Search

Objective: The combination of docetaxel (DTX) with Laser-Activated NanoTherapy (LANT), as a treatment for head and neck cancer (HNC), may enhance the therapeutic efficacy of lower doses of DTX, thereby minimizing the effective dosage, side effects and treatment times. Material and methods: Three HNSCC cell lines, Detroit 562, FaDu, and CAL 27, were treated with four combinations of DTX + LANT to evaluate DTX dose reduction and cell viability. Results: The 1 nM DTX + 5 nM LANT combination was the most effective treatment, increasing cell death over its corresponding DTX monotreatment with approximately 86.6%, 80.7%, and 92.1% cell death for Detroit 562, FaDu, and CAL 27, respectively. In Detroit 562, the 1 nM DTX + 5 nM LANT combination treatment resulted in the highest percentage of DTX dose reduction at 84.6%, in FaDu and CAL 27, the 0.5 nM DTX + 5 nM LANT combination treatment resulted in the highest percentage of DTX dose reduction at 78.2% and 82.4%, respectively. Conclusion: LANT may increase the therapeutic efficacy of DTX at significantly lower doses, which could improve patient outcomes.

Immunotherapy has revolutionized the treatment of cancer, including head and neck squamous cell carcinoma (HNSCC). Most immune therapies consist of biologics, including monoclonal antibodies, vaccines, and cell therapy. This article reviews basic tumor immunology and provides an overview of immunotherapeutic strategies used for HNSCC. The current indications for use of programmed cell death protein 1 immune checkpoint inhibitors in recurrent/metastatic HNSCC are summarized. In addition, new immunotherapeutic biologics and combinations under investigation in early-phase clinical trials are highlighted.

Biologics have been widely adopted in multiple subspecialties of otolaryngology. This article provides an overview of past, present, and future uses of biologics in otolaryngology with emphasis on allergic rhinitis, chronic rhinosinusitis with polyposis, head and neck squamous cell carcinoma, salivary and skull base tumors, hearing loss, and other otologic disorders.

Purpose: Surgical resection of primary tumor with regional lymphadenectomy remains the treatment of choice for patients with advanced human papillomavirus–negative head and neck squamous cell carcinoma. However, even when pathologic disease-free margins can be achieved, locoregional and/or distant disease relapse remains high. Perioperative immunotherapy may improve outcomes, but mechanistic data supporting the use of neoadjuvant or adjuvant treatment clinically are sparse. Experimental Design: Two syngeneic models of oral cavity carcinoma with defined T-cell antigens were treated with programmed death receptor 1 (PD-1) mAb before or after surgical resection of primary tumors, and antigen-specific T-cell responses were explored with functional and in vivo challenge assays. Results: We demonstrated that functional immunodominance developed among T cells targeting multiple independent tumor antigens. T cells specific for subdominant antigens expressed greater levels of PD-1. Neoadjuvant, but not adjuvant, PD-1 immune checkpoint blockade broke immunodominance and induced T-cell responses to dominant and subdominant antigens. Using tumors lacking the immunodominant antigen as a model of antigen escape, neoadjuvant PD-1 immune checkpoint blockade induced effector T-cell immunity against tumor cells lacking immunodominant but retaining subdominant antigen. When combined with complete surgical excision, neoadjuvant PD-1 immune checkpoint blockade led to formation of immunologic memory capable of preventing engraftment of tumors lacking the immunodominant but retaining subdominant antigen. Conclusions: Together, these results implicate PD-1 expression by T cells in the mechanism of functional immunodominance among independent T-cell clones within a progressing tumor and support the use of neoadjuvant PD-1 immune checkpoint blockade in patients with surgically resectable carcinomas.

Objective: The combination of docetaxel (DTX) with Laser-Activated NanoTherapy (LANT), as a treatment for head and neck cancer (HNC) may enhance the therapeutic efficacy of lower doses of DTX, thereby minimizing the effective dosage, side effects and treatment times. Material and methods: Three HNSCC cell lines, Detroit 562, FaDu, and CAL 27, were treated with four combinations of DTX + LANT to evaluate DTX dose reduction and cell viability. Results: The 1 nM DTX + 5 nM LANT combination was the most effective treatment, increasing cell death over its corresponding DTX monotreatment with approximately 86.6%, 80.7%, and 92.1% cell death for Detroit 562, FaDu, and CAL 27, respectively. In Detroit 562, the 1 nM DTX + 5 nM LANT combination treatment resulted in the highest percentage of DTX dose reduction at 84.6%; in FaDu and CAL 27, the 0.5 nM DTX + 5 nM LANT combination treatment resulted in the highest percentage of DTX dose reduction at 78.2% and 82.4%, respectively. Conclusion: LANT may increase the therapeutic efficacy of DTX at significantly lower doses, which could improve patient outcomes.

Purpose: Human papillomavirus–negative (HPV−) head and neck squamous cell carcinomas (HNSCC) harbor frequent genomic amplification of Fas-associated death domain, with or without concurrent amplification of Baculovirus inhibitor of apoptosis repeat containing (BIRC2/3) genes encoding cellular inhibitor of apoptosis proteins 1/2 (cIAP1/2). Antagonists targeting cIAP1 have been reported to enhance sensitivity of HPV−, but not HPV+ tumors, to TNF family death ligands (TNF and TRAIL) and radiation. Experimental Design: We tested a novel dual cIAP/XIAP antagonist ASTX660 in HPV+ and HPV− cell lines in combination with death ligands TNFα and TRAIL, and in preclinical xenograft models with radiation, an inducer of death ligands. The dependence of activity on TNF was examined by antibody depletion. Results: ASTX660 sensitized subsets of HPV− and HPV+ HNSCC cell lines to TNFα and TRAIL. These antitumor effects of ASTX660 are the result of both apoptosis and/or necroptosis among HPV− cells, and primarily by apoptosis (caspase 3 and caspase 8 cleavage) in HPV+ cells. ASTX660 enhanced restoration of protein expression and inhibitory activity of proapoptotic tumor suppressor TP53 in HPV+ HNSCC. Furthermore, ASTX660 combined with radiotherapy, an inducer of death ligands, significantly delayed growth of both HPV− and HPV+ human tumor xenografts, an effect attenuated by anti-TNFα pretreatment blockade. Conclusions: IAP1/XIAP antagonist, ASTX660, sensitizes HPV+ HNSCC to TNFα via a mechanism involving restoration of TP53. These findings serve to motivate further studies of dual cIAP/XIAP antagonists and future clinical trials combining these antagonists with radiotherapy to treat both HPV+ and HPV− HNSCC.

BACKGROUND: Cisplatin is widely used to treat adult and pediatric cancers. It is the most ototoxic drug in clinical use, resulting in permanent hearing loss in approximately 50% of treated patients. There is a major need for therapies that prevent cisplatin-induced hearing loss. Studies in mice suggest that concurrent use of statins reduces cisplatin-induced hearing loss. METHODS: We examined hearing thresholds from 277 adults treated with cisplatin for head and neck cancer. Pretreatment and posttreatment audiograms were collected within 90 days of initiation and completion of cisplatin therapy. The primary outcome measure was a change in hearing as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). RESULTS: Among patients on concurrent atorvastatin, 9.7% experienced a CTCAE grade 2 or higher cisplatin-induced hearing loss compared with 29.4% in nonstatin users (P < 0.0001). A mixed-effect model analysis showed that atorvastatin use was significantly associated with reduced cisplatin-induced hearing loss (P ≤ 0.01). An adjusted odds ratio (OR) analysis indicated that an atorvastatin user is 53% less likely to acquire a cisplatin-induced hearing loss than a nonstatin user (OR = 0.47; 95% CI, 0.30–0.78). Three-year survival rates were not different between atorvastatin users and nonstatin users (P > 0.05). CONCLUSIONS: Our data indicate that atorvastatin use is associated with reduced incidence and severity of cisplatin-induced hearing loss in adults being treated for head and neck cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03225157. FUNDING: Funding was provided by the Division of Intramural Research at the National Institute on Deafness and Other Communication Disorders (1 ZIA DC000079, ZIA DC000090).

Objective: To discuss some of the challenges that can arise in the treatment of patients with oropharyngeal carcinoma and scleroderma, by presenting an illustrative case. Methods: We report a case of a patient with scleroderma who was treated with surgery, radiation and systemic therapy for oropharyngeal squamous cell carcinoma. We also review the literature on treatment of head and neck squamous cell carcinoma (HNSCC) in scleroderma patients. Results: The patient tolerated treatment well, with a typical degree of toxicity and no evidence of recurrence at 3.5 years following adjuvant therapy. Conclusion: Patients with oropharyngeal cancer and scleroderma should be evaluated on a case-by-case basis in conjunction with a rheumatologist to determine the ideal treatment plan. Patients with limited or well-controlled scleroderma may tolerate treatment better than expected based on historical reports in the literature. Keywords: Scleroderma, Connective tissue disorder, Squamous cell carcinoma, Autoimmune, Transoral robotic surgery

Immunotherapy is a rapidly advancing field that has improved survival outcomes for patients with head and neck squamous cell carcinoma (HNSCC). Large phase 3 trials have demonstrated the efficacy of anti-PD-1/PD-L1 monoclonal antibodies in patients with recurrent/metastatic disease, and current investigations will help elucidate the role of these agents in patients with previously untreated, locally advanced disease. Additional immunotherapeutic strategies including antibodies targeting other coinhibitory/costimulatory checkpoints, vaccines, oncolytic viruses, toll-like receptor agonists, adoptive cell therapy, and others are also under active study. As more data emerge regarding the management of immune-related adverse events and potential biomarkers of response, immunotherapeutic approaches will become an increasingly safe and successful therapeutic modality for head and neck cancer.

Although many forms of T cell and natural killer cell-based immunotherapies are under clinical investigation, immune checkpoint inhibitors (ICI) targeting the programmed death (PD) pathway represent a widely available and easy to use FDA-approved immunotherapy available for head and neck squamous cell carcinoma. Patients that benefit from ICI demonstrate durable responses, but overall response rates are low. Rational, mechanism-based combination treatments aimed at enhancing response rates to ICI may improve survival in patients with advanced or recurrent head and neck cancer. A thorough understanding of how anti-tumor immunity should develop, why it may be ineffective, how ICIs work and how altering the immune microenvironment may enhance T cell immunity are needed to design rational combinations to study pre-clinically and in trials. Here, we review these concepts and summarize current studies aimed at enhancing response rates to ICI in patients with advanced or relapsed head and neck cancer.

Introduction: Radiation-associated soft tissue sarcomas of the neck (RASN) constitute a rare and aggressive tumor type. Methods: A retrospective chart review at the authors’ institution revealed 3 patients with RASN. A systematic review of the literature was also conducted using MEDLINE, Ovid, the Cochrane Library, and Embase. Results: Patients within the authors’ institutional chart review presented from 6 to 26 years after neck radiation with neck masses. All patients underwent surgical resection with clear margins, and adjuvant radiation was offered when feasible. Patients had no evidence of disease at most recent follow-up. A total of 867 articles were screened for systematic review, revealing 9 articles detailing outcomes of RASN. Studies were small and heterogeneous, precluding pooled data. The importance of complete surgical extirpation was noted. Conclusions: Complete surgical resection appears to be the mainstay of therapy, but there are limited data on management and outcomes of patients with RASN.

Background The number of elderly patients with oral squamous cell carcinoma (OCSCC) is increasing as the elderly population increases. Unfortunately, evidence to guide the management of these patients is lacking. Methods Patients with OCSCC identified from the National Cancer Database (NCDB) were stratified into age-based cohorts. Demographics, comorbidities, and treatment patterns were analyzed. Patients were stratified into early stage (Stage I/II) and advanced stage (Stage III/IV) disease. The likelihood of receiving multimodality therapy by age was calculated using multinomial logistic regression for each stratum while controlling for potential confounders. Cox proportional hazard regression was used to calculate 5-year mortality risk while controlling for potential confounders. Results Surgery alone or palliative options were offered to older patients more frequently. After controlling for confounders, older patients were less likely to receive multimodality therapy for both early stage and advanced stage disease. Patients with advanced disease across all age cohorts had improved 5-year survival with surgery and adjuvant therapy. Conclusion Our analyses suggest that elderly patients have unique demographic and pathologic features. They frequently receive less treatment than similarly staged younger patients, yet they benefit from multimodality therapy when feasible. These data suggest an urgent need to critically appraise the care of elderly OCSCC patients within the broader context of their individual comorbidity burden, functional status, and treatment goals.

Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T-cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T-cell function and prognostic impact, because PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients (P = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TILs were more frequent in HPV− patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease-free survival and higher hazard ratio for recurrence (P < 0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1–based immunotherapy. Cancer Res; 77(22); 6353–64. ©2017 AACR.

BACKGROUND Human papillomavirus 16 (HPV16) E6 antibodies may be an early marker of the diagnosis and recurrence of human papillomavirus–driven oropharyngeal cancer (HPV-OPC). METHODS This study identified 161 incident oropharyngeal cancer (OPC) cases diagnosed at the University of Pittsburgh (2003-2013) with pretreatment serum. One hundred twelve had preexisting clinical HPV testing with p16 immunohistochemistry and HPV in situ hybridization (87 were dual-positive [HPV-OPC], and 25 were dual-negative [HPV-negative]); 62 had at least 1 posttreatment serum sample. Eighty-six of the 161 tumors were available for additional HPV16 DNA/RNA testing (45 were dual-positive [HPV16–OPC], and 19 were dual-negative [HPV16–negative). HPV16 E6 antibody testing was conducted with multiplex serology. The following were evaluated: 1) the sensitivity and specificity of HPV16 E6 serology for distinguishing HPV-OPC and HPV16–OPC from HPV-negative OPC, 2) HPV16 E6 antibody decay after treatment with linear models accommodating correlations in variance estimates, and 3) pre- and posttreatment HPV16 E6 levels and the risk of recurrence with Cox proportional hazards models. RESULTS Seventy-eight of 87 HPV-OPCs were HPV16 E6–seropositive (sensitivity, 89.7%; 95% confidence interval [CI], 81.3%-95.2%), and 24 of 25 HPV-negative OPCs were HPV16 E6–seronegative (specificity, 96.0%; 95% CI, 79.6%-99.9%). Forty-two of 45 HPV16–OPCs were HPV16 E6–seropositive (sensitivity, 93.3%; 95% CI, 81.7%-98.6%), and 18 of 19 HPV16–negative OPCs were HPV16 E6–seronegative (specificity, 94.7%; 95% CI, 74.0%-99.9%). Posttreatment HPV16 E6 antibody levels did not decrease significantly from the baseline (P = .575; median follow-up, 307 days) and were not associated with the risk of recurrence. However, pretreatment HPV16 E6 seropositivity was associated with an 86% reduced risk of local/regional recurrence (hazard ratio, 0.14; 95% CI, 0.03-0.68; P = .015). CONCLUSIONS HPV16 E6 antibodies may have potential clinical utility for the diagnosis and/or prognosis of HPV-OPC. Cancer 2017;123:4382-90. © 2017 American Cancer Society.

OBJECTIVE: Review of the literature regarding hearing loss in patients with head and neck cancer treated with chemoradiation. DESIGN: Studies in the literature are reviewed that pertain to hearing loss sustained in head and neck cancer patients receiving cisplatin-based chemoradiation. Personal observations noted while treating these patients are also detailed. STUDY SAMPLE: PubMed was searched for pertinent articles regarding hearing loss in head and neck cancer patients receiving cisplatin chemotherapy and/or radiation. RESULTS: Studies on the incidence and severity of hearing loss in head and neck cancer patients are limited, but those studies suggest that the risk of hearing loss is greater with higher-dose regimens. CONCLUSIONS: Newer cisplatin chemotherapy regimens using lower, weekly doses may be associated with a lower incidence and severity of hearing loss; however, large prospective studies are needed. Such information will be paramount to effective pre-treatment counseling of head and neck cancer patients.

BACKGROUND Treatment intensification for resected, high-risk, head and neck squamous cell carcinoma (HNSCC) is an area of active investigation with novel adjuvant regimens under study. In this trial, the epidermal growth-factor receptor (EGFR) pathway was targeted using the IgG2 monoclonal antibody panitumumab in combination with cisplatin chemoradiotherapy (CRT) in high-risk, resected HNSCC. PATIENTS AND METHODS Eligible patients included resected pathologic stage III or IVA squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or human-papillomavirus (HPV)-negative oropharynx, without gross residual tumor, featuring high-risk factors (margins

Objectives Prior studies suggest that oxaliplatin is unique among platinum chemotherapy drugs in its ability to enhance anti-tumor immunity, but the immune mechanisms of different platinum chemotherapy drugs have not been previously compared in preclinical models of head and neck squamous cell carcinoma (HNSCC). Materials and methods Human HNSCC cell lines were treated with cisplatin or oxaliplatin, then assessed for markers associated with immunogenic cell death (ICD) and antigen processing. A syngeneic mouse model of oral cancer was then used to compare the effects of cisplatin vs. oxaliplatin, alone or in combination with anti-PD-1 immunotherapy, on tumor growth and survival. A subset of spleens and tumors were analyzed for ICD markers and immune cell infiltrates by flow cytometry. Results Cisplatin and oxaliplatin both increased cell surface levels of calreticulin, HSP70, MHC class I and PD-L1 in multiple cell lines. Inoculation of immunocompetent mice with cells killed in vitro by either drug resulted in failure of subsequently-injected live tumor cells to establish and grow in a small proportion of animals. Systemic cisplatin and oxaliplatin induced similar tumor growth delay when combined with anti-PD-1 therapy. Conclusions Treatment of HNSCC cells with platinum chemotherapy appears to induce some features of anti-tumor immunity, which may be enhanced by anti-PD-1 therapy. Cisplatin, the standard drug for HNSCC, appears to affect anti-tumor immunity in a similar fashion to oxaliplatin in these preclinical models.

Background/Objectives: Cisplatin and other cytotoxic chemotherapy drugs may induce senescence, rather than cell death, at sublethal doses. We hypothesized that the senolytic drug ABT-263 (navitoclax) might enhance cisplatin cytotoxicity and anti-tumor immunity in preclinical models of head and neck squamous cell carcinoma (HNSCC). Methods/Results: When human HNSCC cell lines were treated with sublethal doses of cisplatin for 72 hours, they expressed increased levels of senescence markers p16 and beta-galactosidase. In additional experiments, cells were rendered senescent with cisplatin and then treated for another 72 hours with navitoclax, which enhanced cisplatin-induced cell death. Three different cisplatin-sensitive syngeneic mouse models were then used to investigate whether the addition of navitoclax can enhance cisplatin-induced tumor cell death in vivo. Mice were treated with weekly cycles consisting of cisplatin on day 1 (5-6 mg/kg IP) followed by navitoclax on days 3, 4, and 5 (100 mg/kg, OG). The addition of navitoclax caused an early, very slight improvement in tumor growth delay in the TC-1 model, but not in the MEER or MOC1 models. We next investigated whether navitoclax might enhance the anti-tumor immune effects of cisplatin and/or tumor infiltrating leukocytes (TIL) ex vivo. Naive tumors were harvested and TIL were cultured with IL-2 for 10-14 days, then sorted. Murine tumor cells were then cultured with cisplatin, navitoclax, and/or TIL. In the TC-1 and MOC1 models, but not in the MEER model, navitoclax modestly enhanced tumor-cell killing by TIL. Tumor cell killing was greatest with cisplatin, navitoclax, and TIL in combination. We then investigated whether navitoclax might enhance the anti-tumor activity of cisplatin and anti-PD-1 in vivo. With twice-weekly anti-PD-1 antibody alone or added to the cisplatin and/or navitoclax in the TC-1 model, no additional anti-tumor activity was noted; flow cytometry of naïve TC-1 tumors showed extremely low numbers of CD8+ T cells as a possible explanation. Similar experiments in the MOC1 model, along with mechanistic experiments to investigate resistance to navitoclax in vivo, are in progress. Conclusions: Navitoclax enhances cisplatin-induced death of human HNSCC cells in vitro and enhances the killing of murine tumor cells when cultured with TIL ex vivo. However, in multiple syngeneic mouse models, navitoclax failed to enhance anti-tumor activity of cisplatin or anti-PD-1 checkpoint blockade. Possible mechanisms of navitoclax resistance in vivo may include enhanced trafficking of immunosuppressive cells to the tumor microenvironment following secretion of senescence-associated cytokines by cisplatin-treated tumor cells. Supported by NIDCD intramural project number ZIA-DC000090. Citation Format: Youji Hong, Sreenivasulu Gunti, Yvette Robbins, Nicole C. Schmitt. Senolytic drug ABT-263 enhances cisplatin- and TIL-induced cell death in vitro but has limited in vivo activity in preclinical models of head and neck cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5830.

Background/Rationale: The Cancer Genome Atlas (TCGA) analysis of head and neck squamous cell carcinomas (HNSCCs) has revealed common alterations in the Tumor Necrosis Factor (TNF) Receptor signaling pathway, with 30% overexpressing genes encoding for Fas-Associated Death Domain (FADD) and/or cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2). We have previously shown that ASTX660, an antagonist of cIAP1/2 and XIAP, sensitizes murine oral cancer (MOC) cells to TNFα and also demonstrates synergistic antitumor activity when used in combination with radiation therapy (XRT) and PD-1 immune checkpoint blockade, leading to tumor growth delay or eradication in a syngeneic mouse model (Xiao et al., OncoImmunology 2018). These combination treatments also enhanced the number and function of CD8+ T cells and dendritic cells. However, the immune effects of IAP antagonists at the tumor cell level are still unknown. We hypothesized that ASTX660 enhances immune-based killing of tumor cells through induction of immunogenic cell death (ICD) and upregulation of antigen-processing machinery (APM) components. Methods/Results: We performed ICD vaccination experiments in two syngeneic mouse models of HNSCC. We vaccinated mice with MOC1 cells killed by XRT, mitoxantrone (MTX), ASTX660 + TNFα or the combination of ASTX660 + TNFα + XRT in the left flank. One week later we rechallenged with live MOC1 cells in the right flank and monitored subsequent tumor formation/growth. Positive controls XRT and MTX, known ICD inducers, resulted in tumor rejection rates of 40% and 20%, respectively. Cells treated with ASTX660 + TNFα demonstrated growth of tumors at the vaccination site on the left flank, but 90% rejection when rechallenged with viable cells on the right. Combination vaccination group ASTX660 + TNFα + XRT showed 100% tumor rejection with no vaccination site growth. Similar results were obtained with the MEER (HPV-positive) mouse model. To test our hypothesis that ASTX660 upregulates APM components, we analyzed expression of intracellular APM components by flow cytometry in human HNSCC cell lines (UMSCC-46, -11B, and -74A) treated with interferon gamma (positive control), ASTX660 alone, TNFα alone, or ASTX660 + TNFα. Changes in APM components were variable among cell lines treated with ASTX660 + TNFα, though HLA-A,B,C was consistently upregulated. Conclusions/Future Directions: Our results demonstrate that ASTX660 induces ICD and upregulates APM components, providing a mechanism contributing to synergism between IAP antagonists with XRT as an effective treatment modality for HNSCC. Furthermore, with a significantly more favorable drug toxicity profile than cisplatin, combination treatment with ASTX660 + XRT may be a potential replacement for traditional chemoradiation in HNSCC. Citation Format: Wenda Ye, Sreenivasulu Gunti, Carter Van Waes, Nicole C. Schmitt. Antagonist of cIAP1/2 and XIAP induces immunogenic cell death and alters antigen-processing machinery in preclinical head and neck cancer models [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B11.

Immune checkpoint inhibition used in combination with standard cisplatin-based chemotherapy regimens is currently under evaluation in clinical trials for head and neck squamous cell carcinoma (HNSCC). The impact of anti–PD-1 therapy on cisplatin-induced ototoxicity and nephrotoxicity has not been established. Here we use a murine model of cisplatin-induced hearing loss to investigate the impact of anti–PD-1 immunotherapy on auditory brainstem responses (ABRs), distortion product otoacoustic emissions (DPOAEs), serum creatinine, and hair cell and renal histology. We demonstrate only mild worsening of DPOAEs at 14.4 and 16 kHz as well as a mild increase in serum creatinine. Renal and hair cell histology as well as ABR measures were unchanged by PD-1 inhibition. Thus, our data suggest that the use of PD-1 inhibition in conjunction with cisplatin results in toxicities that are similar to those of cisplatin alone.

Inflammation is a process that is involved in several stages of development and malignant progression of head and neck squamous cell carcinoma. Tobacco and alcohol, human papillomaviruses (HPV), or Epstein-Barr viruses (EBV) can initiate and establish chronic inflammation through a variety of mechanisms. Genomic alterations or viral oncoproteins that induce signaling via phosphatidylinositol 3-kinase (PI3K) and transcription factor nuclear factor-kappaB (NF-κB) regulate numerous genes that promote survival of cancer cells, while they induce inflammatory myeloid-derived suppressor cell (MDSC) and T regulatory (Treg) cell responses that interfere with effector T-cell immunity. Molecular therapies targeting signaling in cancer cells and these deleterious inflammatory cells are being combined with new PD-L1/PD-1 and CTLA-4 immune checkpoint inhibitors to explore better ways to harness the immune system in control of cancer.

This article reviews recent information on outcomes, indications, techniques, and cost of transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC). New information on comparisons between TORS, conventional surgery techniques, and chemoradiation is also highlighted.Consistent with prior reports, recent studies show excellent oncologic and functional outcomes with TORS for OPSCC. As surgeon experience with this relatively new technique has increased, outcomes continue to improve and complications are rare. TORS may also have a role in management of carcinoma of unknown primary site. Compared with other treatment modalities, TORS for OPSCC may result in similar oncologic outcomes, improved functional outcomes, and decreased cost.TORS for OPSCC results in excellent functional and oncologic outcomes. Randomized clinical trials are needed to compare TORS with adjuvant therapy to definitive chemoradiation and will determine whether adjuvant therapy and associated morbidity can be decreased without compromising survival.

The tumor antigen (TA)-targeted monoclonal antibodies (mAb) cetuximab and panitumumab target the human epidermal growth factor receptor and have been integrated into treatment regimens for advanced squamous cell carcinoma of the head and neck (SCCHN). The therapeutic efficacy of these mAbs has been found to be enhanced when combined with radiotherapy and chemotherapy. However, clinical trials indicate that these findings are limited to fewer than 20% of treated patients. Therefore, identifying patients who are likely to benefit from these agents is crucial to improving therapeutic strategies. Interestingly, it has been noted that TA-targeted mAbs mediate their effects by contributing to cell-mediated cytotoxicity in addition to inhibition of downstream signaling pathways. Here, we describe the potential immunogenic mechanisms underlying these clinical findings, their role in the varied clinical response and identify the putative biomarkers of antitumor activity. We review potential immunological biomarkers that affect mAb therapy in SCCHN patients, the implications of these findings and how they translate to the clinical scenario, which are critical to improving patient selection and ultimately outcomes for patients undergoing therapy.

The objective of this study is to establish normative waveform data for the external branch of the superior laryngeal nerve (SLN) utilizing laryngeal surface electrodes and intraoperative neurophysiological monitoring (IONM) in conjunction with a clinical neurophysiologist. A retrospective chart review of 91 consecutive at-risk SLN were identified in 51 patients in whom IONM using laryngeal surface electrodes was performed by a clinical neurophysiologist using Dragonfly (Neurovision Medical Products, Ventura, CA) recording electrodes and a Protektor (Natus Medical Inc., San Carlos, CA)16 channel- intraoperative nerve monitoring system. Inclusion criteria were met for 30 SLN. Data collected included preoperative diagnosis, surgical procedure, rates of nerve identification and stimulation, and waveform characteristics. Waveform analysis for 30 SLN yielded a peak latency of 4.0 ± 0.2 ms, onset latency 2.3 ± 0.1 ms, peak-to-peak amplitude of 220.4 ± 31.1 µV, onset-to-peak amplitude of 186.0 ± 25.0 µV, and stimulation current threshold of 0.55 ± 0.03 mA (data = mean ± SEM). Two patients had abnormal SLN function documented clinically on postoperative laryngoscopic examination. Laryngeal surface electrodes were successfully utilized to identify and monitor SLN function intraoperatively. IONM using laryngeal surface electrodes enables analysis of waveform morphology and latency in addition to threshold and amplitude data obtained with the traditional NIM system, potentially improving the performance of nerve monitoring during thyroid surgery. Clin. Anat. 28:460–466, 2015. © 2014 Wiley Periodicals, Inc.

Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide, with more than half a million new cases every year (1). Over half of these originate from the Asia Pacific region, where HNSCC accounts for a much greater proportion of newly diagnosed cancers (2). While the annual incidence of HNSCC in North America and Europe ranges from 5–10% of new cancer cases, this figure may be as high as 37.5% in some areas of Asia (3).

Importance Salivary duct carcinoma is a rare, aggressive malignancy of the salivary glands. Owing to its rare nature, clinical data are limited, and only a few clinical studies comprise more than 50 patients. Objective To review the University of Pittsburgh Medical Center’s experience with salivary duct carcinoma over a 20-year period, focusing on demographics, presentation, treatment, and outcome. Design, Setting, and Participants This investigation was a retrospective cohort study in a multihospital institution with tertiary referral. A pathology database was reviewed for all cases of histopathologically diagnosed salivary duct carcinoma from January 1, 1995, to October 20, 2014. Patients who were referrals for pathology review only and were never seen at the institution were excluded. In total, 75 study patients were identified. The electronic medical record was reviewed for details regarding demographics, presentation, treatment, and outcome, including overall survival (OS) and disease-free survival (DFS). This study was supplemented with a review of the institution’s Head and Neck Oncology Database for further clinical details. Main Outcomes and Measures Primary outcome measures consisted of OS and DFS. Results The study sample comprised 75 participants with a mean age at diagnosis of 66.0 years (age range, 33-93 years), and 29% (n = 22) were female. Most primary tumors were from the parotid gland (83%), with the next most frequent site being the submandibular gland (12%). Overall, 41% of the cases were carcinoma ex pleomorphic adenoma. Rates of other histologic features included the following: perineural invasion (69%), extracapsular spread (58%), ERBB2 (formerly HER2 ) positivity (31%) (62% of those who were tested), and vascular invasion (61%). The median OS was 3.1 years, and the median DFS was 2.7 years. Univariate Kaplan-Meier survival analyses demonstrated that facial nerve sacrifice and extracapsular spread were associated with lower OS (2.38 vs 5.11 years and 2.29 vs 6.56 years, respectively) and DFS (2.4 vs 3.88 years and 1.44 vs 4.5 years, respectively). Although underpowered, multivariable analysis demonstrated significantly worse OS in patients with N2 and N3 disease (hazard ratio [HR] 8.42, 95% CI, 1.84-38.5) but did not show significantly worse DFS or OS for facial nerve sacrifice or extracapsular spread. There was no association between ERBB2 positivity and survival and no difference in survival between patients receiving radiation therapy vs radiation therapy plus chemotherapy. No patients had recurrence or distant metastasis after 5 disease-free years. Conclusions and Relevance Salivary duct carcinoma is an aggressive disease. A large number of cases in this review were carcinoma ex pleomorphic adenoma and had classic negative prognostic indicators, such as perineural invasion, vascular invasion, and extracapsular spread. ERBB2 positivity was not associated with any difference in survival. Facial nerve involvement appears to indicate worse prognosis, as does nodal stage higher than N1. Recurrence and metastasis after 5 years are rare.

Human papillomavirus type 16 (HPV16) infection is causing an increasing number of oropharyngeal cancers in the United States and Europe. The aim of our study was to investigate whether HPV antibodies are associated with head and neck cancer risk when measured in prediagnostic sera.We identified 638 participants with incident head and neck cancers (patients; 180 oral cancers, 135 oropharynx cancers, and 247 hypopharynx/larynx cancers) and 300 patients with esophageal cancers as well as 1,599 comparable controls from within the European Prospective Investigation Into Cancer and Nutrition cohort. Prediagnostic plasma samples from patients (collected, on average, 6 years before diagnosis) and control participants were analyzed for antibodies against multiple proteins of HPV16 as well as HPV6, HPV11, HPV18, HPV31, HPV33, HPV45, and HPV52. Odds ratios (ORs) of cancer and 95% CIs were calculated, adjusting for potential confounders. All-cause mortality was evaluated among patients using Cox proportional hazards regression.HPV16 E6 seropositivity was present in prediagnostic samples for 34.8% of patients with oropharyngeal cancer and 0.6% of controls (OR, 274; 95% CI, 110 to 681) but was not associated with other cancer sites. The increased risk of oropharyngeal cancer among HPV16 E6 seropositive participants was independent of time between blood collection and diagnosis and was observed more than 10 years before diagnosis. The all-cause mortality ratio among patients with oropharyngeal cancer was 0.30 (95% CI, 0.13 to 0.67), for patients who were HPV16 E6 seropositive compared with seronegative.HPV16 E6 seropositivity was present more than 10 years before diagnosis of oropharyngeal cancers.

The human communicating nerve (HCN) is a connection between the superior and recurrent laryngeal nerves that has been described in cadaveric studies. We report a case of an extralaryngeal variant of the HCN that was identified and stimulated intraoperatively during thyroidectomy. This appears to be the first case of intraoperative identification of this anatomic variant, of which the functional significance remains unclear.

Head and neck squamous cell carcinomas (HNSCCs) frequently harbor genomic mutations in cell death pathways. Nearly 30% of HNSCCs overexpress Fas-Associated Death Domain (FADD), with or without BIRC2/3 genes encoding cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2), critical components of the Tumor Necrosis Factor (TNF) Receptor signaling pathways. ASTX660 is a novel non-peptidomimetic antagonist of cIAP1/2 and XIAP under evaluation in a clinical trial for advanced solid tumors and lymphomas. Herein, we show that ASTX660, at nanomolar concentrations, sensitized Murine Oral Cancer (MOC1) cells to TNFα. Using syngeneic mouse models, ASTX660 showed additive anti-tumor activity with radiation therapy (XRT), cisplatin chemotherapy, and PD-1 blockade to significantly delay or eradicate MOC1 tumors. These combinations significantly increased CD8 + T cells and dendritic cells, as well as T cell activity. ASTX660 stimulated cytotoxic T lymphocyte (CTL) killing of MOC1 cells expressing ovalbumin. Early stages of CTL killing were predominantly mediated by perforin/granzyme B, whereas later stages were mediated by death ligands TNFα, TRAIL, and FasL. Correspondingly, depletion of CD8 + T cells and NK cells in vivo revealed both types of immune cells to be important components of the complete anti-tumor response enhanced by ASTX660+XRT. These findings serve to inform future studies of IAP inhibitors and support the potential for future clinical trials investigating ASTX660 with XRT and immunotherapies like PD-1/PD-L1 blockade in HNSCC.

Salivary duct carcinoma (SDC) is a rare salivary malignancy that often presents at advanced stage. Outcomes of low T stage patients with SDC have not been previously examined in detail. We queried our institution's cancer database and identified 28 patients with SDC in situ or T1/T2 SDC. A retrospective chart review was performed, followed by comparison of clinicopathologic features with N stage, disease-free survival, and overall survival. Patients tended to be male, in their sixties, with a high incidence of regional metastases, as in prior reports. Five-year disease-free and overall survival were 49%. Median disease-free survival was 3.24 years, and overall survival was 4.65 years. Parotid location, vascular invasion, facial nerve sacrifice, and extracapsular extension were associated with worse survival. This study provides practical information for counseling of patients who undergo surgery for a parotid mass and are found to have this aggressive malignancy.

Importance Evidence supports short courses of perioperative antibiotics for patients receiving minor head and neck procedures. Few studies have addressed antibiotic prophylaxis for patients undergoing free flap reconstruction of head and neck defects. Objective To determine ideal antibiotic prophylaxis in patients undergoing head and neck free flap reconstruction. Design, Setting, and Participants Retrospective cohort study of 427 adults receiving free flap reconstruction of head and neck defects at 2 affiliated tertiary care academic hospitals between January 1, 2006, and January 28, 2013. Exposures Prophylactic antibiotic type and duration were recorded from patient records. Main Outcomes and Measures Outcome data were abstracted from patients’ medical records including infection at the surgical sites and distant nonsurgical sites and flap site complications including flap compromise, dehiscence, or fistula. Multivariate logistic regression was used to determine the association of risk factors with the primary outcome of any infection within 30 days of surgery. Results Ninety-six patients (22.5%) received prophylactic antibiotics for 24 hours or less, and 331 patients received prolonged courses of prophylactic antibiotics. The majority of patients received ampicillin-sulbactam alone for prophylaxis (53.2%), while 36.5% received clindamycin alone and 10.3% received an alternative regimen. Postoperative infections occurred in 46% of patients, and 22% of patients had an infection at the flap inset site or neck incision. The use of clindamycin (odds ratio [OR], 2.54; 95% CI, 1.25-5.14 [ P = .01]) was associated with an increased risk of postoperative infection; extended duration of antibiotics (OR, 0.63; 95% CI, 0.34-1.19 [ P = .18]) was not associated with increased risk of postoperative infection. By multivariate analysis, use of clindamycin (OR, 6.71; 95% CI, 1.83-24.60 [ P = .004]) and oral tobacco use (OR, 1.20; 95% CI, 1.04-1.39 [ P = .02]), but not extended course of prophylactic antibiotics (OR, 0.75; 95% CI, 0.30-1.86 [ P = .53]), were associated with a higher risk of postoperative flap or neck infections. Conclusions and Relevance The choice of antibiotic appears to affect the rate of all postoperative infections and flap site infections more than the duration of antibiotics following head and neck free flap reconstruction. At our institutions , ampicillin-sulbactam is the preferred prophylactic antibiotic for major clean-contaminated head and neck procedures when possible.

The epidemiology of human papillomavirus (HPV)-associated cancers indicates dramatically increased rates for HPV-related oropharyngeal squamous cell carcinoma (OPSCC) over the past two decades. This development accounts for the increasing significance and research focus in the fields of immunology, oncology, and otolaryngology. In this review, we provide an overview of the most important and recent developments in pathogenesis and therapy in HPV-related OPSCC with a focus on the disease’s immune escape mechanisms and strategies for their reversal. In order to introduce the therapeutic approaches that are currently used and under development, we summarize the viral pathway, genomic alterations, and functional carcinogenesis in relation to antiviral immunity. The different viral strategies to evade the host immune system and their influence in carcinogenesis provide a unique tumor microenvironment that is not completely understood. Immunotherapies under development aim to prevent viral and tumor immunoevasion and may provide new insights into why—despite manifold immunoevasion strategies—an improved clinical outcome can be observed in HPV-related OPSCC.

Human papillomavirus (HPV) is increasingly identified as a causative agent for oropharyngeal squamous cell carcinoma (OPSCC), often in relatively young patients lacking traditional carcinogenic risk factors such as tobacco and alcohol use. A growing body of literature has highlighted the importance of immune impairment in the pathogenesis of HPV-related premalignant and malignant lesions in the uterine cervix and, more recently, the oropharynx. This chapter will summarize current knowledge of the mechanisms that human papillomaviruses have evolved to evade the host immune system in the development of malignancy and will conclude with a discussion on preventive and therapeutic strategies that exploit these immune modulatory mechanisms.

Rationale: Cisplatin, which remains the most commonly used systemic drug for head and neck squamous cell carcinoma (HNSCC), reduces numbers of circulating immune cells. However, recent studies suggest that cisplatin may enhance some aspects of anti-tumor immunity in the tumor microenvironment. We previously found that cisplatin increases expression of major histocompatibility (MHC) class I and programmed death ligand 1 (PD-L1) in HNSCC cell lines in vitro. Methods: In the current study, we investigated other components of the antigen processing machinery (APM) by flow cytometry following treatment with cisplatin. Using the syngeneic mouse oral cancer 1 (MOC1) model of HNSCC, we then investigated the effects of cisplatin and anti-PD-1 antibody, alone or in combination, on tumor growth and survival. Results: Using three different HNSCC cell lines, we found that levels of the APM components LMP2, ERp57 and calreticulin increased in all cell lines treated with cisplatin, whereas TAP1/2 increased dramatically only in one cisplatin-treated cell line with wildtype TP53 (UMSCC-74A). In MOC1 tumor-bearing mice, tumor growth was partially delayed by treatment with cisplatin and anti-PD-1 antibody alone and substantially delayed when these agents were given in combination, with resultant increased survival. Comparison of different treatment schedules suggested that concurrent administration is more effective than giving cisplatin one day prior to anti-PD-1 or giving anti-PD-1 one day prior to cisplatin. Conclusions: Despite upregulating PD-L1 on tumor cells and decreasing levels of circulating immune cells, cisplatin may enhance some aspects of anti-tumor immunity in the tumor microenvironment. While no mice were cured with concurrent cisplatin and anti-PD-1 antibody, tumor growth was substantially delayed. These results suggest a rationale for combining cisplatin and anti-PD-1 monoclonal antibodies, perhaps with radiation or other therapies, in additional preclinical studies and clinical trials of HNSCC. Supported by NIDCD intramural project ZIA-DC-DC000090. Citation Format: Linda Tran, Clint T. Allen, So-Jin Park, Roy Xiao, Carter Van Waes, Nicole C. Schmitt. Anti-tumor activity of cisplatin is enhanced by PD-1 blockade in preclinical models of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2637. doi:10.1158/1538-7445.AM2017-2637

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer with a five-year survival of ~50%. HNSCC are linked to human papillomavirus (HPV+) or tobacco carcinogenesis (HPV-). The Cancer Genome Atlas recently analyzed 279 HNSCC, revealing that 30% overexpress FADD (Fas-Associated Death Domain), with or without BIRC2/3 genes encoding cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2), which are critical components of the Tumor Necrosis Factor (TNF) Receptor signaling pathways that determine cell death or survival. The frequency of such mutations provides a window for potential therapeutics, as IAP antagonists have been shown to switch cancer cell TNFα signaling from being pro-survival to pro-apoptotic. We recently showed that birinapant, a second mitochondrial activator of caspases (SMAC) mimetic that promotes IAP degradation, sensitizes HNSCC to cell death by TNFα and eradicates tumors in combination with radiation in HPV- HNSCC models overexpressing FADD+/-BIRC2. ASTX660 (developed by Astex Pharmaceuticals) is a novel dual cIAP1/XIAP antagonist currently in clinical trials for treating advanced solid tumors and lymphomas. The objective of the present study is to determine the therapeutic effects of ASTX660 in HPV+/- HNSCC preclinical models. ASTX660 at nanomolar concentrations was found to potently inhibit cell proliferation (measured using XTT assays) and induce apoptosis (Annexin/7-AAD flow cytometry), and displayed combinatorial activity with TNFα, TRAIL, or cisplatin in multiple human HPV+/- HNSCC cell lines. Western blotting showed near complete degradation of cIAP1 expression at nanomolar concentrations in human HNSCC cell lines. Flow cytometry revealed that ASTX660 in combination with either TNFα or cisplatin reduced MHC-I expression and increased PD-L1 expression, suggesting that potential synergistic efficacy could be observed in combination with immune checkpoint inhibitors. Our results demonstrate that ASTX660 is a potential therapeutic agent for both HPV+/- HNSCC. Experiments evaluating the anti-tumor effects of ASTX660 as a monotherapy and in combination with radiation, cisplatin, and anti-PD-1 therapies are ongoing, using both human HNSCC xenograft and syngeneic mouse oral cancer (MOC) models. Supported by NIDCD intramural projects (ZIA-DC-000016, 73 and 74). Citation Format: Roy Xiao, Yi An, Adeeb Derakhshan, Zhong Chen, Nicole C. Schmitt, Carter Van Waes. Novel dual cIAP1/XIAP antagonist ASTX660 activity in preclinical models of human papillomavirus(+) and (-) head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2016. doi:10.1158/1538-7445.AM2017-2016

The goal of this study was to determine whether osteopontin, a molecule with a variety of biologic effects including cell death inhibition, plays an important role in protection of the inner ear and kidney from the toxic effects of the chemotherapeutic drug cisplatin.In vivo study using a model system of cisplatin toxicity in adult mice.Virginia Merrill Bloedel Hearing Research Center, University of Washington.Osteopontin+/+ and Osteopontin-/- adult mice were treated with intraperitoneal cisplatin (20 mg/kg) or saline (control). Osteopontin levels were investigated by immunohistochemistry. Auditory brainstem response thresholds and cochlear histology were used to assess ototoxicity, while serum creatinine and renal histology were used to assess nephrotoxicity. For quantitative experiments, 8 to 18 animals were included in each treatment group.At 72 hours after cisplatin treatment, there was a slight increase in osteopontin levels within the kidney but not in the inner ear. There was no difference in auditory brainstem response threshold shifts, outer hair cell death, or serum creatinine between Osteopontin+/+ and Osteopontin-/- mice. Cochlear and renal histologic damage following cisplatin appeared to be similar in Osteopontin+/+ and Osteopontin-/- mice.Osteopontin is not required for development of normal auditory or renal function. Osteopontin is unlikely to play a role in protection of the inner ear or kidney from acute cisplatin toxicity. Slight increases in renal osteopontin 72 hours after cisplatin injury may be important for regeneration of proximal tubule cells.

Meeting abstracts Prognosis varies dramatically in head and neck squamous cell carcinoma (HNSCC) based on HPV status. In HPV+ patients, programmed death (PD)-1 expression has been linked to a better clinical outcome. We hypothesized that extent of PD-1 expression may differentially impact T cell

6090 Background: Treatment intensification for human papillomavirus (HPV)-negative HNC is an active area of investigation. Targeting the epidermal growth-factor receptor pathway using the monoclonal antibody pmAb with C chemoradiation was investigated in high-risk resected, primarily HPV- HNC patients. Methods: Eligible were pts with ECOG performance status 0-1 with pathologic stage III or IVA squamous cell carcinoma of the oral cavity, larynx, or hypopharynx, without gross residual tumor and with high-risk factors (margins

A 3-MONTH-OLD boy presented to our emergency department with a 1-month history of a left-sided neck mass. He was initially diagnosed as having bacterial lymphadenitis at an outside emergency department, and amoxicillin was prescribed. On the day of admission, he was brought to our emergency department because the neck mass had worsened and had spread to the back of his neck. He was febrile but was in no distress. His birth, medical, and family histories were unremarkable. His vital signs were as follows: temperature, 38.8°C; heart rate, 140 beats/min; respiration rate, 22 breaths/min; and blood pressure, 100/55 mm Hg. A 3 4-cm firm, nontender, nonerythematous mass was noted in the left posterior cervical area. The abdomen was soft and nontender. The edge of the liver was palpable 1 to 2 cm below the right costal margin. Laboratory data on admission revealed a white blood cell count of 50000/μL, with 23% band cells, 47% polymorphonuclear leukocytes, 20% lymphocytes, 9% monocytes, and 1% eosinophils. The hemoglobin level was 8.4 g/dL, and the platelet count was 937 10/μL. A chest radiograph illustrated a left lower lobe infiltrate, and a computed tomographic scan revealed multiple hypolucent lesions in the left parapharyngeal space and neck (Figure 1). Surgical exploration was performed. A large parapharyngeal abscess and a 7-cm multiloculated cervical abscess were identified and drained. The surgical tissue revealed a mixed inflammatory infiltrate consistingof lymphocytes,neutrophils, and histiocytes (Figure 2). The contents of the abscess yielded Klebsiella pneumoniae. Intravenous ceftriaxone disodium therapy was initiated. The patient’s hospital course was complicated by recurrent cervical abscesses that required 2 additional surgical drainage procedures. The cultures continued to yield K pneumoniae, which was susceptible to ceftriaxone. A thoracoscopy and wedge biopsy of left lungwereperformedlater in thepatient’shospital course because of the persistent infiltrate and because a computed tomographic scan of the chest revealed a cavitary lesion. The surgical tissue showed well-formed granulomas, with epithelioid histiocytes, multinucleated giant cells, and central neutrophilic inflammation (Figure 3). A definitive diagnostic test was obtained. What is your diagnosis?