Submental Island Flaps for Lateral Reconstruction: Technical Refinements for Optimal Outcomes and Resource Efficiency.

Objective: To describe our modifications to the submental island flap (SMIF) in a case series that demonstrates improved reproducibility, shortened length of stay (LOS), and reduced utilization of hospital resources. Study Design: This retrospective case series with chart review included adult patients who underwent resection of malignant or benign tumors resulting in lateral facial, parotid, or temporal bone defects, which were reconstructed with SMIF. Setting: A tertiary-care academic referral center. Methods: Retrospective case series included all adult patients who underwent SMIF reconstruction between March 2020 and August 2021. Patient demographic and clinical data were collected. Primary outcomes were measures of hospital utilization including duration of surgery, LOS, and postoperative outcomes. Results: Twenty-eight patients were included with a mean age of 71.7 years. Eighty percent were male. All patients underwent parotidectomy, and the mean operative time was 347 minutes. The median LOS was 2.5 days (range 0-16 days). Seventy-five percent of the flaps drained into the internal jugular vein, and 25% drained into the external jugular vein. No patients required reoperation or readmission. All flaps survived. Conclusion: SMIFs are a safe and effective option for reconstruction of lateral facial, parotid, and temporal bone defects. Compared to free flap reconstruction, SMIFs offer reduced length of surgery, decreased use of health care resources, and lower rate of reoperation. As health care resource allocation is increasingly important, the SMIF offers an excellent alternative to free flap reconstruction of lateral defects.

Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node.

Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a CD8+ PD-1+ Tcf-1+ stem-like T cell subset in the tumor-draining lymph node (TdLN). Using murine melanoma models, we found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. Our data indicate that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor.

Characterization of the tumor microenvironment in the mouse oral cancer (MOC1) model after orthotopic implantation in the buccal mucosa.

BACKGROUND: Preclinical models are invaluable for studies of head and neck cancer. There is growing interest in the use of orthotopic syngeneic models, wherein cell lines are injected into the oral cavity of immunocompetent mice. In this brief report, we describe injection of mouse oral cancer 1 (MOC1) cells into the buccal mucosa and illustrate the tumor growth pattern, lymph node response, and changes in the tumor immune microenvironment over time. METHODS: MOC1 cells were injected into the buccal mucosa of C57BL6 mice. Animals were sacrificed at 7, 14, 21, or 27 days. Tumors and lymph nodes were analyzed by flow cytometry. RESULTS: All mice developed tumors by day 7 and required euthanasia for tumor burden and/or weight loss by day 27. Lymph node mapping showed that these tumors reliably drain to a submandibular lymph node. The proportion of intratumoral CD8+ T cells decreased over time, while neutrophilic myeloid cells increased dramatically. Growth of orthotopic MOC2 and MOC22 also showed similar growth patterns versus published data in flank tumors. CONCLUSIONS: When used orthotopically in the buccal mucosa, the MOC1 model induces a robust lymph node response and distinct pattern of immune cell infiltration, with peak immune infiltration by day 14.

Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer.

BACKGROUND: While T cell-activating immunotherapies against recurrent head and neck squamous cell carcinoma (HNSCC) have shown impressive results in clinical trials, they are often ineffective in the majority of patients. NK cells are potential targets for immunotherapeutic intervention; however, the setback in monalizumab-based therapy in HNSCC highlights the need for an alternative treatment to enhance their antitumor activity. METHODS: Single-cell RNA sequencing (scRNA-seq) and TCGA HNSCC datasets were used to identify key molecular alterations in NK cells. Representative HPV-positive ( +) and HPV-negative ( -) HNSCC cell lines and orthotopic mouse models were used to validate the bioinformatic findings. Changes in immune cells were examined by flow cytometry and immunofluorescence. RESULTS: Through integration of scRNA-seq data with TCGA data, we found that the impact of IL6/IL6R and CCL2/CCR2 signaling pathways on evasion of immune attack by NK cells is more pronounced in the HPV - HNSCC cohort compared to the HPV + HNSCC cohort. In orthotopic mouse models, blocking IL6 with a neutralizing antibody suppressed HPV - but not HPV + tumors, which was accompanied by increased tumor infiltration and proliferation of CD161+ NK cells. Notably, combining the CCR2 chemokine receptor antagonist RS504393 with IL6 blockade resulted in a more pronounced antitumor effect that was associated with more activated intratumoral NK cells in HPV - HNSCC compared to either agent alone. CONCLUSIONS: These findings demonstrate that dual blockade of IL6 and CCR2 pathways effectively enhances the antitumor activity of NK cells in HPV-negative HNSCC, providing a novel strategy for treating this type of cancer.

Orthotopic injection of an established syngeneic mouse oral cancer cell line (MOC1) induces a robust draining lymph node response.

Background: Preclinical models are invaluable for studies on the pathogenesis and treatment of head and neck cancer. In recent years, there has been growing interest in the use of orthotopic syngeneic models, wherein head and neck cancer cell lines are injected into the oral cavity of immunocompetent mice. However, few such orthotopic models have been described in detail. In this brief report, we describe techniques for injection of mouse oral cancer 1 (MOC1) cells into the buccal mucosa and illustrate the tumor growth pattern, lymph node response, and changes in the tumor immune microenvironment over time. Methods: MOC1 cells were injected into the buccal mucosa of C57BL6 mice. Animals were sacrificed at 7, 14, 21, or 27 days. Tumors and lymph nodes were harvested and analyzed for immune cell subsets by flow cytometry. Results: All inoculated mice developed palpable buccal tumors by day 7 and required euthanasia for tumor burden and/or weight loss by day 27. Lymph node mapping showed that these tumors reliably drain to a submandibular lymph node, which enlarges considerably over time. As in MOC1 tumors in the flank, the proportion of intratumoral CD8+ T cells decreased over time, while neutrophilic myeloid cells increased dramatically. However, the pattern and time course of immune changes in the TME were slightly different in the orthotopic buccal model. Conclusions: When used orthotopically in the buccal mucosa, the MOC1 model induces a robust lymph node response and distinct pattern of immune cell infiltration, with peak immune infiltration by day 14.

Rescue of NLRC5 expression restores antigen processing machinery in head and neck cancer cells lacking functional STAT1 and p53.

The antigen processing machinery (APM) components needed for a tumor cell to present an antigen to a T cell are expressed at low levels in solid tumors, constituting an important mechanism of immune escape. More than most other solid tumors, head and neck squamous cell carcinoma (HNSCC) cells tend to have low APM expression, rendering them insensitive to immune checkpoint blockade and most other forms of immunotherapy. In HNSCC, this APM deficiency is largely driven by high levels of EGFR and SHP2, leading to low expression and activation of STAT1; however, recent studies suggest that p53, which is often mutated in HNSCCs, may also play a role. In the current study, we aimed to investigate the extent to which STAT1 and p53 individually regulate APM component expression in HNSCC cells. We found that in cells lacking functional p53, APM expression could still be induced by interferon-gamma or DNA-damaging chemotherapy (cisplatin) as long as STAT1 expression remained intact; when both transcription factors were knocked down, APM component expression was abolished. When we bypassed these deficient pathways by rescuing the expression of NLRC5, APM expression was also restored. These results suggest that dual loss of functional STAT1 and p53 may render HNSCC cells incapable of processing and presenting antigens, but rescue of downstream NLRC5 expression may be an attractive strategy for restoring sensitivity to T cell-based immunotherapy.

Effects of socioeconomic status on enrollment in clinical trials for cancer: A systematic review.

BACKGROUND: To achieve equitable access to cancer clinical trials (CCTs), patients must overcome structural, clinical, and attitudinal barriers to trial enrollment. The goal of this systematic review was to study the relationship between socioeconomic status (SES), assessed either by direct or proxy measures, and CCT enrollment. METHODS: The review team and medical librarian developed search strategies for each database to identify studies for this systematic review, which was conducted according to PRISMA guidelines. Inclusion criteria were as follows: studies published in relevant scientific journals between January 2000 and July 2022, primary sources, English literature, and studies conducted in the US. Sixteen studies fulfilled the inclusion criteria and were reviewed. The risk of bias assessment was conducted independently by two reviewers using the Newcastle Ottawa scale. RESULTS: The initial search yielded 4070 citations, and 16 studies were included in our review. Four of the studies included used patient reported annual income as a measure of SES, while the remaining 12 studies used patient zip code as a proxy measurement of SES. Consistent with our hypothesis, 13 studies showed a positive association between high SES (patient-reported or proxy measurement) and CCT enrollment. Two studies showed a negative association, and one study showed no relationship. CONCLUSIONS: The existing literature suggests that low SES is associated with lower participation in CCT. The small number of studies identified on this topic highlights the need for additional research on SES and other barriers to CCT participation.

The evolving landscape of salivary gland tumors.

Salivary gland cancers are a rare, histologically diverse group of tumors. They range from indolent to aggressive and can cause significant morbidity and mortality. Surgical resection remains the mainstay of treatment, but radiation and systemic therapy are also critical parts of the care paradigm. Given the rarity and heterogeneity of these cancers, they are best managed in a multidisciplinary program. In this review, the authors highlight standards of care as well as exciting new research for salivary gland cancers that will strive for better patient outcomes.

The expanding role of IAP antagonists for the treatment of head and neck cancer.

Inhibitors of apoptosis proteins (IAPs) inhibit the intrinsic and extrinsic cell death pathways, promoting cell survival. Antagonists of these pathways are under study as anti-cancer therapeutics. A high proportion of head and neck squamous cell carcinomas (HNSCCs) have genomic alterations in IAP pathways, resulting in the dysregulation of cell death pathways and rendering them susceptible to IAP antagonist therapy. Preclinical studies suggest IAP antagonists, also known as second mitochondria-derived activator of caspases mimetics, may be effective treatments for HNSCC, especially when combined with radiation. Mechanistic studies have shown both molecular mechanisms (i.e., enhanced cell death) and immune mechanisms (e.g., immunogenic cell death and T-cell activation), underlying the efficacy of these drugs in preclinical models. Phase I/II clinical trials have shown promising results, portending a future where this class of targeted therapies becomes incorporated into the treatment paradigm for head and neck cancers. IAP antagonists have shown great promise for head and neck cancer, especially in combination with radiation therapy. Here, we review recent preclinical and clinical studies on the use of these novel targeted agents for head and neck cancer.

Quality of life and decisional regret after total glossectomy with laryngectomy: A single-institution case series.

OBJECTIVES: Total glossectomy with total laryngectomy is a life-altering procedure reserved for extensive or recurrent head and neck cancer. There is minimal literature describing quality of life in these patients, partly due to high mortality rates. METHODS: Patients who had undergone a total glossectomy with laryngectomy between 2014 and 2021 at our institution, identified by chart review, were eligible. Four validated scales were used to assess quality of life and satisfaction with decision. RESULTS: Four of five survivors agreed to participate. The average scores for the Satisfaction with Decision scale and the University of Washington Quality of Life scale were 4.4/5 and 70/100, respectively, showing that patients were satisfied with their decision and quality of life. However, the average function score for the UW-QoL scale, 36.4/100, highlights negative effects of the procedure on mood, oral function, and activity. CONCLUSIONS: This case description provides a picture of patients' quality of life after total glossectomy with laryngectomy, which may be useful for counseling future patients.

Laryngeal Anatomy, Molecular Biology, Cause, and Risk Factors for Laryngeal Cancer.

Laryngeal cancer is declining in incidence in many parts of the world, as smoking becomes a less common habit. However, challenging cases of laryngeal cancer still exist and require expertise from otolaryngologists. This article reviews the relevant anatomy and lymphatic drainage pathways of the larynx because they pertain to cancer spread. The molecular and immune landscapes of laryngeal cancer, which are tightly linked to smoking, are also discussed.

Pembrolizumab and cabozantinib in recurrent metastatic head and neck squamous cell carcinoma: a phase 2 trial.

Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors, have immunomodulatory properties and have offered promising results when combined with anti-PD-1 agents. We conducted a phase 2, multicenter, single-arm trial of pembrolizumab and cabozantinib in patients with RMHNSCC who had Response Evaluation Criteria in Solid Tumors v.1.1 measurable disease and no contraindications to either agent. We assessed the primary end points of tolerability and overall response rate to the combination with secondary end points of progression-free survival and overall survival and performed correlative studies with PDL-1 and combined positive score, CD8+ T cell infiltration and tumor mutational burden. A total of 50 patients were screened and 36 were enrolled with 33 evaluable for response. The primary end point was met, with 17 out of 33 patients having a partial response (52%) and 13 (39%) stable disease with an overall clinical benefit rate of 91%. Median and 1-year overall survival were 22.3 months (95% confidence interval (CI) = 11.7-32.9) and 68.4% (95% CI = 45.1%-83.5%), respectively. Median and 1-year progression-free survival were 14.6 months (95% CI = 8.2-19.6) and 54% (95% CI = 31.5%-72%), respectively. Grade 3 or higher treatment-related adverse events included increased aspartate aminotransferase (n = 2, 5.6%). In 16 patients (44.4%), the dose of cabozantinib was reduced to 20 mg daily. The overall response rate correlated positively with baseline CD8+ T cell infiltration. There was no observed correlation between tumor mutational burden and clinical outcome. Pembrolizumab and cabozantinib were well tolerated and showed promising clinical activity in patients with RMHNSCC. Further investigation of similar combinations are needed in RMHNSCC. The trial is registered at ClinicalTrials.gov under registration no. NCT03468218 .

Free Flap Fat Volume is Not Associated With Recurrence or Wound Complications in Oral Cancer.

Objective: Adipose stem cells (ASCs) have been shown in many preclinical studies to be potent suppressors of the immune system. Prior studies suggest that ASCs may promote cancer progression and wound healing. However, clinical studies investigating the effects of native, or fat-grafted adipose tissue on cancer recurrence have generated mixed results. We investigated whether adipose content in reconstructive free flaps for oral squamous cell carcinoma (OSCC) is associated with disease recurrence and/or reduction in wound complications. Study Design: Retrospective chart review. Setting: Academic medical center. Methods: We performed a review of 55 patients undergoing free flap reconstruction for OSCC over a 14-month period. Using texture analysis software, we measured the relative free flap fat volume (FFFV) in postoperative computed tomography scans and compared fat volume with patient survival, recurrence, and wound healing complications. Results: We report no difference in mean FFFV between patients with or without recurrence: 13.47 cm3 in cancer-free survivors and 17.99 cm3 in cases that recurred (p = .56). Two-year recurrence-free survival in patients with high and low FFFV was 61.0% and 59.1%, respectively (p = .917). Although only 9 patients had wound healing complications, we found no trend in the incidence of wound healing complications between patients with high versus low FFFV. Conclusion: FFFV is not associated with recurrence or wound healing in patients undergoing free flap reconstruction for OSCC, suggesting adipose content should not be of concern to the reconstructive surgeon.

Long-Term Follow-up of Parenteral Bevacizumab In Patients with Recurrent Respiratory Papillomatosis.

OBJECTIVE: The clinical course of recurrent respiratory papillomatosis (RRP) varies from spontaneous remission to severe airway obstruction with wide variability in recurrence. Standard treatment involves debulking to improve voice and/or breathing. Non-surgical therapies are emerging in hopes of non-operative disease control. This retrospective review analyzes long-term safety, efficacy, and durability of clinical control in the largest reported series of parenteral bevacizumab in adults with RRP. METHODS: Twenty-three patients with known RRP who have been receiving off-label systemic bevacizumab were included. Dosage, infusion interval, number of cycles, debulking requirements, subjective outcomes, adverse events, and reasons for treatment termination were investigated. RESULTS: Patients have been followed for an average of 791.43 (21-1468) days. The most common starting dosing regimen was 15 mg/kg at 3 weeks in 11 followed by 10 mg/kg at 6 weeks intervals in 6 individuals. Long-term maintenance dosage varied with the least intensive regimen being 10 mg/kg at 14-week intervals. Subjective improvement of voice and/or breathing was reported in 18/23 subjects. The median time for patients that needed a procedure after treatment was 634 days. Procedures after infusions decreased from 3.08 ± 2.48 procedures in the year prior to 0.52 ± 1.12 during systemic Bevacizumab, and to 0.86 ± 2.05 after stopping bevacizumab. Therapy termination occurred in 8 subjects where only 3 were due to adverse events. CONCLUSION: Parenteral bevacizumab remains a well-tolerated treatment for patients with recalcitrant RRP. There appears to be a durable reduction in the frequency of debulking surgery requirements although on a maintenance regimen. Laryngoscope, 133:2725-2733, 2023.

Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models.

BACKGROUND: Anti-PD-1 immune checkpoint blockade is approved for first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but few patients respond. Statin drugs (HMG-CoA reductase inhibitors) are associated with superior survival in several cancer types, including HNSCC. Emerging data suggest that manipulation of cholesterol may enhance some aspects of antitumor immunity. METHODS: We used syngeneic murine models (mouse oral cancer, MOC1 and TC-1) to investigate our hypothesis that a subset of statin drugs would enhance antitumor immunity and delay tumor growth. RESULTS: Using an ex vivo coculture assay of murine cancer cells and tumor infiltrating lymphocytes, we discovered that all seven statin drugs inhibited tumor cell proliferation. Simvastatin and lovastatin also enhanced T-cell killing of tumor cells. In mice, daily oral simvastatin or lovastatin enhanced tumor control and extended survival when combined with PD-1 blockade, with rejection of MOC1 tumors in 30% of mice treated with lovastatin plus anti-PD-1. Results from flow cytometry of tumors and tumor-draining lymph nodes suggested T cell activation and shifts from M2 to M1 macrophage predominance as potential mechanisms of combination therapy. CONCLUSIONS: These results suggest that statins deserve further study as well-tolerated, inexpensive drugs that may enhance responses to PD-1 checkpoint blockade and other immunotherapies for HNSCC.

Role of HER2 in Prognosis of Salivary Duct Carcinoma: A Systematic Review and Meta-Analysis.

OBJECTIVES: Salivary duct carcinoma (SDC) is a rare, aggressive malignancy with a poor prognosis. These tumors frequently stain positive for HER2/ErbB2, but data on the prognostic significance of HER2 status in SDC are mixed. We sought to determine whether HER2 status affects survival outcomes in SDC. METHODS: PubMed, Embase, and Web of Science databases were searched from inception to October 2020. Eligibility was restricted to studies reporting HER2/ErbB2 overexpression in histologically confirmed de novo SDC or SDC ex pleomorphic adenoma, with corresponding overall (OS) and disease-free (DFS) survival measures. Separate multivariable and univariable meta-analyses were performed using random-effects models. Statistical heterogeneity was estimated by Cochran's Q and I2 tests. Funnel plots were generated and Egger's test was used to assess for publication bias. The risk of bias was assessed with the Newcastle-Ottawa Scale. RESULTS: Of 183 unique citations, 14 studies of 663 patients were included. Most included studies determined HER2 status according to ASCO/CAP guidelines. The univariable meta-analysis did not reveal an effect between HER2 status and OS (HR 1.09, 95% CI 0.84-1.42). In the multivariable analysis, HER2 positivity was associated with a HR of 1.49 for OS (95% CI 0.96-2.30). Fewer studies reported data for DFS than OS, with no relationship between HER2 status and DFS found on multivariable or univariable meta-analyses. CONCLUSION: In patients with salivary duct carcinoma, HER2 positivity was not found to be associated with worse overall survival. This information may be useful when counseling patients and considering treatment options. Laryngoscope, 133:476-484, 2023.

Specimen-Based Resection Margins and Local Control during Transoral Robotic Surgery for Oropharyngeal HPV-Mediated Squamous Cell Carcinoma.

OBJECTIVES: The aim of the study was to investigate the association of surgical margin conditions, including positive specimen margins revised to negative relative to local recurrence, disease-free survival, and overall survival (OS) within a cohort of HPV-mediated oropharyngeal squamous cell carcinoma (OPSCC) who underwent en bloc resection via transoral robotic surgery (TORS). MATERIALS AND METHODS: Retrospective cohort of patients with untreated HPV-mediated OPSCC cT1 or T2 undergoing TORS resection between October 2014 and March 2020. The methodologic description of our interdisciplinary institutional approach, number of cut-through margins (CTMs) during intraoperative consultation, percentage of final positive margin cases, and disease-free survival and OS stratified by margin status and margin tumor-free distance is identified. RESULTS: 135 patients with primary cT1/T2 HPV-mediated OPSCC met inclusion criteria. Twenty-eight of 135 (20.7%) specimens revealed CTM and were revised during the same operative setting. Three of 135 (2.2%) surgical cases had positive final margin status. Local control rate was 97%. On univariate analysis, margin distance did not impact OS. CTM and final positive margins had lower OS than initially negative margins (p = 0.044). Pathologic N-stage significantly impacted OS (p < 0.001). CONCLUSIONS: High local control rate and low final positive margin status confound the study of specimen margin-based techniques in HPV-mediated OPSCC resected en bloc with TORS. Pathologic N-stage may impact OS more than margin status. Larger numbers are needed to confirm differences.

Survival and functional outcomes after total glossectomy with total laryngectomy: Case series from a high-volume tertiary institution.

OBJECTIVES: Total glossectomy with total laryngectomy (TGTL) is indicated for some cases of advanced oral squamous cell carcinoma. However, this procedure is rarely performed, as quality of life outcomes are often considered poor. Consequently, few studies to date have reported survival and functional outcomes in patients undergoing TGTL. Here, we present the largest cases series to date of TGTL patients and provide relevant data on survival and functional outcomes. METHODS: Patients met inclusion criteria if they underwent TGTL (concurrent or staged) indicated for head and neck squamous cell carcinoma. Patient demographics and disease characteristics, survival outcomes, functional oral intake scores, time to oral intake, gastrostomy tube dependence, and communication methods post-surgery were retrospectively extracted from the electronic medical record. RESULTS: Survival in patients undergoing TGTL was poor. Most patients in this study were eventually approved for some oral intake of restricted consistencies but remained gastrostomy tube dependent for most of their nutritional needs. Baseline oral intake was suboptimal in most patients but often re-achieved approximately 12 months following surgery. Communication methods following surgery included writing, text-to-speech, and augmentative and alternative communication devices. CONCLUSION: Our data provide new insights comparing survival and functional outcomes of patients undergoing TGTL. Additional investigation particularly on patient-perceived quality of life following TGTL is needed to better understand the risks and benefits for patients who are candidates for TGTL.

Critical review of the current and future prospects of VEGF-TKIs in the management of squamous cell carcinoma of head and neck.

As the prognosis for squamous cell carcinoma of the head and neck remains unsatisfactory when compared to other malignancies, novel therapies targeting specific biomarkers are a critical emerging area of great promise. One particular class of drugs that has been developed to impede tumor angiogenesis is vascular endothelial growth factor-tyrosine kinase inhibitors. As current data is primarily limited to preclinical and phase I/II trials, this review summarizes the current and future prospects of these agents in squamous cell carcinoma of the head and neck. In particular, the combination of these agents with immunotherapy is an exciting area that may be a promising option for patients with recurrent or metastatic disease, evidenced in recent trials such as the combination immune checkpoint inhibitors with lenvatinib and cabozantinib. In addition, the use of such combination therapy preoperatively in locally advanced disease is another area of interest.