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Purpose: We evaluated X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) protein in head and neck squamous cell carcinoma (HNSCC) patients in association with outcome.Experimental Design: XRCC1 protein expression was assessed by immunohistochemical (IHC) staining of pretreatment tissue samples in 138 consecutive HNSCC patients treated with surgery (n = 31), radiation (15), surgery and radiation (23), surgery and adjuvant chemoradiation (17), primary chemoradiation (51), and palliative measures (1).Results: Patients with high XRCC1 expression by IHC (n = 77) compared with patients with low XRCC1 expression (n = 60) had poorer median overall survival (OS; 41.0 months vs. OS not reached, P = 0.009) and poorer progression-free survival (28.0 months vs. 73.0 months, P = 0.031). This association was primarily due to patients who received chemoradiation (median OS of high- and low-XRCC1 expression patients, 35.5 months and not reached respectively, HR 3.48; 95% CI: 1.44–8.38; P = 0.006). In patients treated with nonchemoradiation modalities, there was no survival difference by XRCC1 expression. In multivariable analysis, high XRCC1 expression and p16INK4a-positive status were independently associated with survival in the overall study population (HR = 2.62; 95% CI: 1.52–4.52; P < 0.001 and HR = 0.21; 95% CI: 0.06–0.71; P = 0.012, respectively) and among chemoradiation patients (HR = 6.02; 95% CI: 2.36–15.37; P < 0.001 and HR = 0.26; 95% CI: 0.08–0.92, respectively; P = 0.037).Conclusions: In HNSCC, high XRCC1 protein expression is associated with poorer survival, particularly in patients receiving chemoradiation. Future validation of these findings may enable identification of HNSCC expressing patients who benefit from chemoradiation treatment. Clin Cancer Res; 17(20); 6542–52. ©2011 AACR.

Cachexia is frequently accompanied by severe metabolic derangements, although the mechanisms responsible for this debilitating condition remain unclear. Pyruvate dehydrogenase kinase (PDK)4, a critical regulator of cellular energetic metabolism, was found elevated in experimental models of cancer, starvation, diabetes, and sepsis. Here we aimed to investigate the link between PDK4 and the changes in muscle size in cancer cachexia. High PDK4 and abnormal energetic metabolism were found in the skeletal muscle of colon-26 tumor hosts, as well as in mice fed a diet enriched in Pirinixic acid, previously shown to increase PDK4 levels. Viral-mediated PDK4 overexpression in myotube cultures was sufficient to promote myofiber shrinkage, consistent with enhanced protein catabolism and mitochondrial abnormalities. On the contrary, blockade of PDK4 was sufficient to restore myotube size in C2C12 cultures exposed to tumor media. Our data support, for the first time, a direct role for PDK4 in promoting cancer-associated muscle metabolic alterations and skeletal muscle atrophy.-Pin, F., Novinger, L. J., Huot, J. R., Harris, R. A., Couch, M. E., O'Connell, T. M., Bonetto, A. PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia.

Background Cancer cachexia is a metabolic disorder involving perturbed energy balance and altered mitochondrial function. Chemotherapy is a primary treatment option for many types of cancer, but there is substantial evidence that some chemotherapeutic agents can also lead to the development and progression of cachexia. In this study, we apply a comprehensive and systems level metabolomics approach to characterize the metabolic perturbations in murine models of cancer‐induced and chemotherapy‐induced cachexia. Knowledge of the unique pathways through which cancer and chemotherapy drive cachexia is necessary in order to develop effective treatments. Methods The murine Colon26 (C26) adenocarcinoma xenograft model was used to study the metabolic derangements associated with cancer‐induced cachexia. In vivo administration of Folfiri (5‐fluorouracil, irinotecan, and leucovorin) was used to model chemotherapy‐induced cachexia. Comprehensive metabolic profiling was carried out using both nuclear magnetic resonance‐based and mass spectrometry‐based platforms. Analyses included plasma, muscle, and liver tissue to provide a systems level profiling. Results The study involved four groups of CD2F1 male mice (n = 4–5), including vehicle treated (V), C26 tumour hosts (CC), Folfiri treated (F), and C26 tumour hosts treated with Folfiri (CCF). Significant weight loss including skeletal muscle was observed for each of the experimental groups with the tumour hosts showing the most dramatic change (−3.74 g vs. initial body weight in the CC group). Skeletal muscle loss was evident in all experimental groups compared with V, with the CCF combination resulting in the most severe depletion of quadriceps mass (−38% vs. V; P

Simple Summary More than 80% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia, characterized by loss of muscle and fat. However, most cachexia studies were predominantly focused on muscle. Our clinical study showed adipose tissue loss as a prognosticator in PDAC cachexia. Our study aims to understand the concurrent muscle and adipose changes using transcriptome profiling. We identified tissue-specific gene expression profiles with changes in adipose being more dynamic. Pathway analysis suggests that muscle and adipose wasting may be mediated through independently targetable mechanisms which may have therapeutic implications. Many of the well-known and novel cachexia genes have been validated using an external muscle and adipose datasets. The study provides the groundwork for future studies to understand if fat wasting precedes muscle wasting in PDAC and if adipose can be targeted for therapeutic interventions. The study also shows that age related muscle loss has distinct mechanisms compared to cachexia. Abstract The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n = 11) and patients with PDAC (n = 24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.

Purpose of review Cancer patients undergoing chemotherapy often experience very debilitating side effects, including unintentional weight loss, nausea, and vomiting. Changes in body composition, specifically lean body mass (LBM), are known to have important implications for anticancer drug toxicity and cancer prognosis. Currently, chemotherapy dosing is based on calculation of body surface area, although this approximation does not take into consideration the variability in lean and adipose tissue mass. Recent findings Patients with depletion of muscle mass present higher chemotherapy-related toxicity, whereas patients with larger amounts of LBM show fewer toxicities and better outcomes. Commonly used chemotherapy regimens promote changes in body composition, primarily by affecting skeletal muscle, as well as fat and bone mass. Experimental evidence has shown that pro-atrophy mechanisms, abnormal mitochondrial metabolism, and reduced protein anabolism are primarily implicated in muscle depletion. Muscle-targeted pro-anabolic strategies have proven successful in preserving lean tissue in the occurrence of cancer or following chemotherapy. Summary Muscle wasting often occurs as a consequence of anticancer treatments and is indicative of worse outcomes and poor quality of life in cancer patients. Accurate assessment of body composition and preservation of muscle mass may reduce chemotherapy toxicity and improve the overall survival.

BACKGROUND Cachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally under-studied in OC due to a limited number of pre-clinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC. METHODS Nod SCID gamma mice (n = 6-10) were injected intraperitoneally with 1 × 107 ES-2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumour-derived effects on muscle fibres were investigated in C2C12 myotube cultures. IL-6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections. RESULTS In about 2 weeks, ES-2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ES-2 tumours caused severe cachexia with marked loss of body weight (-12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 ± 1.5 mL). Skeletal muscles appeared markedly smaller in the tumour-bearing mice (approximately -35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle cross-sectional area (-34%, P < 0.01) and muscle weakness (-50%, P < 0.001). Body composition assessment by dual-energy X-ray absorptiometry revealed decreased bone mineral density (-8%, P < 0.01) and bone mineral content (-19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by micro-CT imaging of bone morphometry. In the ES-2 mouse model, cachexia was also associated with high tumour-derived IL-6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phospho-STAT3 (+274%, P < 0.001), reduced phospho-AKT (-44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ES-2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (-16%, P < 0.001), consistent with elevated phospho-STAT3 (+1.4-fold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the IL-6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size. CONCLUSIONS Our results suggest that the development of ES-2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated IL-6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC.

Author(s): Kays, Joshua K; Shahda, Safi; Stanley, Melissa; Bell, Teresa M; O'Neill, Bert H; Kohli, Marc D; Couch, Marion E; Koniaris, Leonidas G; Zimmers, Teresa A | Abstract: BackgroundBy the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here, we measure the longitudinal body composition changes in patients with advanced PDAC undergoing 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy.MethodsWe performed a retrospective review of 53 patients with advanced PDAC on 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement by computed tomography (CT), trend, univariate, and multivariate analysis were performed.ResultsAmong all patients, three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle and Fat Wasting (MFW), while 17% had Fat-Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (P = 0.02). FW (HR = 5.2; 95% confidence interval = 1.5-17.3) and MFW (HR = 1.8; 95% confidence interval = 1.1-2.9) were associated with an increased risk of mortality compared with NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumours were also associated with decreased OMS. On multivariate analysis, cachexia phenotype and chemotherapy response were independently associated with survival. Notably, CT-based body composition analysis detected tissue loss of g5% in 81% of patients, while the traditional definition of g5% body weight loss identified 56.6%.ConclusionsDistinct cachexia phenotypes were observed in this homogeneous population of patients with equivalent stage, diagnosis, and first-line treatment. This suggests cellular, molecular, or genetic heterogeneity of host or tumour. Survival among patients with FW was as poor as for MFW, indicating adipose tissue plays a crucial role in cachexia and PDAC mortality. Adipose tissue should be studied for its mechanistic contributions to cachexia.

Chemotherapy promotes the development of cachexia, a debilitating condition characterized by muscle and fat loss. ACVR2B/Fc, an inhibitor of the Activin Receptor 2B signaling, has been shown to preserve muscle mass and prolong survival in tumor hosts, and to increase bone mass in models of osteogenesis imperfecta and muscular dystrophy. We compared the effects of ACVR2B/Fc on muscle and bone mass in mice exposed to Folfiri. In addition to impairing muscle mass and function, Folfiri had severe negative effects on bone, as shown by reduced trabecular bone volume fraction (BV/TV), thickness (Tb.Th), number (Tb.N), connectivity density (Conn.Dn), and by increased separation (Tb.Sp) in trabecular bone of the femur and vertebra. ACVR2B/Fc prevented the loss of muscle mass and strength, and the loss of trabecular bone in femurs and vertebrae following Folfiri administration. Neither Folfiri nor ACVR2B/Fc had effects on femoral cortical bone, as shown by unchanged cortical bone volume fraction (Ct.BV/TV), thickness (Ct.Th) and porosity. Our results suggest that Folfiri is responsible for concomitant muscle and bone degeneration, and that ACVR2B/Fc prevents these derangements. Future studies are required to determine if the same protective effects are observed in combination with other anticancer regimens or in the presence of cancer.

Summary Background & aims Cancer patients frequently experience weight loss, with negative consequences for functionality and prognosis. The extent to which muscle atrophy contributes to weight loss, however, is not clear, as few studies have directly measured muscle fiber morphology in cancer patients. Methods Whole body and regional tissue composition were measured, along with the cross-sectional area (CSA) and fiber type of mechanically-isolated, single muscle fibers, in 19 cancer patients (8 with a history of weight loss, 11 weight-stable) and 15 non-diseased controls. Results Whole body fat mass was reduced in cancer patients with a history of weight loss, but no differences in whole body or leg fat-free mass were apparent. In contrast, reductions (∼20%) in single muscle fiber CSA were found in both slow-twitch, myosin heavy chain (MHC) I and fast-twitch, MHC IIA fibers in both weight-stable patients and those with a history of weight loss. Fiber type distribution showed a shift towards a fast-twitch phenotype compared to controls, which may preserve muscle function in cancer patients despite atrophy, as positive relationships were found between the fractions of hybrid MHC IIAX and I/IIA fibers and 6-min walk performance. Conclusions Our results suggest that, although not apparent from whole body or regional measurements, cancer is associated with reduced skeletal muscle fiber size independent of weight loss history and a shift towards fast-twitch fibers, phenotypes that resemble adaptations to muscle disuse.

Some chemotherapeutic agents have been shown to lead to the severe wasting syndrome known as cachexia resulting in dramatic losses of both skeletal muscle and adipose tissue. Previous studies have shown that chemotherapy-induced cachexia is characterized by unique metabolic alterations. Recent results from our laboratory and others have shown that the use of ACVR2B/Fc, a soluble form of the activin receptor 2B (ACVR2B), can mitigate muscle wasting induced by chemotherapy, although the underlying mechanisms responsible for such protective effects are unclear. In order to understand the biochemical mechanisms through which ACVR2B/Fc functions, we employed a comprehensive, multi-platform metabolomics approach. Using both nuclear magnetic resonance (NMR) and mass-spectrometry (MS), we profiled the metabolome of both serum and muscle tissue from four groups of mice including (1) vehicle, (2) the chemotherapeutic agent, Folfiri, (3) ACVR2B/Fc alone, and (4) combined treatment with both Folfiri and ACVR2B/Fc. The metabolic profiles demonstrated large effects with Folfiri treatment and much weaker effects with ACVR2B/Fc treatment. Interestingly, a number of significant effects were observed in the co-treatment group, with the addition of ACVR2B/Fc providing some level of rescue to the perturbations induced by Folfiri alone. The most prominent of these were a normalization of systemic glucose and lipid metabolism. Identification of these pathways provides important insights into the mechanism by which ACVR2B/Fc protects against chemotherapy-induced cachexia.

Background Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice. Methods Isoform‐specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed‐forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes. Results Murine PDAC tumour‐derived cell lines expressed activin‐βA but not activin‐βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin‐low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin‐high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin‐βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not. Conclusions Pancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ‐specific and gene‐specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle‐specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene‐specific and organ‐specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.

Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy with high rates of cachexia. Serum activin correlates with PDAC cachexia and mortality, while activin administration causes cachexia in mice. We studied activin in human tumors and in mice with orthotopic or genetic PDAC. Cachexia severity correlated with activin expression in tumor lines. Activins were expressed in both cancer and tumor stromal cells, but also in organs in murine PDAC cachexia. Tumor cells expressed activin-βA, orInhba, while organs expressed both activin-βA and activin-βB, orInhbb. PDAC elicits activin expression; PDAC conditioned medium induced activin and atrophy of myotubes. Treatment with the activin trap, ACVR2B/Fc, reduced cachexia and prolonged survival in mice with activin-low tumors, and reduced cachexia in activin-high tumors, without affecting activin expression in organs. Mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not survival. Overall our results indicate that PDAC induces a systemic activin response, leading to cachexia, and that activin targets might include organs beyond muscle. Targeting of both tumor-derived and host-derived activins could improve cachexia therapy.

A compounding feature of greater than 50% of all cancers is the high incidence of the cachexia syndrome, a complex metabolic disorder characterized by extreme weight loss due mainly to the gross depletion of skeletal muscle tissue. Although studies into the cause of cancer cachexia has spanned over multiple decades, little is known about the effects of various cancer treatments themselves on cachexia. For example, chemotherapy agents induce side effects such as nausea and anorexia, but these symptoms do not fully account for the changes seen with cancer cachexia. In this study we examine the effects of chemotherapeutic compounds, specifically, cisplatin in the colon-26 adenocarcinoma model of cancer cachexia. We find that although cisplatin is able to reduce tumor burden as expected, muscle wasting in mice nevertheless persists. Strikingly, cisplatin alone was seen to regulate muscle atrophy, which was independent of the commonly implicated ubiquitin proteasome system. Finally, we show that cisplatin is able to induce NF-κB activity in both mouse muscles and myotube cultures, suggesting that an additional side effect of cancer treatment is the regulation of muscle wasting that may be mediated through activation of the NF-κB signaling pathway.

ObjectiveThis survey was developed to assess the prevalence and effects of the perception of shame in otolaryngology–head and neck surgery residency training in the United States.Study DesignSurvey.SettingUS otolaryngology training programs.SubjectsFaculty and trainees in US otolaryngology training programs.MethodsA 14-item survey to assess the prevalence of the experience of shame and the attitudes toward use of shame in otolaryngology residency training was sent to all otolaryngology–head and neck surgery program directors for distribution among their respective faculty and resident cohorts.ResultsA total of 267 responses were received (women, 24.7%; men, 75.3%): 42.7% of respondents were trainees; 7.0% of trainees thought that shame was a necessary/effective tool, compared with 11.4% of faculty; 50% of respondents felt that they had been personally shamed during residency; and 69.9% of respondents had witnessed another trainee being shamed during residency training. Trainees were most commonly shamed i...

The pathophysiology of cancer cachexia remains complex. A comprehensive literature search was performed up to April 2013 using PubMed, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, and the Google search engine. In this review, we focus on the different mediators of impaired anabolism and upregulated catabolism that alter the skeletal muscle homeostasis resulting in the wasting of cancer cachexia. We present recent evidence of targeted treatment modalities from clinical trials along with their potential mechanisms of action. We also report on the most current evidence from randomized clinical trials using multimodal treatments in patients with cancer cachexia, but also the evidence from head and neck cancer-specific trials. A more complete understanding of the pathophysiology of the syndrome may lead to more effective targeted therapies and improved outcomes for patients.

Growth differentiation factor 11 (GDF11), a TGF-beta super-family member, is highly homologous to myostatin and essential for embryonic patterning and organogenesis. Reports of GDF11 effects on adult tissues are conflicting, with some describing anti-aging and pro-regenerative activities on the heart and skeletal muscle while others opposite or no effects. Herein, we sought to determine the in vivo cardiac and skeletal muscle effects of excess GDF11. Mice were injected with GDF11 secreting cells, an identical model to that used to initially identify the in vivo effects of myostatin. GDF11 exposure in mice induced whole body wasting and profound loss of function in cardiac and skeletal muscle over a 14-day period. Loss of cardiac mass preceded skeletal muscle loss. Cardiac histologic and echocardiographic evaluation demonstrated loss of ventricular muscle wall thickness, decreased cardiomyocyte size and decreased cardiac function 10 days following initiation of GDF11 exposure. Changes in skeletal muscle after GDF11 exposure were manifest at day 13 and associated with wasting, decreased fiber size, and reduced strength. Changes in cardiomyocytes and skeletal muscle fibers were associated with activation of SMAD2, the ubiquitin-proteasome pathway and autophagy. GDF11 over administration in vivo results in cardiac and skeletal muscle loss, dysfunction and death. Serum levels of GDF11 by Western blotting were 1.5 fold increased over controls. Although GDF11 effects in vivo are likely dose, route, and duration dependent, its physiologic changes are similar to myostatin and other Activin receptors ligands. These data support that GDF11, like its other closely related TGF-beta family members, induces loss of cardiac and skeletal muscle mass and function.

Background By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here, we measure the longitudinal body composition changes in patients with advanced PDAC undergoing 5‐fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy. Methods We performed a retrospective review of 53 patients with advanced PDAC on 5‐fluorouracil, leucovorin, irinotecan, and oxaliplatin as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement by computed tomography (CT), trend, univariate, and multivariate analysis were performed. Results Among all patients, three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle and Fat Wasting (MFW), while 17% had Fat‐Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (P = 0.02). FW (HR = 5.2; 95% confidence interval = 1.5–17.3) and MFW (HR = 1.8; 95% confidence interval = 1.1–2.9) were associated with an increased risk of mortality compared with NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumours were also associated with decreased OMS. On multivariate analysis, cachexia phenotype and chemotherapy response were independently associated with survival. Notably, CT‐based body composition analysis detected tissue loss of >5% in 81% of patients, while the traditional definition of >5% body weight loss identified 56.6%. Conclusions Distinct cachexia phenotypes were observed in this homogeneous population of patients with equivalent stage, diagnosis, and first‐line treatment. This suggests cellular, molecular, or genetic heterogeneity of host or tumour. Survival among patients with FW was as poor as for MFW, indicating adipose tissue plays a crucial role in cachexia and PDAC mortality. Adipose tissue should be studied for its mechanistic contributions to cachexia.

Growth differentiation factor 11 (GDF11), a TGF-beta superfamily member, is highly homologous to myostatin and essential for embryonic patterning and organogenesis. Reports of GDF11 effects on adult tissues are conflicting, with some describing anti-aging and pro-regenerative activities on the heart and skeletal muscle while others opposite or no effects. Herein, we sought to determine the in vivo cardiac and skeletal muscle effects of excess GDF11. Mice were injected with GDF11 secreting cells, an identical model to that used to initially identify the in vivo effects of myostatin. GDF11 exposure in mice induced whole body wasting and profound loss of function in cardiac and skeletal muscle over a 14-day period. Loss of cardiac mass preceded skeletal muscle loss. Cardiac histologic and echocardiographic evaluation demonstrated loss of ventricular muscle wall thickness, decreased cardiomyocyte size, and decreased cardiac function 10 days following initiation of GDF11 exposure. Changes in skeletal muscle after GDF11 exposure were manifest at day 13 and were associated with wasting, decreased fiber size, and reduced strength. Changes in cardiomyocytes and skeletal muscle fibers were associated with activation of SMAD2, the ubiquitin-proteasome pathway and autophagy. Thus, GDF11 over administration in vivo results in cardiac and skeletal muscle loss, dysfunction, and death. Here, serum levels of GDF11 by Western blotting were 1.5-fold increased over controls. Although GDF11 effects in vivo are likely dose, route, and duration dependent, its physiologic changes are similar to myostatin and other Activin receptors ligands. These data support that GDF11, like its other closely related TGF-beta family members, induces loss of cardiac and skeletal muscle mass and function.

Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and ApcMin/+. The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the ApcMin/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia.

Cachexia is a profoundly debilitating wasting syndrome that affects patients with head and neck cancer and often contributes to their demise. A comprehensive literature search was performed up to April 2013 using PubMed, the Cochrane Library, CINAHL, and the Google search engine. For the meta-analyses, pooled prevalence estimates were calculated with a confidence interval of 95% (95% CI) by using random effects modeling. In this review, we outlined the unique challenges of cancer cachexia among patients with head and neck cancer by reviewing its impacts on quality of life (QOL), morbidity, and mortality. We explored the prevalence of different clinical markers of cachexia at the time of diagnosis and before and after treatment. Finally, we present updates regarding the diagnosis of cancer cachexia and recent findings, such as cardiac dysfunction that warrant clinical attention to more carefully identify patients at risk and potentially lead to better outcomes.

Objectives: Patients with head and neck cancer (HNC) frequently present with weight loss secondary to dysphagia and malnutrition. We sought to determine the relationship between weight loss and in-hospital mortality, complications, length of hospitalization, and costs in HNC surgery. Methods: We analyzed discharge data from the Nationwide Inpatient Sample for 93,663 patients who underwent an ablative procedure for malignant oral cavity, laryngeal, hypopharyngeal, or oropharyngeal neoplasms between 2003 and 2008. Results: Weight loss was significantly associated with dysphagia (relative risk ratio [RRR] = 3.0; p < 0.001), alcohol abuse (RRR = 2.0; p < 0.001), advanced comorbidity (RRR = 1.8; p < 0.001), Medicaid payor status (RRR = 1.6; p = 0.002), urgent or emergent admission (RRR = 1.7; p = 0.015), and major surgical procedures (RRR = 2.3; p < 0.001). Patients with weight loss had increased risks of acute cardiac events, pneumonia, renal failure, sepsis, pulmonary failure (RRR = 2.6; p < 0.001), and postoperative wound healing complications, including fistula, dehiscence, and surgical site infection (RRR = 2.0; p < 0.001). After we controlled for all other variables, weight loss was associated with significantly increased length of hospitalization and hospital-related costs. Conclusions: Weight loss is associated with increases in medical complications, surgical complications, length of hospitalization, and hospital-related costs in HNC surgical patients. Aggressive preoperative identification and treatment of underlying dysphagia and malnutrition may reduce the medical and surgical morbidity in this high-risk population.

Many patients with cancer experience physical disability following diagnosis, although little is known about the mechanisms underlying these functional deficits. To characterize skeletal muscle adaptations to cancer in humans, we evaluated skeletal muscle structure and contractile function at the molecular, cellular, whole-muscle, and whole-body level in 11 patients with cancer (5 cachectic, 6 noncachectic) and 6 controls without disease. Patients with cancer showed a 25% reduction in knee extensor isometric torque after adjustment for muscle mass ( P < 0.05), which was strongly related to diminished power output during a walking endurance test ( r = 0.889; P < 0.01). At the cellular level, single fiber isometric tension was reduced in myosin heavy chain (MHC) IIA fibers ( P = 0.05) in patients with cancer, which was explained by a reduction ( P < 0.05) in the number of strongly bound cross-bridges. In MHC I fibers, myosin-actin cross-bridge kinetics were reduced in patients, as evidenced by an increase in myosin attachment time ( P < 0.01); and reductions in another kinetic parameter, myosin rate of force production, predicted reduced knee extensor isometric torque ( r = 0.689; P < 0.05). Patients with cancer also exhibited reduced mitochondrial density (−50%; P < 0.001), which was related to increased myosin attachment time in MHC I fibers ( r = −0.754; P < 0.01). Finally, no group differences in myofilament protein content or ultrastructure were noted that explained the observed functional alterations. Collectively, our results suggest reductions in myofilament protein function as a potential molecular mechanism contributing to muscle weakness and physical disability in human cancer.

Background Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Inhibiting the signaling of the transcription factor nuclear factor kappa B (NF-κB) largely prevents cancer-induced muscle wasting in murine models. We have previously shown the utility of Compound A, a highly selective novel NF-κB inhibitor that targets the IκB kinase complex, to provide clinical benefit in cancer-induced skeletal muscle and cardiac atrophy. Methods Using a metabolomics approach, we describe the changes found between cachectic and noncachectic gastrocnemius muscles before and after Compound A treatment at various doses. Results Of the 234 metabolites in the gastrocnemius, cachexia-induced changes in gastrocnemius metabolism reset the steady-state abundances of 42 metabolites (p

Cancer is a physically disabling condition. Functional disability, defined as an inability or impaired ability to perform simple tasks of daily life, afflicts a large majority of the cancer population and dramatically impacts patient well-being, negatively affecting treatment decisions, quality of life, and clinical outcomes. Our current understanding of the fundamental mechanisms underlying physical disability in cancer patients, however, is limited. This review will evaluate how cancer and cancer treatments and their pathological sequelae alter skeletal muscle structure and function to promote functional disability. Briefly, factors associated with cancer and its treatment can diminish skeletal muscle size and contractile function, which lead to a reduced physiological capacity for work and, in turn, functional disability. We outline the clinical evidence for the involvement of each of these factors in disability in cancer patients and then review structural and functional evidence at various anatomic levels to explore the tissue, cellular, and molecular mechanisms underlying cancer-related disability.

Despite recent consensus definitions, lack of specific biomarkers remains a hurdle towards a more accurate and efficient diagnosis of cancer cachexia, distinguishing cachexia as a separate entity from other wasting syndromes. In a previous pilot study, we have shown that cancer-cachectic mice have a unique metabolic fingerprint with distinct glucose and lipid alterations compared to healthy controls. Further metabolomics studies were carried out to investigate differences in metabolic profiles of cancer-cachectic mice to tumor-bearing non-cachectic mice, calorie-restricted mice, and surgically treated cancer-cachectic mice. CD2F1 mice were divided into: (1) Cachexia Group received cachexia-inducing C26 undifferentiated colon carcinoma cells; (2) Tumor-Burden Group received, non-cachectic, P388 lymphoma cells; (3) Caloric-Restriction Group, remaining cancer-free, but subjected to caloric-restriction; (4) Surgery Group, similar to Cachexia Group, but tumors resected mid-experiment; and (5) Control Group aged intact. Baseline, mid-experiment and final serum samples were collected for 1H NMR spectroscopic analysis. After data reduction, unsupervised principal component analysis and orthogonal projections to latent structures analyses demonstrate that the unique metabolic fingerprint is independent of tumor-burden and distinct from profiles of caloric-restriction and aging. Hyperlipidemia, hyperglycemia, and reduced branched-chain amino acids distinguish cachexia from other groups. Furthermore, the profile of surgically treated mice differs from that of cachectic mice, reverting to a profile more congruent with healthy controls indicating cachexia is amenable to correction where surgical cure is possible. That metabolomic analysis of murine serum is able to differentiate cachexia from tumor-burden and caloric-restriction warrants similar translational investigations in patients to explore cancer cachexia’s unique biomarkers.

The “Cochrane Corner” is a section in the journal that highlights systematic reviews relevant to otolaryngology–head and neck surgery, with invited commentary to aid clinical decision making. This installment features a Cochrane Review, “Interventions for the Prevention of Postoperative Ear Discharge after Insertion of Ventilation Tubes (Grommets) in Children,” that concludes if a surgeon has a high rate of postoperative otorrhea in children, then saline irrigation or antibiotic ear drops at the time of surgery would significantly reduce that rate. If topical drops are chosen, a single application at the time of surgery is suggested to reduce the cost and potential for ototoxic damage (if applicable).

Objectives Blunt cerebrovascular injury (BCVI) is a known sequela of high-energy craniomaxillofacial (CMF) trauma and can result in stroke or death. The objective of this systematic review is to 1) identify CMF trauma patients who may benefit from BCVI screening and 2) describe the optimal diagnostic and treatment modalities. Study Design Systematic review of the literature (1946–2013). Methods An a priori study protocol was created using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. The authors conducted a search of Ovid/Medline, PubMed, and Cochrane databases for articles related to BCVI and CMF fractures. All abstracts were reviewed, and data was extracted to determine the incidence of BCVI in the setting of CMF trauma. Individual fracture patterns were analyzed using descriptive statistics. Results Twenty-one studies met inclusion criteria. The overall incidence of CMF fracture-associated BCVI was 0.45%. The majority of patients (86.6%) sustained BCVI in the setting of high-energy trauma. The distribution of CMF fractures among BCVI patients was the mandible (12.5%), followed by the maxilla (11.8%). Computed tomographic angiography (CTA) was the most common diagnostic modality. A total of 63.1% of patients with BCVI were managed medically. The mortality among CMF patients with BCVI was 23.9%, and stroke rate was 47.1%. Conclusion Blunt cerebrovascular injury is a rare but devastating complication of blunt trauma. The recommended screening modality is CTA, and the most common treatment is antiplatelet/anticoagulant medication. Mandibular and LeFort fractures were the most common isolated CMF injury associated with BCVI, highlighting the need for prospective trials to expand current screening criteria. Level of Evidence N/A. Laryngoscope, 2016

The aim of this study was to examine biomolecular profiles in a cohort of young adults with squamous cell cancers (SCCs) of the oral tongue.We identified all patients aged 18 to 39 years diagnosed with SCC of the oral tongue at our institution. Immunohistochemical (IHC) staining was performed for p16(INK4a) , epidermal growth factor receptor (EGFR), phosphorylated-EGFR (pEGFR), p53, and ERCC1. Human papillomavirus (HPV) testing was performed using in situ hybridization (ISH) and polymerase chain reaction (PCR). Biomarker expression and HPV status were correlated with outcomes.We identified 25 patients with sufficient tumor samples. Median age at diagnosis was 30 years (range, 20-39 years). p16(INK4a) overexpression was observed in 11 of 25 patients, whereas HPV-16 positivity was observed in none of the tumor samples by ISH and 2 of the tumor samples by PCR. p16(INK4a) positivity was correlated with improved relapse-free survival (hazard ratio [HR] = 0.23, p = .01) and overall survival (HR = 0.28, p = .05). Neither EGFR, pEGFR, p53, nor excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1) expression correlated with outcome on univariate analysis.p16(INK4a) overexpression was common and was a marker of favorable prognosis. p16(INK4a) overexpression was not a reliable predictor of HPV positivity in our cohort.

Aliment Pharmacol Ther 2011; 33: 225–234 Summary Background Cough may be a manifestation of gastro-oesophageal reflux disease (GERD). The utility of acid suppression in GERD-related cough is uncertain. Aim To assess the impact of high-dose acid suppression with proton pump inhibitors (PPI) on chronic cough in subjects with rare or no heartburn. Methods Subjects were nonsmokers without history of asthma, with chronic cough for >8 weeks. All subjects underwent a baseline 24-h pH/impedance study, methacholine challenge test and laryngoscopy. Subjects were randomised to either 40 mg of esomeprazole twice daily or placebo for 12 weeks. The primary outcome measure was the Cough-Specific Quality of Life Questionnaire (CQLQ). Secondary outcomes were response on Fisman Cough Severity/Frequency scores and change in laryngeal findings. Results Forty subjects were randomised (22 PPI, 18 placebo) and completed the study. There was no difference between PPI and placebo in CQLQ (mean improvement 9.8 vs. 5.9 respectively, P = 0.3), or Fisman Cough Severity/Frequency scores. Proportion of patients who improved by >1 s.d. on the CQLQ was 27.8% (five of 18) and 31.8% (seven of 22) in the placebo and PPI groups respectively. Conclusion In subjects with chronic cough and rare or no heartburn, high-dose proton pump inhibitor does not improve cough-related quality of life or symptoms.

Background Treatment of head, neck, and esophageal cancers with radiation therapy can lead to esophageal strictures. In some cases, these can progress to complete esophageal obstruction, precluding typical antegrade endoscopic dilation. Objective The aim of this study was to review our experience with a combined antegrade/retrograde technique for dilation of complete esophageal strictures. Design Case series. Setting Tertiary-care referral center. Patients Twelve patients with complete esophageal radiation-induced strictures. Interventions In collaboration with otolaryngologists who performed direct antegrade esophagoscopy, retrograde endoscopy via gastrostomy was simultaneously performed. While visualizing the stricture from both sides and transilluminating, it was recannulated with use of a biliary or spring-tipped guidewire, and then dilated. Main Outcome Measurements Dilation method, complications, and postdilation oral intake. Results Combined antegrade and retrograde dilation was technically possible in 10 of the 12 patients (83%). Two cases were unsuccessful due to an inability to achieve transillumination. The only significant complication was a contained esophageal perforation that was managed nonoperatively. The mean number of repeat dilations was 7 (range, 1-22); none were complicated by perforation. Esophageal patency allowing at least some oral intake and tolerance of secretions was ultimately successful in 8 patients (67%). Limitations Retrospective, single center. Conclusions A combined antegrade/retrograde approach for dilation of complete esophageal radiation-induced strictures in collaboration with colleagues from otolaryngology is a viable treatment option. The procedure is technically feasible, effective, and well tolerated, although there may be an increased risk of esophageal perforation. This strategy may obviate a more invasive surgical approach.

We describe 2 nonsmoking, nondrinking couples who developed human papillomavirus (HPV)-associated tonsillar cancer within 12 months of each other. After histopathologic evaluation, HPV L1, E2, E6, and LCR regions were amplified, and phylogenetic analysis of amplimers was determined. Quantitative polymerase chain reaction targeting HPV-16/18 L1 and E7 regions and P16 immunohistochemistry were performed. Tissues were HPV-16 positive, with distinct intercouple nucleotide differences and multiple unique intracouple similarities identified. Diffuse nuclear P16 expression was detected in tumor cells. This report demonstrates matching HPV-16 strains in 2 couples with concurrent development of tonsillar carcinoma who did not have other risk factors, revealing the potential infectious nature of oropharyngeal cancer.

Objectives/hypothesis Despite its negative impact on cancer patients, there are few animal models of cancer cachexia. Our hypothesis was that different human cell lines would variably induce cachexia. Study design Prospective animal study. Methods We established two xenograft models in athymic mice and compared these with a cachexigenic cell line, the murine adenocarcinoma 16 (MAC16) cell line. Eight-week-old female, athymic mice were injected with human head and neck cell lines (JHU022, JHU012) and the MAC16 cell line. Body weight, food intake, body composition, leg weights, serum cytokines, and lipid mobilizing factor (LMF) were compared. Results Mean food intake for all groups was equivalent. Mean percent change in body weight after 18 days was 18%, 19%, 12%, and 3% for control, JHU012, JHU022, and MAC16 experimental groups, respectively. Both JHU022- and MAC16-injected mice showed wasting even when tumor burden was low. In contrast, mice injected with JHU012 developed larger tumors yet lacked evidence of cachexia. These mice demonstrated loss of lean body mass but not fat mass. Serum cytokine levels for interleukin (IL)-1 alpha and IL-1 beta were elevated in JHU022-bearing mice, whereas IL-1 alpha, IL-6, interferon (IFN)-gamma, and tumor necrosis factor alpha (TNF)-alpha were elevated in MAC16-bearing mice. LMF was present in both the JHU022 and JHU012 cell lines. Conclusions The JHU022 cell line caused more severe cachexia than the JHU012 cells, suggesting these cell lines may be used to further study cancer cachexia. IL-1 alpha and IL-1 beta in the JHU022 model may be mediators of cachexia, whereas TNF-alpha, IFN-gamma, and IL-6 may be mediators in MAC16-induced cachexia.

Purpose: To determine if serologic recognition of p53 mutations at the protein level depends upon the ability of mutant p53 to express new peptide epitopes that bind to human leukocyte antigen (HLA) class II molecules, we used anti-p53 antibody production as a marker for HLA class II–restricted T-cell involvement in head and neck cancer.Experimental Design: An anti-p53 antibody response was correlated with specific p53 mutations and the patients' HLA class II alleles and haplotypes. HLA binding studies and in vitro stimulation (IVS) of peripheral blood mononuclear cells were done using a mutant versus wild-type HLA-DQ7-binding p53 peptide.Results: Certain HLA-DQ and HLA-DR alleles were frequently present in p53 seropositive patients who produced serum anti-p53 antibodies. Selected mutated p53 peptides fit published allele-specific HLA class II binding motifs for the HLA-DQ7 or HLA-DR1 molecules. Moreover, a mutant p53 peptide bound with a 10-fold greater affinity than the wild-type p53 peptide to HLA-DQ7 molecules. IVS of CD4+ T cells from seven healthy HLA-DQ7+ donors using this mutant p53 peptide (p53220C) was associated with a partial T helper type 2 phenotype compared with IVS using the wild-type p53210-223 peptide.Conclusions: Our results support the hypothesis that mutated p53 neoantigens can bind to specific HLA class II molecules, leading to a break in tolerance. This may lead to skewing of the CD4+ T lymphocyte response toward a tumor-permissive T helper type 2 profile in head and neck cancer patients, as manifested by seropositivity for p53.

Castleman's disease is a rare lymphoproliferative disorder that is easily misdiagnosed. When it occurs in the head/neck and thorax, it can pose a diagnostic dilemma because of its lack of any specific presenting characteristics and distinguishing radiographic features. An accurate histopathologic diagnosis and careful staging are crucial to planning treatment. The highly vascular nature of the tumor makes surgical management challenging, and it warrants preoperative embolization whenever possible. We report 3 cases of Castleman's disease that involved the head/neck and thorax. We also review the presenting clinical features of Castleman's disease, its histopathologic characteristics, and the diagnostic and treatment challenges that it poses.

Cancer cachexia is a morbid wasting syndrome common among patients with head and neck cancer. While its clinical manifestations have been well characterized, its pathophysiology remains complex. A comprehensive literature search on cancer cachexia was performed using the National Library of Medicine's PubMed. The Cochrane Library and Google search engine were also used. Recent evidence and new concepts on the pathophysiology of cancer cachexia are summarized. Targeted therapies are presented, and new concepts are highlighted. Cancer cachexia is characterized by complex, multilevel pathogenesis. It involves up-regulated tissue catabolism and impaired anabolism, release of tumor-derived catabolic factors and inflammatory cytokines, and neuroendocrine dysfunction. These culminate to create an energy-inefficient state characterized by wasting, chronic inflammation, neuroendocrine dysfunction, and anorexia.

This invited article reviews the grant process to include the following objectives: (1) to provide an understanding of otolaryngology funding mechanisms in the context of career progression; (2) to outline key components of a well-written grant; (3) to highlight vital members of a successful research team, with emphasis on the mentor-mentee relationship; and (4) to clarify grant scoring with emphasis on common pitfalls to avoid. Current otolaryngology funding mechanisms and up-to-date resources are provided. The review is aimed to assist otolaryngology residents, faculty new to the grant process, as well as experienced researchers striving to improve their grant review scores.

Due to the relatively subtle symptoms caused by lesions in the pharynx, oropharyngeal squamous cell carcinomas (OPSCC) are frequently not identified until they are at an advanced stage. Neck masses are commonly the presenting symptom, with small primary masses in the oropharynx. In addition, patients with human papilloma virus (HPV)-associated head and neck cancer have a very different set of clinicodemographic characteristics than oropharyngeal cancer associated with smoking and alcohol usage. This may lead to physicians underestimating the significance of neck masses or throat pain in this younger, healthier patient population. This chapter will review the relevant clinical epidemiology, risk factors, and patient characteristics of HPV-related oropharyngeal cancer, as well as the anatomy of the oropharynx and the adjacent structures. The typical clinical presentation and appropriate evaluation for these carcinomas will be outlined and the challenges of diagnosing these patients will be discussed. Second primaries and patterns of recurrence will be compared between HPV (+) and (−) OPSCC. And finally, the need for a revised staging system will be explored.

Head and neck cancers (HNC) encompass a diverse group of tumors in terms of clinical behavior and involved subsites. There are an estimated 55,000 new cases of HNC diagnosed each year in the USA, and worldwide represents the sixth most common cancer. The vast majority of HNC is caused by squamous cell carcinoma (SCC), with tobacco and alcohol abuse being the two most common risk factors. However, over the last 20 years, there has been an emergence of a biologically distinct disease in HPV-related oropharyngeal SCC. This virally related carcinoma is increasing at epidemic rates within the USA and is not associated with typical risk factors. Along with these changes have come technological advancements in the treatment of this disease and other head and neck cancers. Minimally invasive surgical options, including transoral laser microsurgery (TLM), transoral roboti surgery (TORS), and endoscopic skull base surgery (ESBS), have allowed for surgical treatment of disease processes with decreased morbidity and side effects. Similarly, the nonsurgical treatment of HNC has advanced as well. Image-guidance and more precise treatment planning options have advanced head and neck radiation treatment, while new chemotherapeutic and biologic regimens have allowed for decreased treatment-related morbidity. Genomic and molecular advances will continue to drive future improvements in the care for patients with head and neck cancers as well.