The evolving landscape of salivary gland tumors.

Salivary gland cancers are a rare, histologically diverse group of tumors. They range from indolent to aggressive and can cause significant morbidity and mortality. Surgical resection remains the mainstay of treatment, but radiation and systemic therapy are also critical parts of the care paradigm. Given the rarity and heterogeneity of these cancers, they are best managed in a multidisciplinary program. In this review, the authors highlight standards of care as well as exciting new research for salivary gland cancers that will strive for better patient outcomes.

An update on the immune landscape in lung and head and neck cancers.

Immunotherapy has dramatically changed the treatment landscape for patients with cancer. Programmed death-ligand 1/programmed death-1 checkpoint inhibitors have been in the forefront of this clinical revolution. Currently, there are 6 US Food and Drug Administration-approved checkpoint inhibitors for approximately 18 different histologic types of cancer. Lung cancer and head and neck squamous cell carcinoma (HNSCC) are 2 diseases that have led the way in the development of immunotherapy. Atezolizumab, durvalumab, nivolumab, and pembrolizumab are all currently used as part of standard-of-care treatment for different stages of lung cancer. Similarly, nivolumab and pembrolizumab have US regulatory approval as treatment for advanced metastatic HNSCC. This is significant because lung cancer represents the most common and most fatal cancer globally, and HNSCC is the sixth most common. Currently, most of the approvals for the use of immunotherapy agents are for patients diagnosed in the metastatic setting. However, research is ongoing to evaluate these drugs in earlier stage disease. There is plausible biological rationale to expect that pharmacologic activation of the immune system will be effective for early-stage and smaller tumors. In addition, selecting patients who are more likely to respond to immunotherapy and understanding why resistance develops are crucial areas of ongoing research. The objective of this review was to provide an overview of the current immune landscape and future directions in lung cancer and HNSCC.

Defining HPV-specific B cell responses in patients with head and neck cancer.

Tumours often contain B cells and plasma cells but the antigen specificity of these intratumoral B cells is not well understood1-8. Here we show that human papillomavirus (HPV)-specific B cell responses are detectable in samples from patients with HPV-positive head and neck cancers, with active production of HPV-specific IgG antibodies in situ. HPV-specific antibody secreting cells (ASCs) were present in the tumour microenvironment, with minimal bystander recruitment of influenza-specific cells, suggesting a localized and antigen-specific ASC response. HPV-specific ASC responses correlated with titres of plasma IgG and were directed against the HPV proteins E2, E6 and E7, with the most dominant response against E2. Using intratumoral B cells and plasma cells, we generated several HPV-specific human monoclonal antibodies, which exhibited a high degree of somatic hypermutation, consistent with chronic antigen exposure. Single-cell RNA sequencing analyses detected activated B cells, germinal centre B cells and ASCs within the tumour microenvironment. Compared with the tumour parenchyma, B cells and ASCs were preferentially localized in the tumour stroma, with well-formed clusters of activated B cells indicating ongoing germinal centre reactions. Overall, we show that antigen-specific activated and germinal centre B cells as well as plasma cells can be found in the tumour microenvironment. Our findings provide a better understanding of humoral immune responses in human cancer and suggest that tumour-infiltrating B cells could be harnessed for the development of therapeutic agents.

Functional HPV-specific PD-1+ stem-like CD8 T cells in head and neck cancer.

T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer1,2. Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1+ CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1+ stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1+TCF-1+ stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1+TCF-1+CD45RO+ stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth.

DNA methylation profiles of cancer-related fatigue associated with markers of inflammation and immunometabolism.

Cancer patients are commonly affected by fatigue. Herein, we sought to examine epigenetic modifications (i.e., DNA methylation) related to fatigue in peripheral blood among patients during and after treatment for head and neck cancer (HNC). Further, we determined whether these modifications were associated with gene expression and inflammatory protein markers, which we have previously linked to fatigue in HNC. This prospective, longitudinal study enrolled eligible patients with data collected at pre-radiotherapy, end of radiotherapy, and six months and one-year post-radiotherapy. Fatigue data were reported by patients using the Multidimensional Fatigue Inventory (MFI)-20. DNA methylation (Illumina MethylationEPIC) and gene expression (Applied Biosystems Clariom S) arrays and assays for seven inflammatory markers (R&D Systems multiplex) were performed. Mixed models and enrichment analyses were applied to establish the associations. A total of 386 methylation loci were associated with fatigue among 145 patients (False Discovery Rate [FDR] < 0.05). Enrichment analyses showed the involvement of genes related to immune and inflammatory responses, insulin and lipid metabolism, neuropsychological disorders, and tumors. We further identified 16 methylation-gene expression pairs (FDR < 0.05), which were linked to immune and inflammatory responses and lipid metabolism. Ninety-one percent (351) of the 386 methylation loci were also significantly associated with inflammatory markers (e.g., interleukin 6, c-reactive protein; FDR < 0.05), which further mediated the association between methylation and fatigue (FDR < 0.05). These data suggest that epigenetic modifications associated with inflammation and immunometabolism, in conjunction with relevant gene expression and protein markers, are potential targets for treating fatigue in HNC patients. The findings also merit future prospective studies in other cancer populations as well as interventional investigations.

The effect of neighborhood socioeconomic disadvantage on smoking status, quit attempts, and receipt of cessation support among adults with cancer: Results from nine ECOG-ACRIN Cancer Research Group trials.

BACKGROUND: Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer. METHODS: A modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) was administered to patients enrolled in nine ECOG-ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression. RESULTS: A total of 740 patients completing the C-TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69-7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64-10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02-0.58; p = .0086) versus those in the least disadvantaged neighborhoods. CONCLUSIONS: Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

Rescue of NLRC5 expression restores antigen processing machinery in head and neck cancer cells lacking functional STAT1 and p53.

The antigen processing machinery (APM) components needed for a tumor cell to present an antigen to a T cell are expressed at low levels in solid tumors, constituting an important mechanism of immune escape. More than most other solid tumors, head and neck squamous cell carcinoma (HNSCC) cells tend to have low APM expression, rendering them insensitive to immune checkpoint blockade and most other forms of immunotherapy. In HNSCC, this APM deficiency is largely driven by high levels of EGFR and SHP2, leading to low expression and activation of STAT1; however, recent studies suggest that p53, which is often mutated in HNSCCs, may also play a role. In the current study, we aimed to investigate the extent to which STAT1 and p53 individually regulate APM component expression in HNSCC cells. We found that in cells lacking functional p53, APM expression could still be induced by interferon-gamma or DNA-damaging chemotherapy (cisplatin) as long as STAT1 expression remained intact; when both transcription factors were knocked down, APM component expression was abolished. When we bypassed these deficient pathways by rescuing the expression of NLRC5, APM expression was also restored. These results suggest that dual loss of functional STAT1 and p53 may render HNSCC cells incapable of processing and presenting antigens, but rescue of downstream NLRC5 expression may be an attractive strategy for restoring sensitivity to T cell-based immunotherapy.

Initial surgical management of sporadic medullary thyroid cancer: Guidelines based optimal care - A systematic review.

INTRODUCTION: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor from parafollicular cells that produce calcitonin (Ct). Despite several existing guidelines for the surgical management of sporadic MTC (sMTC), optimal initial surgical management of the thyroid, the central and the lateral neck remains a matter of debate. METHODS: A systematic review in PubMed and Scopus for current guidelines addressing the surgical management of sMTC and its referenced citations was conducted as per the PRISMA guidelines. RESULTS: Two-hundred and one articles were identified, of which 7 met the inclusion criteria. Overall, guidelines vary significantly in their recommendations for the surgical management of sMTC. Only one guideline recommended partial thyroidectomy for limited disease, but the possibility to avoid completion thyroidectomy in selected cases is acknowledged in 42% (3/7) of the remaining guidelines. The majority of guidelines (71.4%; 5/7) recommended prophylactic central neck dissection (CND) for all patients while the remaining two guidelines recommended CND based on Ct level and tumor size. The role of prophylactic lateral neck dissection based on preoperative Ct levels was recommended by 42% (3/7) of guidelines. Overall, these guidelines are based on low-quality evidence, mostly single-center retrospective series, some of which are over 20 years old. CONCLUSION: Current surgical management guidelines of sMTC should be revised, and ought to be based on updated data challenging current recommendations, which are based on historic, low-quality evidence. Partial thyroidectomy may become a viable option for small, limited tumors. Prospective, multi-center studies may be useful to conclude whether prophylactic ND is necessary in all sMTC patients.

An update on larynx cancer.

Answer questions and earn CME/CNE Laryngeal cancer remains one of the most common tumors of the respiratory tract. Fortunately, significant advancements have been made over the past decade in the treatment of laryngeal cancer. Although surgery has been the historical mainstay for localized disease and still is an integral part of treatment, nonsurgical options like radiation and systemic therapy have emerged as viable options. In addition, in the metastatic setting, novel agents are showing promise for this patient population. The care for patients with laryngeal cancer continues to evolve and truly requires a multidisciplinary team-based approach. Unique morbidities, such as loss of natural voice, respiration, and airway protection during swallowing, are observed with this disease and require special consideration. CA Cancer J Clin 2017;67:31-50. © 2016 American Cancer Society.

Circulating short chain fatty acids and fatigue in patients with head and neck cancer: A longitudinal prospective study.

Fatigue among patients with head and neck cancer (HNC) has been associated with higher inflammation. Short-chain fatty acids (SCFAs) have been shown to have anti-inflammatory and immunoregulatory effects. Therefore, this study aimed to examine the association between SCFAs and fatigue among patients with HNC undergoing treatment with radiotherapy with or without concurrent chemotherapy. Plasma SCFAs and the Multidimensional Fatigue Inventory-20 were collected prior to and one month after the completion of treatment in 59 HNC patients. The genome-wide gene expression profile was obtained from blood leukocytes prior to treatment. Lower butyrate concentrations were significantly associated with higher fatigue (p = 0.013) independent of time of assessment, controlling for covariates. A similar relationship was observed for iso/valerate (p = 0.025). Comparison of gene expression in individuals with the top and bottom 33% of butyrate or iso/valerate concentrations prior to radiotherapy revealed 1,088 and 881 significantly differentially expressed genes, respectively (raw p < 0.05). The top 10 Gene Ontology terms from the enrichment analyses revealed the involvement of pathways related to cytokines and lipid and fatty acid biosynthesis. These findings suggest that SCFAs may regulate inflammatory and immunometabolic responses and, thereby, reduce inflammatory-related symptoms, such as fatigue.

Iron, Ferroptosis, and Head and Neck Cancer.

Ferroptosis is an iron-dependent regulatory form of cell death characterized by the accumulation of intracellular reactive oxygen species and lipid peroxidation. It plays a critical role not only in promoting drug resistance in tumors, but also in shaping therapeutic approaches for various malignancies. This review aims to elucidate the relationship between ferroptosis and head and neck cancer treatment by discussing its conceptual framework, mechanism of action, functional aspects, and implications for tumor therapy. In addition, this review consolidates strategies aimed at improving the efficacy of head and neck cancer treatment through modulation of ferroptosis, herein serving as a valuable reference for advancing the treatment landscape for this patient population.

Immune check point inhibitors in advanced cutaneous squamous cell carcinomas: "Repeat and replicate".

Recent evidence confirmed the significant clinical benefit from using immune check point inhibitors, namely PD-1 inhibitors, in patients with advanced cutaneous squamous cell carcinomas. The activity of these different agents seems to be strikingly equivalent. This phase 2 trial confirms a similar clinical benefit to single agent nivolumab in treating this disease. The replication of these findings raises the question of whether substitution of these immunotherapeutic agents can be justified based on smaller confirmatory trials.

A network analysis of self-reported psychoneurological symptoms in patients with head and neck cancer undergoing intensity-modulated radiotherapy.

BACKGROUND: Patients with head and neck cancer experience psychoneurological symptoms (PNS) (i.e., depression, fatigue, sleep disturbance, pain, and cognitive dysfunction) during intensity-modulated radiotherapy (IMRT) that decrease their functional status, quality of life, and survival rates. The purpose of this study was to examine and visualize the relationships among PNS within networks over time and evaluate for demographic and clinical characteristics associated with symptom networks. METHODS: A total of 172 patients (mean age, 59.8 ± 9.9 years; 73.8%, male; 79.4%, White) completed symptom questionnaires four times, namely, before IMRT (T1), 1 month (T2), 3 months (T3), and 12 months (T4) post IMRT. Network analysis was used to examine the symptom-symptom relationships among PNS. Centrality indices, including strength, closeness, and betweenness, were used to describe the degrees of symptom network interconnections. Network comparison test was used to assess the differences between two symptom networks. RESULTS: Depression was associated with the other four symptoms, and fatigue was associated with the other three symptoms across the four assessments. Based on the centrality indices, depression (rstrength  = 1.3-1.4, rcloseness  = 0.06-0.08, rbetweeness  = 4-10) was the core symptom in all symptom networks, followed by fatigue. Female gender, higher levels of stress, and no alcohol use were associated with stronger symptom networks in network global strength before IMRT. CONCLUSION: Network analysis provides a novel approach to gain insights into the relationships among self-reported PNS and identify the core symptoms and associated characteristics. Clinicians may use this information to develop symptom management interventions that target core symptoms and interconnections within a network. LAY SUMMARY: This study describes the symptom-symptom relationships for five common symptoms in patients with head and neck cancer receiving radiotherapy. Depression and fatigue appeared to be two core symptoms that were connected with sleep disturbance, pain, and cognitive dysfunction within a network. Several characteristics (i.e., female, higher stress, no alcohol use) were associated with stronger symptom networks.

Head and neck cancer.

Head and neck cancer is the seventh most common type of cancer worldwide and comprise of a diverse group of tumours affecting the upper aerodigestive tract. Although many different histologies exist, the most common is squamous cell carcinoma. Predominant risk factors include tobacco use, alcohol abuse, and oncogenic viruses, including human papillomavirus and Epstein-Barr virus. Head and neck malignancies remain challenging to treat, requiring a multidisciplinary approach, with surgery, radiotherapy, and systemic therapy serving as key components of the treatment of locally advanced disease. Although many treatment principles overlap, treatment is generally site-specific and histology-specific. This Seminar outlines the current understanding of head and neck cancer and focuses on treatment principles, while also discussing future directions to improve the outcomes of patients with these malignancies.

Long-term Outcomes with Nivolumab as First-line Treatment in Recurrent or Metastatic Head and Neck Cancer: Subgroup Analysis of CheckMate 141.

In the randomized, phase 3 CheckMate 141 trial, nivolumab significantly improved overall survival (OS) versus investigator's choice (IC) of chemotherapy at primary analysis among 361 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) post-platinum therapy. Nivolumab versus IC as first-line treatment also improved OS among patients with R/M SCCHN who progressed on platinum therapy for locally advanced disease in the adjuvant or primary setting at 1-year follow-up. In the present long-term follow-up analysis of patients receiving first-line treatment, OS benefit with nivolumab (n = 50) versus IC (n = 26) was maintained (median: 7.7 months versus 3.3 months; hazard ratio: 0.56; 95% confidence interval, 0.34-0.94) at 2 years. No new safety signals were identified. In summary, this long-term 2-year analysis of CheckMate 141 supports the use of nivolumab as a first-line treatment for patients with platinum-refractory R/M SCCHN.

Comparison of the Seventh and Eighth Edition of American Joint Committee on Cancer (AJCC) Staging for Selected and Nonselected Oropharyngeal Squamous Cell Carcinomas.

OBJECTIVES: The eighth edition American Joint Committee on Cancer (AJCC) Staging incorporates significant changes to the seventh edition in the staging of oropharyngeal squamous cell carcinomas (OPSCC). An important change was the inclusion of OPSCC associated with the human papilloma virus (HPV). Our goal is to compare the performance of both staging systems for patients with HPV-selected and unselected clinical characteristics for OPSCC. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, 2004-2016, we identified patients with likely HPV-associated OPSCC based on surrogate markers (white males aged <65 years old with squamous cell carcinomas of the tonsil and base of tongue), excluding those who underwent surgery. We re-classified these patients using seventh and eighth edition staging for HPV-selected OPSCC and compared the prediction performance of both staging editions for overall survival (OS) and disease-specific survival (DSS). We performed the same analysis for clinically unselected patients with OPSCC. RESULTS: Our analysis included 9554 patients with a median follow-up of 67 months. Comparing the eighth versus seventh edition for our HPV-selected cohort, clinical staging changed for 92.3% of patients and 10-year OS was 62.2%, 61.2%, 35.3%, and 15.5% for Stage I, II, III, and IV, versus 52.9%, 59.2%, 61.6%, 55.1%, 38.3%, and 15.5% for stage I, II, III, IVA, IVB, and IVC, respectively. A similar pattern was observed for 10-year DSS. The concordance statistics for our HPV-selected cohort were improved for both AJCC 7 (0.6260) and AJCC 8 (0.6846) compared with the unselected cohort, 0.5860 and 0.6457 for AJCC 7 and 8, respectively. CONCLUSION: The overall performance of discrimination improved from AJCC 7 to AJCC 8 for both clinically selected and unselected patients, but more notably for our HPV-selected cohort. Despite the lack of statistically significant differentiation between Stages I and II in AJCC 8 in either groups, markedly improved discrimination was observed between Stages I/II, III, and IV in the HPV-selected cohort.

TP53 mutations in head and neck cancer.

Head and neck squamous cell carcinomas (HNSCCs) arising in the mucosal linings of the upper aerodigestive tract are highly heterogeneous, aggressive, and multifactorial tumors affecting more than half a million patients worldwide each year. Classical etiological factors for HNSCC include alcohol, tobacco, and human papillomavirus (HPV) infection. Current treatment options for HNSCCs encompass surgery, radiotherapy, chemotherapy, or combinatorial remedies. Comprehensive integrative genomic analysis of HNSCC has identified mutations in TP53 gene as the most frequent of all somatic genomic alterations. TP53 mutations are associated with either loss of wild-type p53 function or gain of functions that promote invasion, metastasis, genomic instability, and cancer cell proliferation. Interestingly, disruptive TP53 mutations in tumor DNA are associated with aggressiveness and reduced survival after surgical treatment of HNSCC. This review summarizes the current evidence and impact of TP53 mutations in HNSCC.

Epigenetic age acceleration, fatigue, and inflammation in patients undergoing radiation therapy for head and neck cancer: A longitudinal study.

BACKGROUND: The authors measured epigenetic age acceleration (EAA) during and after cancer treatment and its association with inflammation and fatigue, which is a debilitating symptom in patients with cancer. METHODS: Patients who had head and neck cancer without distant metastases were assessed before, immediately after, and at 6 months and 12 months postradiotherapy. Blood DNA methylation was assessed using a proprietary bead chip (the Illumina MethylationEPIC BeadChip). EAA was calculated using the Levine epigenetic clock (DNAmPhenoAge), adjusted for chronological age. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. Inflammatory markers were measured using standard techniques. RESULTS: Most patients (N = 133) were men, White, had advanced disease, and received concurrent chemoradiation. EAA changes over time were significant, with the largest increase (4.9 years) observed immediately after radiotherapy (P < .001). Increased EAA was associated with elevated fatigue (P = .003) over time, and patients who had severe fatigue experienced 3.1 years higher EAA than those who had low fatigue (P < .001), which was more prominent (5.6 years; P = .018) for patients who had human papillomavirus-unrelated disease at 12 months posttreatment. EAA was also positively associated with inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), over time (P < .001), and patients who had high CRP and IL-6 levels exhibited increases of 4.6 and 5.9 years, respectively, in EAA compared with those who had low CRP and IL-6 levels (P < .001). CRP and IL-6 mediated the association between EAA and fatigue (CRP: 95% CI, 0.060-0.279; IL-6: 95% CI, 0.024-0.220). CONCLUSIONS: Patients with head and neck cancer experienced increased EAA, especially immediately after treatment completion. EAA was associated with greater fatigue and inflammation, including 1 year after treatment. Inflammation may be a target to reduce the impact of age acceleration on poor functional outcomes.

Association Among Glucocorticoid Receptor Sensitivity, Fatigue, and Inflammation in Patients With Head and Neck Cancer.

OBJECTIVE: Fatigued cancer patients often have high peripheral inflammation; however, the biological mechanisms of this association remain unclear. We examined whether decreased sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids may contribute to inflammation and fatigue in head and neck cancer (HNC) patients during treatment. METHODS: HNC patients without distant metastasis and with curative intent (n = 77) were studied 1 week before intensity-modulated radiotherapy (IMRT) and 1 month after IMRT. At each time point, fatigue was measured by the Multidimensional Fatigue Inventory-20 along with plasma inflammation markers and glucocorticoid receptor (GR) sensitivity as determined by in vitro dexamethasone suppression of lipopolysaccharide-induced interleukin 6. Linear regression models were used. RESULTS: In contrast to our hypothesis, GR sensitivity increased during treatment; however, increased fatigue was associated with a lesser increase in GR sensitivity from baseline to 1 month after IMRT (unstandardized estimate = 4.07, p = .02). This effect was more prominent in human papillomavirus-unrelated HNCs (unstandardized estimate = 8.22, p = .002). Lower increases in GR sensitivity were also associated with increased inflammation at 1 month after IMRT as represented by C-reactive protein, interleukin 6, and tumor necrosis factor α. Addition of inflammation markers to models of GR sensitivity predicting fatigue indicated that these inflammation markers were stronger predictors of fatigue than GR sensitivity. CONCLUSIONS: Lower increases in GR sensitivity during HNC treatment were significantly predictive of increased fatigue and inflammation markers. Inflammation markers in turn predicted fatigue above and beyond levels of GR sensitivity. Our findings indicate that HNC patients with cancer-related fatigue may exhibit a decreased capacity for glucocorticoids to regulate inflammatory processes, as evidenced by a lower increase in GR sensitivity. Larger studies are necessary to verify the findings.