Disease and toxicity outcomes for a modern cohort of patients with squamous cell carcinoma of cutaneous origin involving the parotid gland: Comparison of volumetric modulated arc therapy and pencil beam scanning proton therapy.

OBJECTIVES: We sought to describe outcomes for locally advanced cutaneous squamous cell carcinoma (SCC) involving the parotid treated with volumetric modulated arc therapy (VMAT) versus pencil beam scanning proton beam therapy (PBT). MATERIALS AND METHODS: Patients were gathered from 2016 to 2022 from 5 sites of a large academic RT department; included patients were treated with RT and had parotid involvement by: direct extension of a cutaneous primary, parotid regional spread from a previously or contemporaneously resected but geographically separate cutaneous primary, or else primary parotid SCC (with a cutaneous primary ostensibly occult). Acute toxicities were provider-reported (CTCAE v5.0) and graded at each on treatment visit. Statistical analyses were conducted. RESULTS: Median follow-up was 12.9 months (1.3 - 72.8); 67 patients were included. Positive margins/extranodal extension were present in 34 cases; gross disease in 17. RT types: 39 (58.2 %) VMAT and 28 (41.8 %) PBT. Concurrent systemic therapy was delivered in 10 (14.9 %) patients. There were 17 treatment failures (25.4 %), median time of 168 days. Pathologically positive neck nodes were associated with locoregional recurrence (p = 0.015). Oral cavity, pharyngeal constrictor, and contralateral parotid doses were all significantly lower for PBT. Median weight change was -3.8 kg (-14.1 - 5.1) for VMAT and -3 kg (-16.8 - 3) for PBT (p = 0.013). Lower rates of ≥ grade 1 xerostomia (p = 0.002) and ≥ grade 1 dysguesia (p < 0.001) were demonstrated with PBT. CONCLUSIONS: Cutaneous SCC involving the parotid can be an aggressive clinical entity despite modern multimodal therapy. PBT offers significantly lower dose to organs at risk compared to VMAT, which seemingly yields diminished acute toxicities.

Regionalization of Head and Neck Oncology Tumor Boards: Perspectives of Collaborating Physicians.

Objectives: To survey academic and community physician preferences regarding the virtual multidisciplinary tumor board (MTB) for further improvement and expansion. Study Design: This anonymous 14-question survey was sent to individuals that participated in the head and neck virtual MTBs. The survey was sent via email beginning August 3, 2021, through October 5, 2021. Setting: The University of Maryland Medical Center and regional practices in the state of Maryland. Methods: Survey responses were recorded and presented as percentages. Subset analysis was performed to obtain frequency distributions by facility and provider type. Results: There were 50 survey responses obtained with a response rate of 56%. Survey participants included 11 surgeons (22%), 19 radiation oncologists (38%), and 8 medical oncologists (16%), amongst others. More than 96% of participants found the virtual MTB to be useful when discussing complex cases and impactful to future patient care. A majority of respondents perceived a reduction in time to adjuvant care (64%). Community and academic physician responses strongly agreed that the virtual MTB improved communication (82% vs 73%), provided patient-specific information for cancer care (82% vs 73%), and improved access to other specialties (66% vs 64%). Academic physicians, more so than community physicians, strongly agreed that the virtual MTB improves access to clinical trial enrollment (64% vs 29%) and can be useful in obtaining CME (64% vs 55%). Conclusion: Academic and community physicians view the virtual MTB favorably. This platform can be adapted regionally and further expanded to improve communication between physicians and improve multidisciplinary care for patients.

Gross tumor volume margin and local control in p16-positive oropharynx cancer patients treated with intensity modulated proton therapy.

BACKGROUND: To determine if the extent of high-dose gross tumor volume (GTV) to clinical target volume (CTV) expansion is associated with local control in patients with p16-positive oropharynx cancer (p16+ OPC) treated with definitive intensity modulated proton therapy (IMPT). METHODS: We performed a retrospective analysis of patients with p16+ OPC treated with IMPT at a single institution between 2016 and 2021. Patients with a pre-treatment PET-CT and restaging PET-CT within 4 months following completion of IMPT were analyzed. RESULTS: Sixty patients were included for analysis with a median follow-up of 17 months. The median GTV to CTV expansion was 5 mm (IQR: 2 mm). Thirty-three percent of patients (20 of 60) did not have a GTV to CTV expansion. There was one local failure within the expansion group (3%). CONCLUSION: Excellent local control was achieved using IMPT for p16+ OPC independent of GTV expansion. IMPT with minimal target expansions represent a potential harm-minimization technique for p16-positive oropharynx cancer.

Human Papillomavirus Impact on Temporal Treatment Trends in Oropharyngeal Carcinoma: 2010-2016.

INTRODUCTION: The study objective was to identify practice patterns in oropharyngeal cancer management from 2010 to 2016 among human papillomavirus (HPV)-associated and non-HPV-associated oropharyngeal squamous-cell carcinoma (OPSCC) patients. METHODS: The National Cancer Database was utilized to identify OPSCC patients from 2010 to 2016. Frequency distributions and multivariable analyses were generated to identify practice patterns and predictors of treatment modality. RESULTS: A total of 35,956 patients with nonmetastatic OPSCC were included. HPV status was not associated with a treatment modality preference. At academic centers, the proportion of HPV-associated OPSCC patients versus non-HPV-associated OPSCC patients undergoing surgical management was similar (35.7%; 35.9%). Community cancer programs treated patients less often surgically but with no significant treatment preference based on HPV status. Within each facility type, HPV status was not a predictor of surgical or nonsurgical management. CONCLUSION: HPV association does not appear to significantly influence treatment modality preference among OPSCC patients. The proportion of OPSCC patients undergoing surgical treatment declined from 2010 to 2016.

Impact of the Novel Coronavirus 2019 (COVID-19) Pandemic on Head and Neck Cancer Care.

OBJECTIVE: The study aimed to assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on head and neck oncologic care at a tertiary care facility. STUDY DESIGN: This was a cross-sectional study conducted between March 18, 2020, and May 20, 2020. The primary planned outcome was the rate of treatment modifications during the study period. Secondary outcome measures were tumor conference volume, operative volume, and outpatient patient procedure and clinic volumes. SETTING: This single-center study was conducted at a tertiary care academic hospital in a large metropolitan area. METHODS: The study included a consecutive sample of adult subjects who were presented at a head and neck interdepartmental tumor conference during the study period. Patients were compared to historical controls based on review of operative data, outpatient procedures, and clinic volumes. RESULTS: In total, 117 patients were presented during the review period in 2020, compared to 69 in 2019. There was an 8.4% treatment modification rate among cases presented at the tumor conference. There was a 61.3% (347 from 898) reduction in outpatient clinic visits and a 63.4% (84 from 230) reduction in procedural volume compared to the prior year. Similarly, the operative volume decreased by 27.0% (224 from 307) compared to the previous year. CONCLUSION: Restrictions related to the COVID-19 pandemic resulted in limited treatment modifications. Transition to virtual tumor board format observed an increase in case presentations. While there were reductions in operative volume, there was a larger proportion of surgical cases for malignancy, reflecting the prioritization of oncologic care during the pandemic.

The association of active and passive tobacco smoke exposure with chronic rhinosinusitis symptom severity: A cross-sectional study.

BACKGROUND: Chronic rhinosinusitis (CRS) causes a great deal of morbidity. There are a multitude of causal factors, though their precise contribution to symptom severity has yet to be defined.  We hypothesized that exposure to both primary and secondhand tobacco smoke would correlate with more severe symptoms of CRS. METHODS: This is a prospective cross-sectional study performed at an academic tertiary care medical center from 2010 to 2013. A total of 85 consecutive patients with chronic sinusitis were screened; 70 with medically refractory CRS requiring functional Endoscopic sinus surgery (FESS) were enrolled. Recent tobacco exposure was assessed using serum cotinine levels. Sinonasal mucosa was biopsied to assess ciliary architecture. Demographics, medical history, tobacco and environmental exposures, and computed tomography (CT) imaging were also collected. Two quality of life (QOL) surveys were administered: one disease specific, Sinonasal Outcomes Test-20 (SNOT-20), and one general, Short Form-12 (SF-12). Results were correlated with the aforementioned exposures. RESULTS: The 70 patients had an average age of 46 years, and 42% were male.  Variables that correlated with worse SNOT-20 scores included serum cotinine (r = 0.43, p = 0.002), number of cigarettes smoked daily (r = 0.27, p = 0.03), and number of secondhand cigarettes exposed to per day (r = 0.29, p = 0.04). There were no significant correlations between SNOT-20 scores and Lund-MacKay or axonemal ultrastructural abnormalities (AUA)-ciliary scores. The two five-variable models best predicted disease-specific QOL. CONCLUSIONS: Increased amounts of serum cotinine and primary and secondhand smoke exposure were associated with worse sinonasal QOL. This study establishes an objective relationship between smoke exposure and patient-perceived severity of CRS, emphasizing the importance of tobacco cessation counseling as part of management.

New Medical Device and Therapeutic Approvals in Otolaryngology: State of the Art Review 2020.

OBJECTIVES: To evaluate new drugs and devices relevant to otolaryngology-head and neck surgery that were approved by the US Food and Drug Administration (FDA) in 2020. DATA SOURCES: Publicly available device and therapeutic approvals from ENT (ear, nose, and throat), anesthesia, neurology (neurosurgery), and plastic and general surgery FDA committees. REVIEW METHODS: Members of the American Academy of Otolaryngology-Head and Neck Surgery's Medical Devices and Drugs Committee reviewed new therapeutics and medical devices from a query of the FDA's device and therapeutic approvals. Two independent reviewers assessed the drug's or device's relevance to otolaryngology, classified to subspecialty field, with a critical review of available scientific literature. CONCLUSIONS: The Medical Devices and Drugs Committee reviewed 53 new therapeutics and 1094 devices (89 ENT, 140 anesthesia, 511 plastic and general surgery, and 354 neurology) approved in 2020. Ten drugs and 17 devices were considered relevant to the otolaryngology community. Rhinology saw significant improvements around image guidance systems; indications for cochlear implantation expanded; several new monoclonal therapeutics were added to head and neck oncology's armamentarium; and several new approvals appeared for facial plastics surgery, pediatric otolaryngology, and comprehensive otolaryngology. IMPLICATIONS FOR PRACTICE: New technologies and pharmaceuticals offer the promise of improving how we care for otolaryngology patients. However, judicious introduction of innovations into practice requires a nuanced understanding of safety, advantages, and limitations. Working knowledge of new drugs and medical devices approved for the market helps clinicians tailor patient care accordingly.

A Novel Device for Placement of a Secondary Tracheoesophageal Voice Prosthesis: A Preliminary Feasibility Study.

BACKGROUND: Tracheoesophageal puncture (TEP) for post-laryngectomy speech rehabilitation can be performed at the time of laryngectomy (primary) or at a subsequent time (secondary). Traditionally, the secondary procedure is performed using a rigid esophagoscope. Diseases like esophageal stricture, limited neck extension, and soft-tissue fibrosis can make this procedure technically challenging or impossible. We developed a novel device to perform a secondary tracheoesophageal puncture using a flexible esophagoscope. OBJECTIVE: To test the feasibility of a novel device used to create a secondary TEP in post-laryngectomy cadavers. METHODS: In this study, we performed a total laryngectomy on 3 fresh cadavers to establish the feasibility of our prototype. In each cadaver, a flexible esophagoscope was passed into the pharynx with the prototype. The prototype was passed through a working port and deployed to distend the esophagus. The puncture was visualized and a wire was passed via the newly established fistula. The device was activated, securing the wire, and then the esophagoscope and device were removed. RESULTS: There was 100% successful deployment of the prototype device, allowing rapid creation of the puncture and security of the guide wire in each cadaver. There was no evidence of collateral mucosal injury or esophageal perforation. CONCLUSIONS: The prototype device offers an alternative method to safely and efficiently perform a secondary TEP without the requirement of rigid esophagoscopy which can sometimes be technically impossible in this patient population.

Intrabronchial Catheter Resuscitation for Respiratory and Cardiorespiratory Arrest.

INTRODUCTION: We sought to determine whether intrabronchial oxygenation would provide adequate gas exchange during both anesthesia induced apneic and cardiopulmonary arrest and cardiac massage (CPR). METHODS: Ten pigs underwent general anesthesia with mechanical ventilation. Blood gases were measured in each animal at 4 min intervals for up to 28 min. An intrabronchial catheter (4 L/min O2) was inserted through an endotracheal tube after respirator cessation. Group A animals (6) were resuscitated with the catheter but without CPR. Group B animals (4) were rendered apneic and cardioplegic and resuscitated by CPR for 28 min using the intrabronchial device. RESULTS: All group A animals were resuscitated and survived after 24 min of apnea. Mean pO2 decreased from 378 mmHg (95% confidence interval [CI], 288-468) to 292 mmHg (95% CI, 246-339), P = 0.009; pCO2 increased from 52 mmHg (95% CI, 43-61) to 137 mmHg (95% CI, 116-158), P < 0.0001; and pH decreased from 7.32 (7.29-7.36) to 6.98 (6.92-7.03), P < 0.0001. In a control animal bronchial catheter oxygen flow ceased at baseline and pO2 decreased from 268 to 30 mmHg by 20 min. In group B animals mean pO2 decreased from 426 mmHg (95% CI, 273-579) to 130 mmHg (95% CI, 92-168) after 28 min, P < 0.0001; pCO2 increased from 49 mmHg (95% CI, 41-58) to 73 mmHg (95% CI, 61-86), P = 0.03; and pH decreased from 7.34 (7.33-7.35) to 7.07 (6.98-7.16), P < 0.0001. In the control receiving intratracheal oxygen pO2 decreased from 324 to 88 mmHg after 16 minu of CPR. CONCLUSIONS: Intrabronchial oxygenation provides sustained hyperoxemia during complete apnea and cardiac arrest with CPR.

Retained crossbow bolt after penetrating facial trauma.

We present an unusual case of a retained crossbow bolt in the maxillofacial area of a 31-year-old man. While crossbow injuries are rare, this case is of interest because otolaryngologists are often faced with treating retained foreign objects after penetrating facial trauma. These cases are difficult to manage because of the complexity and variety of injuries that can occur during both the initial trauma and the removal. We focus on the management of the bolt's removal and provide a brief discussion of the relevant literature on crossbow injuries to the head and neck.

The influence of intraoperative frozen section analysis in patients with total or extended maxillectomy.

BACKGROUND: Intraoperative frozen sections and final pathology may influence treatment with regards to intraoperative and postoperative treatments, respectively. STUDY DESIGN: A retrospective study comparing intraoperative frozen section analysis with final pathologic analysis in patients who had total or extended maxillectomies for malignant disease between 2008 and 2013. RESULTS: Twenty-five patients met the inclusion criteria. The mean age was 67.8 years. The majority of patients (76%) had stage IV disease (American Joint Committee on Cancer [AJCC] staging). Intraoperative frozen sections were positive in 24% (n = 6) compared with 60% (n = 15) on final pathologic analysis. Frozen section analysis had a sensitivity of 40%. Positive margins were resected where possible, unless limited by proximity to vital structures. Patients were statistically more likely to follow a recommendation for adjuvant therapy (P < .05) compared with adjuvant chemotherapy (P > .05). CONCLUSIONS: Intraoperative frozen section analyses are unreliable in predicting positive margins in patients with late-stage maxillary malignancies. Patients were more likely to accept adjuvant radiation than adjuvant chemotherapy.

Oropharyngeal cancer as a driver of racial outcome disparities in squamous cell carcinoma of the head and neck: 10-year experience at the University of Maryland Greenebaum Cancer Center.

BACKGROUND: Racial outcome disparities have been observed in head and neck squamous cell carcinoma (HNSCC) with diminished survival for black patients compared with white patients. METHODS: We retrospectively analyzed 1318 patients with primary HNSCC treated at the University of Maryland Greenebaum Cancer Center (UMGCC) from 2000 to 2010. RESULTS: Of all the patients, 65.9% were white, 30.7% were black, and 3.3% were of other races. Black patients were less likely to present with oral cavity cancer, and more likely to present with laryngeal or hypopharyngeal cancers. White patients were more likely to have early stage disease, especially in the oral cavity. Black race was independently associated with worse overall survival (OS) in the entire cohort. Black patients had a significantly worse OS among oral cavity and oropharyngeal cancers, with the largest disparity in oropharyngeal cancer. However, in multivariate analysis, race was only still significant in oropharyngeal cancer. CONCLUSION: We observed differences by race in distribution of disease site, stage, and OS. Survival disparity in the entire cohort was driven mostly by differences among oropharyngeal cancer.

Quality of life factors and survival after total or extended maxillectomy for sinonasal malignancies.

PURPOSE: Total and extended maxillectomy results in significant morbidity that can have an effect on quality of life factors. Modern reconstructive techniques have ameliorated this effect, but they have not been quantified. The purpose of the present study was to evaluate the quality of life factors and survival of patients undergoing total or extended maxillectomy for malignant disease. MATERIALS AND METHODS: A retrospective study was performed of all patients who had undergone total or extended maxillectomy at a tertiary care cancer center from January 2008 to May 2013. The minimum follow-up period was 6 months. The quality of life factors analyzed included swallowing function and diet consistency, pain control, and postoperative complications. RESULTS: A total of 25 patients (13 women and 12 men) met the inclusion criteria. Using the American Joint Committee on Cancer staging system, 76% of the patients had stage IV disease. Of the 25 patients, 13 received a free tissue transfer, 11 an obturator flap, and 1 a regional flap. None of the patients with a free tissue transfer experienced failure. The tumor size had no systemic influence on the reconstructive method chosen (P = .32 to P = .98). The median follow-up period was 41 weeks (range 24 to 252). One death was recorded, and 10 patients were lost to follow-up. Eleven patients progressed to a regular diet. Fifteen patients required a tracheostomy, and all were decannulated at a mean of 14 days postoperatively. One patient had dental implants placed. The type of reconstruction did not influence swallowing function (P = .49) or long-term pain (P = .38). The mean pain score was 4.9 ± 2.7. Pain management proved difficult in 7 patients. Also, 6 patients developed a surgical site infection, 3 of whom required a return to the operating room. Seven patients were readmitted to the hospital for complications; however, the reconstructive method did not influence the incidence of complications (P = .64). CONCLUSIONS: The inevitable morbidity, with respect to quality of life factors, that result from the disfiguring effects of total or extended maxillectomy can be deemed acceptable by patients. We recommend discussing all reconstructive options regarding the management of late-stage maxillary malignancies and the potential effect they can have on patients' quality of life.

A phase I dose escalation trial of MAGE-A3- and HPV16-specific peptide immunomodulatory vaccines in patients with recurrent/metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN).

BACKGROUND: We conducted a phase I dose escalation study to evaluate the safety and immunologic response to peptide immunomodulatory vaccines GL-0810 (HPV16) and GL-0817 (MAGE-A3) in HPV16 and MAGE-A3-positive RM-SCCHN patients, respectively. METHODS: Three dose levels (500, 1,000, and 1,500 µg) of GL-0810 or GL-0817 with adjuvants Montanide (1.2 ml) and GM-CSF (100 µg/m2) were administered subcutaneously q2 weeks for a total of four vaccinations in HPV16 and MAGE-A3-positive RM-SCCHN patients, respectively. RESULTS: Nine and seven patients were enrolled in the HPV16 and MAGE-A3 cohorts, respectively. No dose-limiting toxicities were observed, and toxicity was predominantly local and grade 1 (erythema, pain, and itching at the injection site). In those patients who received all four vaccinations, 80 % (4/5) of the HPV16 cohort and 67 % (4/6) of the MAGE-A3 cohort developed antigen-specific T cell and antibody responses to the vaccine. Significant concordance between T cell and antibody responses was observed for both groups. No clear dose-response correlation was seen. All patients progressed by RECIST at first repeat imaging, except for one patient in the MAGE-A3 500 µg cohort who had stable disease for 10.5 months. The median PFS and OS for the MAGE-A3 cohorts were 79 and 183 days, respectively, and for the HPV16 cohort 80 and 196 days, respectively. CONCLUSIONS: GL-0810 and GL-0817 were well tolerated in patients with RM-SCCHN with T cell and antibody responses observed in the majority of patients who received all four vaccinations.

Intraorbital erosion of a malar implant resulting in mastication-induced vision changes.

Complications of cosmetic malar augmentation are uncommon. We describe the unusual case of a 60-year-old woman who experienced vision disturbances (flashing lights and diplopia) while masticating. Ten years earlier, she had undergone bilateral malar enhancement with silicone implants. Imaging studies revealed that the implant on the right side had become displaced. The prosthesis had entered the orbit in the retrobulbar area and eroded the lateral zygomaticomaxillary buttress and the orbital floor. Both implants were removed, and the patient's symptoms immediately resolved. To the best of our knowledge, no case of vision changes secondary to erosion of the posterior orbit by a silicone malar implant has been previously described in the literature.

Plasmacytoid dendritic cells accumulate and secrete interferon alpha in lymph nodes of HIV-1 patients.

Circulating plasmacytoid dendritic cells (pDC) decline during HIV-1 infection, but at the same time they express markedly higher levels of interferon alpha (IFNalpha), which is associated with HIV-1 disease progression. Here we show an accumulation of pDC in lymph nodes (LN) of treatment-naïve HIV-1 patients. This phenomenon was associated with elevated expression of the LN homing marker, CCR7, on pDC in peripheral blood of HIV-1 patients, which conferred increased migratory capacity in response to CCR7 ligands in ex vivo functional assays. LN-homed pDC of HIV-1 patients presented higher CD40 and lower BDCA2 levels, but unchanged CD83 and CD86 expression. In addition, these cells expressed markedly higher amounts of IFNalpha compared to uninfected individuals, and were undergoing faster rates of cell death. These results demonstrate for the first time that in asymptomatic, untreated HIV-1 patients circulating pDC up-regulate CCR7 expression, accumulate in lymph nodes, and express high amounts of IFNalpha before undergoing cell death. Since IFNalpha inhibits cell proliferation and modulates immune responses, chronically high levels of this cytokine in LN of HIV-1 patients may impair differentiation and immune function of bystander CD4(+) T cells, thus playing into the mechanisms of AIDS immunopathogenesis.

FcgammaRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck.

PURPOSE: The interaction of Fc fragments of antibodies with the Fcgamma receptors is an essential checkpoint in antibody-dependent cellular cytotoxicity (ADCC). Specific polymorphisms at position 158 enhance FcgammaRIIIa affinity for IgG1 and are associated with improved clinical outcome in lymphoma patients treated with IgG1 anti-CD20 antibody. The role of ADCC in the therapeutic effects of the alpha-epidermal growth factor receptor (EGFR) mAb, cetuximab, in patients with squamous cell carcinoma of the head and neck (SCCHN) is poorly defined. We employed three SCCHN cell lines to test two hypotheses: (1) SCCHN is susceptible to cetuximab-mediated ADCC, (2) efficacy of ADCC is associated with polymorphisms at position 158 of FcgammaRIIIa. EXPERIMENTAL DESIGN: FcgammaRIIIa-158 polymorphisms were determined for healthy donors, and their purified NK cells were used as effector cells against three SCCHN cell lines in ADCC assays. Cytotoxicity levels were compared for each polymorphism class. Proliferation and cell cycle assays were done to examine the direct effects of cetuximab. RESULTS: Our results indicate that SCCHN is susceptible to cetuximab-mediated ADCC in vitro. NK cytotoxic efficiency correlates with donor 158-polymorphisms in FcgammaRIIIa. Overall cytotoxicity was greatest for individuals having a single V allele when compared to homozygous F/F individuals; the cumulative percent cytotoxicity for each polymorphism among the cell lines was 58.2% V/V, 50.6% V/F, and 26.1% F/F (P < 0.001). Additionally, the presence of a V allele correlated with superior natural cytotoxicity against NK sensitive targets. CONCLUSION: These data have both prognostic and therapeutic relevance and support the design of a prospective trial to determine the influence of FcgammaRIIIa polymorphisms on the clinical outcome of patients with SCCHN treated with alpha-EGFR mAbs.

MRSA with progression from otitis media and sphenoid sinusitis to clival osteomyelitis, pachymeningitis and abducens nerve palsy in an immunocompetent 10-year-old patient.

A previously healthy 10-year-old patient with headache, otalgia, and hearing loss was diagnosed with pachymeningitis and methicillin-resistant Staphylococcus aureus otitis media and bacteremia. Despite antimicrobial therapy, intracranial extension progressed, including clival osteomyelitis, sphenoid sinusitis, cavernous sinus inflammation and cranial nerve palsies, until the sphenoid sinus was drained. This case exemplifies an aggressive MRSA intracranial infection that advanced despite antibiotic therapy.

Oral lactoferrin results in T cell-dependent tumor inhibition of head and neck squamous cell carcinoma in vivo.

PURPOSE: Human lactoferrin is a naturally occurring glycoprotein that inhibits cancer growth. Our purpose was to evaluate recombinant human lactoferrin as a chemotherapeutic agent against head and neck squamous cell carcinoma. EXPERIMENTAL DESIGN: Controlled experiments both in vitro and in the murine model evaluating both the effect and mechanism of lactoferrin on cancer growth. RESULTS: In both human and murine cell lines, lactoferrin induced dose-dependent growth inhibition. Using flow cytometric analysis, lactoferrin was shown to induce G(1)-G(0) growth arrest. This arrest seemed to be modulated by down-regulation of cyclin D1. In the in vitro model, luminex data revealed that lactoferrin inhibited cellular release of proinflammatory and prometastatic cytokines, including interleukin-8, interleukin-6, granulocyte macrophage colony-stimulating factor, and tumor necrosis factor-alpha. Lactoferrin up-regulated the cellular activation of nuclear factor-kappaB within 4 h of cellular exposure. In C3h/HeJ mice implanted with SCCVII tumors, orally delivered lactoferrin inhibited tumor growth by 75% compared with control mice. Immunohistochemical analysis of harvested tumors revealed up to 20-fold increases of lymphocytes within treated animals. When mice were depleted of CD3(+) cells, all lactoferrin-induced tumor inhibition was abrogated. CONCLUSION: We conclude that human recombinant lactoferrin can inhibit the growth of head and neck squamous cell carcinoma via direct cellular inhibition as well as systemically via immunomodulation. Our data support the study of human lactoferrin as an immunomodulatory compound with therapeutic potential.