Analysis of B7-H4 Expression Across Salivary Gland Carcinomas Reveals Adenoid Cystic Carcinoma-Specific Prognostic Relevance.

B7-H4 (VTCN1), a member of the B7 family, is overexpressed in several types of cancer. Here we investigated the pattern of expression of B7-H4 in salivary gland carcinomas (SGC) and assessed its potential as a prognostic marker and therapeutic target. Immunohistochemistry (IHC) analyses were performed in a cohort of 340 patient tumors, composed of 124 adenoid cystic carcinomas (ACC), 107 salivary duct carcinomas (SDC), 64 acinic cell carcinomas, 36 mucoepidermoid carcinomas (MEC), 9 secretory carcinomas (SC), as well as 20 normal salivary glands (controls). B7-H4 expression was scored and categorized into negative (<5% expression of any intensity), low (5%-70% expression of any intensity or >70% with weak intensity), or high (>70% moderate or strong diffuse intensity). The associations between B7-H4 expression and clinicopathologic characteristics, as well as overall survival, were assessed. Among all tumors, B7-H4 expression was more prevalent in ACC (94%) compared with those of SC (67%), MEC (44%), SDC (32%), and acinic cell carcinomas (0%). Normal salivary gland tissue did not express B7-H4. High expression of B7-H4 was found exclusively in ACC (27%), SDC (11%), and MEC (8%). In SDC, B7-H4 expression was associated with female gender (P = .002) and lack of androgen receptor expression (P = .012). In ACC, B7-H4 expression was significantly associated with solid histology (P < .0001) and minor salivary gland primary (P = .02). High B7-H4 expression was associated with a poorer prognosis in ACC, regardless of clinical stage and histologic subtype. B7-H4 expression was not prognostic in the non-ACC SGC evaluated. Our comparative study revealed distinct patterns of B7-H4 expression according to SGC histology, which has potential therapeutic implications. B7-H4 expression was particularly high in solid ACC and was an independent prognostic marker in this disease but not in the other SGC assessed.

Proton Therapy for HPV-Associated Oropharyngeal Cancers of the Head and Neck: a De-Intensification Strategy.

OPINION STATEMENT: The rise in the incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPC), the relatively young age at which it is diagnosed, and its favorable prognosis necessitate the use of treatment techniques that reduce the likelihood of side effects during and after curative treatment. Intensity-modulated proton therapy (IMPT) is a form of radiotherapy that de-intensifies treatment through dose de-escalation to normal tissues without compromising dose to the primary tumor and involved, regional lymph nodes. Preclinical studies have demonstrated that HPV-positive squamous cell carcinoma is more sensitive to proton radiation than is HPV-negative squamous cell carcinoma. Retrospective studies comparing intensity-modulated photon (X-ray) radiotherapy to IMPT for OPC suggest comparable rates of disease control and lower rates of pain, xerostomia, dysphagia, dysgeusia, gastrostomy tube dependence, and osteoradionecrosis with IMPT-all of which meaningfully affect the quality of life of patients treated for HPV-associated OPC. Two phase III trials currently underway-the "Randomized Trial of IMPT versus IMRT for the Treatment of Oropharyngeal Cancer of the Head and Neck" and the "TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer (TORPEdO)" trial-are expected to provide prospective, level I evidence regarding the effectiveness of IMPT for such patients.

Correction to: Notch Signaling and Human Papillomavirus-Associated Oral Tumorigenesis.

Unfortunately the book was published without correcting a typo in the author name in chapter 8. The author name has been corrected now to read as follows.

Notch Signaling and Human Papillomavirus-Associated Oral Tumorigenesis.

The NOTCH pathway is critical for the development of many cell types including the squamous epithelium lining of cutaneous and mucosal surfaces. In genetically engineered mouse models, Notch1 acts as one of the first steps to commit basal keratinocytes to terminally differentiate. Similarly, in human head and neck squamous cell cancers (HNSCCs), NOTCH1 is often lost consistent with its essential tumor-suppressive role for initiating keratinocyte differentiation. However, constitutive NOTCH1 activity in the epithelium results in expansion of the spinous keratinocyte layers and impaired terminal differentiation is consistent with the role of NOTCH1 as an oncogene in other cancers, especially in T-cell acute lymphoblastic leukemia. We have previously observed that NOTCH1 plays a dual role as both a tumor suppressor and oncogene, depending on the mutational context of the tumor. Namely, gain or loss or NOTCH1 activity promotes the development of human papillomavirus (HPV)-associated cancers. The additional HPV oncogenes likely disrupt the tumor-suppressive activities of NOTCH and enable the oncogenic pathways activated by NOTCH to promote tumor growth. In this review, we detail the role of NOTCH pathway in head and neck cancers with a focus on HPV-associated cancers.

Cooperation of genes in HPV16 E6/E7-dependent cervicovaginal carcinogenesis trackable by endoscopy and independent of exogenous estrogens or carcinogens.

Human papillomavirus (HPV) infection is necessary but insufficient for progression of epithelial cells from dysplasia to carcinoma-in situ (CIS) to invasive cancer. The combination of mutant cellular and viral oncogenes that regulate progression of cervical cancer (CC) remains unclear. Using combinations of HPV16 E6/E7 (E+), mutant Kras (mKras) (K+) and/or loss of Pten (P-/-), we generated autochthonous models of CC without exogenous estrogen, carcinogen or promoters. Furthermore, intravaginal instillation of adenoCre virus enabled focal activation of the oncogenes/inactivation of the tumor suppressor gene. In P+/+ mice, E6/E7 alone (P+/+E+K-) failed to cause premalignant changes, while mKras alone (P+/+E-K+) caused persistent mucosal abnormalities in about one-third of mice, but no cancers. To develop cancer, P+/+ mice needed both E6/E7 and mKras expression. Longitudinal endoscopies of P+/+E+K+ mice predicted carcinoma development by detection of mucosal lesions, found on an average of 23 weeks prior to death, unlike longitudinal quantitative PCRs of vaginal lavage samples from the same mice. Endoscopy revealed that individual mice differed widely in the time required for mucosal lesions to appear after adenoCre and in the time required for these lesions to progress to cancer. These cancers developed in the transition zone that extends, unlike in women, from the murine cervix to the distal vagina. The P-/-E+K+ genotype led to precipitous cancer development within a few weeks and E6/E7-independent cancer development occurred in the P-/-E-K+ genotype. In the P-/-E+K- genotype, mice only developed CIS. Thus, distinct combinations of viral and cellular oncogenes are involved in distinct steps in cervical carcinogenesis.

Association between hospital volume and receipt of treatment and survival in patients with glioblastoma.

The relation between hospital volume and outcomes for patients with glioblastoma is unknown. We undertook this study to determine the effect of hospital volume on treatment received and its effect on survival in patients with glioblastoma. We included patients from the National Cancer Database diagnosed with a glioblastoma from 2006 to 2013. Hospital volume was calculated by examining the treating facilities average number of cases per year and grouping them into tertiles: (low < 9.25, medium 9.26-23.88, and high ≥ 23.39). Treatment was defined as receiving any type of therapeutic surgery, radiation or chemotherapy. Using regression models we examined the relation between hospital volume to treatment received and survival with adjustment for clinical, socioeconomic and institutional factors. The study included 68,726 patients of which 91.8% received treatment. Among patients diagnosed at low volume facilities, 90.1% received treatment versus 94.2% in high volume facilities (p < 0.0001). Compared to low volume centers, the odds ratio of receiving any treatment was 1.01 (CI 95% CI: 0.95-1.09) and 1.43 (95% CI: 1.31-1.55) for medium volume and high volume facilities, respectively. On multivariate analysis for survival among those who received treatment, the hazard of mortality was decreased at high volume (HR 0.92, 95% CI 0.89-0.94) facilities compared to low volume facilities. Patients diagnosed with glioblastoma at a high volume facility (≥23.39 cases per year) have an increased likelihood of receiving treatment. Furthermore, glioblastoma patients may significantly improve their survival by choosing to receive care at a high-volume hospital.

Angiotensin-converting enzyme inhibitors predict acute kidney injury during chemoradiation for head and neck cancer.

Head and neck cancer patients undergoing chemoradiation experience considerable toxicities including acute kidney injury (AKI). However, it remains unclear what factors predispose patients to renal toxicity during treatment. Here, we assessed the predictors and outcomes of patients experiencing AKI during chemoradiation. We carried out a retrospective cohort study to assess the maximum changes in serum creatinine (Cr) in 173 patients with stage III-IV head and neck cancer treated with chemoradiation between 1999 and 2012. We defined AKI as Cr increases 26.5 µmol/l or more over the pretreatment baseline. AKI was associated with angiotensin-converting enzyme inhibitor (ACEI) use (33.0 vs. 11.0%; P=0.0004), but no other medications or comorbidities. On multivariate analysis, ACEI use, weight loss 10% or more of body weight, and performance status 70 or more predicted for Cr increments 26.5 µmol/l or more, whereas only ACEI use predicted for Cr increments of 44.2 µmol/l or greater. Furthermore, on multivariate analysis, AKI predicted for more interventions during radiotherapy including intravenous fluid use (P=0.0005) and hospitalizations (P=0.007), as well as long-term renal dysfunction (P<0.0001). Renal toxicity was not associated with worse locoregional control, progression-free survival, or overall survival. Renal toxicity during chemoradiation was associated with ACEI use alone or coupled with weight loss 10% or more of body weight during therapy. Our results suggest that actively managing ACEI use and intravascular volume status during chemoradiation may avoid AKI, minimize subsequent interventions, and reduce the risk for long-term renal dysfunction.

Racial parities in outcomes after radiotherapy for head and neck cancer.

BACKGROUND: Although black patients experience worse outcomes after treatment for squamous cell carcinoma of the head and neck (HNSCC), these conclusions were based on populations in which blacks comprised a minority of patients. The objective of the current study was to determine the impact of race on outcomes in patients with HNSCC who received radiotherapy at an institution in which blacks comprised the majority of patients. METHODS: In this retrospective cohort study, the authors reviewed 366 black patients and 236 white patients who had nonmetastatic HNSCC for which they received radiotherapy between 1990 and 2012. The primary study outcome measures were locoregional control, freedom from distant metastasis, progression-free survival, and overall survival. RESULTS: The median follow-up was 18.3 months for all patients. The 2-year locoregional control rate was 71.9% for black patients compared with 64.2% for white patients (hazard ratio, 0.72; P=.03). There was no difference between blacks and whites regarding 2-year freedom from distant metastasis, progression-free survival, or overall survival. Among the patients who had stage III through IVB disease, blacks and whites had similar outcomes. On multivariate analysis, race was not statistically significant for locoregional control, freedom from distant metastasis, progression-free survival, or overall survival. Despite these similar outcomes, black patients had worse socioeconomic factors and increased comorbidities but had similar treatment compliance compared with white patients. CONCLUSIONS: With more adverse prognostic factors, black patients experienced oncologic outcomes similar to the outcomes of white patients after receiving radiotherapy for HNSCC. The current data suggest that centers that treat large percentages of minority patients who receive radiotherapy for HNSCCs may overcome existing health care disparities through improved treatment compliance.

Clinical acceptability of automatically generated lymph node levels and structures of deglutition and mastication for head and neck radiation therapy.

Background and Purpose: Auto-contouring of complex anatomy in computed tomography (CT) scans is a highly anticipated solution to many problems in radiotherapy. In this study, artificial intelligence (AI)-based auto-contouring models were clinically validated for lymph node levels and structures of swallowing and chewing in the head and neck. Materials and Methods: CT scans of 145 head and neck radiotherapy patients were retrospectively curated. One cohort (n = 47) was used to analyze seven lymph node levels and the other (n = 98) used to analyze 17 swallowing and chewing structures. Separate nnUnet models were trained and validated using the separate cohorts. For the lymph node levels, preference and clinical acceptability of AI vs human contours were scored. For the swallowing and chewing structures, clinical acceptability was scored. Quantitative analyses of the test sets were performed for AI vs human contours for all structures using overlap and distance metrics. Results: Median Dice Similarity Coefficient ranged from 0.77 to 0.89 for lymph node levels and 0.86 to 0.96 for chewing and swallowing structures. The AI contours were superior to or equally preferred to the manual contours at rates ranging from 75% to 91%; there was not a significant difference in clinical acceptability for nodal levels I-V for manual versus AI contours. Across all AI-generated lymph node level contours, 92% were rated as usable with stylistic to no edits. Of the 340 contours in the chewing and swallowing cohort, 4% required minor edits. Conclusions: An accurate approach was developed to auto-contour lymph node levels and chewing and swallowing structures on CT images for patients with intact nodal anatomy. Only a small portion of test set auto-contours required minor edits.

Initial Management of BRAF V600E-Variant Anaplastic Thyroid Cancer: The FAST Multidisciplinary Group Consensus Statement.

Importance: BRAF/MEK inhibitors revolutionized the treatment of BRAF V600E-variant anaplastic thyroid carcinoma (BRAFv-ATC), offering improved outcomes for patients with this previously incurable disease. Observations: Anaplastic thyroid carcinoma (ATC) accounts for approximately half of thyroid cancer-related deaths. It presents as a rapidly growing tumor that often invades locoregional structures and spreads to distant sites early; therefore, prompt diagnosis, staging, and treatment initiation are of the essence in the treatment of ATC. Although most oncologists will encounter a patient with ATC in their practice, the rarity of this disease makes treatment challenging, particularly because those with BRAFv-ATC no longer have a dismal prognosis. BRAF/MEK kinase inhibitors have transformed the outlook and treatment of BRAFv-ATC. Therefore, molecular profiling to identify these patients is critical. More recently, the addition of immunotherapy to BRAF/MEK inhibitors as well as the use of the neoadjuvant approach were shown to further improve survival outcomes in BRAFv-ATC. Many of these recent advances have not yet been incorporated in the currently available guidelines, allowing for disparities in the treatment of patients with BRAFv-ATC across the US. With the increasing complexity in the management of BRAFv-ATC, this Consensus Statement aims to formulate guiding recommendations from a group of experts to facilitate therapeutic decision-making. Conclusions and Relevance: This Consensus Statement from the FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment) group at MD Anderson Cancer Center emphasizes that rapid identification of a BRAF V600E pathogenic variant and timely initiation of sequential therapy are critical to avoid excess morbidity and mortality in patients with BRAFv-ATC. In the past decade, remarkable progress has been made in the treatment of patients with BRAFv-ATC, justifying these new evidence-based recommendations reached through a consensus of experts from a high-volume center.

Induced sensitization of tumor stroma leads to eradication of established cancer by T cells.

Targeting cancer cells, as well as the nonmalignant stromal cells cross-presenting the tumor antigen (Ag), can lead to the complete destruction of well-established solid tumors by adoptively transferred Ag-specific cytotoxic T lymphocytes (CTLs). If, however, cancer cells express only low levels of the Ag, then stromal cells are not destroyed, and the tumor escapes as Ag loss variants. We show that treating well-established tumors expressing low levels of Ag with local irradiation or a chemotherapeutic drug causes sufficient release of Ag to sensitize stromal cells for destruction by CTLs. This was shown directly using high affinity T cell receptor tetramers for visualizing the transient appearance of tumor-specific peptide-MHC complexes on stromal cells. Maximum loading of tumor stroma with cancer Ag occurred 2 d after treatment and coincided with the optimal time for T cell transfer. Under these conditions, tumor rejection was complete. These findings may set the stage for developing rational clinical protocols for combining irradiation or chemotherapy with CTL therapy.

Radiation for hematologic malignancies: from cell killing to immune cell priming.

Over the past half-century, the role of radiotherapy has been revolutionized, in part, by a shift from intent to directly kill cancer cells to the goal of priming anti-tumor immune responses that attack both irradiated and non-irradiated tumors. Stimulation of anti-tumor immunity depends on the interplay between radiation, the tumor microenvironment, and the host immune system, which is a burgeoning concept in cancer immunology. While the interplay of radiotherapy and the immune system has been primarily studied in solid tumors, we are beginning to understand this interplay in hematological malignancies. The intent of this review is to lead readers through some of the important recent advances in immunotherapy and adoptive cell therapy, highlighting the best available evidence in support of incorporating radiation therapy and immunotherapy into the treatment of hematological malignancies. Evidence is presented regarding how radiation therapy 'converses' with the immune system to stimulate and enhance anti-tumor immune responses. This pro-immunogenic role of radiotherapy can be combined with monoclonal antibodies, cytokines and/or other immunostimulatory agents to enhance the regression of hematological malignancies. Furthermore, we will discuss how radiotherapy facilitates the effectiveness of cellular immunotherapies by acting as a "bridge" that facilitated CAR T cell engraftment and activity. These initial studies suggest radiotherapy may help catalyze a shift from using chemotherapy-intensive treatment to treatment that is "chemo-free" by combining with immunotherapy to target both the radiated and non-irradiated disease sites. This "journey" has opened the door for novel uses of radiotherapy in hematological malignancies due to its ability to prime anti-tumor immune responses which can augment immunotherapy and adoptive cell-based therapy.

Increased Utilization of Stereotactic Body Radiotherapy is Associated with Decreased Disparities and Improved Survival for Early-Stage NSCLC.

INTRODUCTION: We sought to determine if increased use of stereotactic body radiation therapy (SBRT) was associated with decreased disparities in the receipt of definitive treatment for early-stage non-small cell lung cancer (NSCLC). METHODS: The National Cancer Database (NCDB) was utilized to determine the proportion of patients with NSCLC receiving surgery, SBRT, or no definitive treatment for clinical cT1-2aN0M0 NSCLC from 2004-2017. Univariable and multivariable logistic regressions were used. Age-adjusted mortality rates were calculated using the Surveillance, Epidemiology, and End Result (SEER) database. RESULTS: From 2004 to 2017, the proportion of early-stage NSCLC undergoing no definitive treatment declined from 22% to 10.5% (P<.001), while the proportion receiving SBRT increased from 1% (0.9%-1.3%) to 22% (21.4%-22.3%; P<.001). Among Whites, the proportion undergoing no definitive treatment decreased from 21% to 10% (P<.001), as compared to Blacks, which had a higher decrease, of 32% to 15% (P<.001). The proportion of Blacks receiving SBRT increased from 1% (0.3%-1.7%) to 22% (20.8%-23.5%) (P<.001). Between 2011 and 2017 likelihood of Blacksreceiving curative therapy increased compared to Whites [OR: 0.55 (0.48-0.64) to 0.70 (0.62-0.79; P<.001]. Furthermore, the age-adjusted mortality rate of early-stage NSCLC decreased from 4.3 (4.0-4.5) in 2004 to 0.8 (0.7-0.9) in 2017 (P<.001). CONCLUSIONS: Increased utilization of SBRT significantly increased the proportion of patients receiving curative therapy for early-stage NSCLC and was associated with an improvement in mortality.  Furthermore, the use of SBRT reduced previously seen disparities in receipt of treatment between Whites and Blacks. SBRT was also associated with decreased mortality from early-stage NSCLC.

Prevalence of pituitary hormone dysfunction following radiotherapy for sinonasal and nasopharyngeal malignancies.

BACKGROUND: There are limited studies and no surveillance protocols on pituitary dysfunction for adults who underwent anterior skull base radiation. METHODS: Cross-sectional study of 50 consecutive patients with sinonasal or nasopharyngeal cancer who underwent definitive radiotherapy. The mean radiation doses, prevalence of pituitary dysfunction, and associated factors were calculated. RESULTS: Pituitary hormone levels were abnormal in 23 (46%) patients, including 6 (12%) with symptomatic abnormalities requiring treatment. The most common hormonal abnormality was hyperprolactinemia (30%), central hypothyroidism (8%) and central hypogonadism (6%). Patients with abnormal pituitary hormone values received higher mean radiation doses to the pituitary gland (1143 cGy, P = 0.04), pituitary stalk (1129 cGy, P = 0.02), optic chiasm (1094 cGy, P = 0.01), and hypothalamus (900 cGy, P = 0.01). CONCLUSIONS: Nearly half of the patients had abnormal pituitary function, including over a tenth requiring treatment. There may be a dose-dependent association between hormonal dysfunction and radiation.

Hypothyroidism following Radiotherapy for Head and Neck Cancer: A Systematic Review of the Literature and Opportunities to Improve the Therapeutic Ratio.

(1) Background: Radiotherapy (RT) is a central component for the treatment of many head and neck cancers. In this systematic review of the literature, we aimed to characterize and quantify the published evidence on RT-related hypothyroidism, including estimated incidence, clinical risk factors, and dosimetric parameters that may be used to guide clinical decision making. Furthermore, we aimed to identify potential areas of improvement in the prevention and clinical management of RT-induced hypothyroidism, including the role of modern advanced therapeutic techniques. (2) Methods: We conducted a systemic review of the literature in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. PubMed and Google Scholar were searched to identify original research articles describing the incidence, mechanism, dosimetry, treatment, or prevention of radiation-related hypothyroidism for adults receiving RT for the treatment of head and neck cancers. The snowball method was used to identify additional articles. For identified articles, we tabulated several datapoints, including publication date, patient sample size, estimated hypothyroidism incidence, cancer site/type, follow-up period, radiation modality and technique, use of multimodality therapy, method of thyroid function evaluation, and proposed dosimetric predictors of hypothyroidism. (3) Results: One hundred and eleven articles met inclusion criteria, reflecting a range of head and neck cancer subtypes. There was a large variation in the estimated incidence of RT-related hypothyroidism, with a median estimate of 36% (range 3% to 79%). Reported incidence increased in later publication dates, which was likely related to improved screening and longer follow up. There were a wide variety of predictive metrics used to identify patients at high risk of hypothyroidism, the most common of which were volumetric and mean dosimetrics related to the thyroid gland (Vxx%, Dmean). More recently, there has been increasing evidence to suggest that the thyroid gland volume itself and the volume of the thyroid gland spared from high-dose radiation (VSxx) may better predict thyroid function after RT. There were no identified studies investigating the role of advanced radiotherapeutic techniques such as MRI-guided RT or particle therapy to decrease RT-related hypothyroidism. Conclusions: Hypothyroidism is a common toxicity resulting from therapeutic radiation for head and neck cancer with recent estimates suggesting 40-50% of patients may experience hypothyroidism after treatment. Dosimetric predictive models are increasingly able to accurately identify patients at risk of hypothyroidism, especially those utilizing thyroid VS metrics. Further investigation regarding the potential for advanced radiotherapeutic therapies to decrease RT-induced thyroid dysfunction is needed.

Surgery After BRAF-Directed Therapy Is Associated with Improved Survival in BRAFV600E Mutant Anaplastic Thyroid Cancer: A Single-Center Retrospective Cohort Study.

Background: The aim of this study was to describe the oncologic outcomes of patients with BRAFV600E-mutated anaplastic thyroid cancer (ATC) who had neoadjuvant BRAF-directed therapy with subsequent surgery. For context, we also reviewed patients who received BRAF-directed therapy after surgery, and those who did not have surgery after BRAF-directed therapy. Methods: This was a single-center retrospective cohort study conducted at a tertiary care cancer center in Texas from 2017 to 2021. Fifty-seven consecutive patients with BRAFV600E-mutated ATC and at least 1 month of BRAF-directed therapy were included. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Results: All patients had stage IVB (35%) or IVC (65%) ATC. Approximately 70% of patients treated with BRAF-directed therapy ultimately had surgical resection of residual disease. Patients who had neoadjuvant BRAF-directed therapy followed by surgery (n = 32) had 12-month OS of 93.6% [confidence interval (CI) 84.9-100] and PFS of 84.4% [CI 71.8-96.7]. Patients who had surgery before BRAF-directed therapy (n = 12) had 12-month OS of 74.1% [CI 48.7-99.5] and PFS of 50% [CI 21.7-78.3]. Finally, patients who did not receive surgery after BRAF-directed therapy (n = 13) had 12-month OS of 38.5% [CI 12.1-64.9] and PFS of 15.4% [CI 0-35.0]. Neoadjuvant BRAF-directed therapy reduced tumor size, extent of surgery, and surgical morbidity score. Subgroup analysis suggested that any residual ATC in the surgical specimen was associated with significantly worse 12-month OS and PFS (OS = 83.3% [CI 62.6-100], PFS = 61.5% [CI 35.1-88]) compared with patients with pathologic ATC complete response (OS = 100%, PFS = 100%). Conclusions: We observed that neoadjuvant BRAF-directed therapy reduced extent of surgery and surgical morbidity. While acknowledging potential selection bias, the 12-month OS rate appeared higher in patients who had BRAF-directed therapy followed by surgery as compared with BRAF-directed therapy without surgery; yet, it was not significantly different from surgery followed by BRAF-directed therapy. PFS appeared higher in patients treated with neoadjuvant BRAF-directed therapy relative to patients in the other groups. These promising results of neoadjuvant BRAF-directed therapy followed by surgery for BRAF-mutated ATC should be confirmed in prospective clinical trials.

Temporal characterization of acute pain and toxicity kinetics during radiation therapy for head and neck cancer. A retrospective study.

Objectives: Pain during Radiation Therapy (RT) for oral cavity/oropharyngeal cancer (OC/OPC) is a clinical challenge due to its multifactorial etiology and variable management. The objective of this study was to define complex pain profiles through temporal characterization of pain descriptors, physiologic state, and RT-induced toxicities for pain trajectories understanding. Materials and methods: Using an electronic health record registry, 351 OC/OPC patients treated with RT from 2013 to 2021 were included. Weekly numeric scale pain scores, pain descriptors, vital signs, physician-reported toxicities, and analgesics were analyzed using linear mixed effect models and Spearman's correlation. Area under the pain curve (AUCpain) was calculated to measure pain burden over time. Results: Median pain scores increased from 0 during the weekly visit (WSV)-1 to 5 during WSV-7. By WSV-7, 60% and 74% of patients reported mouth and throat pain, respectively, with a median pain score of 5. Soreness and burning pain peaked during WSV-6/7 (51%). Median AUCpain was 16% (IQR (9.3-23)), and AUCpain significantly varied based on gender, tumor site, surgery, drug use history, and pre-RT pain. A temporal increase in mucositis and dermatitis, declining mean bodyweight (-7.1%; P < 0.001) and mean arterial pressure (MAP) 6.8 mmHg; P < 0.001 were detected. Pulse rate was positively associated while weight and MAP were negatively associated with pain over time (P < 0.001). Conclusion: This study provides insight on in-depth characterization and associations between dynamic pain, physiologic, and toxicity kinetics. Our findings support further needs of optimized pain control through temporal data-driven clinical decision support systems for acute pain management.

Decreased overall survival in patients with locally advanced head and neck cancer receiving definitive radiotherapy and concurrent cetuximab: National Cancer Database analysis.

BACKGROUND: Recently, randomized trials have questioned the efficacy of cetuximab-based bioradiotherapy compared to chemoradiation for patients with squamous cell carcinoma of the oropharynx, larynx, and hypopharynx (HNSCC). We compared the OS of patients treated with radiotherapy alone (RTonly), chemoradiotherapy (chemoRT), and bioradiotherapy (cetuxRT). METHODS: Patients with stage III-IVB HNSCC treated with RTonly, chemoRT, or cetuxRT were identified in the National Cancer Database. OS was estimated using Cox proportional hazards. Analyses were conducted on the overall cohort and propensity matched cohorts. RESULTS: 31 014 patients were treated with RTonly (22%), chemoRT (72%), or cetuxRT (6%) from 2013 to 2016. The 2-year OS was 69% for RTonly, 79% for chemoRT, and 66% for cetuxRT (p < 0.001). In the overall and propensity-matched cohorts, chemoRT and RTonly were associated with improved OS as compared to cetuxRT (p ≤ 0.001). CONCLUSION: Compared to chemoRT or RTonly, cetuxRT is associated with decreased OS for patients with HNSCC, suggesting minimal benefit of bioradiotherapy in this population.

Genetic Changes Driving Immunosuppressive Microenvironments in Oral Premalignancy.

Oral premalignant lesions (OPLs) are the precursors to oral cavity cancers, and have variable rates of progression to invasive disease. As an intermediate state, OPLs have acquired a subset of the genomic alterations while arising in an oral inflammatory environment. These specific genomic changes may facilitate the transition to an immune microenvironment that permits malignant transformation. Here, we will discuss mechanisms by which OPLs develop an immunosuppressive microenvironment that facilitates progression to invasive cancer. We will describe how genomic alterations and immune microenvironmental changes co-evolve and cooperate to promote OSCC progression. Finally, we will describe how these immune microenvironmental changes provide specific and unique evolutionary vulnerabilities for targeted therapies. Therefore, understanding the genomic changes that drive immunosuppressive microenvironments may eventually translate into novel biomarker and/or therapeutic approaches to limit the progression of OPLs to potential lethal oral cancers.