Comparing Free-Flap Reconstruction After Robot-Assisted Neck Dissection via a Retroauricular Approach and a Traditional Transcervical Approach: Single-Surgeon Experiences of 90 Consecutive Cases.

BACKGROUND: Predominant traditional approaches for most patients who have advanced-stage oral cancer with transcervical incision lines left irreversible scars. To address this, surgeons have continuously refined minimally invasive surgery (MIS) techniques, including robot-assisted neck surgeries. This article introduces and discusses the feasibility, versatility, and availability of free-flap reconstruction via the retroauricular approach (RA), considered difficult to date. METHODS: This study retrospectively analyzed 90 consecutive patients who had free-flap reconstruction performed by a single surgeon (D.K.) in the Department of Oral and Maxillofacial Surgery, Yonsei University, from March 2021 to April 2022. The type of defects and flaps, hospitalization days, total operation time, and type of vessels and anastomoses were compared statistically. RESULTS: The type of vessels used did not differ between the RA and the transcervical approach (TA) groups, nor in duration of hospital stays. Likewise, the total reconstruction time did not differ significantly between the TA group (240 min) and the RA group (245 min) (p = 0.756). However, the total operation time was about 1 h less in the TA group, a statistically significant difference (TA group [593 ± 152 min] vs. RA group [655 ± 117 min]; p = 0.044). All flaps were successful in the RA group, whereas one flap in the TA group led to a total loss (TA group [98.3%] vs. RA group [100.0%]; p = 1.000). CONCLUSIONS: Even for patients with advanced oral cancer who require massive tumor ablation, it is feasible to obtain an aesthetic and functional surgical outcome by performing free-flap reconstruction via the retroauricular approach.

Current Issues in Treatment of Parotid Gland Cancer and Advanced Surgical Technique of Robotic Parotidectomy.

PURPOSE OF REVIEW: This paper analyzed previous research data to identify the most important issues to be considered during treatment of parotid gland cancer (PGC) and reviewed recent advancements in techniques in parotid surgery. RECENT FINDINGS: For successful treatment of PGC, a preoperative surgical plan should be designed with consideration of the histologic characteristics and anatomical complexity of the tumor, and the functional and anatomical integrity of the facial nerve should be carefully inspected during surgery and damage to the nerve minimized. The need for adjuvant radiotherapy should be determined based on intraoperative findings and pathologic findings of the specimen after surgery. Surgery and radiotherapy are the main treatment options for PGC. To optimize treatment outcomes for PGC, the extent of surgery should be decided according to histologic characteristics and extent of tumor resection, and use of adjuvant radiotherapy should be considered based on risk stratification.

Recommendations for head and neck surgical oncology practice in a setting of acute severe resource constraint during the COVID-19 pandemic: an international consensus.

The speed and scale of the global COVID-19 pandemic has resulted in unprecedented pressures on health services worldwide, requiring new methods of service delivery during the health crisis. In the setting of severe resource constraint and high risk of infection to patients and clinicians, there is an urgent need to identify consensus statements on head and neck surgical oncology practice. We completed a modified Delphi consensus process of three rounds with 40 international experts in head and neck cancer surgical, radiation, and medical oncology, representing 35 international professional societies and national clinical trial groups. Endorsed by 39 societies and professional bodies, these consensus practice recommendations aim to decrease inconsistency of practice, reduce uncertainty in care, and provide reassurance for clinicians worldwide for head and neck surgical oncology in the context of the COVID-19 pandemic and in the setting of acute severe resource constraint and high risk of infection to patients and staff.

Molecular subtypes of oropharyngeal cancer show distinct immune microenvironment related with immune checkpoint blockade response.

BACKGROUND: Oropharyngeal cancer (OPC) exhibits diverse immunological properties; however, their implications for immunotherapy are unknown. METHODS: We analysed 37 surgically resected and nine recurrent or metastatic anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-treated OPC tumours. OPCs were classified into immune-rich (IR), mesenchymal (MS) and xenobiotic (XB) subtypes based on RNA-sequencing data. RESULTS: All IR type tumours were human papillomavirus (HPV) positive, most XB types were HPV negative, and MS types showed mixed HPV status. The IR type showed an enriched T cell exhaustion signature with PD-1+ CD8+ T cells and type I macrophages infiltrating the tumour nest on multiplex immunohistochemistry. The MS type showed an exclusion of CD8+ T cells from the tumour nest and high MS and tumour growth factor-ß signatures. The XB type showed scant CD8+ T cell infiltration and focal CD73 expression. The IR type was associated with a favourable response signature during anti-PD-1/PD-L1 therapy and showed a high APOBEC mutation signature, whereas the MS and XB types showed resistance signature upregulation. Among anti-PD-1/PD-L1-treated OPC patients, the IR type showed a favourable clinical response (3/4 patients), whereas the XB type showed early progression (3/3 patients). CONCLUSION: Our analysis classified OPCs into three subtypes with distinct immune microenvironments that are potentially related to the response to anti-PD-1/PD-L1 therapy.

Correction: Molecular subtypes of oropharyngeal cancer show distinct immune microenvironment related with immune checkpoint blockade response.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mouse-human co-clinical trials demonstrate superior anti-tumour effects of buparlisib (BKM120) and cetuximab combination in squamous cell carcinoma of head and neck.

BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) is a common cancer with high recurrence and mortality. Current treatments have low response rates (RRs). METHODS: Fifty-three patients with R/M SCCHN received continuous oral buparlisib. In parallel, patient-derived xenografts (PDXs) were established in mice to evaluate resistance mechanisms and efficacy of buparlisib/cetuximab combination. Baseline and on-treatment tumour genomes and transcriptomes were sequenced. Based on the integrated clinical and PDX data, 11 patients with progression under buparlisib monotherapy were treated with a combination of buparlisib and cetuximab. RESULTS: For buparlisib monotherapy, disease control rate (DCR) was 49%, RR was 3% and median progression-free survival (PFS) and overall survival (OS) were 63 and 143 days, respectively. For combination therapy, DCR was 91%, RR was 18% and median PFS and OS were 111 and 206 days, respectively. Four PDX models were originated from patients enrolled in the current clinical trial. While buparlisib alone did not inhibit tumour growth, combination therapy achieved tumour inhibition in three of seven PDXs. Genes associated with apoptosis and cell-cycle arrest were expressed at higher levels with combination treatment than with buparlisib or cetuximab alone. CONCLUSIONS: The buparlisib/cetuximab combination has significant promise as a treatment strategy for R/M SCCHN. CLINICAL TRIAL REGISTRATION: NCT01527877.

Comparison of Surgical Outcomes of Robotic and Conventional Approaches in Patients with Pre- and Poststyloid Parapharyngeal Space Tumors.

BACKGROUND: Benefits and drawbacks of robotic surgical approaches for parapharyngeal space (PPS) tumors remain undetermined. The purpose of this study is to compare surgical outcomes of PPS tumor patients who underwent robotic surgery with those of patients who received conventional surgical treatment. PATIENTS AND METHODS: We retrospectively analyzed clinicopathologic data from 136 patients who underwent surgical removal of PPS tumors via conventional or robotic approaches. RESULTS: We identified PPS tumors in pre- and poststyloid regions in 87 (64%) and 49 (36%) patients, respectively. There were 48 (35.3%) pleomorphic adenomas, 36 (26.5%) schwannomas, and 24 (17.6%) paragangliomas. Conventional surgical techniques were performed in 83 patients, and robotic surgical approaches were administered to 53 patients. Transcervical-parotid and transcervical approaches were most commonly performed in conventional surgery, while transoral and retroauricular approaches were the preferred surgical methods in robotic surgery for pre- and poststyloid PPS tumors, respectively. Robotic surgery resulted in less estimated blood loss during poststyloid PPS tumor surgery. Postoperative cranial nerve complications were noted in 36 of 83 cases (43.4%) in the conventional surgery group and in 17 of 53 cases (32.1%) in the robotic surgery group. Intraoperative tumor spillage of pleomorphic adenoma showed no significant differences between the two groups (13.6% in conventional vs. 15.4% in robotic surgery). The mean follow-up time was 4.9 ± 3.4 years, and recurrences were observed in two patients during follow-up without a significant difference between the two groups (4.5% in conventional vs. 3.8% in robotic surgery). CONCLUSIONS: Robotic surgery in PPS tumors is feasible through transoral, retroauricular, or combined approaches and provides treatment outcomes comparable to those of conventional open surgery.

Prognostic implications of Fibroblast growth factor receptor 1 (FGFR1) gene amplification and protein overexpression in hypopharyngeal and laryngeal squamous cell carcinoma.

BACKGROUND: The gene encoding fibroblast growth factor receptor 1 (FGFR1) is emerging as a therapeutic and prognostic biomarker in various cancer types, including head and neck squamous cell carcinoma (SCC). Here, we investigated the clinicopathologic implication of FGFR1 gene amplification and protein overexpression in hypopharyngeal and laryngeal SCC. METHODS: Fluorescence in situ hybridization and immunohistochemistry were performed to determine FGFR1 gene amplification and protein overexpression in 209 surgically resected cases. RESULTS: FGFR1 amplification observed in 8 (8/66, 12.1%; 6 hypopharynx and 2 larynx) patients and high FGFR1 expression in 21 (21/199, 10.6%) patients significantly correlated with lymph node metastasis and advanced pathological stages. FGFR1 amplification was also associated with worse disease-free survival in multivariate analysis (hazard ratio = 4.527, P = 0.032). High FGFR1 expression was more frequently observed, consistent with the worsening of the degree of histologic differentiation. CONCLUSIONS: FGFR1 amplification may serve as an independent prognostic factor for disease-free survival in hypopharyngeal and laryngeal SCC. Aberrant FGFR signaling caused by FGFR1 gene amplification or protein overexpression may play a crucial role in the malignant evolution and progression of hypopharyngeal and laryngeal SCC, and offer novel therapeutic opportunities in patients with hypopharyngeal and laryngeal SCC that usually lack specific therapeutic targets.

Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer.

BACKGROUND: We investigated whether head and neck squamous cell carcinoma (HNSCC) patient-derived xenografts (PDXs) reaffirm patient responses to anti-cancer therapeutics. METHODS: Tumors from HNSCC patients were transplanted into immunodeficient mice and propagated via subsequent implantation. We evaluated established PDXs by histology, genomic profiling, and in vivo anti-cancer efficacy testing to confirm them as the authentic in vivo platform. RESULTS: From 62 HNSCCs, 15 (24%) PDXs were established. The primary cancer types were tongue (8), oropharynx (3), hypopharynx (1), ethmoid sinus cancer (1), supraglottic cancer (1), and parotid gland (1); six PDXs (40%) were established from biopsy specimens from advanced HNSCC. PDXs mostly retained donor characteristics and remained stable across passages. PIK3CA (H1047R), HRAS (G12D), and TP53 mutations (H193R, I195T, R248W, R273H, E298X) and EGFR, CCND1, MYC, and PIK3CA amplifications were identified. Using the acquisition method, biopsy showed a significantly higher engraftment rate when compared with that of surgical resection (100% [6/6] vs. 16.1% [9/56], P < 0.001). Specimens obtained from metastatic sites showed a significantly higher engraftment rate than did those from primary sites (100% [9/9] vs. 11.3% [6/53], P < 0.001). Three PDX models from HPV-positive tumors were established, as compared to 12 from HPV-negative (15.8% [3/19] and 27.9% [12/43] respectively, P = 0.311), suggesting that HPV positivity tends to show a low engraftment rate. Drug responses in PDX recapitulated the clinical responses of the matching patients with pan-HER inhibitors and pan-PI3K inhibitor. CONCLUSIONS: Genetically and clinically annotated HNSCC PDXs could be useful preclinical tools for evaluating biomarkers, therapeutic targets, and new drug discovery.

Does p16+ Predict a Favorable Prognosis for Oropharyngeal Cancer? Risk Factors for Treatment Failure for Patients Who Underwent Surgery-Based Therapy.

BACKGROUND: This study aimed to identify prognostic clinicopathologic factors that could predict treatment failure and to analyze clinical data from p16+ oropharyngeal squamous cell carcinoma (OPSCC) patients who underwent surgery. METHODS: Data from p16+ OPSCC patients who underwent surgery at Severance Hospital of Yonsei University were retrospectively reviewed. RESULTS: The average smoking history was 14.6 pack-years (range 0-94 pack-years). Of the 188 patients, 73 (38.8%) underwent transoral robotic surgery (TORS) for surgical treatment of their primary lesions, and the remaining 115 patients (61.2%) underwent conventional surgery. Extracapsular nodal spread was detected in 87 patients (46.3%). At histologic examination, 67 patients (35.6%) showed positive surgical margins, and 121 patients (64.4%) had negative surgical margins. Postoperative adjuvant treatment was performed for 167 patients (88.8%). During the follow-up period, there were 18 recurrences including 2 local recurrences, 10 regional recurrences, and 6 distant metastases. During the study period, 17 deaths occurred. The univariate analysis showed that the American Joint Committee on Cancer (AJCC) 8th-edition staging system, lymphovascular invasion, more than four metastatic lymph nodes, and a smoking history of more than 10 pack-years were significantly associated with treatment failure. In the multivariate analysis, only the AJCC 8th-edition staging system was significantly associated with the patient's survival. CONCLUSION: Surgical treatment methods including TORS for p16+ OPSCC patients showed excellent oncologic results, and many previously known clinicopathologic factors did not show a significant relationship with patient prognosis. Only the newly revised AJCC 8th-edition staging system showed a significant relationship with patient survival, and this should be considered in the setting of p16+ OPSCC treatment guidelines in the future.

The First Human Trial of Transoral Robotic Surgery Using a Single-Port Robotic System in the Treatment of Laryngo-Pharyngeal Cancer.

BACKGROUND: This study aimed to evaluate the feasibility and safety of the DaVinci SP system for performing transoral robotic surgery (TORS) in patients with head and neck cancer. METHODS: From October 2018 to April 2019, the medical records of 41 patients who underwent TORS using the DaVinci SP system were retrospectively reviewed. RESULTS: During TORS, three robotic arms could be used to perform a geometric resection of the lesion in a narrow working space. The mean total operation time was 60 min, and the average time required to set up the robotic system was 10 min or less. All patients successfully underwent TORS. All robotic arms were inserted through a single port, which widened the working space around the patient's head and allowed the operative assistant an easy approach to the patient during the operation. The joggle joint of the robotic arms aided easy manipulation within the confined working space. The joggle joints of the endoscopic arm were controlled through the navigation system, which was very helpful in securing superior visualization of the surgical site, especially in the area of the larynx and the hypopharynx. CONCLUSION: The study confirmed that the DaVinci SP system provided technical advantages above the Si and Xi systems for performing TORS. It was especially helpful in ensuring proper visualization of the surgical field and in performing precise surgery during surgery to the tongue base or the hypopharyngeal lesion.

Gasless transoral endoscopic thyroidectomy vestibular approach (gasless TOETVA).

BACKGROUND: The transoral endoscopic thyroidectomy vestibular approach (TOETVA) has been the subject of increasing interest from several institutions around the world over the last 2 years. Recently, we successfully performed TOETVA in live human patients without CO2 gas using our newly designed retractable blade. METHODS: We reviewed the medical records of 15 consecutive patients who underwent gasless TOETVA using a self-retaining retractor. RESULTS: We successfully performed 13 thyroid lobectomies and 2 total thyroidectomies in 15 patients. No patient exhibited serious postoperative complications such as recurrent laryngeal nerve palsy and permanent hypocalcemia. One patient developed transient hypocalcemia but recovered within 2 months. No patient developed a wound infection; furthermore, no visible scar or dimpling was evident on the neck of any patient. CONCLUSION: Gasless TOETVA provides enough working space and good visibility to perform thyroid surgery without any risk of CO2 gas-related complications.

Transoral Robotic Surgery With Transoral Retropharyngeal Lymph Node Dissection in Patients With Tonsillar Cancer: Anatomical Points, Surgical Techniques, and Clinical Usefulness.

OBJECTIVE: The purpose of this study was to evaluate the clinical usefulness of TORS and transoral robotic retropharyngeal lymph node (RPLN) dissection in tonsillar cancer patients with suspicious RPLN metastasis. METHODS: From April 2008 to March 2014, 71 patients with tonsillar cancer underwent transoral robotic surgery and standard neck dissection at the Yonsei Head and Neck Cancer Center. RESULTS: Three patients underwent transoral robotic ropharyngectomy with transoral robotic RPLN dissection because of suspicious RPLN metastasis. The mean age of the patients was 42 years (range, 31-50 years). There were no cases of wound infection or serious complications related to wound healing. Mild nasal regurgitation was observed during an oral diet immediately after surgery, but all patients spontaneously resolved without surgical treatment. There was no significant bleeding due to great vessel injury during surgery or swallowing difficulty due to cranial nerve IX injury. CONCLUSION: Although the oncologic stability and usefulness of this technique should be confirmed based on large-scale research, RPLN can be easily accessed and resected through our approach with less morbidity compared to the conventional surgical approach. In addition, because RPLN metastasis can be performed pathologically based on obtained specimens, it will be helpful to explore whether to perform adjuvant radiation.

Fibroblast growth factor receptor 3-mediated reactivation of ERK signaling promotes head and neck squamous cancer cell insensitivity to MEK inhibition.

Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) has been a longstanding challenge for head and neck oncologists, and current treatments still have limited efficacy. ERK is aberrantly overexpressed and activated in HNSCC. Herein, we aimed to investigate the cause of the limited therapeutic effect of selumetinib, a selective inhibitor of MEK in HNSCC, as MEK/ERK reactivation inevitably occurs. We assessed the effects of combining selumetinib with fibroblast growth factor receptor 3 (FGFR3) inhibitor (PD173074) on tumor growth. Selumetinib transiently inhibited MAPK signaling and reactivated ERK signaling in HNSCC cells. Rebound in the ERK and Akt pathways in HNSCC cells was accompanied by increased FGFR3 signaling after selumetinib treatment. Feedback activation of FGFR3 was a result of autocrine secretion of the FGF2 ligand. The FGFR3 inhibitor PD173074 prevented MAPK rebound and sensitized the response of HNSCC cells to selumetinib. These results provided rational therapeutic strategies for clinical studies of this subtype of patients that show a poor prognosis with selumetinib. Our data provide a rationale for combining a MEK inhibitor with inhibitors of feedback activation of FGFR3 signaling in HNSCC cells. ERK rebound as a result of the upregulation of FGFR3 and the ligand FGF2 diminished the antitumor effects of selumetinib, which was overcome by combination treatment with the FGFR3 inhibitor.

c-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition.

BRAF (V600E) mutation is the most commonly detected genetic alteration in thyroid cancer. Unlike its high treatment response to selective BRAF inhibitor (PLX4032) in metastatic melanoma, the treatment response in thyroid cancer is reported to be low. The purpose of this study is to investigate the resistance mechanism responsible for this low treatment response to BRAF inhibitor in order to maximize the effect of targeted therapy. We examined the expression of feedback regulation mechanisms and alterations in the upper signal transduction pathway in thyroid cancer cell lines harboring BRAF mutation. Also, we investigated the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C (anaplastic thyroid cancer) and BCPAP (papillary thyroid cancer) were selected and treated with PLX4032 and its drug sensitivity were examined and compared. Further investigation on the changes in signals responsible for the different treatment response to PLX4032 was carried out and the same experiment was performed on orthotopic xenograft mouse models. Unlike BCPAP cells, 8505C cells presented drug resistance to PLX4032 treatment and this was mainly due to increased expression of c-Met. Effective inhibitions of c-Met, p-AKT, and p-ERK were achieved after dual treatment with BRAF inhibitor (PLX4032) and c-Met inhibitor (PHA665752). Similar results were confirmed by in vivo study with orthotopic xenograft mouse model. c-Met-mediated reactivation of the PI3K/AKT pathway and MAPK pathway contributes to the relative insensitivity of BRAF (V600E) mutant anaplastic thyroid cancer cells to PLX4032. Dual inhibition of BRAF and c-Met leads to sustained treatment response. © 2015 Wiley Periodicals, Inc.

Human Papillomavirus and Epidermal Growth Factor Receptor in Oral Cavity and Oropharyngeal Squamous Cell Carcinoma: Correlation With Dynamic Contrast-Enhanced MRI Parameters.

OBJECTIVE: The objective of this study was to investigate differences in dynamic contrast-enhanced MRI (DCE-MRI) parameters on the basis of the status of human papillomavirus (HPV) and epidermal growth factor receptor (EGFR) biomarkers in patients with squamous cell carcinoma (SCC) of the oral cavity and oropharynx by use of histogram analysis. MATERIALS AND METHODS: A total of 22 consecutive patients with oral cavity and oropharyngeal SCC underwent DCE-MRI before receiving treatment. DCE parameter maps of the volume transfer constant (K(trans)), the flux rate constant (kep), and the extravascular extracellular volume fraction (ve) were obtained. The histogram parameters were calculated using the entire enhancing tumor volume and were compared between the patient subgroups on the basis of HPV and EGFR biomarker statuses. RESULTS: The cumulative histogram parameters of K(trans) and kep showed lower values in the HPV-negative and EFGR-overexpression group than in the HPV-positive EGFR-negative group. These differences were statistically significant for the mean (p = 0.009), 25th, 50th, and 75th percentile values of K(trans) and for the 25th percentile value of kep when correlated with HPV status in addition to the mean K(trans) value (p = 0.047) and kep value (p = 0.004) when correlated with EGFR status. No statistically significant difference in ve was found on the basis of HPV and EGFR status. CONCLUSION: DCE-MRI is useful for the assessment of the tumor microenvironment associated with HPV and EGFR biomarkers before treatment of patients with oral cavity and oropharyngeal SCC.

Application of Dynamic Contrast-Enhanced MRI Parameters for Differentiating Squamous Cell Carcinoma and Malignant Lymphoma of the Oropharynx.

OBJECTIVE: The purpose of this study was to investigate the usefulness of histogram analysis of dynamic contrast-enhanced MRI (DCE-MRI) parameters for the differentiation of squamous cell carcinoma (SCC) and malignant lymphoma of the oropharynx. MATERIALS AND METHODS: Pretreatment DCE-MRI was performed in 21 patients with pathologically confirmed oropharyngeal SCC and six patients with malignant lymphoma. DCE-MRI parameter maps including the volume transfer constant (K(trans)), flux rate constant (kep), and extravascular extracellular volume fraction (ve) based on the Tofts model were obtained. Enhancing tumors were manually segmented on each slice of the parameter maps, and the data were collected to obtain a histogram for the entire tumor volume. The Wilcoxon rank sum test was used to compare the histogram parameters of each DCE-MRI-derived variable of oropharyngeal SCC and lymphoma. RESULTS: Histogram analysis of K(trans) and ve maps revealed that the median and mode of K(trans) were significantly higher in SCC than in lymphoma (p = 0.039 and 0.032, respectively), and the mode, skewness, and kurtosis of ve were significantly different in SCC than in lymphoma (p = 0.046, 0.039, and 0.032, respectively). On ROC analysis, the kurtosis of ve had the best discriminative value for distinguishing between oropharyngeal SCC and lymphoma (AUC, 0.865; cutoff value, 2.60; sensitivity, 83.3%; specificity, 90.5%). CONCLUSION: Our preliminary evidence using histogram analysis of DCE-MRI parameters based on the whole tumor volume suggests that it might be useful for differentiating SCC from malignant lymphoma of the oropharynx.

Endoscopic retroauricular thyroidectomy: preliminary results.

BACKGROUND: We sought to seek the potential role of endoscopic thyroidectomy with the retroauricular (RA) approach prior to future comparative study with the robotic RA thyroidectomy. Therefore, this study aims to verify the surgical feasibility of endoscopic RA thyroidectomy. METHODS: Eighteen patients who underwent endoscopic RA thyroidectomy for clinically suspicious papillary thyroid carcinoma or benign lesions from January to December 2013 were retrospectively reviewed and analyzed. RESULTS: All endoscopic operations via RA or modified facelift approach were successfully performed, without any significant intraoperative complications or conversion to open surgery. Based on patient-reported outcome questionnaires, all patients were satisfied with their postoperative surgical scars. CONCLUSION: Endoscopic RA thyroidectomy is technically feasible and safe with satisfactory cosmetic results for patients where indicated.