Preclinical evidence suggests that high-dose hypofractionated ionizing radiation (IR) can enhance anti-tumor immunity and result in significant tumor control when combined with immune checkpoint blockade (ICB). However, low-dose daily fractioned IR used for many tumor types including head and neck squamous cell carcinoma results in lymphopenia and may be immunosuppressive. We compared immune correlates, primary tumor and abscopal tumor control rates following the addition of PD-1 mAb to either high-dose hypofractioned (8Gyx2) or low-dose daily fractionated (2Gyx10) IR in syngeneic models of cancer. When compared to 2Gyx10 IR, 8Gyx2 IR preserved peripheral and tumor-infiltrating CD8 T-lymphocyte accumulation and activation and reduced peripheral and tumor gMDSC accumulation. Regulatory T-lymphocytes were largely unaltered. Type I and I IFN levels and expression of IFN-responsive MHC class I and PD-L1 was enhanced in tumors treated with 8Gyx2 compared to 2Gyx10 IR. Functionally, tumor-specific CD8 T-lymphocyte IFN responses within tumor draining lymph nodes were enhanced following 8Gyx2 IR but suppressed following 2Gyx10 IR. When combined with PD-1 mAb, reversal of adaptive immune resistance and subsequent enhancement of CD8+ cell dependent primary and abscopal tumor control was observed following 8Gyx2 but not 2Gyx10 IR. These data strongly support that compared to daily fractionated low-dose IR, high-dose hypofractionated IR preserves or enhances anti-tumor immunity and, when combined with PD-1 mAb to reverse adaptive immune resistance, promotes anti-tumor immunity to control primary and distant tumors. These data critically inform the rational design of trials combining IR and ICB.

BackgroundNatural killer (NK) cells recognize and lyse target tumor cells in an MHC-unrestricted fashion and complement antigen- and MHC-restricted killing by T-lymphocytes. NK cells and T-lymphocytes mediate early killing of targets through a common granzyme B-dependent mechanism. Tumor cell resistance to granzyme B and how this alters NK cell killing is not clearly defined.MethodsTumor cell sensitivity to cultured murine KIL and human high affinity NK (haNK) cells in the presence or absence of AZD1775, a small molecule inhibitor of WEE1 kinase, was assessed via real time impedance analysis. Mechanisms of enhanced sensitivity to NK lysis were determined and in vivo validation via adoptive transfer of KIL cells into syngeneic mice was performed.ResultsCultured murine KIL cells lyse murine oral cancer 2 (MOC2) cell targets more efficiently than freshly isolated peripheral murine NK cells. MOC2 sensitivity to granzyme B-dependent KIL cell lysis was enhanced by inhibition of WEE1 kinase, reversing G2/M cell cycle checkpoint activation and resulting in enhanced DNA damage and apoptosis. Treatment of MOC2 tumor-bearing wild-type C57BL/6 mice with AZD1775 and adoptively transferred KIL cells resulted in enhanced tumor growth control and survival over controls or either treatment alone. Validating these findings in human models, WEE1 kinase inhibition sensitized two human head and neck cancer cell lines to direct lysis by haNK cells. Further, WEE1 kinase inhibition sensitized these cell lines to antibody-dependent cell-mediated cytotoxicity when combined with the anti-PD-L1 IgG1 mAb Avelumab.ConclusionsTumor cell resistance to granzyme B-induced cell death can be reversed through inhibition of WEE1 kinase as AZD1775 sensitized both murine and human head and neck cancer cells to NK lysis. These data provide the pre-clinical rationale for the combination of small molecules that reverse cell cycle checkpoint activation and NK cellular therapies.

Purpose: Surgical resection of primary tumor with regional lymphadenectomy remains the treatment of choice for patients with advanced human papillomavirus-negative head and neck squamous cell carcinoma. However, even when pathologic disease-free margins can be achieved, locoregional and/or distant disease relapse remains high. Perioperative immunotherapy may improve outcomes, but mechanistic data supporting the use of neoadjuvant or adjuvant treatment clinically are sparse.Experimental Design: Two syngeneic models of oral cavity carcinoma with defined T-cell antigens were treated with programmed death receptor 1 (PD-1) mAb before or after surgical resection of primary tumors, and antigen-specific T-cell responses were explored with functional and in vivo challenge assays.Results: We demonstrated that functional immunodominance developed among T cells targeting multiple independent tumor antigens. T cells specific for subdominant antigens expressed greater levels of PD-1. Neoadjuvant, but not adjuvant, PD-1 immune checkpoint blockade broke immunodominance and induced Tcell responses to dominant and subdominant antigens. Using tumors lacking the immunodominant antigen as a model of antigen escape, neoadjuvant PD-1 immune checkpoint blockade induced effector T-cell immunity against tumor cells lacking immunodominant but retaining subdominant antigen. When combined with complete surgical excision, neoadjuvant PD-1 immune checkpoint blockade led to formation of immunologic memory capable of preventing engraftment of tumors lacking the immunodominant but retaining subdominant antigen.Conclusions: Together, these results implicate PD-1 expression by T cells in the mechanism of functional immunodominance among independent T-cell clones within a progressing tumor and support the use of neoadjuvant PD-1 immune checkpoint blockade in patients with surgically resectable carcinomas.

Background The most important purpose of reconstruction is to increase or restore the patient's quality of life (QOL). The purpose of our study was to evaluate the QOL and aesthetic outcomes of patients after autologous versus implant-based breast reconstruction. Methods Patients who underwent breast reconstruction between 2009 and 2011 were included. The Breast-Q, a validated breast reconstruction QOL questionnaire, was used along with postoperative photographs panel analyses using a multiparameter breast-specific aesthetic outcome scale and retrospective evaluation of demographic and treatment data. Results Of 820 patients, 261 complete questionnaires were evaluated. On the multivariable linear regression, the “satisfaction with breasts” was positively influenced by autologous and bilateral reconstructions, whereas radiation therapy (RTx), the time between the reconstruction and the questionnaire, and the number of surgeries due to complications were negative factors (adjusted R 2 = 0.183; P < 0.001). The same factors influenced the “satisfaction with the outcomes.” The mean “overall breast appearance” was also positively influenced by autologous and bilateral reconstructions, and RTx and the total number of surgeries were negative predictive factors (adjusted R 2 = 0.311, P < 0.001). Conclusions The aesthetic result and QOL after breast reconstruction for breast cancer treatment are positively influenced by the use of autologous tissue and bilaterality. Factors that negatively influenced the aesthetic result and the QOL include use of RTx, a higher number of surgeries needed for the reconstruction, reoperations due to complications, higher body mass index, and a longer time elapsed between reconstruction and the questionnaire.

Purpose of review Frontal sinus fracture management is evolving. This article will highlight recent literature and provide an evidence-based algorithm in the contemporary management of frontal sinus fractures. Recent findings The role of transnasal endoscopic treatment of frontal sinus fractures has expanded to include fracture reduction and posterior table reconstruction. Evidence continues to support the safety of nonoperative management in select frontal sinus outflow tract fractures. Summary The management of frontal sinus fractures with frontal sinus outflow tract injury continues to evolve with a trend toward observation and minimally invasive approaches. Restoration of the frontal sinus outflow tracts with transnasal endoscopic techniques is being used increasingly in the acute and delayed setting. For severe fractures, the role of conservative treatment paradigms requires further research.

Objectives Determine if direct tumor cell cytotoxicity, antigen release, and susceptibility to T-lymphocyte killing following radiation treatment is dose-dependent. Materials and Methods Mouse oral cancer cells were engineered to express full-length ovalbumin as a model antigen. Tumor antigen release with uptake and cross presentation of antigen by antigen presenting cells with subsequent priming and expansion of antigen-specific T-lymphocytes following radiation was modeled in vitro and in vivo. T-lymphocyte mediated killing was measured following radiation treatment using a novel impedance-based cytotoxicity assay. Results Radiation treatment induced dose-dependent induction of executioner caspase activity and apoptosis in MOC1 cells. In vitro modeling of antigen release and T-lymphocyte priming demonstrated enhanced proliferation of OT-1 T-lymphocytes with 8 Gy treatment of MOC1ova cells compared to 2 Gy. This was validated in vivo following treatment of established MOC1ova tumors and adoptive transfer of antigen-specific T-lymphocytes. Using a novel impedance – based cytotoxicity assay, 8 Gy enhanced tumor cell susceptibility to T-lymphocyte killing to a greater degree than 2 Gy. Conclusion In the context of using clinically-relevant doses of radiation treatment as an adjuvant for immunotherapy, 8 Gy is superior to 2 Gy for induction of antigen-specific immune responses and enhancing tumor cell susceptibility to T-lymphocyte killing. These findings have significant implications for the design of trials combining radiation and immunotherapy.

Background Telemedicine has become increasingly popular in the care of rhinologic patients during the COVID-19 pandemic. This change in practice patterns may place patients at risk of a perceived lower-quality exchange with their healthcare provider, which may in turn impact satisfaction. Objective This study compares patient satisfaction scores between in-person clinic visits and telemedicine video visits in patients with chronic rhinosinusitis (CRS). Methods Sixty-nine patients with CRS presenting to an academic rhinology clinic between March to April 2020 were retrospectively divided into video visits (VV) and clinic visits (CV) groups based on mandated state quarantine orders on March 19. Patient demographics, disease severity measures, and Patient Satisfaction Questionnaire-18 (PSQ-18) scores were collected and analyzed. Chi square test and Fisher’s exact test were performed. Results There were no significant differences in age (p = 0.81), gender (p = 0.55), CRS phenotype (p = 0.16), and disease severity measures (Sinonasal Outcomes Test-22 (SNOT-22) (p = 0.92); Lund-Mackay score (p = 0.96)) between the video and clinic visit groups. There were no significant differences in PSQ-18 total scores (VV PSQ-18 mean score = 78.1, CV PSQ-18 mean score = 78.4; p = 0.67) or the following subdomain scores between the two groups: general satisfaction (p = 0.73), technical quality (p = 0.62), interpersonal manner (p = 0.41), communication (p = 0.31), financial aspects (p = 0.89), time spent with doctor (p = 0.88), and accessibility and convenience (p = 0.47). Conclusion Patient satisfaction with telemedicine in the COVID-19 pandemic parallels that of traditional in-person visits. Video visits can serve as a viable alternative to clinic visits, while still maintaining high satisfaction.

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