Neighborhood-Level Disadvantage and Delayed Adjuvant Therapy in Head and Neck Cancer.

Importance: For patients with head and neck squamous cell carcinoma (HNSCC), initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery is recommended by the National Comprehensive Cancer Network Guidelines and the Commission on Cancer. Although individual-level measures of socioeconomic status are associated with receipt of timely, guideline-adherent PORT, the role of neighborhood-level disadvantage has not been examined. Objective: To characterize the association of neighborhood-level disadvantage with delays in receiving PORT. Design, Setting, and Participants: This retrospective cohort study included 681 adult patients with HNSCC undergoing curative-intent surgery and PORT from 2018 to 2020 at 4 US academic medical centers. The data were analyzed between June 21, 2023, and March 5, 2024. Main Outcome Measures and Measures: The primary outcome was delay in initiating guideline-adherent PORT (ie, >6 weeks after surgery). Time-to-PORT (TTP) was a secondary outcome. Census block-level Area Deprivation Index (ADI) scores were calculated and reported as national percentiles (0-100); higher scores indicate greater deprivation. The association of ADI scores with PORT delay was assessed using multivariable logistic regression adjusted for demographic, clinical, and institutional characteristics. PORT initiation across ADI score population quartiles was evaluated with cumulative incidence plots and Cox models. Results: Among 681 patients with HNSCC undergoing surgery and PORT (mean [SD] age, 61.5 [11.2] years; 487 [71.5%] men, 194 [29.5%] women) the PORT delay rate was 60.8% (414/681) and median (IQR) TTP was 46 (40-56) days. The median (IQR) ADI score was 62.0 (44.0-83.0). Each 25-point increase in ADI score was associated with a corresponding 32% increase in the adjusted odds ratio (aOR) of PORT delay (aOR, 1.32; 95% CI, 1.07-1.63) on multivariable regression adjusted for institution, age, race and ethnicity, insurance, comorbidity, cancer subsite, stage, postoperative complications, care fragmentation, travel distance, and rurality. Increasing ADI score population quartiles were associated with increasing TTP (hazard ratio of PORT initiation, 0.71; 95% CI, 0.53-0.96; 0.59; 95% CI, 0.44-0.77; and 0.54; 95% CI, 0.41-0.72; for ADI quartiles 2, 3, and 4 vs ADI quartile 1, respectively). Conclusions and Relevance: Increasing neighborhood-level disadvantage was independently associated with a greater likelihood of PORT delay and longer TTP in a dose-dependent manner. These findings indicate a critical need for the development of multilevel strategies to improve the equitable delivery of timely, guideline-adherent PORT.

Moving from conventional to adaptive risk stratification for oropharyngeal cancer.

Oropharyngeal cancer (OPC) poses a complex therapeutic dilemma for patients and oncologists alike, made worse by the epidemic increase in new cases associated with the oncogenic human papillomavirus (HPV). In a counterintuitive manner, the very thing which gives patients hope, the high response rate of HPV-associated OPC to conventional chemo-radiation strategies, has become one of the biggest challenges for the field as a whole. It has now become clear that for ~30-40% of patients, treatment intensity could be reduced without losing therapeutic efficacy, yet substantially diminishing the acute and lifelong morbidity resulting from conventional chemotherapy and radiation. At the same time, conventional approaches to de-escalation at a population (selected or unselected) level are hampered by a simple fact: we lack patient-specific information from individual tumors that can predict responsiveness. This results in a problematic tradeoff between the deleterious impact of de-escalation on patients with aggressive, treatment-refractory disease and the beneficial reduction in treatment-related morbidity for patients with treatment-responsive disease. True precision oncology approaches require a constant, iterative interrogation of solid tumors prior to and especially during cancer treatment in order to tailor treatment intensity to tumor biology. Whereas this approach can be deployed in hematologic diseases with some success, our ability to extend it to solid cancers with regional metastasis has been extremely limited in the curative intent setting. New developments in metabolic imaging and quantitative interrogation of circulating DNA, tumor exosomes and whole circulating tumor cells, however, provide renewed opportunities to adapt and individualize even conventional chemo-radiation strategies to diseases with highly variable biology such as OPC. In this review, we discuss opportunities to deploy developing technologies in the context of institutional and cooperative group clinical trials over the coming decade.

p90RSK pathway inhibition synergizes with cisplatin in TMEM16A overexpressing head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and often metastasizes to lymph nodes. Platinum-based chemotherapeutic drugs are commonly used for treatment of a wide range of cancers, including HNSCC. Its mode of action relies on its ability to impede DNA repair mechanisms, inducing apoptosis in cancer cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combinational therapeutic strategies to overcome cisplatin resistance. In the current study, we identified p90RSK, an ERK1/2 downstream target, as a key mediator and a targetable signaling node against cisplatin resistance. Our results strongly support the role of p90RSK in cisplatin resistance and identify the combination of p90RSK inhibitor, BI-D1870, with cisplatin as a novel therapeutic strategy to overcome cisplatin resistance. In addition, we have identified TMEM16A expression as a potential upstream regulator of p90RSK through the ERK pathway and a biomarker of response to p90RSK targeted therapy in the context of cisplatin resistance.

Outcome Comparison of Functional Laryngectomy for the Dysfunctional Larynx to Salvage Laryngectomy.

OBJECTIVE: To compare functional outcomes of total laryngectomy (TL) with microvascular free tissue transfer (MVFTT) reconstruction in the treatment of dysfunctional larynx (DL) versus salvage therapy for locally recurrent disease in patients with a history of laryngeal squamous cell carcinoma (SCC). METHODS: Retrospective review from a tertiary medical center between August 2015 and August 2022. RESULTS: Sixty-nine patients underwent TL with MVFTT following primary laryngeal radiation or chemoradiation; 15 (22%) patients underwent functional laryngectomy (FL) and 54 (78%) underwent a salvage laryngectomy (SL). There were no total flap failures. Four (6%) patients developed a pharyngocutaneous fistula; one (7%) FL patient and 3 (6%) in the SL cohort. There was no significant difference in average hospital length of stay (LOS) between the cohorts (8.6 ± 3.0 days vs. 12.8 ± 10.1 days, p = 0.12). All patients (100%) in the FL cohort achieved a total oral diet compared to 41 (76%) in the SL cohort (p = 0.03). Two (13%) and 10 (19%) patients developed pharyngoesophageal stenosis in the FL and SL cohorts, respectively (p = 1.0). Nine (60%) and 23 (43%) patients in the FL and SL cohorts underwent tracheoesophageal puncture (TEP) placement, with 89% and 91% achieving fluency, respectively (p = 0.23). CONCLUSION: Although the role of TL for the definitive treatment of laryngeal SCC has decreased over the past 30 years, organ-preservation protocols can impact speech, swallowing, and airway protection with life-threatening consequences. The use of elective FL with MVFTT for the treatment of DL results in similar or better functional outcomes compared to SL for recurrent disease. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:222-227, 2024.

Delays Starting Postoperative Radiotherapy Among Head and Neck Cancer Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: Initiating postoperative radiotherapy (PORT) within 6 weeks (42 days) of surgery is the first and only Commission on Cancer (CoC) approved quality metric for head and neck squamous cell carcinoma (HNSCC). No study has systematically reviewed nor synthesized the literature to establish national benchmarks for delays in starting PORT. DATA SOURCES: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we performed a systematic review of PubMed, Scopus, and CINAHL. REVIEW METHODS: Studies that described time-to-PORT or PORT delays in patients with HNSCC treated in the United States after 2003 were included. Meta-analysis of proportions and continuous measures was performed on nonoverlapping datasets to examine the pooled frequency of PORT delays and time-to-PORT. RESULTS: Thirty-six studies were included in the systematic review and 14 in the meta-analysis. Most studies utilized single-institution (n = 17; 47.2%) or cancer registry (n = 16; 44.4%) data. Twenty-five studies (69.4%) defined PORT delay as >6 weeks after surgery (the definition utilized by the CoC and National Comprehensive Cancer Network Guidelines), whereas 4 (11.1%) defined PORT delay as a time interval other than >6 weeks, and 7 (19.4%) characterized time-to-PORT without defining delay. Meta-analysis revealed that 48.6% (95% confidence interval [CI], 41.4-55.9) of patients started PORT > 6 weeks after surgery. Median and mean time-to-PORT were 45.8 (95% CI, 42.4-51.4 days) and 47.4 days (95% CI, 43.4-51.4 days), respectively. CONCLUSION: Delays in initiating guideline-adherent PORT occur in approximately half of patients with HNSCC. These meta-analytic data can be used to set national benchmarks and assess progress in reducing delays.

FAK Drives Resistance to Therapy in HPV-Negative Head and Neck Cancer in a p53-Dependent Manner.

PURPOSE: Radiation and platinum-based chemotherapy form the backbone of therapy in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcomes in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remains unclear. EXPERIMENTAL DESIGN: We performed an in vivo shRNA screen using targetable libraries to identify novel therapeutic sensitizers for radiation and chemotherapy. RESULTS: We identified FAK as an excellent target for both radio- and chemosensitization. Because TP53 is mutated in over 80% of HPV-negative HNSCC, we hypothesized that mutant TP53 may facilitate FAK-mediated therapy resistance. FAK inhibitor increased sensitivity to radiation, increased DNA damage, and repressed homologous recombination and nonhomologous end joining repair in mutant, but not wild-type, TP53 HPV-negative HNSCC cell lines. The mutant TP53 cisplatin-resistant cell line had increased FAK phosphorylation compared with wild-type, and FAK inhibition partially reversed cisplatin resistance. To validate these findings, we utilized an HNSCC cohort to show that FAK copy number and gene expression were associated with worse disease-free survival in mutant TP53, but not wild-type TP53, HPV-negative HNSCC tumors. CONCLUSIONS: FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance.

Outcomes of Head and Neck Microvascular Free Tissue Transfer for Advanced Cutaneous Squamous Cell Carcinoma: A Comparison of Solid Organ Transplant Recipients to Nontransplant Patients.

BACKGROUND: Patients with solid organ transplant (SOT) are at increased risk of developing aggressive cutaneous malignancies due to their immunosuppression, particularly cutaneous squamous cell carcinoma (cSCC). PURPOSE: There is limited data regarding SOT patients with locally advanced cSCC requiring radical surgery and microvascular free tissue transfer (MVFTT). Our objectives were to characterize outcomes in SOT patients and compare them with a non-SOT cohort. STUDY DESIGN: This is a retrospective cohort study of patients undergoing MVFTT for advanced cSCC of the head and neck between January 2016 and May 2020 at a tertiary referral center. Patients who underwent MVFTT as part of curative intent surgery for advanced cSCC during the study were considered for inclusion. Exclusion criteria included distant metastasis, palliative intent treatment, age less than 18 years, and lip primaries. PREDICTOR: The predictor variable was SOT status. A cohort of non-SOT patients was matched to the SOT cohort based on age, smoking status, tumor stage, and defect size. MAIN OUTCOME VARIABLES: The primary reconstructive outcome was the major surgical complications and secondary outcome measures included major medical complications and minor surgical complications. The primary oncologic outcome was overall survival and the secondary outcome was disease-specific survival. The primary predictor was transplant status. COVARIATES: Covariates included patient comorbidities, prior treatment, tumor stage, type of reconstruction, pathologic findings, and adjuvant therapy. ANALYSIS: Continuous and categorical variables were compared using Student's T test and Fisher's exact test. Survival was calculated using the Kaplan-Meier method and differences in survival between groups were calculated using the log-rank test. Statistical significance was set a priori at P ≤ .05. RESULTS: Fourteen SOT and 14 matched non-SOT patients met inclusion criteria. There was not a statistically significant difference in the rate of major surgical complications (7 vs 7%, P = .74) between the SOT and non-SOT cohorts. Rates of minor (21 vs 43%, P = .26) wound complications and medical complications (0 vs 14%, P = .24) were also similar between the SOT and non-SOT cohorts. Locoregional recurrences and distant metastasis were more common for SOT patients, though this was not statistically significant. Overall survival was significantly worse for SOT patients (21.7 vs 31.0 months, P = .04), though there was not a significant difference in disease-free survival (9.8 vs 31.0 months, P = .17). CONCLUSIONS AND RELEVANCE: MVFTT in the management of SOT patients with locally advanced head and neck cSCC demonstrates similar complication rates with non-SOT patients. While survival and oncologic outcomes are worse in the SOT cohort, aggressive surgical intervention with MVFTT can be performed with comparable complication rates to patients without a history of SOT.

Patient Navigation for Timely, Guideline-Adherent Adjuvant Therapy for Head and Neck Cancer: A National Landscape Analysis.

BACKGROUND: Aligned with the NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers, in November 2021 the Commission on Cancer approved initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery for head and neck cancer (HNC) as its first and only HNC quality metric. Unfortunately, >50% of patients do not commence PORT within 6 weeks, and delays disproportionately burden racial and ethnic minority groups. Although patient navigation (PN) is a potential strategy to improve the delivery of timely, equitable, guideline-adherent PORT, the national landscape of PN for this aspect of care is unknown. MATERIALS AND METHODS: From September through November 2022, we conducted a survey of health care organizations that participate in the American Cancer Society National Navigation Roundtable to understand the scope of PN for delivering timely, guideline-adherent PORT for patients with HNC. RESULTS: Of the 94 institutions that completed the survey, 89.4% (n=84) reported that at least part of their practice was dedicated to navigating patients with HNC. Sixty-eight percent of the institutions who reported navigating patients with HNC along the continuum (56/83) reported helping them begin PORT. One-third of HNC navigators (32.5%; 27/83) reported tracking the metric for time-to-PORT at their facility. When estimating the timeframe in which the NCCN and Commission on Cancer guidelines recommend commencing PORT, 44.0% (37/84) of HNC navigators correctly stated ≤6 weeks; 71.4% (60/84) reported that they did not know the frequency of delays starting PORT among patients with HNC nationally, and 63.1% (53/84) did not know the frequency of delays at their institution. CONCLUSIONS: In this national landscape survey, we identified that PN is already widely used in clinical practice to help patients with HNC start timely, guideline-adherent PORT. To enhance and scale PN within this area and improve the quality and equity of HNC care delivery, organizations could focus on providing better education and support for their navigators as well as specialization in HNC.

Recurrent Oropharyngeal Squamous Cell Carcinomas Maintain Anti-tumor Immunity and Multinucleation Levels Following Completion of Radiation.

OBJECTIVE: Oropharyngeal squamous cell carcinoma (OPSCC) recurrence is almost universally fatal. Development of effective therapeutic options requires an improved understanding of recurrent OPSCC biology. METHODS: We analyzed paired primary-recurrent OPSCC from Veterans treated at the Michael E. DeBakey Veterans Affairs Medical Center between 2000 and 2020 who received curative intent radiation-based treatment (with or without chemotherapy). Patient tumors were analyzed using standard immunohistochemistry and automated imaging of infiltrating lymphocytes and multinucleated tumor cells coupled to machine learning algorithms. RESULTS: Primary and recurrent tumors demonstrated high concordance via p16 and p53 immunohistochemistry, with comparable levels of multinucleation. In contrast, recurrent tumors demonstrated significantly higher levels of CD8+ tumor infiltrating lymphocytes (p<0.05) and higher levels of PD-L1 expression (p<0.05). CONCLUSION: Exposure to chemo-radiation and recurrence following treatment preserves critical features of intrinsic tumor biology and the tumor immune microenvironment suggesting that novel treatment regimens may be as effective in the salvage setting as in the definitive intent setting.

Secretory Carcinoma with ETV6-NTRK3 Gene Fusion and Lymph Node Metastasis in Maxillary Gingiva: A Case Report with Pathological and Molecular Correlative Studies.

Secretory carcinoma (SC), also known as mammary analogue secretory carcinoma (MASC), is a rare salivary gland neoplasm with distinctive morphology that harbors a diagnostic ETV6 gene rearrangement. MASC was first described as a type of salivary gland neoplasm in 2010 and resembles breast secretory carcinoma. It is often mistaken for other neoplasms. It usually acts as an indolent tumor but can occasionally behave in an aggressive manner. We present a rare case of a patient with an aggressive SC/MASC of maxillary gingivobuccal sulcus with microcystic, solid and papillary patterns that showed ETV6 gene rearrangement by fluorescence in situ hybridization. Next-generation sequencing revealed t(12;15)(p13;q25) ETV6-NTRK3 translocation. Because SC/MASCs harbor the ETV6-NTRK3 translocation, molecular studies and immunostains are crucial to confirm the diagnosis and direct therapy.

Recurrent oropharyngeal squamous cell carcinomas maintain anti-tumor immunity and multinucleation levels following completion of radiation.

Objective: Oropharyngeal squamous cell carcinoma (OPSCC) recurrence is almost universally fatal. Development of effective therapeutic options requires an improved understanding of recurrent OPSCC biology. Methods: We analyzed paired primary-recurrent OPSCC from Veterans treated at the Michael E. DeBakey Veterans Affairs Medical Center between 2000 and 2020 who received curative intent radiation-based treatment (with or without chemotherapy). Patient tumors were analyzed using standard immunohistochemistry and automated imaging of infiltrating lymphocytes and multinucleated tumor cells coupled to machine learning algorithms. Results: Primary and recurrent tumors demonstrated high concordance via p16 and p53 immunohistochemistry, with comparable levels of multinucleation. In contrast, recurrent tumors demonstrated significantly higher levels of CD8+ tumor infiltrating lymphocytes (p<0.05) and higher levels of PD-L1 expression (p<0.05). Conclusion: Exposure to chemo-radiation and recurrence following treatment does not appear deleterious to underlying biological characteristics and anti-tumor immunity of oropharyngeal cancer, suggesting that novel treatment regimens may be as effective in the salvage setting as in the definitive intent setting.

Operationalizing a Free Flap Program for Head and Neck Reconstruction at a Veterans Affairs Hospital.

Objectives: We aimed to operationalize a head and neck microvascular free tissue transfer (MVFTT) program at a Veterans Affairs (VA) hospital with the emphasis on initiating radiotherapy within 6 weeks of surgery for cancer patients and minimizing readmissions. Study Design: Case series. Setting: Tertiary care VA hospital. Methods: A retrospective analysis was performed on consecutive head and neck MVFTT patients from May 1, 2017 and April 30, 2022. Demographics, patient and disease characteristics, per-operative data and postoperative outcomes were recorded from the electronic medical record. We sought to compare our rate of 30-day readmissions with those published in the literature. Results: One hundred and forty-one procedures were performed in the queried timeframe. Eighty-four percent (119) were performed after oncologic resections and 16% (22) were for nononcologic procedures. The rate of total flap loss was <1% and the rate of partial flap loss was 3.5%. For mucosal defects, the fistula rate was 2.3%. The rate of return to the OR for any reason within 30 days was 7.8%. The 30-day readmission rate was 6.4% while the rates reported in the literature range from 13% to 20%. One hundred and four patients required postoperative radiotherapy (PORT) and 76% started PORT within 42 days of surgery. Conclusion: Operationalizing a head and neck MVFTT program with a VA hospital is safe and allows for the successful delivery of multimodality treatment to cancer patients. These resources can be expanded for the care of head and neck cancer treatment sequelae, such as osteoradionecrosis, and other nononcologic patient needs.

Multidimensional biomarker predicts disease control in response to immunotherapy in recurrent or metastatic head and neck squamous-cell carcinoma.

PURPOSE: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. METHODS: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. RESULTS: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009). CONCLUSION: This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy.

Deployment of cisplatin in Veterans with oropharyngeal cancer: toxicity and impact on oncologic outcomes.

Objective: Cisplatin forms the backbone of systemic chemotherapy treatment for oropharyngeal squamous cell carcinoma (OPSCC). The ideal cisplatin dosing regimen remains yet to be fully defined for achieving optimal efficacy and toxicity profiles in patients with comorbidity. Methods: We retrospectively reviewed oncologic and toxicity data for patients with OPSCC treated at the Michael E. DeBakey Veterans Affairs Medical Center between 2000 and 2020 who initiated curative intent, definitive chemo-radiation with one of three single agent regimens: high dose (HD) cisplatin, low dose (LD) cisplatin or cetuximab. Results: Patients with HPV-associated tumors and nonsmokers demonstrated improved overall and disease-free survival along with locoregional and distant metastatic control regardless of chemotherapy regimen. Regardless of regimen selection, patients which received a cumulative cisplatin dose ≥200 mg/m2 had a lower rate of distant metastasis. The HD regimen resulted in a greater fraction (75% vs. 50%) of patients receiving a cumulative cisplatin dose ≥200 mg/m2 and a comparable measured toxicity burden compared to the LD regimen. Conclusions: Both HD and LD cisplatin regimens can be safely delivered to a Veteran OPSCC patient population which should allow for straightforward application of conclusions drawn from completed and active clinical trials testing cisplatin regimens. Level of Evidence: 4.

Phase I / II trial of metformin as a chemo-radiosensitizer in a head and neck cancer patient population.

OBJECTIVES: Retrospective studies have shown that head and neck squamous cell carcinoma (HNSCC) patients taking metformin demonstrate superior survival compared to their counterparts. We sought to determine whether metformin combined with chemoradiation would improve HNSCC patient survival compared to historical controls. MATERIALS AND METHODS: We conducted a Phase I/II prospective, single arm clinical trial in patients with newly diagnosed HNSCC (NCT02949700). Patients received platinum-based chemoradiation in combination with orally dosed metformin at one of 2 doses- 850 mg BID or 1500 mg BID administered during radiation, with a 2-week lead-in phase. Toxicity, disease response and survival metrics were ascertained throughout the study period. RESULTS: A total of 25 patients were evaluable for toxicity and survival; 9 failed to reach the predetermined 70% compliance with the study drug. No dose limiting toxicities were identified in the Phase I component and there were no grade 4 adverse events likely related to metformin throughout the study. The primary outcome for the Phase II component was met with a response rate of 96%. Three-year overall survival was ∼70% in the per protocol p16 + cohort and 0% in the per protocol p16- cohort. Survival among participants with a ≥70% metformin compliance to <70% metformin compliance demonstrated a trend towards improvement in the ≥70% compliance cohort, though this did not reach significance. CONCLUSION: Metformin is well tolerated during concurrent chemoradiation for HNSCC. Its effectiveness as a chemo-radiosensitizer remains unclear and will require further study with randomized controlled clinical trials in this patient population.

Machine learning driven index of tumor multinucleation correlates with survival and suppressed anti-tumor immunity in head and neck squamous cell carcinoma patients.

OBJECTIVES: Matching treatment intensity to tumor biology is critical to precision oncology for head and neck squamous cell carcinoma (HNSCC) patients. We sought to identify biological features of tumor cell multinucleation, previously shown by us to correlate with survival in oropharyngeal (OP) SCC using a machine learning approach. MATERIALS AND METHODS: Hematoxylin and eosin images from an institutional OPSCC cohort formed the training set (DTr). TCGA HNSCC patients (oral cavity, oropharynx and larynx/hypopharynx) formed the validation set (DV). Deep learning models were trained in DTr to calculate a multinucleation index (MuNI) score. Gene set enrichment analysis (GSEA) was then used to explore correlations between MuNI and tumor biology. RESULTS: MuNI correlated with overall survival. A multivariable nomogram that included MuNI, age, race, sex, T/N stage, and smoking status yielded a C-index of 0.65, and MuNI was prognostic of overall survival (2.25, 1.07-4.71, 0.03), independent of the other variables. High MuNI scores correlated with depletion of effector immunocyte subsets across all HNSCC sites independent of HPV and TP53 mutational status although the correlations were strongest in wild-type TP53 tumors potentially due to aberrant mitotic events and activation of DNA-repair mechanisms. CONCLUSION: MuNI is associated with survival in HNSCC across subsites. This may be driven by an association between high levels of multinucleation and a suppressive (potentially exhausted) tumor immune microenvironment. Mechanistic studies examining the link between multinucleation and tumor immunity will be required to characterize biological drivers of multinucleation and their impact on treatment response and outcomes.

Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.

BACKGROUND: Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring. METHODS: To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic backgrounds by whole-exome sequencing, RNA-seq, mass spectrometry, steady state and flux metabolomics. RESULTS: Inactivating KEAP1 mutations or reductions in KEAP1 RNA correlated with Nrf2 activation in CDDP-resistant cells, which functionally contributed to resistance. Proteomics identified elevation of downstream Nrf2 targets and the enrichment of enzymes involved in generation of biomass and reducing equivalents, metabolism of glucose, glutathione, NAD(P), and oxoacids. This was accompanied by biochemical and metabolic evidence of an enhanced reductive state dependent on coordinated glucose and glutamine catabolism, associated with reduced energy production and proliferation, despite normal mitochondrial structure and function. CONCLUSIONS: Our analysis identified coordinated metabolic changes associated with CDDP resistance that may provide new therapeutic avenues through targeting of these convergent pathways.

Human Papillomavirus Vaccination Prevalence and Disproportionate Cancer Burden Among US Veterans.

This cross-sectional study examines the rate of HPV vaccination and the number eligible for this vaccination among younger veterans and civilians.