4PD Functionalized Dendrimers: A Flexible Tool for In Vivo Gene Silencing of Tumor-Educated Myeloid Cells.

Myeloid cells play a key role in tumor progression and metastasis by providing nourishment and immune protection, as well as facilitating cancer invasion and seeding to distal sites. Although advances have been made in understanding the biology of these tumor-educated myeloid cells (TEMCs), their intrinsic plasticity challenges our further understanding of their biology. Indeed, in vitro experiments only mimic the in vivo setting, and current gene-knockout technologies do not allow the simultaneous, temporally controlled, and cell-specific silencing of multiple genes or pathways. In this article, we describe the 4PD nanoplatform, which allows the in vivo preferential transfection and in vivo tracking of TEMCs with the desired RNAs. This platform is based on the conjugation of CD124/IL-4Rα-targeting peptide with G5 PAMAM dendrimers as the loading surface and can convey therapeutic or experimental RNAs of interest. When injected i.v. in mice bearing CT26 colon carcinoma or B16 melanoma, the 4PD nanoparticles predominantly accumulate at the tumor site, transfecting intratumoral myeloid cells. The use of 4PD to deliver a combination of STAT3- and C/EBPß-specific short hairpin RNA or miR-142-3p confirmed the importance of these genes and microRNAs in TEMC biology and indicates that silencing of both genes is necessary to increase the efficacy of immune interventions. Thus, the 4PD nanoparticle can rapidly and cost effectively modulate and assess the in vivo function of microRNAs and mRNAs in TEMCs.

En bloc resection of lacrimal sac tumors and simultaneous orbital reconstruction: surgical and functional outcomes.

PURPOSE: To describe a surgical technique of en bloc resection of lacrimal sac tumors by the shared expertise of 2 specialists to achieve optimal tumor margin clearance and the simultaneous reconstruction of the bony defect to preserve ocular functions and cosmesis. METHODS: All patients who had resection of malignant nasolacrimal drainage system tumors using the combined technique and posttreatment protocol between 1997 and 2011 were studied in this retrospective, noncomparative, interventional case series. A combined medial maxillectomy and medial orbitotomy for en bloc resection of the lacrimal sac tumor was followed by reconstruction with a tailored contoured titanium mesh to support the globe and eyelid. Disease relapse, disease survival, ocular functions (vision loss, motility, globe dystopia, and diplopia), and cosmesis (medial canthal tendon dystopia and eyelid retraction) were documented. RESULTS: Fourteen patients with malignant lacrimal sac tumors underwent en bloc resection. Postoperative radiation was ultimately administered to 9 patients. All patients but one were alive at last follow up. Tumor recurred locally in 2 patients with a regional recurrence in a third patient. Complications from radiation therapy included skin breakdown over the mesh (9/14 patients) with nasocutaneous fistula, medial canthal tendon dystopia (2/14 patients), and corneal perforation in a patient with recurrent disease. Despite removal of the tear drainage system, only 7 of 14 patients reported epiphora. None of the patients developed diplopia after resection and radiation therapy. CONCLUSIONS: The combined sinus-orbit approach is an effective method of managing lacrimal sac tumors to achieve optimal tumor clearance from the orbit and nasal cavity. Simultaneous reconstruction of the bony defect with a contoured titanium mesh provides a fixation anchor for the medial canthal tendon and globe support and serves as a supporting platform for the lower eyelid and cheek to minimize midface collapse. Postoperative radiation is associated with skin flap breakdown and nasocutaneous fistula formation.

The Tumor Immune Microenvironment Architecture Correlates with Risk of Recurrence in Head and Neck Squamous Cell Carcinoma.

Emerging evidence suggests that not only the frequency and composition of tumor-infiltrating leukocytes but also their spatial organization might be a major determinant of tumor progression and response to therapy. Therefore, mapping and analyzing the fine tumor immune architecture could potentially provide insights for predicting cancer prognosis. Here, we performed an explorative, prospective clinical study to assess whether structures within the tumor microenvironment can predict recurrence after salvage surgery in head and neck squamous cell carcinoma (HNSCC). The major immune subsets were measured using flow cytometry and co-detection by indexing (CODEX) multiparametric imaging. Flow cytometry underestimated the number of PMN-MDSCs and neutrophils in the tumor and overestimated the tumor-infiltrating lymphocyte frequency. An ad hoc computational framework was used to identify and analyze discrete cellular neighborhoods. A high frequency of tertiary lymphoid structures composed of CD31highCD38high plasma cells was associated with reduced recurrence after surgery in HNSCC. These data support the notion that the structural architecture of the tumor immune microenvironment plays an essential role in tumor progression and indicates that type 1 tertiary lymphoid structures and long-lived CD31highCD38high plasma cells are associated with good prognosis in HNSCC. SIGNIFICANCE: Imaging the spatial tumor immune microenvironment and evaluating the presence of type 1 tertiary lymphoid structures enables prediction of recurrence after surgery in patients with head and neck squamous cell carcinoma.

Mesenchymal Neoplasms of Salivary Glands: A Clinicopathologic Study of 68 Cases.

Salivary gland neoplasms are uncommon, and most exhibit epithelial differentiation. Mesenchymal neoplasms of the salivary gland are rare, and the incidence ranges from 1.9% to 5%. The aim of this study is to identify the types and clinical-pathological features of mesenchymal salivary neoplasm and review their differential diagnosis. A retrospective search for mesenchymal neoplasms of salivary glands from our institution's pathology archives from the 2004-2021 period and consultation files of one of the authors (AER) was performed. The clinical data were obtained from available medical records, and the histological slides and ancillary studies were retrieved and reviewed. We identified a total of 68 cases that form the study cohort. Thirty-five patients were male, and thirty-three patients were female, with a mean age of 48 years (range, 7 months-79 years), and the male to female ratio was 1:.94. Sixty-three (92.6%) of sixty-eight tumors were benign and included: 38 (56%) lipomas, 9 (13%) hemangiomas, 7 (10.3%) schwannomas, 3 (4.4%) neurofibromas, 3 (4.4%) lymphangioma, 2 (3%) solitary fibrous tumors, 1 (1.5%) myofibroma. Five of sixty-eight (7.4%) were malignant and included: 3 (4.4%) Adamantinoma-like Ewing sarcomas, 1 (1.5%) malignant peripheral nerve sheath tumor (MPNST), and 1 (1.5%) malignant solitary fibrous tumor. The involved sites included: parotid (55), submandibular gland (5), parapharyngeal space (5), buccal mucosa minor salivary gland (2), and sublingual gland (1). Sixty-seven patients underwent surgical resection. One patient with lymphangioma manifested a recurrence/persistence a week post-surgery. One patient with a parotid hemangioma developed post-operative numbness, and another patient developed chronic postauricular pain after surgery. Two patients with MPNST and one patient with adamantinoma-like Ewing sarcoma underwent neoadjuvant chemoradiation and were disease-free after treatment. The remaining 37 patients with available follow-up ranging from 7 days to 96 months (mean, 18 months) had a favorable outcome and were disease-free after treatment. Mesenchymal neoplasms of salivary gland are rare; most are benign and demonstrate adipocytic, endothelial, and schwannian differentiation; awareness of their development is important for adequate diagnosis. The mainstay of treatment is surgical excision, with the extent determined by tumor type. Adjuvant therapy is reserved for high-grade sarcomas and may be given in a neoadjuvant or adjuvant setting.

Primary Sarcomas of the Larynx: A Clinicopathologic Study of 27 Cases.

Primary sarcomas of the larynx are rare and are associated with diagnostic and treatment challenges. Studies of these tumors are limited, and most examples have been reported as small series. To further increase our understanding of laryngeal sarcomas, we reviewed our experience of an adult cohort. A retrospective search for laryngeal sarcomas from our pathology archives and consultation files of one of the authors was performed. We studied 27 primary laryngeal sarcomas that included 25 males, and 2 females, with a mean age of 60 years (range 33-85). The cases included conventional chondrosarcoma (16), well-differentiated liposarcoma (2), clear cell chondrosarcoma (1), leiomyosarcoma (2), high grade myxofibrosarcoma (2), high grade myofibroblastic sarcoma (1), low-grade myofibroblastic sarcoma (1), malignant granular cell tumor (1), and Kaposi sarcoma (1). Data on treatment and follow-up was available in 17 and 16 cases, respectively. 12 patients underwent partial laryngeal resection; five had total laryngectomy, and the patient with Kaposi sarcoma received combined highly active antiretroviral therapy and chemotherapy. Three patients developed local recurrence, and two patients developed metastases. The remaining patients with follow up had a favorable outcome and were disease-free after treatment. The important differential diagnosis of spindle cell sarcoma is sarcomatoid squamous cell carcinoma, and their distinction often requires extensive sampling of the mucosal surface and immunohistochemical analysis. The mainstay of treatment for laryngeal sarcomas is surgical removal, with the extent dictated by tumor type and grade. Adjuvant therapy is reserved for high-grade sarcomas and may be given in a neoadjuvant or adjuvant setting.

Aptamers against mouse and human tumor-infiltrating myeloid cells as reagents for targeted chemotherapy.

Local delivery of anticancer agents has the potential to maximize treatment efficacy and minimize the acute and long-term systemic toxicities. Here, we used unsupervised systematic evolution of ligands by exponential enrichment to identify four RNA aptamers that specifically recognized mouse and human myeloid cells infiltrating tumors but not their peripheral or circulating counterparts in multiple mouse models and from patients with head and neck squamous cell carcinoma (HNSCC). The use of these aptamers conjugated to doxorubicin enhanced the accumulation and bystander release of the chemotherapeutic drug in both primary and metastatic tumor sites in breast and fibrosarcoma mouse models. In the 4T1 mammary carcinoma model, these doxorubicin-conjugated aptamers outperformed Doxil, the first clinically approved highly optimized nanoparticle for targeted chemotherapy, promoting tumor regression after just three administrations with no detected changes in weight loss or blood chemistry. These RNA aptamers recognized tumor infiltrating myeloid cells in a variety of mouse tumors in vivo and from human HNSCC ex vivo. This work suggests the use of RNA aptamers for the detection of myeloid-derived suppressor cells in humans and for a targeted delivery of chemotherapy to the tumor microenvironment in multiple malignancies.

Advanced head and neck surgery training during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has significantly impacted medical training. Here we assess its effect on head and neck surgical education. METHODS: Surveys were sent to current accredited program directors and trainees to assess the impact of COVID-19 on the fellow's experience and employment search. Current fellows' operative logs were compared with those of the 2018 to 2019 graduates. RESULTS: Despite reduction in operative volume, 82% of current American Head and Neck Society fellows have reached the number of major surgical operations to support certification. When surveyed, 86% of program directors deemed their fellow ready to enter practice. The majority of fellows felt prepared to practice ablative (96%), and microvascular surgery (73%), and 57% have secured employment to follow graduation. Five (10%) had a pending job position put on hold due to the pandemic. CONCLUSIONS: Despite the impact of the COVID-19 pandemic, current accredited trainees remain well-positioned to obtain proficiency and enter the work-force.

Meta-analysis comparing outcomes of different transoral surgical modalities in management of oropharyngeal carcinoma.

BACKGROUND: Optimal transoral surgical modality for oropharyneal carcinoma is currently unclear. Transoral laser surgery (TLS), transoral robotic surgery (TORS), and conventional direct transoral (DT) oropharyngectomy are the main current transoral surgical modalities for oropharyngeal carcinoma. METHODS: MEDLINE was systematically searched through PubMed. Reference lists were reviewed. Random-effects models were used to combine studies within each group. Tests for heterogeneity were used to explore difference in effect size between groups in subgroup analysis. RESULTS: Nine studies (404 patients) in TORS arm, five studies (498 patients) in TLS arm, and three studies (335 patients) in DT arm were included. Early T classification (T1-T2) for TORS and DT were higher compared to TLS group (P < .001). There was no significant difference between groups in the rate of invaded margin, post-operative oropharyngeal bleeding, temporary tracheotomy, and gastrostomy dependence. CONCLUSION: The available data do not yet provide clear evidence of superiority of any one modality.

The Reversal of Immune Exclusion Mediated by Tadalafil and an Anti-tumor Vaccine Also Induces PDL1 Upregulation in Recurrent Head and Neck Squamous Cell Carcinoma: Interim Analysis of a Phase I Clinical Trial.

Myeloid Derived suppressor cells (MDSCs) play a key role in the progression and recurrence of human malignancies and in restraining the efficacy of adjuvant therapies. We have previously shown that Tadalafil lowers MDSCs and regulatory T cells (Treg) in the blood and in the tumor, primes a tumor specific immune response, and increases the number of activated intratumoral CD8+T cells in patients with primary Head and Neck Squamous Cell Carcinoma (HNSCC). However, despite these important immune modulatory actions, to date no clinically significant effects have been reported following PDE5 inhibition. Here we report for the first time interim results of our ongoing phase I clinical trial (NCT02544880) in patients with recurrent HNSCC to evaluate the safety of and immunological effects of combining Tadalafil with the antitumor vaccine composed of Mucin1 (MUC1) and polyICLC. The combined treatment of Tadalafil and MUC1/polyICLC vaccine was well-tolerated with no serious adverse events or treatment limiting toxicities. Immunologically, this trial also confirms the positive immunomodulation of Tadalafil in patients with recurrent HNSCC and suggests an adjuvant effect of the anti-tumor vaccine MUC1/polyICLC. Additionally, image cytometry analysis of scanned tumors indicates that the PDE5 inhibitor Tadalafil in conjunction with the MUC1/polyICLC vaccine effectively reduces the number of PDL1+macrophages present at the tumor edge, and increases the number of activated tumor infiltrating T cells, suggesting reversion of immune exclusion. However, this analysis shows also that CD163 negative cells within the tumor upregulate PDL1 after treatment, suggesting the instauration of additional mechanisms of immune evasion. In summary, our data confirm the safety and immunologic potential of PDE5 inhibition in HNSCC but also point to PDL1 as additional mechanism of tumor evasion. This supports the rationale for combining checkpoint and PDE5 inhibitors for the treatment of human malignancies.

Definitive radiotherapy for a head and neck Merkel cell carcinoma and comprehensive nodal volumes: a case for using a computer-designed variable-thickness compensator to reduce risk and severity of mucositis.

When contemplating how to treat head and neck primary cancers and regional lymph nodes with radiotherapy, we often select the contemporary intensity-modulated radiotherapy (IMRT) without much consideration of older methods that may give fewer side effects and be more cost-effective. For an 87-year-old female with a 1.5-cm Merkel cell carcinoma (MCC) located 1.5 cm lateral to the orbital rim, we were challenged to deliver 50 Gy to comprehensive elective nodal regions and 70 Gy to the primary. We were particularly concerned about the potential adverse acute effects of radiotherapy to mucosal structures in this elderly female. Acute mucositis could impair nutrition, quality of life, and treatment intensity especially given her age. We compared 3 techniques that are appropriate for this target: step-and-shoot IMRT, matched electron fields (MEF), and electron conformal therapy (BolusECT™). We selected and treated her with BolusECT™ because of better sparing of larynx, pharynx, oral cavity and lips, and shortest treatment time. This is a reasonable option for treating ipsilateral head and neck target volumes at centers where only these 3 techniques are available.

Utilization of free tissue transfer in head and neck surgery.

OBJECTIVE: Free tissue transfer is frequently incorporated into the reconstructive algorithm for a multitude of defects in the head and neck. With the increasing usage of free tissue transfer we undertook to review the most current advances in the field. DATA SOURCES: PubMed search of all pertinent articles as they related to oropharyngeal reconstruction, flap choice, new technologies and techniques, and outcomes. Articles were chosen based on reviewer selection. METHODS: The microvascular committee met and discussed the current important topics in free tissue transfer. A priority list was created and ranked. Topics were assigned to the authors who conducted a narrative review of the literature. RESULTS: Free tissue transfer has evolved to the point where a limited number of specific flaps are now utilized for most defects. Composite tissue is used to reconstruct composite defects. The coupling device and implantable Doppler are demonstrating a positive impact on flap survival and efficiency. Finally, outcomes in terms of quality of life, swallowing, and return to function have been shown to improve with the use of free tissue transfer. CONCLUSION: Free tissue transfer continues to be the reconstructive modality of choice for head and neck defects.

Head and neck second primary cancer rates in the human papillomavirus era: A population-based analysis.

BACKGROUND: Patients with head and neck cancer are at high risk for second primary malignancies. Human papillomavirus (HPV)-driven tumors are generally high-grade oropharyngeal cancers. We analyzed the incidence of second primary malignancy of the head and neck in patients with primary squamous cell carcinoma (SCC) of the head and neck and temporal trends in the HPV era. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients with SCC of the head and neck (range, 1973-2008). Cumulative incidence rates of second primary malignancy of the head and neck were compared based on competing risk analysis. RESULTS: A total of 104,639 cases were included in this study, of which 4616 patients had second primary malignancy of the head and neck. Oropharyngeal cancer incidence increased over time. Estimated incidence rate/10,000 person-years (105.5, 80.6, and 50.2 for 1973-1989, 1990-1999, and 2000-2008, respectively) and cumulative incidence rates (10-year rates of 6.68%, 5.72%, and 4.59% for 1973-1989, 1990-1999, and 2000-2008, respectively) of second primary malignancies of the head and neck for patients with oropharyngeal cancer decreased over time (p < .001). The second primary malignancy of the head and neck incidence rate was significantly lower in patients with high-grade oropharyngeal cancer from 2000 to 2008 (30.3 vs 65.5 and 54.6 from 1973-1989 and 1990-1999, respectively; p < .001). CONCLUSION: The incidence of second primary malignancy of the head and neck in patients with head and neck cancer has decreased over time. This is driven by lower rates in patients with high-grade oropharyngeal cancer, is temporally related with increases in HPV-associated oropharyngeal cancer, and suggests that incidence rates of second primary malignancy of the head and neck may be lower for HPV-associated cancer. © 2015 Wiley Periodicals, Inc. Head Neck 38: E873-E883, 2016.

Recruitment of underserved, high-risk participants to a head and neck cancer screening program.

OBJECTIVES/HYPOTHESIS: Early detection is essential in head and neck cancer treatment as prognosis varies greatly with stage at diagnosis. Underserved populations often present with advanced disease, and individuals with tobacco and heavy alcohol use demonstrate a higher head and neck cancer incidence. This study aims to evaluate whether various promotional methods differentially recruited behavioral risk factor positive and/or underserved populations to our screening event. STUDY DESIGN: Prospective cross-sectional study. METHODS: A hospital-based, medical student-run, free head and neck cancer screening event for 187 participants was held in April 2015. Medical campus-based, community-based, and media-based promotions were implemented to recruit participants. Event participants filled out questionnaires to determine how they were recruited, their risk-factor history, and their socioeconomic status. Prevalence of the higher-risk population across the various promotional methods was analyzed. RESULTS: Community-based promotions were significantly associated with the recruitment of participants in the underserved subgroups, namely uninsured (P = .019), unemployed (P = .006), and those with an annual household income <$20,000 (P < .001). Although not statistically significant, participants with behavioral risk factors reported a higher percentage of recruitment by media-based promotions. Campus-based promotions led to the highest absolute number, but not percentage, of higher-risk participants. CONCLUSIONS: Community-based promotions most efficiently recruit underserved guests to participate in a hospital-based head and neck cancer screening event as compared to media and campus-based promotions. Institutions interested in recruiting higher proportions of underserved guests to these screening events should consider focusing attention and allocation of resources to community-based promotions. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2699-2704, 2016.

Educational Value of a Medical Student-Led Head and Neck Cancer Screening Event.

OBJECTIVE: To evaluate improvement of medical student knowledge of head and neck cancer (HNC) through participation in HNC screening fairs run by medical students. STUDY DESIGN: Prospective cohort study of surveys assessing medical students' knowledge of HNC before and after volunteering at screening fairs. SETTING: Four screening fairs held at the University of Miami Miller School of Medicine during Oral, Head and Neck Cancer Awareness Week. SUBJECTS: Medical student screening fair volunteers. METHODS: Four HNC screening fairs were organized by medical student volunteers. All students completed a preevent survey assessing baseline knowledge and participated in an otolaryngologist-led training session about HNC and the screening examination. During the screening events, students educated guests about HNC and performed physician-guided history and physical examinations. Finally, students completed identical surveys 1 week and 3 months after the event. RESULTS: Thirty-four (n = 34) students completed the preevent surveys. At baseline, 59%, 44%, and 24% named tobacco, alcohol, and human papilloma virus as risk factors, compared with 84%, 81%, and 69% on 3 month follow-up, respectively. Out of 6 analyzed questions, the median total number of correctly answered questions improved from 2 on pretest to 5 at 3 months (P < .0001). CONCLUSION: Volunteer participation in a HNC screening program improves medical students' knowledge of HNC risk factors and symptoms. This innovative approach to students' education via participation and organization of screening events is a useful method of improving their HNC knowledge.

Salivary soluble CD44: a potential molecular marker for head and neck cancer.

OBJECTIVE: Head and neck squamous cell carcinoma (HNSCC) is a debilitating disease which is cured only 50% of the time. If diagnosed early, survival rates could reach 80%, but there is currently no practical method for early detection. CD44 comprises a family of isoforms that, in certain tumors, are alternatively spliced and overexpressed in tissues and circulation. Here we examine salivary soluble CD44 (solCD44) expression in HNSCC patients and normal controls to determine its potential as a screening tool. METHOD: We did a solCD44 ELISA on saliva from 26 HNSCC patients, 10 normal volunteers, conditioned media (CM) of 4 HNSCC cell lines, and 1 CD44-negative cell line (COS-7). Western blot was done on CM from 2 HNSCC cell lines (UMSS11B and FaDu), COS-7, 3 HNSCC, and 2 normal saliva specimens to verify ELISA antibody specificity. SolCD44 levels were significantly elevated in HNSCC patients compared with normal controls (7.85 ng/mL for HNSCC patients and 1.09 ng/mL for normal controls, P < 0.001). RESULTS: The test detected 79% of mucosally invasive HNSCC using preliminary cutoff points. SolCD44 levels did not vary significantly with tumor size, stage, recurrence, history of radiation treatment, or tobacco and alcohol risk factors. A 65 to 75 kDa band, corresponding to solCD44, was detected in all of the HNSCC cell line CM and saliva whereas normal samples showed a fainter band or were undetectable. CONCLUSION: In this preliminary analysis, the salivary solCD44 ELISA seems to effectively detect HNSCC at all stages. Further study is indicated because early detection is clearly important in this disease.

Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma.

PURPOSE: Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of our preclinical data demonstrating that phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor tadalafil can revert tumor-induced immunosuppression and promote tumor immunity in patients with HNSCC. EXPERIMENTAL DESIGN: First, we functionally and phenotypically characterized MDSCs in HNSCCs and determined, retrospectively, whether their presence at the tumor site correlates with recurrence. Then, we performed a prospective single-center, double-blinded, randomized, three-arm study in which patients with HNSCC undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with tadalafil 10 mg/day, 20 mg/day, or placebo for at least 20 days preoperatively. Blood and tumor MDSC and Treg presence and CD8(+) T-cell reactivity to tumor antigens were evaluated before and after treatment. RESULTS: MDSCs were characterized in HNSCC and their intratumoral presence significantly correlates with recurrence. Tadalafil treatment was well tolerated and significantly reduced both MDSCs and Treg concentrations in the blood and in the tumor (P < 0.05). In addition, the concentration of blood CD8(+) T cells reactive to autologous tumor antigens significantly increased after treatment (P < 0.05). Tadalafil immunomodulatory activity was maximized at an intermediate dose but not at higher doses. Mechanistic analysis suggests a possible off-target effect on PDE11 at high dosages that, by increasing intracellular cAMP, may negatively affect antitumor immunity. CONCLUSIONS: Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in patients with HNSCC by lowering MDSCs and Tregs and increasing tumor-specific CD8(+) T cells in a dose-dependent fashion.

Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma.

PURPOSE: To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in patients with head and neck cancer through inhibition of myeloid-derived suppressor cells (MDSC). EXPERIMENTAL DESIGN: We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in patients with head and neck squamous cell carcinoma (HNSCC). RESULTS: Tadalafil augmented immune response, increasing ex vivo T-cell expansion to a mean 2.4-fold increase compared with 1.1-fold in control patients (P = 0.01), reducing peripheral MDSC numbers to mean 0.81-fold change compared with a 1.26-fold change in control patients (P = 0.001), and increasing general immunity as measured by delayed type hypersensitivity response (P = 0.002). Tumor-specific immunity in response to HNSCC tumor lysate was augmented in tadalafil-treated patients (P = 0.04). CONCLUSIONS: These findings demonstrate that tadalafil augments general and tumor-specific immunity in patients with HNSCC and has therapeutic potential in HNSCC. Evasion of immune surveillance and suppression of systemic and tumor-specific immunity is a significant feature of head and neck cancer development. This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor-specific immune suppression in patients with head and neck cancer, with potential for therapeutic application.

Treatment of recurrent and advanced stage squamous cell carcinoma of the head and neck.

Despite advances in our ability to safely treat patients with recurrent cancer of the upper aerodigestive tract, outcomes for retreatment are generally poor and the first chance to cure these patients remains the best chance. Thorough knowledge of the outlook and options for patients with recurrent disease is also of significance in choosing therapy for patients with newly diagnosed disease. This is especially true for newly diagnosed patients making the choice between surgery and nonsurgical ("organ-sparing") options, who need to know the outlook for salvage surgery, should they recur after radiation with or without concomitant chemotherapy. Salvage surgery is generally the best option for previously irradiated patients who are faced with resectable, recurrent disease. Unfortunately, the results of surgical salvage are generally poor for patients with advanced stage recurrence and for those who recur after treatment of advanced disease. The site of initial and recurrent disease is important. Surgical salvage is most effective for patients with recurrent laryngeal cancer, least effective for recurrent cancer of the pharynx, and is intermediate for recurrence in the oral cavity. Patients choosing nonsurgical treatment for newly diagnosed cancer of the pharynx cannot rely on salvage surgery in the event of recurrence. Reirraditation for patients who have failed initial treatment that included radiation therapy has been used at a number of institutions with some success. Experience using reirradiation with or without concomitant chemotherapy continues to evolve. Palliative chemotherapy is an option for most patients, but response rates are generally poor and of short duration, after failure of initial treatment that includes radiation therapy. The best approach for many patients and families who face advanced recurrent disease is honest but compassionate communication and supportive care with the help of a hospice organization.

MUC4 and ErbB2 expression in squamous cell carcinoma of the upper aerodigestive tract: correlation with clinical outcomes.

OBJECTIVES/HYPOTHESIS: Expression of the membrane mucin MUC4 has been associated with a variety of malignancies, including squamous cell carcinoma of the upper aerodigestive tract. MUC4 modulates cell signaling pathways as an intramembrane ligand of ErbB2. The hypotheses of the study were that MUC4 expression would correlate with ErbB2 expression and that MUC4 expression would correlate with clinical outcomes in squamous cell carcinoma of the upper aerodigestive tract. STUDY DESIGN: Retrospective chart review was combined with immunohistochemical analysis of paraffin-embedded tumor specimens from patients treated with initial definitive surgical resection at an academic tertiary care medical center. METHODS: MUC4 and ErbB2 receptor expression was localized by immunohistochemical studies using archival formalin-fixed and paraffin-embedded tissue. A limited number of fresh-frozen tissues were further analyzed by Western blot. Clinical outcomes and histopathological parameters were determined by retrospective chart review and correlated with immunohistochemical findings. RESULTS: One hundred fifty-four patients were analyzed with a median follow-up of 12 months among 54 patients who died and 49 months among 100 surviving patients. Membrane expression of MUC4 and ErbB2 was seen in 12% and 13% of tumors, respectively. MUC4 expression was not correlated with pathological grade. A significant correlation was found between MUC4 expression and ErbB2 expression. Multivariate survival analyses revealed that patients whose tumors exhibited MUC4 membrane expression had statistically significant improvement in survival and longer time to recurrence compared with patients whose tumors did not express MUC4 as defined by immunohistochemical staining patterns. No correlations between ErbB2 expression and survival or recurrence were observed. CONCLUSION: Patients with tumors that retain MUC4 expression exhibit improved survival and decreased recurrence in squamous cell carcinoma of the upper aerodigestive tract. Correlations between MUC4 expression patterns and ErbB2 expression are also observed, suggesting that MUC4-ErbB2 mediated cell signaling pathways may provide insights into this clinical result.