino boys in Hartford, CT. Specifically, the present study explored (a) what attracted minority boys to participate in youth development programs, (b) what kept them involved, and (c) whether their involvement translated into positive developmental outcomes. METHOD: The study used semistructured individual interviews to collect data from 8 participants and their parents. The research team deductively coded interviews in accordance with the a-priori framework of the Five Cs and Sixth C of youth development (i.e., competence, character, caring, confidence, connection, and contribution; Roth & Brooks-Gunn, 2003). In addition, interviews were deductively coded to investigate why participants became involved in the program and why they continued participation. RESULTS: Findings from the study indicated that participants became involved with the Sport Hartford Boys (SHB) program mainly due to its emphasis on sport-related activities. Moreover, findings related to the youths' continued involvement revealed their value for the SHB program as a safe place that kept them out of trouble and provided experiences that led to positive personal development. Furthermore, results indicated that participation in the program facilitated the development of each "C" of youth development. CONCLUSION: By promoting positive relationships and providing opportunities for self-exploration in a safe and trusting environment, afterschool programs can cultivate positive youth development in minority boys, at least in the short-term.

Preadolescent female development through sport and physical activity: a case study of an urban after-school program.

Youth development research has found that children become more engaged and benefit more from being incorporated as decision makers. Thus participation helps promote development and encourages engagement. Based in theories of engagement and free-choice learning, the current research focused on a program combining sport/physical activity, life skills, and mentoring while promoting healthy life choices for preadolescent girls of color The co-investigators, all women, conducted two 2-hr visits per week for two 12-week periods with a group of 8 girls at a community recreation center in Hartford, Connecticut, including lessons in nutrition and life skills and participation in a sport/physical activity. Five of the girls completed every stage of data collection, including participant journals and four individual interviews with each participant and her parents, over the course of the 24 weeks. The co-investigators also kept journals throughout the program. The results reflected the following themes: self-esteem/self-worth, accountability/responsibility for self connections to community and a sense of belonging, knowledge and acquisition of health/life skills, application of those skills, and planning and recognizing one's own influence on self and others.

Work-family conflict, part I: Antecedents of work-family conflict in national collegiate athletic association division I-A certified athletic trainers.

CONTEXT: Work-family conflict (WFC) involves discord that arises when the demands of work interfere with the demands of family or home life. Long work hours, minimal control over work schedules, and time spent away from home are antecedents to WFC. To date, few authors have examined work-family conflict within the athletic training profession. OBJECTIVE: To investigate the occurrence of WFC in certified athletic trainers (ATs) and to identify roots and factors leading to quality-of-life issues for ATs working in the National Collegiate Athletic Association Division I-A setting. DESIGN: Survey questionnaire and follow-up, in-depth, in-person interviews. SETTING: Division I-A universities sponsoring football. PATIENTS OR OTHER PARTICIPANTS: A total of 587 ATs (324 men, 263 women) responded to the questionnaire. Twelve ATs (6 men, 6 women) participated in the qualitative portion: 2 head ATs, 4 assistant ATs, 4 graduate assistant ATs, and 2 AT program directors. DATA COLLECTION AND ANALYSIS: Multiple regression analysis was performed to determine whether workload and travel predicted levels of WFC. Analyses of variance were calculated to investigate differences among the factors of sex, marital status, and family status. Interviews were transcribed verbatim and then analyzed using computer software as well as member checks and peer debriefing. The triangulation of the data collection and multiple sources of qualitative analysis were utilized to limit potential researcher prejudices. RESULTS: Regression analyses revealed that long work hours and travel directly contributed to WFC. In addition to long hours and travel, inflexible work schedules and staffing patterns were discussed by the interview participants as antecedents to WFC. Regardless of sex (P = .142), marital status (P = .687), family status (P = .055), or age of children (P = .633), WFC affected Division I-A ATs. CONCLUSIONS: No matter their marital or family status, ATs employed at the Division I-A level experienced difficulties balancing their work and home lives. Sources of conflict primarily stemmed from the consuming nature of the profession, travel, inflexible work schedules, and lack of full-time staff members.

Work-family conflict, part II: Job and life satisfaction in national collegiate athletic association division I-A certified athletic trainers.

CONTEXT: Previous researchers have shown that work-family conflict (WFC) affects the level of a person's job satisfaction, life satisfaction, and job burnout and intentions to leave the profession. However, WFC and its consequences have not yet been fully investigated among certified athletic trainers. OBJECTIVE: To investigate the relationship between WFC and various outcome variables among certified athletic trainers working in National Collegiate Athletic Association Division I-A settings. DESIGN: A mixed-methods design using a 53-item survey questionnaire and follow-up in-depth interviews was used to examine the prevalence of WFC. SETTING: Division I-A universities sponsoring football. PATIENTS OR OTHER PARTICIPANTS: A total of 587 athletic trainers (324 men, 263 women) responded to the questionnaire, and 12 (6 men, 6 women) participated in the qualitative portion of the mixed-methods study. DATA COLLECTION AND ANALYSIS: We calculated Pearson correlations to determine the relationship between WFC and job satisfaction, life satisfaction, and job burnout. Regression analyses were run to determine whether WFC was a predictor of job satisfaction, job burnout, or intention to leave the profession. Interviews were transcribed verbatim and then analyzed using the computer program N6 as well as member checks and peer debriefing. RESULTS: Negative relationships were found between WFC and job satisfaction (r = -.52, P < .001). Positive were noted between WFC and job burnout (r = .63, P < .001) and intention to leave the profession (r = .46, P < .001). Regression analyses revealed that WFC directly contributed to job satisfaction (P < .001), job burnout (P < .001), and intention to leave the profession (P < .001). CONCLUSIONS: Overall, our findings concur with those of previous researchers on WFC and its negative relationships to job satisfaction and life satisfaction and positive relationship to job burnout and intention to leave an organization. Sources of WFC, such as time, inflexible work schedules, and inadequate staffing, were also related to job burnout and job dissatisfaction in this population.

Listening to the voices: the experiences of African American female student athletes.

"Women of color ... have historically been silenced in society and sport" (Smith, 1992, p. 228). This study examined the sport participation patterns of 12 African American female collegiate student athletes using qualitative methods. Data were collected at a large midwestern university during the 1998-99 academic year. An emergent theme was the effect of silencing by the media, athletic administrators, coaches, and other student athletes on the experiences of African American female student athletes. The findings are presented in the following order: the theoretical framework for the study, an introduction to silencing, an overview of the research analyses, a description of the research setting, and a presentation of the data surrounding the theme of silencing as told through the participants' voices. Following these sections is a discussion and suggestions for future research.

Coaching difference: a case study of 4 African American women student-athletes.

The purpose of the present investigation was to describe the experiences of African American women student-athletes and the role that coaches play in those experiences. This study profiles 4 women who participated in National Collegiate Athletic Association Division I cross-country, crew, track and field, and volleyball. Using data gathered through the qualitative methods of document analysis, background questionnaires, focus groups, grounded surveys, and in-depth individual interviews, the results of the study are focused on how coaches affect individual student-athletes and, most specifically, a particular segment of the athletic world that tends to be overlooked: the African American woman. Results are organized according to the following themes that emerged through the collection of data: (a) the involvement of coaches in African American women student-athletes' exposure to racism through stereotypes, (b) coaches as significant influences on African American women becoming involved and remaining involved in sport, and (c) power structures in sport and society affecting African American women as a form of institutional racism. A practical applications section follows the results.