Outcomes in Minor Salivary Gland Tumors-A 20+ Year Tertiary-Care Center Experience.

Objective: Minor salivary gland carcinomas are challenging to study due to their rarity and heterogeneity. We aim to further characterize clinical characteristics, treatment, and outcomes over 20 years within a single institution. Study Design: Retrospective chart review was conducted on 210 patients who received primary treatment for minor salivary gland malignancy from 2000 to 2022. Setting: Single tertiary-care center. Methods: Multivariable Cox proportional hazards method was used to examine the relationship between pre-determined clinically important variables and outcomes. Results: Five-year overall survival was 77.8% (72.0-84.1). Advanced clinical T stage portended over a 2 times higher risk of death and recurrence. High pathologic grade was associated with a near 3 times higher risk of death and recurrence. There was a predominance of occult nodal metastases in level II for oral cavity and oropharynx site tumors. Conclusion: Clinical T stage and grade were important for overall survival, local, regional, and distant recurrence-free survival. Occult nodal metastases occurred most often in level II.

Effects of Tongue Strength Training on Quality of Life in Head and Neck Cancer Patients: Results From a Pilot Interventional Clinical Trial.

BACKGROUND: Head and neck cancer (HNC) patients often have dysphagia following surgical and/or chemoradiation treatment, which can lead to reduced quality of life. Some patients suffer from decreased tongue strength and mobility that may cause discomfort and difficulty with swallowing. Our group has developed a patented genioglossus muscle strength trainer (GMST) to increase tongue protrusive force that has been used in patients with sleep apnea. We hypothesized that the GMST device would increase tongue strength in the HNC population. METHODS: We conducted an IRB approved, non-randomized, interventional clinical trial of HNC patients with dysphagia to determine the effect of GMST on tongue strength. Our secondary objective was to assess dysphagia quality of life, as determined by questionnaires. Genioglossus muscle strength measurements (measured in Newtons, N) and dysphagia quality of life scores (SWAL-QoL questionnaire) were obtained from enrolled patients at baseline and following 4 weeks of intervention. Treatment was at-home GMST exercise regimen 3 times daily, 5 days per week. Compliance was assessed via review of training logs. Two-sided paired t-tests at significance level α = .05 were performed to assess difference in mean GG muscle strength pre- and post-treatment. RESULTS: Out of 10 patients initially enrolled, 7 patients completed the trial. Eighty-six percent were male and the average age was 60. About 5 patients had surgery plus adjuvant radiation and 2 patients had primary radiation. All patients had baseline dysphagia as determined by patient complaint and/or objective measurement (prior modified barium swallow). No adverse events were reported. We observed a statistically significant increase in genioglossus muscle strength (mean change: 4.0 N, 95% CI 1.1-6.9, P = .015) after 4 weeks of treatment. Patients reported reduced swallowing burden and feeling of stigma around eating based on SWAL-QoL results. CONCLUSIONS: Our data suggest that protrusive tongue-training exercises utilizing a novel tongue trainer device is well-tolerated and increases genioglossus muscle strength in treated HNC patients complaining of dysphagia. Patient-reported outcomes based on the SWAL-QoL survey indicate improvements in quality-of-life post-treatment, although our results are limited by small sample size. Larger studies are needed to see if this device could have clinically meaningful results for this difficult-to-treat patient population.

Patterns of failure after salvage head and neck surgery.

BACKGROUND: Advancements in immunotherapy for recurrent head and neck cancer have necessitated a better understanding of salvage surgical outcomes. This study aimed to determine patterns of failure following salvage head and neck surgery. METHODS: A retrospective cohort study was conducted of 280 patients who underwent salvage surgery for recurrent mucosal squamous cell carcinoma from 1997 to 2018. Cumulative incidence was calculated using the nonparametric Aalen-Johansen estimator. Time to recurrence (TTR) and overall survival (OS) were estimated using the Kaplan-Meier method and multivariable Cox proportional hazard models were used to evaluate associated factors. RESULTS: The 2 and 5-year cumulative incidence rates of second recurrence were 48.3 % (95 % CI 42.4-54.3) and 54.9 % (95 % CI 48.9-60.8), respectively. At 5 years, second locoregional recurrence was twice as common as distant recurrence (41.5 % [95 % CI 35.6-47.4] vs. 21.7 % [95 % CI 16.8-26.6]). The median TTR was 21.1 months (95 % CI 4.4-34.8), which varied by site (38.2 larynx/hypopharynx, 13.9 oral cavity, 8.3 sinonasal, and 7.8 oropharynx, P=.0001). The median OS was 32.1 months (95 % CI 24.1-47.6) and was worse for patients who were Black (hazard ratio [HR] 2.15, 95 % CI 1.19-3.9), current smokers (HR 2.73, 95 % CI 1.53-4.88), former smokers (HR 2.00, 95 % CI 1.19-3.35), ≥ 60 years of age (HR 1.41, 95 % CI 1.01-1.97), or received multimodal primary therapy (HR 1.98, 95 % CI 1.26-3.13). CONCLUSION: Rates of recurrence and mortality after salvage surgery were poor but worse for patients who were Black, older, smoked, had initial multimodal therapy, or had sinonasal or oropharyngeal cancers.

Primary fit tracheoesophageal puncture in primary versus salvage laryngectomy: Short-term and long-term complications and functional outcomes.

BACKGROUND: Primary fit tracheoesophageal puncture (TEP) is widely preferred for individuals who have not undergone prior radiation. However, there is no consensus on the relative utility of primary-fit TEP in the setting of salvage laryngectomy. METHODS: A retrospective, single-center review was conducted of individuals undergoing laryngectomy with primary fit TEP between 2012 and 2018. Multivariable analysis was conducted to compare short-term and long-term complications, as well as speech and swallowing outcomes, of those who underwent primary versus salvage laryngectomy. RESULTS: In this study, 134 patients underwent total laryngectomy with primary fit TEP. Aside from a higher rate of peristomal dehiscence (13.1% vs. 1.4%) found in the salvage group, there was no difference in incidence of all other complications, including pharyngocutaneous fistula formation. The groups had comparable speech and swallow outcomes. CONCLUSION: Primary fit TEP is a safe and effective surgical choice for individuals undergoing salvage laryngectomy who desire a voice prosthesis.

Evaluating the impact of the degree of extranodal extension on outcomes in locally advanced oral cavity cancer.

BACKGROUND: Evaluate whether extranodal extension (ENE) extent impacts outcomes in patients with oral cavity squamous cell carcinoma (OCSCC). METHODS: From an institutional database, patients with OCSCC and pathologic ENE who received adjuvant treatment were included. Surgical slides were reviewed to confirm ENE extent. Multivariable Cox regression was used to relate patient/treatment characteristics with disease-free survival (DFS) and overall survival (OS). ENE was analyzed as both a dichotomous and continuous variable. RESULTS: A total of 113 patients were identified. Between major (>2 mm) versus minor ENE (≤2 mm), there was no significant difference in DFS (HR 1.18, 95%CI 0.72-1.92, p = 0.51) or OS (HR 1.17, 95%CI 0.70-1.96, p = 0.55). There was no significant association between ENE as a continuous variable and DFS (HR 0.97 per mm, 95%CI 0.87-1.4, p = 0.96) or OS (HR 0.96 per mm, 95%CI 0.83-1.11, p = 0.58). CONCLUSION: No significant relationship was seen between ENE extent and DFS or OS in individuals with OCSCC.

The Increasing Problem of Syphilis Manifesting as Head and Neck Cancer: A Case Series.

Syphilis is an infectious disease caused by the spirochete Treponema pallidum. Rates have been rising in the US and globally. Known as the "Great Imitator," syphilis can involve head and neck subsites, and often can masquerade as possible carcinoma of the head and neck. Here, we present three distinct cases of syphilis presenting as suspected head and neck malignancy involving the oropharynx, larynx and oral cavity. All cases were diagnosed on surgical pathologic examination of diseased tissues and treated. It is important for practicing otolaryngologists to understand head and neck manifestations of syphilis to facilitate proper diagnosis and treatment. Laryngoscope, 134:236-239, 2024.

Oral Cavity Cancer Surgical and Nodal Management: A Review From the American Head and Neck Society.

Importance: Lymph node metastases from oral cavity cancers are seen frequently, and there is still inconsistency, and occasional controversies, regarding the surgical management of the neck in patients with oral cancer. This review is intended to offer a surgically focused discussion of the current recommendations regarding management of the neck, focusing on the indications and extent of dissection required in patients with oral cavity squamous cell carcinoma while balancing surgical risk and oncologic outcome. Observations: The surgical management of the neck for oral cavity cancer has been robustly studied, as evidenced by substantial existing literature surrounding the topic. Prior published investigations have provided a sound foundation on which data-driven treatment algorithms can generally be recommended. Conclusions: Existing literature suggests that patients with oral cavity cancer should be fully staged preoperatively, and most patients should receive a neck dissection even when clinically N0. Quality standards supported by the literature include separation of each level during specimen handling and lymph node yield of 18 or more nodes. Sentinel lymph node biopsy can be considered in select tumors and within a well-trained multidisciplinary team.

Identifying locally actionable strategies to increase participant acceptability and feasibility to participate in Phase I cancer clinical trials.

BACKGROUND: Recruitment of cancer clinical trial (CCT) participants, especially participants representing the diversity of the US population, is necessary to create successful medications and a continual challenge. These challenges are amplified in Phase I cancer trials that focus on evaluating the safety of new treatments and are the gateway to treatment development. In preparation for recruitment to a Phase I recurrent head and neck cancer (HNC) trial, we assessed perceived barriers to participation or referral and suggestions for recruitment among people with HNC and community physicians (oncologist, otolaryngologist or surgeon). METHODS: Between December 2020 and February 2022, we conducted a qualitative needs assessment via semistructured interviews with a race and ethnicity-stratified sample of people with HNC (n = 30: 12 non-Hispanic White, 9 non-Hispanic African American, 8 Hispanic and 1 non-Hispanic Pacific Islander) and community physicians (n = 16) within the University of Florida Health Cancer Center catchment area. Interviews were analyzed using a qualitative content analysis approach to describe perspectives and identify relevant themes. RESULTS: People with HNC reported thematic barriers included: concerns about side effects, safety and efficacy; lack of knowledge and systemic and environmental obstacles. Physicians identified thematic barriers of limited physician knowledge; clinic and physician barriers and structural barriers. People with HNC and physicians recommended themes included: improved patient education, dissemination of trial information and interpersonal communication between community physicians and CCT staff. CONCLUSIONS: The themes identified by people with HNC and community physicians are consistent with research efforts and recommendations on how to increase the participation of people from minoritized populations in CCTs. This community needs assessment provides direction on the selection of strategies to increase CCT participation and referral. PATIENT OR PUBLIC CONTRIBUTION: This study focused on people with HNC and community physicians' lived experience and their interpretations of how they would consider a future Phase I clinical trial. In addition to our qualitative data reflecting community voices, a community member reviewed the draft interview guide before data collection and both people with HNC and physicians aided interpretation of the findings.

Margin Assessment Methods in Oral Cavity Squamous Cell Carcinoma and Recurrence: Tumor Bed vs Resection Specimen Sampling.

Importance: Positive margins and margin clearance are risk factors for recurrence in oral cavity squamous cell carcinoma (OCSCC), and these features are used to guide decisions regarding adjuvant radiation treatment. However, the prognostic value of intraoperative tumor bed vs resection specimen sampling is not well defined. Objective: To determine the prognostic implications of intraoperative margin assessment methods (tumor bed vs resection specimen sampling) with recurrence among patients who undergo surgical resection for OCSCC. Design, Setting, and Participants: This was a retrospective study of patients who had undergone surgical resection of OCSCC between January 1, 2000, and December 31, 2021, at a tertiary-level academic institution. Patients were grouped by margin assessment method (tumor bed [defect] or resection specimen sampling). Of 223 patients with OCSCC, 109 patients had localized tumors (pT1-T2, cN0), 154 had advanced tumors, and 40 were included in both cohorts. Disease recurrence after surgery was estimated by the cumulative incidence method and compared between cohorts using hazard ratios (HRs). Data analyses were performed from January 5, 2023, to April 30, 2023. Main Outcome and Measures: Recurrence-free survival (RFS). Results: The study population comprised 223 patients (mean [SD] age, 62.7 [12.0] years; 88 (39.5%) female and 200 [90.0%] White individuals) of whom 158 (70.9%) had defect-driven and 65 (29.1%) had specimen-driven margin sampling. Among the 109 patients with localized cancer, intraoperative positive margins were found in 5 of 67 (7.5%) vs 8 of 42 (19.0%) for defect- vs specimen-driven sampling, respectively. Final positive margins were 3.0% for defect- (2 of 67) and 2.4% for specimen-driven (1 of 42) margin assessment. Among the 154 patients with advanced cancer, intraoperative positive margins were found in 29 of 114 (25.4%) vs 13 of 40 (32.5%) for defect- and specimen-driven margins, respectively. Final positive margins were higher in the defect-driven group (9 of 114 [7.9%] vs 1 of 40 [2.5%]). When stratified by margin assessment method, the 3-year rates of local recurrence (9.7% vs 5.1%; HR, 1.37; 95% CI, 0.51-3.66), regional recurrence (11.0% vs 10.4%; HR, 0.85; 95% CI, 0.37-1.94), and distant recurrence (6.4% vs 5.0%; HR, 1.10; 95% CI, 0.36-3.35) were not different for defect- vs specimen-driven sampling cohorts, respectively. The 3-year rate of any recurrence was 18.9% in the defect- and 15.2% in the specimen-driven cohort (HR, 0.93; 95% CI, 0.48-1.81). There were no differences in cumulative incidence of disease recurrence when comparing defect- vs specimen-driven cases. Conclusions and Relevance: The findings of this retrospective cohort study indicate that margin assessment methods using either defect- or specimen-driven sampling did not demonstrate a clear association with the risk of recurrence after OCSCC resection. Specimen-driven sampling may be associated with reduced surgical margin positivity rates, which often necessitate concurrent chemotherapy with adjuvant radiation therapy.

CYP2D6-guided opioid therapy for adults with cancer pain: A randomized implementation clinical trial.

INTRODUCTION: The CYP2D6 enzyme metabolizes opioids commonly prescribed for cancer-related pain, and CYP2D6 polymorphisms may contribute to variability in opioid response. We evaluated the feasibility of implementing CYP2D6-guided opioid prescribing for patients with cancer and reported pilot outcome data. METHODS: Adult patients from two cancer centers were prospectively enrolled into a hybrid implementation-effectiveness clinical trial and randomized to CYP2D6-genotype-guided opioid selection, with clinical recommendations, or usual care. Implementation metrics, including provider response, medication changes consistent with recommendations, and patient-reported pain and symptom scores at baseline and up to 8 weeks, were assessed. RESULTS: Most (87/114, 76%) patients approached for the study agreed to participate. Of 85 patients randomized, 71% were prescribed oxycodone at baseline. The median (range) time to receive CYP2D6 test results was 10 (3-37) days; 24% of patients had physicians acknowledge genotype results in a clinic note. Among patients with CYP2D6-genotype-guided recommendations to change therapy (n = 11), 18% had a change congruent with recommendations. Among patients who completed baseline and follow-up questionnaires (n = 48), there was no difference in change in mean composite pain score (-1.01 ± 2.1 vs. -0.41 ± 2.5; p = 0.19) or symptom severity at last follow-up (3.96 ± 2.18 vs. 3.47 ± 1.78; p = 0.63) between the usual care arm (n = 26) and genotype-guided arm (n = 22), respectively. CONCLUSION: Our study revealed high acceptance of pharmacogenetic testing as part of a clinical trial among patients with cancer pain. However, provider response to genotype-guided recommendations was low, impacting assessment of pain-related outcomes. Addressing barriers to utility of pharmacogenetics results and clinical recommendations will be critical for implementation success.

Survival Outcomes of Advanced Thyroid Cancer Enriched in Brain Metastases Following Treatment With Small Molecule Inhibitors.

OBJECTIVE: Small molecule inhibitors (SMIs) are targeted therapies increasingly used in advanced thyroid carcinomas. This study aimed to evaluate the survival outcomes of thyroid cancer on SMI treatment, including in patients with brain metastases. METHODS: This retrospective study included patients with thyroid carcinomas who received at least one SMI between 2008 and 2022 at a tertiary level, academic institution. SMI included lenvatinib, sorafenib, dabrafenib-trametinib, selpercatinib, and cabozantinib. Patients were grouped by the presence of brain metastasis. Kaplan-Meier and log-rank tests modeled the overall survival (OS), defined from detection of first metastasis. RESULTS: In total, 116 patients (49.1% female, median age 61.1 years [IQR, 51.1-71.0]) were included. Thyroid cancer subtypes were: 57 (49.6%) papillary, 23 (19.8%) anaplastic, 23 (19.8%) medullary, and 13 (11.2%) follicular. There were 18 (15.5%) patients with brain metastases, and 98 (84.5%) with visceral metastases. Age, sex, thyroid subtype, SMI, and time to recurrence were not different between cohorts. OS was shorter in the brain metastasis cohort (31.7 vs 42.2 months, P =.44) and was not different after excluding anaplastic thyroid cancer (29.1 vs 62.3 months, P =.21). In the case of papillary thyroid cancer, patients with brain metastases trended toward worse OS (22.0 vs 59.9 months, P =.13). Nonanaplastic histology, total thyroidectomy (OR, 40.0; P <.001), number of unique therapies (OR, 10.9; P =.047), and mutation-directed therapy (OR, 24.7; P =.003) were associated with improved OS. CONCLUSION: This single-institutional analysis reports survival outcomes of 116 patients with advanced thyroid cancer on targeted therapies, including 18 patients with brain metastases. Mutation-directed therapy for BRAFV600E mutations, RET mutations, RET fusions, and NTRK fusions had superior survival.

Immunotherapy response in patients with cutaneous squamous cell carcinoma of head and neck with cranial nerve involvement.

BACKGROUND: Metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC) can be treated with immunotherapy (IO). Cranial nerve involvement (CNI) is uncommon in cSCC and is a poor prognostic factor. Our aim is to describe how patients with CNI respond to IO monotherapy and/or as an adjunct to RT. METHODS: Under an IRB approved protocol, patients with histologically proven cSCC of the head and neck with CNI treated with IO were retrospectively reviewed. RESULTS: Twelve patients were included and received cemiplimab or pembrolizumab. Eight patients had CNI at diagnosis, and 4 at time of recurrence after non-IO therapy. Best responses were complete response (1), partial response (7), stable disease (1), progressive disease (2), and pending response (1). Nine patients are alive, 6 of which remain on IO. CONCLUSIONS: In this cohort, IO showed clinical response in 83% of patients, indicating IO can be an effective monotherapy, reserving RT for instances of local failure after IO.

Utilizing Dynamic Risk Stratification in Patients With Tall Cell Variant Papillary Thyroid Cancer.

OBJECTIVES: Tall cell variant (TCV) papillary thyroid cancer (PTC) is a subtype of PTC associated with aggressive tumor behavior, advanced stage, and higher rates of recurrence and mortality. The present study aimed to test an established dynamic risk stratification tool in the TCV population, with the goal of better predicting the postoperative course of these patients. STUDY DESIGN: Retrospective chart review. METHODS: A total of 94 patients with TCV who underwent total thyroidectomy with radioactive iodine ablation were retrospectively reviewed from 1998 through 2020. Biochemical, structural, and overall response to treatment was determined for each patient, based on postoperative thyroglobulin levels and imaging findings. Primary outcomes were locoregional and distant recurrence, presence of disease at final follow-up, need for additional intervention, and disease-specific mortality. RESULTS: Patients with TCV who were stratified as having an excellent overall response to treatment had lower rates of locoregional recurrence than indeterminate, biochemical incomplete, and structural incomplete responses (2.0%, 33.3%, 55.0%, and 85.7% at 5 years respectively, p < 0.001). The same was true for distant recurrence as well (2.0%, 9.0%, 35.1%, and 42.9%, p < 0.001). An excellent response was also associated with lower rates of presence of disease at final follow-up, need for additional intervention, and disease-specific mortality. CONCLUSIONS: Although TCV is an aggressive subtype associated with worse clinical outcomes than classical PTC, patients with an excellent overall response to treatment have significantly improved outcomes when compared to indeterminate, biochemical incomplete, and structural incomplete responses. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2430-2438, 2023.

Association of Suppressive Myeloid Cell Enrichment with Aggressive Oropharynx Squamous Cell Carcinoma.

BACKGROUND: While immune-cell infiltrated tumors, such as human papillomavirus positive (HPV+) ororpharyngeal squamous cell carcinomas (OPSCC) have been associated with an improved clinical prognosis, there is evidence to suggest that OPSCCs are also subjected to increased immunoregulatory influence. The objective of this study was to assess whether patients with clinically aggressive OPSCC have a distinct immunosuppressive immune signature in the primary tumor. METHODS: This retrospective case-control study analyzed 37 pre-treatment tissue samples from HPV+ and HPV-negative OPSCC patients treated at a single institution. The cases were patients with known disease recurrence and the controls were patients without disease recurrence. An mRNA-expression immune-pathway profiling was performed, and correlated to clinical outcomes. The TCGA head and neck cancer database was utilized to make comparisons with the institutional cohort. RESULTS: In our cohort, HPV-negative and HPV+ patients with known disease recurrence both had significantly increased suppressive monoctyte/macrophage and granulocyte cell-expression-profile enrichment. Similar findings were found in the TCGA cohort when comparing HPV-negative to positive patients. CONCLUSIONS: our study demonstrates that patients with recurrent HPV+ OPSCC had suppressive monocyte/macrophage and granulocyte immune-cell enrichment, similar to those seen in the more aggressive HPV-negative OPSCC.

Investigating miR-9 as a mediator in laryngeal cancer health disparities.

Background: For several decades, Black patients have carried a higher burden of laryngeal cancer among all races. Even when accounting for sociodemographics, a disparity remains. Differentially expressed microRNAs have been linked to racially disparate clinical outcomes in breast and prostate cancers, yet an association in laryngeal cancer has not been addressed. In this study, we present our computational analysis of differentially expressed miRNAs in Black compared with White laryngeal cancer and further validate microRNA-9-5p (miR-9-5p) as a potential mediator of cancer phenotype and chemoresistance. Methods: Bioinformatic analysis of 111 (92 Whites, 19 Black) laryngeal squamous cell carcinoma (LSCC) specimens from the TCGA revealed miRNAs were significantly differentially expressed in Black compared with White LSCC. We focused on miR-9-5 p which had a significant 4-fold lower expression in Black compared with White LSCC (p<0.05). After transient transfection with either miR-9 mimic or inhibitor in cell lines derived from Black (UM-SCC-12) or White LSCC patients (UM-SCC-10A), cellular migration and cell proliferation was assessed. Alterations in cisplatin sensitivity was evaluated in transient transfected cells via IC50 analysis. qPCR was performed on transfected cells to evaluate miR-9 targets and chemoresistance predictors, ABCC1 and MAP1B. Results: Northern blot analysis revealed mature miR-9-5p was inherently lower in cell line UM-SCC-12 compared with UM-SCC-10A. UM -SCC-12 had baseline increase in cellular migration (p < 0.01), proliferation (p < 0.0001) and chemosensitivity (p < 0.01) compared to UM-SCC-10A. Increasing miR-9 in UM-SCC-12 cells resulted in decreased cellular migration (p < 0.05), decreased proliferation (p < 0.0001) and increased sensitivity to cisplatin (p < 0.001). Reducing miR-9 in UM-SCC-10A cells resulted in increased cellular migration (p < 0.05), increased proliferation (p < 0.05) and decreased sensitivity to cisplatin (p < 0.01). A significant inverse relationship in ABCC1 and MAP1B gene expression was observed when miR-9 levels were transiently elevated or reduced in either UM-SCC-12 or UM-SCC-10A cell lines, respectively, suggesting modulation by miR-9. Conclusion: Collectively, these studies introduce differential miRNA expression in LSCC cancer health disparities and propose a role for low miR-9-5p as a mediator in LSCC tumorigenesis and chemoresistance.

mRNA challenge predicts brain cancer immunogenicity and response to checkpoint inhibitors.

To prospectively determine whether brain tumors will respond to immune checkpoint inhibitors (ICIs), we developed a novel mRNA vaccine as a viral mimic to elucidate cytokine release from brain cancer cells in vitro. Our results indicate that cytokine signatures following mRNA challenge differ substantially from ICI responsive versus non-responsive murine tumors. These findings allow for creation of a diagnostic assay to quickly assess brain tumor immunogenicity, allowing for informed treatment with ICI or lack thereof in poorly immunogenic settings.

mRNA aggregates harness danger response for potent cancer immunotherapy.

Messenger RNA (mRNA) has emerged as a remarkable tool for COVID-19 prevention but its use for induction of therapeutic cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Herein, we develop a facile approach for substantially enhancing immunogenicity of tumor-derived mRNA in lipid-particle (LP) delivery systems. By using mRNA as a molecular bridge with ultrapure liposomes and foregoing helper lipids, we promote the formation of 'onion-like' multi-lamellar RNA-LP aggregates (LPA). Intravenous administration of RNA-LPAs mimics infectious emboli and elicits massive DC/T cell mobilization into lymphoid tissues provoking cancer immunogenicity and mediating rejection of both early and late-stage murine tumor models. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for toll-like receptor engagement, RNA-LPAs stimulate intracellular pathogen recognition receptors (RIG-I) and reprogram the TME thus enabling therapeutic T cell activity. RNA-LPAs were safe in acute/chronic murine GLP toxicology studies and immunologically active in client-owned canines with terminal gliomas. In an early phase first-in-human trial for patients with glioblastoma, we show that RNA-LPAs encoding for tumor-associated antigens elicit rapid induction of pro-inflammatory cytokines, mobilization/activation of monocytes and lymphocytes, and expansion of antigen-specific T cell immunity. These data support the use of RNA-LPAs as novel tools to elicit and sustain immune responses against poorly immunogenic tumors.

Comparison of real-world outcomes following immunotherapy in recurrent or metastatic head and neck squamous cell carcinoma with outcomes of randomized controlled trials.

OBJECTIVES: Evaluate outcomes of patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy (IO). METHODS: Among patients with R/M HNSCC treated with IO in this retrospective single-institution cohort, Cox regression was used to compare overall survival (OS) for those with platinum-refractory disease and those treated in the first-line setting with OS from KEYNOTE-040/048, respectively. Multivariable Cox regression was used to identify predictors of OS. RESULTS: There was no significant OS difference for those treated in the platinum-refractory setting when compared to patients on KEYNOTE-040 (HR = 1.22, p = 0.27), nor for the first-line setting compared to KEYNOTE-048 (HR = 1.23, p = 0.19). ECOG-PS 1 (HR = 2.00, p = 0.02) and ECOG-PS 2 (HR = 3.13, p < 0.01) were associated with worse OS. Higher absolute lymphocyte count (ALC) was associated with improved OS (HR = 0.93 per 100 cells/µL, p = 0.03). CONCLUSIONS: Real-world outcomes of IO in R/M HNSCC are similar to outcomes in randomized control trials, with performance status and ALC correlating with OS.

Rates of osteoradionecrosis in resected oral cavity cancer reconstructed with free tissue transfer in the intensity-modulated radiotherapy era.

BACKGROUND: Resected oral cavity carcinoma defects are often reconstructed with osteocutaneous or soft-tissue free flaps, but risk of osteoradionecrosis (ORN) is unknown. METHODS: This retrospective study included oral cavity carcinoma treated with free-tissue reconstruction and postoperative IMRT between 2000 and 2019. Risk-regression assessed risk factors for grade ≥2 ORN. RESULTS: One hundred fifty-five patients (51% male, 28% current smokers, mean age 62 ± 11 years) were included. Median follow-up was 32.6 months (range, 1.0-190.6). Thirty-eight (25%) patients had fibular free flap for mandibular reconstruction, whereas 117 (76%) had soft-tissue reconstruction. Grade ≥2 ORN occurred in 14 (9.0%) patients, at a median 9.8 months (range, 2.4-61.5) after IMRT. Post-radiation teeth extraction was significantly associated with ORN. One-year and 10-year ORN rates were 5.2% and 10%, respectively. CONCLUSIONS: ORN risk was comparable between osteocutaneous and soft-tissue reconstruction for resected oral cavity carcinoma. Osteocutaneous flaps can be safely performed with no excess concern for mandibular ORN.

Thyroid Cancer Risk Communication in Patients with Thyroid Nodules.

The objective of this study is to evaluate thyroid cancer risk clinician-patient communication among patients receiving usual counseling and counseling enhanced by a conversation aid. A secondary analysis of clinical visit recordings and post-visit surveys obtained during a trial assessing the impact of a conversation aid for patients with thyroid nodules was conducted. We assessed how thyroid cancer risk was communicated, different risk communication strategies between groups, and predictors of accurate cancer risk perception. Fifty-nine patients were analyzed. Most were women (90%) and middle-aged (median 57 years). A verbal description of thyroid cancer risk was present most frequently (83%) and was more frequent in the conversation aid than the usual care group (100% vs. 63%, p < 0.001). A numerical description using percentages was present in 41% of visits and was more frequent in the conversation aid group (59% vs. 19%, p = 0.012). Natural frequencies (7%) and positive/negative framing (10%) were utilized less commonly. Uncertainty about risks was not discussed. No predictors of accurate risk perception were identified. Clinicians most commonly present a verbal description of thyroid cancer risk. Less commonly, natural frequencies, negative/positive framing, or uncertainty is discussed. Clinicians caring for patients with thyroid nodules should be aware of different strategies for communicating thyroid cancer risk.