Publications by authors named "William C Spanos"

29 Publications

  • Page 1 of 1

Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial.

J Immunother Cancer 2021 Jun;9(6)

Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.

Background: Head and neck squamous cell carcinomas (HNSCCs) are common malignancies caused by carcinogens, including tobacco and alcohol, or infection with human papillomavirus (HPV). Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway are effective against unresectable recurrent/metastatic HNSCC. Here, we explored the safety and efficacy of anti-PD-1 therapy in at-risk resectable HPV-positive and HPV-negative HNSCC in the neoadjuvant setting.

Methods: The phase I/II CheckMate 358 trial in virus-associated cancers assessed neoadjuvant nivolumab in patients with previously untreated, resectable HPV-positive or HPV-negative HNSCC. Patients received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned by day 29. Safety/tolerability (primary endpoint) was assessed by monitoring adverse events (AEs) and surgical delays. Radiographic response was measured before surgery using RECIST v1.1, adapted for a single post-nivolumab evaluation. Pathologic specimens were examined for treatment response using immune-based criteria.

Results: From November 2015 to December 2017, 52 patients with AJCC (seventh edition) stage III-IV resectable HNSCC received neoadjuvant nivolumab (26 HPV-positive, 26 HPV-negative). Any-grade treatment-related AEs (TRAEs) occurred in 19 patients (73.1%) and 14 patients (53.8%) in the HPV-positive and HPV-negative cohorts, respectively; grade 3-4 TRAEs occurred in five (19.2%) and three patients (11.5%), respectively. No patient had a protocol-defined TRAE-related surgical delay (>4 weeks). Thirty-eight patients were reported as undergoing complete surgical resection, 10 had a planned post-nivolumab biopsy instead of definitive surgery due to a protocol misinterpretation, and four did not undergo surgery or biopsy, including two with tumor progression. Radiographic response rates in 49 evaluable patients were 12.0% and 8.3% in the HPV-positive and HPV-negative cohorts, respectively. There were no complete pathologic responses by site or central review in operated patients. Among 17 centrally evaluable HPV-positive tumors, one (5.9%) achieved major pathological response and three (17.6%) achieved partial pathologic response (pPR); among 17 centrally evaluable HPV-negative tumors, one (5.9%) achieved pPR.

Conclusions: Neoadjuvant nivolumab was generally safe and induced pathologic regressions in HPV-positive (23.5%) and HPV-negative (5.9%) tumors. Combinatorial neoadjuvant treatment regimens, and continued postoperative therapy for high-risk tumors, are warranted in future trials to enhance the efficacy of this approach.

Trial Registration Number: ClinicalTrials.gov NCT02488759; https://clinicaltrials.gov/ct2/show/NCT02488759.
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http://dx.doi.org/10.1136/jitc-2021-002568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183204PMC
June 2021

Near-infrared photoimmunotherapy targeting human-EGFR in a mouse tumor model simulating current and future clinical trials.

EBioMedicine 2021 May 29;67:103345. Epub 2021 Apr 29.

Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address:

Background: near-infrared photoimmunotherapy (NIR-PIT) is a cancer treatment that uses antibody-photoabsorber (IRDye700DX, IR700) conjugates (APCs) which bind to target cells and are photoactivated by NIR light inducing rapid necrotic cell death. NIR-PIT targeting human epidermal growth factor receptor (hEGFR) has been shown to destroy hEGFR expressing human tumor cells and to be effective in immunodeficient mouse models. NIR-PIT can also be targeted to cells in the tumor microenvironment, for instance, CD25-targeted NIR-PIT can be used to selectively deplete regulatory T cells (Tregs) within a tumor. The aim of this study was to evaluate the combined therapeutic efficacy of hEGFR and CD25-targeted NIR-PIT in a newly established hEGFR expressing murine oropharyngeal cell line (mEERL-hEGFR).

Methods: panitumumab conjugated with IR700 (pan-IR700) was used as the cancer cell-directed component of NIR-PIT and anti-CD25-F(ab')-IR700 was used as the tumor microenvironment-directed component of NIR-PIT. Efficacy was evaluated using tumor-bearing mice in four groups: (1) non-treatment group (control), (2) pan-IR700 based NIR-PIT (pan-PIT), (3) anti-CD25-F(ab')-IR700 based NIR-PIT (CD25-PIT), (4) combined NIR-PIT with pan-IR700 and anti-CD25- F(ab')-IR700 (combined PIT).

Findings: the combined PIT group showed the greatest inhibition of tumor growth. Destruction of cancer cells likely leads to an immune response which is amplified by the loss of Tregs in the tumor microenvironment.

Interpretation: combined hEGFR and CD25-targeted NIR-PIT is a promising treatment for hEGFR expressing cancers in which Treg cells play an immunosuppressive role.
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http://dx.doi.org/10.1016/j.ebiom.2021.103345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102756PMC
May 2021

nab-Paclitaxel and cisplatin followed by cisplatin and radiation (Arm 1) and nab-paclitaxel followed by cetuximab and radiation (Arm 2) for locally advanced head and neck squamous-cell carcinoma: a multicenter, non-randomized phase 2 trial.

Med Oncol 2021 Mar 8;38(4):35. Epub 2021 Mar 8.

Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.

In locally advanced head and neck squamous-cell carcinoma (LA-HNSCC), clinical complete response (cCR) at the primary site, assessed by clinical examination, after induction chemotherapy predicts for a low relapse risk after subsequent chemoradiotherapy. Prior studies showed a cCR rate of 77% with induction nanoparticle albumin-bound (nab)-paclitaxel given with cisplatin and 5-fluorouracil (APF). The primary aims of this non-randomized phase 2 trial were to determine the cCR rate after induction nab-paclitaxel and cisplatin (Arm 1) and after nab-paclitaxel monotherapy (Arm 2). Eligibility required LA-HNSCC, T2-T4 stage classification, and suitable (Arm 1) or unsuitable (Arm 2) candidates for cisplatin. Arm 1 patients received nab-paclitaxel and cisplatin, then cisplatin with radiation. Arm 2 patients received nab-paclitaxel, then cetuximab with radiation. The primary endpoint was cCR after two cycles of induction chemotherapy. Each arm enrolled forty patients. cCR at the primary site occurred in 28 patients (70%) after nab-paclitaxel and cisplatin and in 8 patients (20%) after nab-paclitaxel monotherapy. The overall clinical response rate was 98% after nab-paclitaxel and cisplatin and 90% after nab-paclitaxel monotherapy. In subset analyses, cCR rates by T stage classifications (T2, T3, T4) were 54, 86, and 69% after nab-paclitaxel and cisplatin, and 14, 11, and 26% after nab-paclitaxel. cCR rates by human papillomavirus status (p16 positive oropharynx vs other) were 72 and 64% after nab-paclitaxel and cisplatin and 35 and 9% after nab-paclitaxel. The cCR rate after nab-paclitaxel and cisplatin was similar to APF; however, the cCR rate after nab-paclitaxel monotherapy was lower. The trial was registered at ClinicalTrials.gov NCT02573493 on October 9, 2015.
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http://dx.doi.org/10.1007/s12032-021-01479-wDOI Listing
March 2021

Nanoparticle albumin-bound paclitaxel with cetuximab and carboplatin as first-line therapy for recurrent or metastatic head and neck cancer: A single-arm, multicenter, phase 2 trial.

Oral Oncol 2021 04 3;115:105173. Epub 2021 Feb 3.

Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States.

Objectives: Macropinocytosis promotes internalization of albumin into cells to serve as a nutrient supply and is constitutively driven by signaling pathways frequently hyperactivated in head and neck squamous-cell carcinoma (HNSCC). In this way, drugs bound to albumin may selectively target HNSCC. nab-paclitaxel is a nanoparticle albumin-bound formulation of paclitaxel that improves drug delivery into tumor compared to paclitaxel. The primary aim of this single-arm, multicenter, phase 2 trial was to determine if nab-paclitaxel, cetuximab, and carboplatin (CACTUX regimen) would result in longer progression-free survival (PFS) than the historical regimen (EXTREME: 5-fluorouracil, cetuximab, and a platinum).

Materials And Methods: Patients with untreated recurrent or metastatic HNSCC received six, three-week cycles of nab-paclitaxel, cetuximab, and carboplatin, followed by maintenance nab-paclitaxel and cetuximab until progression. We hypothesized the median PFS with CACTUX would be 35% longer than with EXTREME (corresponding to 7.6 vs 5.6 months; power 0.80, α = 0.05, one-sided test, n = 70). Secondary outcomes included objective response rate (ORR) and overall survival (OS).

Results: Seventy-four patients enrolled into the trial; seventy were evaluable. The median PFS was 6.1 months (95% CI, 4.1-7.4). The ORR was 60%. Median follow-up was 18 months (IQR: 4.7-23). The median OS was 17.8 months (95% CI, 8.5-21.7) for all patients, and 19.8 months (95% CI, 10.9-22.0) for human papillomavirus (HPV)-related oropharynx SCC and 14.0 months (95% CI, 4.6-23.3) for HPV-unrelated HNSCC.

Conclusion: Among patients with recurrent or metastatic HNSCC, CACTUX did not result in a longer PFS than historical EXTREME. However, CACTUX did result in a more favorable ORR and OS.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105173DOI Listing
April 2021

Adverse event reporting in head and neck transoral robotic surgery: a MAUDE database study.

J Robot Surg 2021 Jan 23. Epub 2021 Jan 23.

Department of Surgery, Sanford Ear, Nose, and Throat Clinic, University of South Dakota Sanford School of Medicine, 1310 W 22nd St., Sioux Falls, SD, 57105, USA.

Transoral robotic surgery (TORS) using the da Vinci Surgical system was approved by the US Food and Drug Administration in 2009. Currently, most available safety information on TORS procedures describes adverse events occurring in the context of clinical trials or series at high-volume academic centers. The goal of this study was to catalog reported adverse events associated with the da Vinci device in head and neck procedures by querying an FDA database. A search was performed on the MAUDE database inspecting for TORS safety incident reports generated from January 2009 through May 2020 using key words "da Vinci" and "Intuitive Surgical". A total of 3312 medical device records were produced. Of these 36 head and neck adverse events, reports were identified through manual screening of the data by the authors. Death was found to be the most common adverse event reported overall, manifesting in 44% of all reported incidents. The most frequent source of mortality was found to be hemorrhaging in the perioperative period rather than incidents of device malfunction or structural damage from surgery. This was found to be similar to the results of other published series for transoral ablative surgery. This study suggests that the small number of reported adverse events related to TORS with the da Vinci system seems to mirror what would be expected from the same procedures using other methods for transoral surgery.
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http://dx.doi.org/10.1007/s11701-020-01185-1DOI Listing
January 2021

Examining the relationship of immunotherapy and wound complications following flap reconstruction in patients with head and neck cancer.

Head Neck 2021 05 8;43(5):1509-1520. Epub 2021 Jan 8.

Department of Plastic Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.

Background: Immunotherapy agents are used to treat advanced head and neck lesions. We aim to elucidate relationship between immunotherapy and surgical wound complications.

Methods: Retrospective multi-institutional case series evaluating patients undergoing ablative and flap reconstructive surgery and immunotherapy treatment.

Main Outcome: wound complications.

Results: Eight-two (62%) patients received preoperative therapy, 89 (67%) postoperative, and 33 (25%) in both settings. Forty-one (31%) patients had recipient site complications, 12 (9%) had donor site. Nineteen (14%) had major recipient site complications, 22 (17%) had minor. There was no statistically significant difference in complications based on patient or tumor-specific variables. Preoperative therapy alone demonstrated increased major complications (odds ratio [OR] 3.7, p = 0.04), and trend to more donor site complications (OR 7.4, p = 0.06), however treatment in both preoperative and postoperative therapy was not.

Conclusions: Preoperative immunotherapy may be associated with increased wound complications. Controlled studies are necessary to delineate this association and potential risks of therapy.
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http://dx.doi.org/10.1002/hed.26601DOI Listing
May 2021

Prognostic Impact of Metastatic Site and Pattern in Patients with Metastatic Head and Neck Cancer.

Laryngoscope 2021 06 24;131(6):E1838-E1846. Epub 2020 Oct 24.

Department of Otolaryngology-Head and Neck Surgery and Communication Disorders, University of Louisville School of Medicine, Louisville, Kentucky, U.S.A.

Objectives/hypothesis: Investigate the relationship between site and pattern of distant metastasis (DM) and overall survival (OS) in a multi-institutional cohort of patients with DM head and neck cancer (HNC).

Study Design: Retrospective review.

Methods: 283 patients treated at 4 academic centers in the Midwest HNC Consortium between 2000 and 2015 were retrospectively reviewed. Disease patterns were divided between solitary metastatic versus polymetastatic (≥2 sites) disease. Survival functions for clinically relevant variables were estimated using Kaplan-Meier and Cox proportional hazards models.

Results: Median OS for all patients was 9.0 months (95% confidence interval [CI]: 7.4-10.6). Lung (n = 220, 77.7%) was the most common site of DM, followed by bone (n = 90, 31.8%), mediastinal lymph nodes (n = 55, 19.4%), liver (n = 41, 14.5%), and brain (n = 17, 6.0%). Bone metastases were independently associated with the worst prognosis (hazard ratio [HR] = 1.6, 95% CI: 1.3-2.1). On univariate analysis, brain metastases were associated with improved prognosis (HR = 0.5, 95% CI: 0.3-0.9), although this was not statistically significant on the multivariate analysis. Polymetastatic disease was present in the majority of patients (n = 230, 81.3%) and was associated with a worse prognosis compared to solitary metastatic disease (HR = 1.4, 95% CI: 1.0-2.0).

Conclusion: Our large, multi-institutional review indicates that both the metastatic pattern and site of DM impact OS. Polymetastatic disease and bone metastasis are associated with worse prognosis, independent of treatment received.

Level Of Evidence: 4 Laryngoscope, 131:E1838-E1846, 2021.
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http://dx.doi.org/10.1002/lary.29208DOI Listing
June 2021

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study.

J Clin Oncol 2020 07 1;38(21):2427-2437. Epub 2020 Jun 1.

Sanford Cancer Center, Sanford Health, Sioux Falls, SD.

Purpose: Pembrolizumab is a humanized monoclonal antibody that blocks interaction between programmed death receptor-1 (PD-1) and its ligands (PD-L1, PD-L2). Although pembrolizumab is approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), its role in the management of locally advanced (LA) disease is not defined. We report a phase IB study evaluating the safety and efficacy of adding pembrolizumab to cisplatin-based chemoradiotherapy in patients with LA HNSCC.

Patients And Methods: Eligible patients included those with oral cavity (excluding lip), oropharyngeal, hypopharyngeal, or laryngeal stage III to IVB HNSCC (according to American Joint Committee on Cancer, 7th edition, staging system) eligible for cisplatin-based, standard-dose (70 Gy) chemoradiotherapy. Pembrolizumab was administered concurrently with and after chemoradiotherapy with weekly cisplatin. Safety was the primary end point and was determined by incidence of chemoradiotherapy adverse events (AEs) and immune-related AEs (irAEs). Efficacy was defined as complete response (CR) rate on end-of-treatment (EOT) imaging or with pathologic confirmation at 100 days postradiotherapy completion. Key secondary end points included overall (OS) and progression-free survival (PFS).

Results: The study accrued 59 patients (human papillomavirus [HPV] positive, n = 34; HPV negative, n = 25) from November 2015 to October 2018. Five patients (8.8%) required discontinuation of pembrolizumab because of irAEs, all of which occurred during concurrent chemoradiotherapy; 98.3% of patients completed the full planned treatment dose (70 Gy) of radiotherapy without any delays ≥ 5 days; 88.1% of patients completed the goal cisplatin dose of ≥ 200 mg/m. EOT CR rates were 85.3% and 78.3% for those with HPV-positive and -negative HNSCC, respectively.

Conclusion: Pembrolizumab in combination with weekly cisplatin-based chemoradiotherapy is safe and does not impair delivery of curative radiotherapy or chemotherapy in HNSCC. Early efficacy data support further investigation of this approach.
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http://dx.doi.org/10.1200/JCO.19.03156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365766PMC
July 2020

The multifarious roles of the chemokine CXCL14 in cancer progression and immune responses.

Mol Carcinog 2020 07 24;59(7):794-806. Epub 2020 Mar 24.

Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado.

The chemokine CXCL14 is a highly conserved, homeostatic chemokine that is constitutively expressed in skin epithelia. Responsible for immune cell recruitment and maturation, as well as impacting epithelial cell motility, CXCL14 contributes to the establishment of immune surveillance within normal epithelial layers. Furthermore, CXCL14 is critical to upregulating major histocompatibility complex class I expression on tumor cells. Given these important roles, CXCL14 is often dysregulated in several types of carcinomas including cervical, colorectal, endometrial, and head and neck cancers. Its disruption has been shown to limit critical antitumor immune regulation and is correlated to poor patient prognosis. However, other studies have found that in certain cancers, namely pancreatic and some breast cancers, overexpression of stromal CXCL14 correlates with poor patient survival due to increased invasiveness. Contributing to the ambiguity CXCL14 plays in cancer is that the native CXCL14 receptor remains uncharacterized, although several candidate receptors have been proposed. Despite the complexity of CXCL14 functions, it remains clear that this chemokine is a key regulatory factor in cancer and represents a potential target for future cancer immunotherapies.
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http://dx.doi.org/10.1002/mc.23188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282946PMC
July 2020

A Rare Presentation of Ameloblastic Carcinoma of the Sinus Cavity and Skull Base.

Cureus 2019 Dec 1;11(12):e6265. Epub 2019 Dec 1.

Oncology, University of South Dakota Sanford School of Medicine, Sioux Falls, USA.

Ameloblastic carcinoma (AC) is an exceedingly rare odontogenic cancer about which there is limited information in the literature. We present a case of AC originating in the sinus cavity and extending to the skull base in a patient in the first trimester of pregnancy. Diagnostic work up was complicated by this pregnancy, which delayed radiation exposure with imaging. Once scans were obtained, diagnosis was further complicated by the radiographic similarities between possible lung metastases and previously undiagnosed sarcoid nodules. After thorough work up to rule out metastatic disease, the patient was successfully treated with primary surgical resection followed by adjuvant chemoradiation. The patient remained disease free at one year after therapy. This case demonstrates the importance of thorough work up in the diagnosis of AC, and is an opportunity to review the literature and discuss therapeutic methods to treat this rare, aggressive neoplasm.
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http://dx.doi.org/10.7759/cureus.6265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937462PMC
December 2019

CXCL14 suppresses human papillomavirus-associated head and neck cancer through antigen-specific CD8 T-cell responses by upregulating MHC-I expression.

Oncogene 2019 11 15;38(46):7166-7180. Epub 2019 Aug 15.

Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Evasion of the host immune responses is critical for both persistent human papillomavirus (HPV) infection and associated cancer progression. We have previously shown that expression of the homeostatic chemokine CXCL14 is significantly downregulated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive head and neck cancer (HNC) cells dramatically suppresses tumor growth and increases survival through an immune-dependent mechanism in mice. Although CXCL14 recruits natural killer (NK) and T cells to the tumor microenvironment, the mechanism by which CXCL14 mediates tumor suppression through NK and/or T cells remained undefined. Here we report that CD8 T cells are required for CXCL14-mediated tumor suppression. Using a CD8 T-cell receptor transgenic model, we show that the CXCL14-mediated antitumor CD8 T-cell responses require antigen specificity. Interestingly, CXCL14 expression restores major histocompatibility complex class I (MHC-I) expression on HPV-positive HNC cells downregulated by HPV, and knockdown of MHC-I expression in HNC cells results in loss of tumor suppression even with CXCL14 expression. These results suggest that CXCL14 enacts antitumor immunity through restoration of MHC-I expression on tumor cells and promoting antigen-specific CD8 T-cell responses to suppress HPV-positive HNC.
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http://dx.doi.org/10.1038/s41388-019-0911-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856418PMC
November 2019

Immune microenvironment modulation unmasks therapeutic benefit of radiotherapy and checkpoint inhibition.

J Immunother Cancer 2019 08 13;7(1):216. Epub 2019 Aug 13.

Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA.

Background: Immune checkpoint inhibitors (ICIs) for solid tumors, including those targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have shown impressive clinical efficacy, however, most patients do not achieve durable responses. One major therapeutic obstacle is the immunosuppressive tumor immune microenvironment (TIME). Thus, we hypothesized that a strategy combining tumor-directed radiation with TIME immunomodulation could improve ICI response rates in established solid tumors.

Methods: Using a syngeneic mouse model of human papillomavirus (HPV)-associated head and neck cancer, mEER, we developed a maximally effective regimen combining PD-1 and CTLA-4 inhibition, tumor-directed radiation, and two existing immunomodulatory drugs: cyclophosphamide (CTX) and a small-molecule inducible nitric oxide synthase (iNOS) inhibitor, L-n6-(1-iminoethyl)-lysine (L-NIL). We compared the effects of the various combinations of this regimen on tumor growth, overall survival, establishment of immunologic memory, and immunologic changes with flow cytometry and quantitative multiplex immunofluorescence.

Results: We found PD-1 and CTLA-4 blockade, and radiotherapy alone or in combination, incapable of clearing established tumors or reversing the unfavorable balance of effector to suppressor cells in the TIME. However, modulation of the TIME with cyclophosphamide (CTX) and L-NIL in combination with dual checkpoint inhibition and radiation led to rejection of over 70% of established mEER tumors and doubled median survival in the B16 melanoma model. Anti-tumor activity was CD8 T cell-dependent and led to development of immunologic memory against tumor-associated HPV antigens. Immune profiling revealed that CTX/L-NIL induced remodeling of myeloid cell populations in the TIME and tumor-draining lymph node and drove subsequent activation and intratumoral infiltration of CD8 effector T cells.

Conclusions: Overall, this study demonstrates that modulation of the immunosuppressive TIME is required to unlock the benefits of ICIs and radiotherapy to induce immunologic rejection of treatment-refractory established solid tumors.
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http://dx.doi.org/10.1186/s40425-019-0698-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693252PMC
August 2019

Cancer exosomes induce tumor innervation.

Nat Commun 2018 10 16;9(1):4284. Epub 2018 Oct 16.

Cancer Biology and Immunotherapies Group, Sanford Research, 2301 East 60th St north, Sioux Falls, SD, 57104, USA.

Patients with densely innervated tumors suffer with increased metastasis and decreased survival as compared to those with less innervated tumors. We hypothesize that in some tumors, nerves are acquired by a tumor-induced process, called axonogenesis. Here, we use PC12 cells as an in vitro neuronal model, human tumor samples and murine in vivo models to test this hypothesis. When appropriately stimulated, PC12 cells extend processes, called neurites. We show that patient tumors release vesicles, called exosomes, which induce PC12 neurite outgrowth. Using a cancer mouse model, we show that tumors compromised in exosome release are less innervated than controls. Moreover, in vivo pharmacological blockade of exosome release similarly attenuates tumor innervation. We characterize these nerves as sensory in nature and demonstrate that axonogenesis is potentiated by the exosome-packaged axonal guidance molecule, EphrinB1. These findings indicate that tumor released exosomes induce tumor innervation and exosomes containing EphrinB1 potentiate this activity.
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http://dx.doi.org/10.1038/s41467-018-06640-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191452PMC
October 2018

β-Adrenergic receptor modulates mitochondrial metabolism and disease progression in recurrent/metastatic HPV(+) HNSCC.

Oncogenesis 2018 Oct 8;7(10):81. Epub 2018 Oct 8.

Cancer Biology and Immunotherapies Group, Sanford Research, 2301 East 60th St North, Sioux Falls, SD, 57104, USA.

The incidence of human papillomavirus-associated head and neck squamous cell carcinoma (HPV[ + ] HNSCC) is rapidly increasing. Although clinical management of primary HPV( + ) HNSCC is relatively successful, disease progression, including recurrence and metastasis, is often fatal. Moreover, patients with progressive disease face limited treatment options and significant treatment-associated morbidity. These clinical data highlight the need to identify targetable mechanisms that drive disease progression in HPV( + ) HNSCC to prevent and/or treat progressive disease. Interestingly, β-adrenergic signaling has recently been associated with pro-tumor processes in several disease types. Here we show that an aggressive murine model of recurrent/metastatic HPV( + ) HNSCC upregulates β-adrenergic receptor (β2AR) expression, concordant with significantly heightened mitochondrial metabolism, as compared with the parental model from which it spontaneously derived. β-Adrenergic blockade effectively inhibits in vitro proliferation and migratory capacity in this model, effects associated with an attenuation of hyperactive mitochondrial respiration. Importantly, propranolol, a clinically available nonselective β-blocker, significantly slows primary tumor growth, inhibits metastatic development, and shows additive benefit alongside standard-of-care modalities in vivo. Further, via CRISPR/Cas9 technology, we show that the hyperactive mitochondrial metabolic profile and aggressive in vivo phenotype of this recurrent/metastatic model are dependent on β2AR expression. These data implicate β2AR as a modulator of mitochondrial metabolism and disease progression in HPV( + ) HNSCC, and warrant further investigation into the use of β-blockers as low cost, relatively tolerable, complementary treatment options in the clinical management of this disease.
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http://dx.doi.org/10.1038/s41389-018-0090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175933PMC
October 2018

Impact of PET/CT on Staging and Treatment of Advanced Head and Neck Squamous Cell Carcinoma.

Otolaryngol Head Neck Surg 2019 02 21;160(2):261-266. Epub 2018 Aug 21.

5 Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa, USA.

Objective: To understand the effects of positron emission tomography/computed tomography (PET/CT) evaluation on patients with previously untreated head and neck squamous cell carcinoma (HNSCC) with clinical evidence of regional lymph node involvement.

Study Design: Prospective blinded study.

Setting: Tertiary care cancer center.

Subjects And Methods: Informed consent was obtained and data collected from 52 consecutive previously untreated patients with HNSCC and clinical evidence of cervical metastasis. All patients underwent conventional evaluation for HNSCC and whole body PET/CT. Data were evaluated by 5 independent reviewers, who performed TNM staging per the American Joint Committee on Cancer (seventh edition) manual and proposed a treatment plan prior to viewing, and after reviewing, PET/CT. Cases where at least 3 of 5 reviewers agreed were considered significant.

Results: There were 0 patients for whom review of the PET/CT altered the T-class assessment (95% CI, 0-6.8), 12 (23.1%) for whom PET/CT altered N classification (95% CI, 12.5-34.5), and 2 (3.8%) for whom PET/CT altered the M classification (95% CI, 0.5-13.2). For 5 patients (9.6%), overall stage was altered per PET/CT review (95% CI, 3.2-21). For 3 patients (5.8%), PET/CT findings prompted reviewers to alter treatment recommendations (95% CI, 1.2-15.9).

Conclusion: When added to more conventional patient evaluation, PET/CT results in changes to the TNM categories, but overall staging and treatment were less frequently affected. Whether PET/CT should be used routinely for patients with stage III and IV HNSCC is still subjective and merits further study.
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http://dx.doi.org/10.1177/0194599818794479DOI Listing
February 2019

Oral Cavity Reconstruction Outcomes Using a Porcine Urinary Bladder Matrix: A Retrospective Case Series.

Wounds 2018 May;30(5):131-137

Sanford Research; Department of Surgery, University of South Dakota Sanford School of Medicine, Sioux Falls, SD.

Objective: The purpose of this study is to assess healing outcomes in full-thickness mucosal wounds following the use of a porcine urinary bladder matrix to augment mixed oral cavity repairs.

Materials And Methods: A retrospective chart analysis was conducted over a 58-month timespan. Participants included individuals with osteoradionecrosis. Descriptive measures obtained in the postoperative setting were used to examine wound healing outcomes.

Results: Thirty-nine encounters with 35 patients met inclusion criteria for assessment. The mean defect size repaired was 14 cm2. Successful healing occurred in 64% of cases. Scarring was observed in 10 cases, and 3 cases demonstrated transient functional deficits. Reapplication of the xenograft was required in 4 cases. Only 1 acute event of hemorrhage and 1 infection were observed in the postoperative period.

Conclusions: Use of porcine urinary bladder matrix grafts for oral cavity reconstruction was well tolerated in a diverse number of wound scenarios with a relatively low risk of postoperative complication. The use of porcine urinary bladder matrix was not observed to provide any noteworthy advantages for the healing of recalcitrant osteoradionecrosis wounds.
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May 2018

Topical superoxide dismutase in posttreatment fibrosis in patients with head and neck cancer.

Head Neck 2018 07 13;40(7):1400-1405. Epub 2018 May 13.

Department of Otolaryngology - Head and Neck Surgery, Sanford University of South Dakota Medical Center, Sanford Research, Sioux Falls, South Dakota.

Background: Topical superoxide dismutase (SOD) has been shown to decrease postradiation fibrosis in some cancers but has not demonstrated an effect in patients with head and neck cancer. The purpose of this study was to determine if topical SOD is an effective treatment for postradiation neck fibrosis.

Methods: This was a randomized prospective blinded clinical study of topical SOD versus placebo for the treatment of neck fibrosis. Measures of fibrosis grade and quality of life were obtained at baseline and after 3 months of treatment.

Results: Improvement in fibrosis score was comparable between the 2 study arms at 3 months.

Conclusion: Both study groups showed improvement but the differences between groups was not statistically significant. Topical SOD likely has limited benefit for posttreatment neck fibrosis but this study confirms other published evidence of benefit from active physical therapy of posttreatment fibrosis in patients with head and neck cancer.
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http://dx.doi.org/10.1002/hed.25119DOI Listing
July 2018

Treatment of Peritonsillar Abscess in Immunosuppressed Patients.

S D Med 2017 Jul;70(7):314-316

Department of Surgery, University of South Dakota Sanford School of Medicine.

Peritonsillar abscess (PTA) is a common pathology in otolaryngology emergency. The treatment of PTA is usually bedside drainage or surgical removal of the tonsils (Quincy tonsillectomy) in combination with antibiotic treatment. However, patients with immune suppression might have a more difficult treatment course. Such difficulties may be further magnified within older patients. This case report will describe successful multi-modality treatment of two separate incidents of PTA developing in the context of immunosuppression. Two separate incidents of PTA occurring in immunosuppressed, thrombocytopenic, cancer patients after recent chemotherapy are presented. Early utilization of incision and drainage, antibiotics, and granulocyte colony stimulating factor (G-CSF, filgrastim) for PTA presenting in the setting of chemotherapy related neutropenia appears to be a viable option in patients with immunosuppression. Review of the current literature also demonstrates that reporting of PTA in older patients is important for future research efforts.
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July 2017

mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC.

Oncotarget 2016 Apr;7(17):24228-41

Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA.

Effective treatments for recurrent/metastatic human papillomavirus-positive (HPV+) head and neck squamous cell cancer (HNSCC) are limited. To aid treatment development, we characterized a novel murine model of recurrent/metastatic HPV+ HNSCC. Further analysis of the parental tumor cell line and its four recurrent/metastatic derivatives led to preclinical testing of an effective treatment option for this otherwise fatal disease. Reverse phase protein arrays identified key signaling cascades in the parental and recurrent/metastatic cell lines. While protein expression profiles differed among the recurrent/metastatic cell lines, activated proteins associated with the mTOR signaling cascade were a commonality. Based on these data, mTOR inhibition was evaluated as an adjuvant treatment for recurrent/metastatic disease. mTOR activity and treatment response were assessed in vitro by western blot, Seahorse, proliferation, clonogenic, and migration assays. Standard-of-care cisplatin/radiation therapy (CRT) versus CRT/rapamycin were compared in vivo. Low-dose rapamycin inhibited mTOR signaling, decreasing proliferation (43%) and migration (62%) while it enhanced CRT-induced cytotoxicity (3.3 fold) in clonogenic assays. Furthermore, rapamycin re-sensitized CRT-resistant, metastatic tumors to treatment in vivo, improving long-term cures (0-30% improved to 78-100%, depending on the recurrent/metastatic cell line) and limiting lymph node metastasis (32%) and lung metastatic burden (30 fold). Studies using immune compromised mice suggested rapamycin's effect on metastasis is independent of the adaptive immune response. These data suggest a role of mTOR activation in HPV+ HNSCC recurrent/metastatic disease and that adjuvant mTOR inhibition may enhance treatment of resistant, metastatic cell populations at the primary site and limit distant metastasis.
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http://dx.doi.org/10.18632/oncotarget.8286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029697PMC
April 2016

Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis.

Oncotarget 2016 Apr;7(17):24194-207

Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA.

Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60-80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis.
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http://dx.doi.org/10.18632/oncotarget.8254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029694PMC
April 2016

Unresectable cutaneous squamous cell carcinoma of the forehead with mutation showing dramatic response to Programmed Cell Death Protein 1 Inhibitor Therapy.

Clin Skin Cancer 2016 Jan 23;1(1):26-29. Epub 2016 Nov 23.

Department of Surgery, University of South Dakota Sanford School of Medicine 1400 W 22 St., Sioux Falls, SD 57105, United States.

Treatment of refractory, unresectable cutaneous squamous cell carcinoma presents a great challenge in head and neck oncology with poor prognosis. Prior case reports have shown off-label pembrolizumab, a programed cell death receptor antagonist, can be effective in unresectable cutaneous squamous cell carcinoma. Furthermore, prior reports have suggested enhanced efficacy when high mutational burden is present. In this study we present a severe case of unresectable cutaneous squamous cell carcinoma invading the orbit and cavernous sinus with documented tumor mutation. The patient had a complete response to palliative, off-label pembrolizumab therapy.
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http://dx.doi.org/10.1016/j.clsc.2016.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766284PMC
January 2016

Pathology quiz case 2. Folliculitis keloidalis nuchae.

JAMA Otolaryngol Head Neck Surg 2013 Apr;139(4):425-6

Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.

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http://dx.doi.org/10.1001/jamaoto.2013.140aDOI Listing
April 2013

Radiation-induced loss of cell surface CD47 enhances immune-mediated clearance of human papillomavirus-positive cancer.

Int J Cancer 2013 Jul 12;133(1):120-9. Epub 2013 Feb 12.

Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD 57104, USA.

The increasing incidence of human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (OSSC) demands development of novel therapies. Despite presenting at a more advanced stage, HPV(+) oropharyngeal squamous cell carcinoma (OSCC) have a better prognosis than their HPV(-) counterparts. We have previously demonstrated that clearance of HPV(+) OSCC during treatment with radiation and chemotherapy requires an immune response which is likely responsible for the improved clinical outcomes. To further elucidate the mechanism of immune-mediated clearance, we asked whether radiation therapy induces tumor cell changes that allow the body to recognize and aid in tumor clearance. Here, we describe a radiation-induced change in tumor surface protein expression that is critical for immune-mediated clearance. Radiation therapy decreases surface expression of CD47, a self-marker. CD47 is frequently overexpressed in head and neck squamous cell carcinoma and radiation induces a decrease of CD47 in a dose-dependent manner. We show that both in vitro and in vivo tumor cell CD47 protein levels are restored over time after sublethal radiation exposure and that protein levels on adjacent, normal tissues remain unaffected. Furthermore, reduction of tumor cell CD47 increases phagocytosis of these cells by dendritic cells and leads to increased interferon gamma and granzyme production from mixed lymphocytes. Finally, decreasing tumor cell CD47 in combination with standard radiation and chemotherapy results in improved immune-mediated tumor clearance in vivo. These findings help define an important mechanism of radiation-related immune clearance and suggest that decreasing CD47 specifically on tumor cells may be a good therapeutic target for HPV related disease.
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http://dx.doi.org/10.1002/ijc.28015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972896PMC
July 2013

Immune response during therapy with cisplatin or radiation for human papillomavirus-related head and neck cancer.

Arch Otolaryngol Head Neck Surg 2009 Nov;135(11):1137-46

Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, USA.

Background: Human papillomavirus (HPV) is the most identifiable cause of head and neck squamous cell cancer (HNSCC). Compared with HPV-negative HNSCC, HPV-positive HNSCC presents at an advanced stage but with significantly better survival. We created a syngeneic mouse model of HPV-positive and HPV-negative HNSCC by transforming mouse primary tonsil epithelial cells with either HPV oncogenes or a nonantigenic RNA interference strategy that affects similar oncogenic pathways.

Objectives: To examine the effect of radiation therapy on HPV-positive and HPV-negative tumors in immune-competent and immune-incompetent mice and to examine responses in human cancer cell lines.

Design: Prospective in vivo murine model.

Main Outcome Measures: Survival and tumor growth.

Results: For human and murine transformed cell lines, HPV-positive cells were more resistant to radiation and cisplatin therapy compared with HPV-negative cells. In vivo, HPV-positive tumors were more sensitive to radiation, with complete clearance at 20 Gy, compared with their HPV-negative counterparts, which showed persistent growth. Cisplatin in vivo cleared HPV-positive tumors but not HPV-negative tumors. However, neither radiation or cisplatin therapy cured immune-incompetent mice. Adoptive transfer of wild-type immune cells into immune-incompetent mice restored HPV-positive tumor clearance with cisplatin therapy.

Conclusions: The HPV-positive tumors are not more curable based on increased epithelial sensitivity to cisplatin or radiation therapy. Instead, radiation and cisplatin induce an immune response to this antigenic cancer. The implications of these results may lead to novel therapies that enhance tumor eradication for HPV-positive cancers.
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http://dx.doi.org/10.1001/archoto.2009.159DOI Listing
November 2009

Unilateral vocal fold paralysis in premature infants after ligation of patent ductus arteriosus: vascular clip versus suture ligature.

Ann Otol Rhinol Laryngol 2009 Oct;118(10):750-3

Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa, USA.

Objectives: We investigated risk factors associated with unilateral iatrogenic vocal fold paralysis (IVFP) in the context of ligation of patent ductus arteriosus (PDA) and compared the rates of paralysis between vascular clip and suture ligation procedures.

Methods: We performed a prospective examination of infants with isolated PDA treated surgically during 1995 to 2005. Statistical significance was determined with a 2-tailed t-test.

Results: Of 68 PDA ligations, 13 cases of left-sided IVFP were diagnosed, for an overall incidence of 19%. All cases of IVFP occurred in 55 infants who weighed less than 1 kg at birth. Suture ligature was used in 60% of all PDA ligation patients, and vascular clips in 40%. The incidence of IVFP in patients with vascular clips (19%) was similar to the incidence in those with suture ligature (20%). Hoarseness or stridor was present in 69% of patients with IVFP, compared to 17% of normal controls (p <0.001). The rate of aspiration was not increased in the IVFP group; however, 15% of the patients with IVFP had episodes of decreased oxygen saturation, versus 7% of infants with normal vocal fold mobility.

Conclusions: A hoarse infant with a birth weight of less than 1 kg who has undergone PDA ligation should be examined for unilateral IVFP. Vascular clips and suture ligature are associated with similar rates of IVFP.
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http://dx.doi.org/10.1177/000348940911801011DOI Listing
October 2009

The PDZ binding motif of human papillomavirus type 16 E6 induces PTPN13 loss, which allows anchorage-independent growth and synergizes with ras for invasive growth.

J Virol 2008 Mar 26;82(5):2493-500. Epub 2007 Dec 26.

University of Iowa Department of Otolaryngology-Head and Neck Surgery, Iowa City, IA 52242, USA.

The human papillomavirus (HPV) oncogene E6 has been shown to perform multiple functions (p53 degradation, telomerase activation, etc.) that play a role in oncogenic transformation. Beyond known E6 functions, an undefined mechanism that allows cellular invasion requires the E6 PDZ binding motif (PDZBM). Here, we show that HPV type 16 (HPV16) E6 interacts with and induces loss of a protein tyrosine phosphatase (PTPN13) in a PDZBM-dependent manner. PTPN13 loss induced either by the presence of E6 or by a short hairpin RNA strategy allows for anchorage-independent growth (AIG) and synergy with a known oncogene, Ras(v12), resulting in invasive growth in vivo. Restoring PTPN13 expression reverses AIG in cells lacking PTPN13. A genomic analysis of colorectal carcinoma has identified an association between PTPN13 loss-of-function mutations and aberrant Ras signaling. Our findings support this correlation and provide methods for further evaluation of the mechanisms by which PTPN13 loss/Ras expression leads to invasive growth, the results of which will be important for treatment of HPV-related and non-HPV cancer.
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http://dx.doi.org/10.1128/JVI.02188-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258903PMC
March 2008

Deletion of the PDZ motif of HPV16 E6 preventing immortalization and anchorage-independent growth in human tonsil epithelial cells.

Head Neck 2008 Feb;30(2):139-47

Department of Otolaryngology - Head and Neck Surgery, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.

Background: Human papillomavirus 16 (HPV16) has been associated with head and neck squamous cell carcinoma (HNSCC) in up to 60% of sampled specimens.

Methods: To understand better the viral genes required to transform human tonsil epithelial cells (HTEC), we isolated HTEC's and transduced them with retroviral vectors containing HPV16 E6 and E7.

Results: Immortalization and anchorage-independent growth of HTEC's only occurred with expression of E6 and E7 with resultant degradation of p53. However, cells expressing E6 lacking the PSD-95/disc-large/Zo-1 (PDZ) motif did not immortalize or grow anchorage independent. Telomerase activity and degradation of p53 were similar for wild-type and mutant E6.

Conclusion: The mechanism of oncogenic transformation by E6 in HTEC's is dependent on the PDZ binding motif. Identification of pathways affected by the interaction of E6 and PDZ domain containing proteins will further our understanding of how HPV causes HNSCC and will provide potential therapeutic targets.
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http://dx.doi.org/10.1002/hed.20673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600880PMC
February 2008

The role of human papillomavirus 16 E6 in anchorage-independent and invasive growth of mouse tonsil epithelium.

Arch Otolaryngol Head Neck Surg 2007 May;133(5):495-502

Department of Otolaryngology-Head and Neck Surgery, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.

Objective: To provide a manipulatable system to study the mechanism of human papillomavirus 16 (HPV16) E6-related transformation of an epithelial cell type affected by HPV16 in humans.

Design: Biochemical and physiological studies of mouse tonsil epithelial cells (MTECs) transformed with HPV16 oncogenes plus H-ras in vitro and in vivo.

Setting: Basic research laboratory.

Participants: C57BL/6 mice.

Interventions: Transduction of the HPV16 oncogenes E6 and E7 in retroviral vectors into MTECs with isolation of multiple individual clones that expressed E6, E7, or both alone or in conjunction with H-ras.

Main Outcome Measures: Growth in culture, anchorage-independent growth, and growth in immune competent, syngeneic mice.

Results: The MTECs that expressed E6 degraded p53 by a mechanism that is inhibited by proteasomal blockade. Although normal MTECs senesced after 20 population doublings, E6 alone or in combination with E7 was sufficient to immortalize MTECs beyond 25 population doublings, lower their population-doubling time, and permit anchorage-independent growth. However, only MTECs that express E6 plus H-ras or E6/E7 plus H-ras formed invasive tumors in immune competent, syngeneic mice at orthotopic intraoral and subdermal sites.

Conclusions: We found that HPV16 E6 and E7 alone are not sufficient for invasive growth. However, the synergistic activity of H-ras and E6 was sufficient to result in invasive growth.
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http://dx.doi.org/10.1001/archotol.133.5.495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917346PMC
May 2007

Cidofovir incorporation into human keratinocytes with episomal HPV 16 results in nonselective cytotoxicity.

Ann Otol Rhinol Laryngol 2005 Nov;114(11):840-6

Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.

Objectives: Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV). Surgical excision is the mainstay of treatment; however, medical therapy including cidofovir, a cytosine analog, has been investigated. Human papillomavirus does not encode a viral DNA polymerase, which is the known target of cidofovir in cytomegalovirus infections.

Methods: In an effort to better understand the usefulness of cidofovir in the treatment of HPV-related disease, we tested cidofovir's ability to inhibit growth, alter gene expression, and inhibit genome replication.

Results: With the use of carbon 14-labeled cidofovir in episomal HPV 16-containing keratinocytes, there was a minimal increase in cidofovir incorporation into episomal DNA versus genomic DNA. Cidofovir decreased the copies of episomal HPV 16 in keratinocytes; however, the copies per cell returned to baseline levels once cidofovir was removed. Expression of a viral oncogene (HPV 16 E6) in transformed keratinocytes with episomal HPV 16 was not decreased by cidofovir. Cytotoxicity in head and neck squamous cell carcinoma lines exposed to cidofovir correlated with cell doubling time, and not with HPV status. Also, tonsil keratinocytes transformed with episomal HPV 16 did not exhibit greater cidofovir-mediated toxicity than did telomerase-transformed keratinocytes.

Conclusions: These findings suggest that any potential in vivo benefit of cidofovir therapy results from non-viral-specific cell toxicity at the site of application.
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http://dx.doi.org/10.1177/000348940511401106DOI Listing
November 2005
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