Factor V Leiden thrombophilia dental considerations.

Factor V Leiden thrombophilia, a relatively common inherited type of hypercoagulability resulting from a mutation in the gene for factor V, has received minimal attention in the dental literature. This review examines related demographic information, risk factors, comorbidities, the thrombotic mechanism, clinical features, diagnostic measures, and medical management strategies. In addition, oral and maxillofacial sequelae and management guidelines are provided. If a patient is known to have the mutation, the clinician should review the patient's potential risk factors for development of thrombosis and ascertain whether any coagulation agents are currently being administered. The practitioner should be prepared to manage instances of prolonged bleeding. The dentist also should be aware of an overall increased risk of systemic thromboembolic events, particularly following head and neck trauma. Rarely, the factor V Leiden mutation has been associated with osteonecrosis of the jaw, usually concurrent with intake of sex hormones.

Is Long-Term Follow-Up Mandatory for Stage I Oral Tongue Cancer?

PURPOSE: The objective of this study was to analyze the outcomes and possible risk factors for late recurrence of pathologic stage I oral tongue squamous cell carcinomas (SCCs) in patients considered disease free at 3 years. MATERIALS AND METHODS: This retrospective study evaluated all patients with pathologic stage I oral tongue cancer within a tertiary care center from 2003 through 2013 who had been followed for a minimum of 36 months. RESULTS: One hundred twelve patients met inclusion criteria for long-term analysis. Despite the high overall survival of 92.2% for true pT1N0M0 disease, initial surgery failed in 25 of 112 patients (22.3%) who developed late disease recurrence (>36-month follow-up) locally (19.6%; n = 22), regionally (4.4%; n = 5), or as second primary disease (11.6%; n = 13). Eleven patients (50%) who had local recurrence could be salvaged with a second surgery, requiring no further treatment (mean, 48.7 months). Projected 10-year disease-free survival and overall survival were 61 and 89%, respectively. Thirty-three percent (n = 3 of 9) of deaths occurred in long-term patients considered disease free at 36 months. CONCLUSION: Stage I tongue SCC is more common in women and is associated with pre-existing leukoplakia. Although overall survival is excellent, a high failure rate from local recurrence or a new second primary is seen over an extended period. Long-term follow-up is mandatory because local salvage rates are excellent if SCC is diagnosed early. Regional failure carries a poor prognosis.

Extensive Regional Metastasis of High-Grade Mucoepidermoid Carcinoma of an Unknown Primary Tumor.

PURPOSE: Mucoepidermoid carcinoma (MEC) is the most common salivary carcinoma. It arises most frequently in the major salivary glands, but can also arise in minor glands or intraosseous sites. MEC of an unknown primary occurs very rarely. The present report documents only the third case reported in medical studies. METHODS: A 66-year-old man with previous carcinoma in situ (CIS) of the left posterior oral tongue that had been excised in 2004 and again in 2010 presented with a hard lymph node, 3 × 2 cm at level II of the right neck in July 2015. Positron emission tomography-computed tomography (PET-CT) revealed multiple, bilateral cervical lymphadenopathy, with no primary site identified. Fine needle aspiration biopsy and cytologic examination from the right neck was positive for malignancy, suggestive of metastatic squamous cell carcinoma. Panendoscopy and biopsy revealed CIS at the tongue bases and tonsils bilaterally (p16-negative). The patient's case was presented to a tumor board, and definitive concurrent cispl.atin-based chemoradiation was recommended for TisN2cM0, stage IVA oropharyngeal CIS, which was completed in November 2015. PET-CT in January 2015 showed complex interval changes, with some areas demonstrating improvement (ie, no uptake in the left neck) and worsening in others (ie, increased metabolic activity in the right neck), suggestive of residual disease. Repeat PET-CT in March 2016 showed increased nodal involvement and increasing standardized uptake value. Bilateral modified radical neck dissection was undertaken, and histologic examination showed high-grade MEC in 51 of 61 lymph nodes with extracapsular spread and soft tissue involvement. RESULTS: The patient died in May 2016 at 2 months after surgery. CONCLUSIONS: Metastatic MEC of an unknown primary is a diagnostic challenge. PET-CT might not be the most reliable diagnostic investigation to identify the primary or metastatic foci, such as was demonstrated in the present case.

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.

Multiple primary squamous cell carcinomas of the oral cavity.

PURPOSE: There is a subset of patients who develop multiple primary squamous cell carcinomas (SCCs) of the oral cavity. The aim of this study was to better characterize this group of patients and determine whether there are any associated risk factors. MATERIALS AND METHODS: This is a retrospective review of all patients treated for oral SCCs at the University of Maryland Department of Oral and Maxillofacial Surgery from November 1989 to February 2013. The inclusion criteria were patients who developed at least 3 primary oral cancers. Lesions were considered separate primaries if they involved different anatomic regions within the oral cavity and were more than 2 cm apart or if they occurred more than 5 years apart. RESULTS: Of 1,478 patients treated during this time frame, 20 met the inclusion criteria. There were 14 women and 6 men (female-to-male ratio, 2.3:1). Nineteen were Caucasian and 1 was of Indian ethnicity. The average number of primaries per patient was 3.9 (range, 3 to 6 primaries). The mean age at first diagnosis was 63.3 years (44 to 86 yr). The mean interval between the different primaries was 32 months (0 to 228 months). The most common site involved was the gingiva (45% of cases), followed by the tongue, buccal mucosa, retromolar fossa, and soft or hard palate. The mean follow-up was 118 months (22 to 342 months). Eleven patients developed nodal disease. Of those 11 patients, 9 died of the disease (<20% survival). The average time to neck involvement was 66.4 months. The average time from last neck involvement to death was 11.5 months. More than half the patients were nonsmokers or had quit more than 10 years before the first diagnosis. All patients quit smoking during the course of their treatment yet continued to develop multiple primaries. Three patients had proliferative verrucous leukoplakia (PVL), and 4 patients had biopsy-proved lichen planus. CONCLUSION: The incidence of multiple primary SCCs within the oral cavity appears to more commonly involve Caucasian women without risk factors, although lichen planus and PVL might play a role. The gingiva appears to be the most commonly involved primary site, and subsequent primaries tend to be restricted to the oral cavity. Close observation and early expectant treatment appear to improve prognosis and survival in these patients. Cervical nodal metastases adversely affected survival (P = .02) as did the development of more than 4 primary carcinomas (P = .04).

Treatment of cT1N0M0 tongue cancer: outcome and prognostic parameters.

PURPOSE: The objective of the present study was to summarize the treatment and outcomes of cT1N0M0 tongue cancer for which the management is less defined. MATERIALS AND METHODS: A total of 65 consecutive cases of cT1 tongue cancer were retrospectively reviewed. The Fisher exact, χ(2), and Wilcoxon tests were used to statistically analyze the data. RESULTS: The tumor depth had a significant relation to the presence of neck metastasis (P < .05). A 3-mm cutoff point provided better predictive value, with a sensitivity of 92.9% and specificity of 43.1%. The biopsy depth combined with palpation was accurate in determining the tumor depth preoperatively in 87.7%. On multivariate analysis, only the tumor site (ventral tongue) and the presence of erythroleukoplakia had any significant relation to disease-free survival (P = .010). CONCLUSIONS: Elective neck dissection should be considered for patients with cT1N0 oral tongue squamous carcinoma with a biopsy depth of 3 mm or greater. The biopsy depth, combined with the clinical examination findings, is a useful method to help determine the tumor depth preoperatively.

Histological pattern of tumor inflammation and stromal density correlate with patient demographics and immuno-oncologic transcriptional profile in oral squamous cell carcinoma.

Introduction: Oral squamous cell carcinoma (OSCC) is the most prevalent oral malignancy, with emerging interest in the characterization of its tumor microenvironment. Herein, we present a comprehensive histological analysis of OSCC stromal density and inflammation and their relationship with patient demographics, clinicopathologic features and immuno-oncologic signatures. Materials-methods: Eighty-seven completely excised OSCC tissues were prospectively collected and scored for histopathologic inflammatory subtypes [HIS]-inflamed (INF), immune-excluded (IE) and immune-desert (ID), peritumoral stromal inflammation (PTSI), and peritumoral stromal fibrosis (PTSF). Scoring of inflammation was complemented by Semaphorin 4D immunohistochemistry. NanoString differential gene expression (DGE) analysis was conducted for eight OSCC cases representative of the inflammatory and stromal subtypes and the demographic groups. Results: PTSF correlated with male gender (p = 0.0043), smoking (p = 0.0455), alcohol consumption (p = 0.0044), increased tumor size (p = 0.0054), and advanced stage (p = 0.002). On the contrary, PTSI occurred predominantly in females (p = 0.0105), non-drinkers (p = 0.0329), and small tumors (p = 0.0044). Transcriptionally, decreased cytokine signaling, and oncogenic pathway activation were observed in HIS-IE. Smokers and males displayed decreased global immune-cell levels and myeloid-cell predominance. Conclusion: Our work describes OSCC stromal and inflammatory phenotypes in correlation with distinct patient groups and DGE, highlighting the translational potential of characterizing the tumor microenvironment for optimal patient stratification.

Differential expression of organic cation transporter OCT-3 in oral premalignant and malignant lesions: potential implications in the antineoplastic effects of metformin.

BACKGROUND: Recent evidence indicates that metformin, a biguanide used as first-line treatment for type 2 diabetes, prevents the conversion of carcinogen-induced oral dysplasias into head and neck squamous cell carcinomas (HNSCC), most likely by inhibiting mammalian target of rapamycin complex 1 (mTORC1) oncogenic signaling. Whether metformin acts directly at the primary tumor site or indirectly by modulating hormonal secretion from extratumoral organs remains unknown. As organic cation transporters (OCT) belonging to the solute carrier 22A gene family, including OCT-1, OCT-2, and OCT-3, mediate metformin uptake and activity, it is critical to define what role they play in the antineoplastic activity of metformin. METHODS: Immunohistochemical and immunoblotting techniques were used in normal, dysplastic and HNSCC tissues, and HNSCC cell lines, respectively, to determine OCTs expression levels. RESULTS: We report that only OCT-3 was highly expressed in a number of HNSCC cell lines, oral epithelial dysplasias, and well to moderately differentiated HNSCC. Indeed, inhibition of OCT-3 expression and activity in HNSCC cells prevented metformin-induced AMP-activated protein kinase activation and mTORC1 pathway inhibition. Moreover, in oral dysplasias, high OCT-3 expression localized to epithelial compartments where mTORC1 signaling was also upregulated suggestive of a potential local effect of metformin. CONCLUSIONS: The concept of using metformin as a chemopreventive agent to control head and neck carcinogenesis is promising. Further work is warranted to elucidate largely unexplored mechanisms of metformin uptake and pharmacologic action that may ultimately influence the selection of the most suitable patients who can benefit from metformin in head and neck cancer chemoprevention.

Maxillofacial metastases: a retrospective review of one institution's 15-year experience.

PURPOSE: Metastasis to the maxillofacial region is a rare occurrence. In our retrospective study of patients with metastasis to the maxillofacial region, the subjects were evaluated to define the clinical behavior patterns in response to the treatment given. MATERIALS AND METHODS: A retrospective record review during a 15-year period (1990 to 2005) was conducted. The patients were selected for inclusion in the present study if they had histologically confirmed maxillofacial metastases. RESULTS: In our retrospective study, during the 15-year period, 1,221 new patients with maxillofacial/oral cancer were seen and evaluated. Of these 1,221 patients, 26 (16 men and 10 women) were identified as having a histologically confirmed metastasis to the maxillofacial region, for an incidence of 2.1%. CONCLUSIONS: Patients with metastasis to the maxillofacial region are often deemed to not be surgical candidates because of the extensive nature of the metastatic disease. We believe that surgical intervention plays a beneficial role in improving quality of life in a properly selected group of patients with metastasis to the maxillofacial region. In our case series, surgery was performed in about 50% of the patients, and palliation and radiotherapy were the most commonly used modalities.

A retrospective analysis of squamous carcinoma of the buccal mucosa: an aggressive subsite within the oral cavity.

PURPOSE: Squamous carcinoma of the buccal mucosa is relatively uncommon in the North American population. It is considered an aggressive cancer, with difficulty in obtaining negative surgical margins and poor locoregional control. This single-institution retrospective analysis attempted to identify prognostic variables, treatment outcomes, and survival patterns of patients with buccal carcinoma. MATERIALS AND METHODS: A retrospective chart review of all patients with buccal carcinoma treated in the Department of Oral and Maxillofacial Surgery, University of Maryland from 1992 through 2008 was conducted. Thirty newly diagnosed and previously untreated patients were reviewed and their outcomes data were analyzed. RESULTS: Thirteen female and 17 male patients were identified (mean age, 64 yr). Eighteen patients had early-stage disease (stages I to II). Fifteen patients (50%) developed recurrence, with 13 patients developing local recurrence despite 80% of patients achieving negative surgical margins. The overall nodal metastasis rate was 43%, with an occult nodal rate of 32%. Overall 2- and 5-year survival rates were 69% and 53%, respectively. Thirty-nine percent of patients not receiving adjuvant therapy developed recurrence. Early recurrence tended to occur more commonly and was a poor prognostic indicator of successful salvage. CONCLUSIONS: Buccal carcinoma is an aggressive disease, with high rates of locoregional disease recurrence independent of surgical margin status. Elective neck dissection and adjuvant therapy should be considered for early-stage disease. Successful salvage is rare in cases of early recurrence.

Extracorporealization of the Mandibular Condyle: Effects on Viability and Function.

Study Design: For certain condylar fractures, extracorporealization of the condylar segment may be performed via extra-oral vertical ramus osteotomy (EVRO) to facilitate reduction and fixation. This approach can similarly be used for condyle-sparing resection of osteochondromas of the condyle. Due to controversy regarding long-term health of the condyle after extracorporealization, we conducted a retrospective analysis of surgical outcomes. Objective: For certain condylar fractures, extracorporealization of the condylar segment may be performed via extra-oral vertical ramus osteotomy (EVRO) to facilitate reduction and fixation. This approach can similarly be used for condyle-sparing resection of osteochondromas of the condyle. Due to controversy regarding long-term health of the condyle after extracorporealization, we investigated the viability of this technique through a retrospective analysis of outcomes. Methods: Twenty-six patients were treated using EVRO with extracorporealization of the condyle for both condylar fractures (18 patients) and osteochondroma (8 patients). Of the 18 trauma patients, 4 were excluded due to limited follow-up. Clinical outcomes were measured, including occlusion, maximum interincisal opening (MIO), facial asymmetry, incidence of infection, and temporomandibular joint (TMJ) pain. Radiographic signs of condylar resorption were investigated, quantified, and categorized using panoramic imaging. Results: Average follow-up was 15.9 months. Average maximum interincisal opening was 36.8 mm. Four patients demonstrated mild resorption and one patient demonstrated moderate resorption. Two cases of malocclusion were attributed to failed repairs of other concurrent facial fractures. Three patients reported TMJ pain. Conclusions: Extracorporealization of the condylar segment with EVRO to facilitate open treatment of condylar fractures is a viable treatment option when more conventional approaches prove unsuccessful.

Immuno-oncologic signature of malignant transformation in oral squamous cell carcinoma.

OBJECTIVE: The purpose of this study is to identify the immuno-oncologic (IO) signature at the surgical tumor margin (TM) of oral squamous cell carcinoma (OSCC) that is involved in the process of malignant transformation. STUDY DESIGN: Under institutional review board approval, TM of 73 OSCC were investigated using immunohistochemistry for the immune biomarker, programmed death ligand-1 (PD-L1). NanoString 770 IO-focused gene set was analyzed in 5 pairs of TM and invasive tumor (T). PD-L1 regulation in response to interferon-gamma (IFN-γ) was investigated in an oral potentially malignant cell line (OPMC). RESULTS: Programmed death ligand-1 expression in the epithelial margin directly correlated with its expression in the underlying immune cells (P = .0082). Differential gene expression showed downregulation of PD-L1 and IFN-γ 6 gene signature in the TM relative to T pair.CD8 and macrophages were higher in TM. CNTFR, LYZ, C7, RORC, and FGF13 downregulation in T relative to TM. TDO2, ADAM12, MMP1, LAMC2, MB21D1, TYMP, OASL, COL5A1, exhausted_CD8, Tregs,and NK_CD56dim were upregulated in T relative to TM. Finally, IFN-γ induced upregulation of PD-L1 in the OPMC. CONCLUSIONS: Our work suggests a role for IFN-γ in PD-L1 upregulation in OPMC and presents novel IO transcriptional signatures for frankly invasive OSCC relative to TM.

Rare presentation of unicentric Castleman's disease in the parotid gland.

Castleman's disease is a rare benign lymphoproliferative disorder of unknown etiology; however, recent data have suggested a strong association with human herpesvirus type 8 and hypersecretion of the cytokine interleukin 6. Castleman's disease can present anywhere throughout the body; however, it is most commonly detected in the chest, neck, or abdomen. Two main forms of the disease have been identified according to location: unicentric and multicentric. Unicentric Castleman's disease differs from the multicentric form in that patients are often asymptomatic, and surgical resection of the lesion is considered curative. This unicentric or multicentric nature often serves as a distinguishing feature between benign or potentially malignant presentations. The diagnosis of Castleman's disease is challenging because of its nonspecific manifestation. The most reliable diagnosis is achieved though surgical resection and histopathologic confirmation. We report a rare case of unicentric Castleman's disease in the parotid gland and emphasize its importance in the differential diagnosis of oral-facial masses.

Venous anastomoses using microvascular coupler in free flap head and neck reconstruction.

PURPOSE: This study is a retrospective review of the experience using the venous coupler for head and neck reconstruction over a 3-year period at the University of Maryland Medical Center, Department of Oral and Maxillofacial Surgery. MATERIALS AND METHODS: One hundred seventy-eight consecutive cases of microvascular free flaps between May 2007 and September 2010 were retrospectively reviewed. Data were collected by demographic information, flap type, recipient vessels, method of anastomosis, coupler size, coupler orientation, complications associated with coupler, and reconstruction results. Fisher exact test was used for statistical analysis. RESULTS: There were 294 anastomotic coupler devices used in 173 flaps, with hand-sewn venous anastomoses performed in 5 patients. The overall flap success rate was 94.9% (169/178). Success rate among cases in which the coupler was used was 95.4% (8/173). Total coupler venous thrombosis rate was 4.0% (7/173), with a statistically significant difference (P < .05) in reference to the number of venous anastomoses performed: 58 cases had a single vein anastomosed, 5 cases developed thrombosis; while the 115 flaps with 2 venous anastomoses, only 2 cases had thrombosis. CONCLUSIONS: The microvascular coupler is reliable for venous anastomosis in free flap head and neck reconstruction; dual-vein anastomoses appear to have better results than single-vein anastomoses. Flow coupler has a promising utility in monitoring buried flaps and flaps that are difficult to observe. The microvascular coupler deserves to be more commonly used in free flap head and neck reconstruction.

Oral squamous cell carcinoma in patients aged 45 and younger: Prognosis, survival, and quality of life.

OBJECTIVE: To perform a detailed analysis of the epidemiology, tumor biology, treatment, overall survival, and quality of life in a young patient (age ≤45 years) cohort with oral squamous cell carcinoma (OSCC). STUDY DESIGN: A retrospective cohort study between 1992 and 2017 at an academic tertiary care center. RESULTS: In total, 80 patients were included (36 female and 44 male) with stage I (American Joint Committee on Cancer eighth ed.) disease and lateral tongue was most common presentation. Mean follow-up was 6.28 years. The overall disease recurrence rate was 28.7% (23 of 80). Human papillomavirus was positive in 22% of patients tested. Free flap reconstruction was not associated with improved margin status (P = .62) but significant for recurrent disease (P < .04). Overall 2-year survival was significantly poorer in patients with close/positive margin status and free flap reconstruction. Patients with early-stage disease (stage II) requiring adjuvant radiotherapy, chemotherapy (all stages), or flap reconstruction (Stage III patients) had significantly worse 5-year survival rates. CONCLUSIONS: OSCC in young patients (age ≤45 years) is an increasingly more common disease that occurs in patients without known risk factors. Despite their earlier presentation of disease pathology, constant vigilance and standard aggressive treatment similar to other age groups will result in similar and improved outcomes and survival.

Juvenile trabecular ossifying fibroma: Immunohistochemical expression of MDM2, CDK4 and p53 compared to conventional ossifying fibroma.

BACKGROUND: Juvenile ossifying fibroma (JOF) is an uncommon benign fibro-osseous lesion of the craniofacial skeleton; compared to conventional ossifying fibroma (OF), JOF is characterized by local aggressiveness and propensity for recurrence. The biologic basis for this different biologic behavior between JOF and OF remains elusive. The aim of this study was to evaluate the immunohistochemical expression of MDM2, CDK4 and p53, molecules associated with bone oncogenesis, in the trabecular variant of JOF. MATERIAL AND METHODS: The study material consisted of five cases of trabecular JOF, affecting three male and two female patients with a mean age of 11.8 years. Three cases arose in the maxilla and two in the mandible. All cases were initially treated by enucleation; two cases recurred necessitating more aggressive treatment. Immunohistochemical study of MDM2, CDK4 and p53 was performed in all cases, as well as in five control cases of conventional OF. RESULTS: CDK4 positivity was noted in all JOF cases; the staining pattern was diffuse and strong in 4 cases and focal and weak in one case. In contrast, 4 out of 5 cases of OF were weakly and focally CDK4 positive, the remaining one being negative. Immunostaining for MDM2 was observed in 3 JOF cases; all OF were MDM2 negative. All cases of OF and JOF were negative for p53, except for one focally positive JOF case. CONCLUSIONS: CDK4 and MDM2 expression in the trabecular variant of JOF is higher compared to conventional OF. In contrast, p53 expression is almost universally negative in JOF and OF. Despite some overlapping features, differential expression patterns of proteins involved in bone oncogenesis can elucidate the pathogenesis and may facilitate accurate diagnosis and prediction of behavior of bone tumors in the craniofacial region. Key words:Juvenile ossifying fibroma, trabecular variant, conventional ossifying fibroma, MDM2, CDK4, p53.

Cytokine profiling in plasma distinguishes the histological inflammatory subtype of head and neck squamous cell carcinoma and a novel regulatory role of osteopontin.

Head and neck squamous cell carcinoma (HNSCC) can be classified according to the histological inflammatory subtype (HIS) into inflamed (HIS-INF) or immune excluded (HIS-IE). HIS-IE was previously associated with higher levels of soluble Semaphorin 4D (HsS4D) in plasma, and higher transcriptional levels of osteopontin (OPN) in the tumor tissue, compared to HIS-INF. The goal of the current study is to investigate whether the HIS inflammatory subtype can be distinguished by a differential cytokine panel in peripheral blood. Retrospectively collected five HIS-INF and five HIS-IE tumor tissue with paired plasma were included in the study. Five healthy donors (HD) and five autoimmune/chronic inflammatory conditions (AI/CI) were controls. The ELISA-Luminex™ system was used to detect 40 traditional cytokines in plasma. Human cytokine array (104 cytokines) was used for the conditioned medium (CM) of the HNSCC HN6 cell line. Semaphorin 4D (Sema4D) siRNA and recombinant human osteopontin (rh-OPN) were used to investigate the effect of OPN on Sema4D expression. The HIS-IE cytokine profile was higher than HIS-INF but comparable to AI/CI. HIS-INF had the lowest cytokine levels. HIS-IE was differentially higher in IP-10 and IL8 compared to HD, while HIS-INF was higher in IL-10. Sema4D inhibition in HN6 resulted in a decrease of OPN in the CM of HN6, and treatment with rh-OPN rescued Sema4D in HN6 cell lysate and associated CM. In conclusion, the current work demonstrates a novel association between the HIS subtypes and a differential pattern of cytokine expression in plasma. These findings can open new avenues for HNSCC patient stratification and hence provide better personalized treatment.

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.

Soluble Sema4D in Plasma of Head and Neck Squamous Cell Carcinoma Patients Is Associated With Underlying Non-Inflamed Tumor Profile.

Semaphorin 4D (Sema4D) is a glycoprotein that is expressed by several tumors and immune cells. It can function as a membrane bound protein or as a cleaved soluble protein (sSema4D). We sought to investigate the translational potential of plasma sSema4D as an immune marker in plasma of patients with head and neck squamous cell carcinoma (HNSCC). Paired peripheral blood and tumor tissue samples of 104 patients with HNSCC were collected at the same time point to allow for real time analysis. Scoring of the histological inflammatory subtype (HIS) was carried out using Sema4D immunohistochemistry on the tumor tissue. sSema4D was detected in plasma using direct ELISA assay. Defining elevated sSema4D as values above the 95th percentile in healthy controls, our data showed that sSema4D levels in plasma were elevated in 25.0% (95% CI, 16.7-34.9%) of the patients with HNSCC and showed significant association with HIS immune excluded (HIS-IE) (p = 0.007), Sema4D+ve tumor cells (TCs) (p = 0.018) and PD-L1+ve immune cells (ICs) (p = 0.038). A multi-variable logistic regression analysis showed that HIS was significantly (P = 0.004) associated with elevated sSema4D, an association not explained by available patient-level factors. Using the IO-360 nanoString platform, differential gene expression (DGE) analysis of 10 HNSCC tumor tissues showed that patients with high sSema4D in plasma (HsS4D) clustered as IFN-γ negative tumor immune signature and were mostly HIS-IE. The IC type in the HsS4D paired tumor tissue was predominantly myeloid, while the lymphoid compartment was higher in the low sSema4D (LsS4D). The Wnt signaling pathway was upregulated in the HsS4D group. Further analysis using the IO-360, 770 gene set, showed significant non-inflamed profile of the HsS4D tumors compared to the LsS4D. In conclusion, our data reveals an association between sSema4D and the histological inflammatory subtype.