Essential data variables for a minimum dataset for head and neck cancer trials and clinical research: HNCIG consensus recommendations and database.

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website.

Mitochondrial DHODH regulates hypoxia-inducible factor 1 expression in OTSCC.

Oral tongue squamous cell carcinoma (OTSCC) was one of the most hypoxic tumors with unfavorable outcomes. Hypoxia-inducible factor-1 (HIF-1) signaling was associated with cancer proliferation, lymph node metastasis, angiogenesis and poor prognosis of OTSCC. Dihydroorotate dehydrogenase (DHODH) catalyzed the rate-limiting step in the de novo pyrimidine biosynthesis. The aim of the study was to explore the biological function of DHODH and investigate whether DHODH regulated HIF-1 signaling in OTSCC. Proliferation, migration and anoikis resistance were used to determine the function of DHODH. Western blot and luciferase activity assays were used to determine the regulatory role of DHODH on HIF-1. We found that increased DHODH expression was associated with advanced tumor stage and poorly differentiated tumor in head and neck cancer patients in The Cancer Genome Atlas (TCGA). DHODH enhanced the proliferation and aggressiveness of OTSCC. Moreover, DHODH prompted tumor growth and metastasis in vivo. DHODH promoted transcription, protein stability, and transactivation activity of HIF1A. DHODH-induced HIF1A upregulation in OTSCC can be reversed by reactive oxygen species (ROS) scavenger, indicating that DHODH enhanced HIF1A expression via ROS production. DHODH inhibitor suppressed DHODH-mediated ROS generation and HIF1A upregulation. Targeting DHODH using clinically available inhibitor, atovaquone, might provide a new strategy to treat OTSCC.

Patient-specific 3D-printed helmet for post-craniectomy defect - a case report.

BACKGROUND: Patients who undergo decompressive craniectomy (DC) are often fitted with a helmet that protects the craniectomy site from injury during rehabilitation. However, conventional "one-size-fits-all" helmets may not be feasible for certain craniectomy defects. We describe the production and use of a custom 3D-printed helmet for a DC patient where a conventional helmet was not feasible due to the craniectomy defect configuration. CASE PRESENTATION: A 65-year-old male with ethmoid sinonasal carcinoma underwent cranionasal resection and DC with free vastus lateralis flap reconstruction to treat cerebrospinal fluid leakage. He required an external helmet to protect the craniectomy site, however, the rim of a conventional helmet compressed the craniectomy site, and the straps compressed the vascular pedicle of the muscle flap. Computed topography (CT) scans of the patient's cranium were imported into 3D modelling software and used to fabricate a patient-specific, strapless helmet using fused deposition modelling (FDM). The final helmet fit the patient perfectly and circumvented the compression issues, while also providing better cosmesis than the conventional helmet. Four months postoperatively, the helmet remains intact and in use. CONCLUSIONS: 3D printing can be used to produce low-volume, patient-specific external devices for rehabilitation where standardized adjuncts are not optimal. Once initial start-up costs and training are overcome, these devices can be produced by surgeons themselves to meet a wide range of clinical needs.

Deep Learning Predicts the Malignant-Transformation-Free Survival of Oral Potentially Malignant Disorders.

Machine-intelligence platforms for the prediction of the probability of malignant transformation of oral potentially malignant disorders are required as adjunctive decision-making platforms in contemporary clinical practice. This study utilized time-to-event learning models to predict malignant transformation in oral leukoplakia and oral lichenoid lesions. A total of 1098 patients with oral white lesions from two institutions were included in this study. In all, 26 features available from electronic health records were used to train four learning algorithms-Cox-Time, DeepHit, DeepSurv, random survival forest (RSF)-and one standard statistical method-Cox proportional hazards model. Discriminatory performance, calibration of survival estimates, and model stability were assessed using a concordance index (c-index), integrated Brier score (IBS), and standard deviation of the averaged c-index and IBS following training cross-validation. This study found that DeepSurv (c-index: 0.95, IBS: 0.04) and RSF (c-index: 0.91, IBS: 0.03) were the two outperforming models based on discrimination and calibration following internal validation. However, DeepSurv was more stable than RSF upon cross-validation. External validation confirmed the utility of DeepSurv for discrimination (c-index-0.82 vs. 0.73) and RSF for individual survival estimates (0.18 vs. 0.03). We deployed the DeepSurv model to encourage incipient application in clinical practice. Overall, time-to-event models are successful in predicting the malignant transformation of oral leukoplakia and oral lichenoid lesions.

Novel approach to reduce SARS-CoV-2 transmission during trans-oral robotic surgery.

This study describes a novel approach in the reduction of SARS-CoV-2 transmission during trans-oral robotic surgery (TORS). Eight patients underwent TORS between 01 February 2020 and 07 September 2020. A sterile plastic sheet draped over sterile supports with water-tight seal around each cannula was used to create a sterile working space within which the robotic arms could freely move during operation. This set-up acts as an additional physical barrier against droplet and aerosol transmission. Operative diagnosis; droplet count and distribution on plastic sheet and face shields of console and assistant surgeons, and scrub nurse were documented. TORS tumour excision was performed for patients with suspected tonsillar tumour (n = 3) and tongue base tumour (n = 2). TORS tonsillectomy and tongue base mucosectomy was performed for cervical nodal metastatic carcinoma of unknown origin (n = 3). Droplet contamination was noted on all plastic drapes (n = 8). Droplet contamination was most severe over the central surface at 97.2% (91.7-100.0%), with the highest droplet count along the centre-most column where it overlies the site of operation in the oral cavity 33.3% (n = 31). Droplet count decreased towards the periphery. Contamination rate was 2.8% (0.0-8.3%) over the right lateral surface. There was no droplet contamination over the vertex and left lateral surface of plastic drapes. No droplet contamination was noted on face shields of all parties. The use of sterile plastic drapes with water-tight seal around each robotic cannula can help reduce viral transmission to healthcare providers during TORS.

Robot-assisted real-time sentinel lymph node mapping in oral cavity cancer: preliminary experience.

This study aims to assess the feasibility of using indocyanine green and robotic near infra-red fluorescent imaging (Firefly®) for sentinel lymph node biopsy in cN0 oral cavity cancer. Ten patients with early squamous cell carcinoma of the tongue (n = 8) and buccal mucosa (n = 2) were included. Peritumoral injection of 10 mg indocyanine green and real-time mapping of sentinel lymph nodes in the neck was performed using Firefly® via a retro-auricular trans-hairline incision. Sentinel lymph node was detected in all patients at 1.2 sentinel lymph node per person. Majority were situated in level II (91.7%). Mean time to detection of sentinel lymph node was 171.0 (68.0-312.0)s. Mean signal-to-background ratio was 5.62 (3.51-7.91). Frozen section of one sentinel lymph node was positive for malignancy, paraffin section of which confirmed the presence of metastatic disease. Modified radical neck dissection was performed for that particular patient, paraffin section of which did not show any tumor deposit. Frozen section and paraffin section of all other sentinel lymph nodes (n = 11) and neck dissection specimens yielded no malignancy. All resection margins were clear. Three patients completed adjuvant radiotherapy for pT2N0 (n = 2) and pT2N1 (n = 1) carcinoma of the tongue. Mean follow-up was 12.0 (4.0-18.0) months. All patients were alive at last follow-up with no disease recurrence. There were no adverse outcomes associated with the use of indocyanine green and robot-assisted neck dissection. Indocyanine green and Firefly® for sentinel lymph node biopsy in cN0 oral cavity cancer is feasible with no adverse effects.

CD38 triggers inflammasome-mediated pyroptotic cell death in head and neck squamous cell carcinoma.

BACKGROUND: Pyroptosis is a form of inflammatory cell death. Although it is recognized that NLRP3 (nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3) inflammasome is involved in pyroptosis activation, the mechanism by which head and neck squamous cell carcinoma (HNSCC) inhibits pyroptotic cell death remains undefined. This study aims to delineate the role of calcium regulator CD38 in NLRP3 inflammasome-dependent pyroptosis in HNSCC. METHODS: CD38 overexpressing HNSCC cell lines (SAS, CAL27, SNU899) were generated using lentiviral vectors. NLRP3 and gasdermin D (GSDMD) quantity were detected using Western blot. Caspase-1 activity changes were measured using the Caspase-Glo® 1 inflammasome assay. Cell death proportion was determined by flow cytometry analysis. Proliferation assay was performed using xCELLigence RTCA system. Mouse xenotransplantation was performed to evaluate the potential oncogenic or tumor-suppressive function of CD38. ChIP assay was conducted to verify whether transcription factor NFAT1-mediated NLRP3 expression. RESULTS: Exogenous calcium treatment can lead to a significant increase in caspase-1 activity in HNSCC. This feature was also observed in HNSCC cells with stable CD38 overexpression. CD38-overexpressing cell lines showed a significant reduction in proliferation. Further, expression of NLRP3 protein level was significantly increased in CD38-overexpressing cell lines. The N-terminal effector domain of GSDMD was remarkably increased in the CD38-overexpressing HNSCC. ChIP assay indicated that calcium-sensitive transcription factor NFAT1 was possibly involved in the transcriptional upregulation of NLRP3 observed in CD38-overexpressing HNSCC. The pre-clinical xenograft model revealed that CD38 expression had an inhibiting function on HNSCC progression. CONCLUSION: In conclusion, our results suggested that activation of pyroptosis in HNSCC is a calcium-dependent process. Reduced expression of calcium ion regulator CD38 functions could prevent inflammasome-induced pyroptosis in HNSCC. CD38 may function as a tumor suppressor in HNSCC progression.

NADPH oxidase 5α promotes the formation of CD271 tumor-initiating cells in oral cancer.

Oral tongue squamous cell carcinoma (OTSCC) has a distinctive cell sub-population known as tumor-initiating cells (TICs). CD271 is a functional TIC receptor in head and neck cancers. The molecular mechanisms governing CD271 up-regulation remains unclear. Oxidative stress is a contributing factor in TIC development. Here, we explored the potential role of NADPH oxidase 5 (NOX5) and its regulatory mechanism on the development of CD271-expressing OTSCC. Our results showed that the splice variant NOX5α is the most prevalent form expressed in head and neck cancers. NOX5α enhanced OTSCC proliferation, migration, and invasion. Overexpression of NOX5α increased the size of OTSCC xenograft significantly in vivo. The tumor-promoting functions of NOX5α were mediated through the reactive oxygen species (ROS)-generating property. NOX5α activated ERK singling and increased CD271 expression at the transcription level. Also, NOX5α reduces the sensitivity of OTSCC to cisplatin and natural killer cells. The findings indicate that NOX5α plays an important part in the development of TIC in OTSCC.

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.

Recommendations for surgical management of recurrent nasopharyngeal carcinoma during COVID-19 pandemic.

Nasopharyngeal carcinoma is endemic in southern parts of China including Hong Kong. Primary treatment entails radiotherapy ± chemotherapy depending on disease stage at presentation. Surgery is offered as a means of salvage for persistent and recurrent disease. Comprehensive preoperative work-up, careful patient selection, attention to details perioperation and multidisciplinary approach is essential in ensuring optimal outcomes after salvage surgery for recurrent nasopharyngeal carcinoma patients. Since the COVID-19 outbreak, we are faced with unprecedented challenges with priorities of care and resources being shifted to combat the virus. These include patient selection and timing of treatment, while preventing disease transmission to heath care providers. Practices and recommendations made in this document are intended to support safe clinical practice and efficient use of resources during this challenging time.

Tracheostomy during COVID-19 pandemic-Novel approach.

BACKGROUND: This study describes a novel approach in reducing SARS-CoV-2 transmission during tracheostomy. METHODS: Five patients underwent tracheostomy between April 1, 2020 and April 17, 2020. A clear and sterile plastic drape was used as an additional physical barrier against droplets and aerosols. Operative diagnosis; droplet count and distribution on plastic sheet and face shields were documented. RESULTS: Tracheostomy was performed for patients with carcinoma of tonsil (n = 2) and nasopharynx (n = 1), and aspiration pneumonia (n = 2). Droplet contamination was noted on all plastic sheets (n = 5). Droplet contamination was most severe over the central surface at 91.5% (86.7%-100.0%) followed by the left and right lateral surfaces at 5.2% (6.7%-10.0%) and 3.3% (6.7%-10.0%), respectively. No droplet contamination was noted on all face shields. CONCLUSION: Plastic drapes can help reduce viral transmission to health care providers during tracheostomy. Face shields may be spared which in turn helps to conserve resources during the novel coronavirus disease 2019 pandemic.

Conservation of personal protective equipment for head and neck cancer surgery during COVID-19 pandemic.

BACKGROUND: COVID-19 pandemic has led to a global shortage of personal protective equipment (PPE). This study aims to stratify face shield needs when performing head and neck cancer surgery. METHODS: Fifteen patients underwent surgery between March 1, 2020 and April 9, 2020. Operative diagnosis and procedure; droplet count and distribution on face shields were documented. RESULTS: Forty-five surgical procedures were performed for neck nodal metastatic carcinoma of unknown origin (n = 3); carcinoma of tonsil (n = 2), tongue (n = 2), nasopharynx (n = 3), maxilla (n = 1), and laryngopharynx (n = 4). Droplet contamination was 57.8%, 59.5%, 8.0%, and 0% for operating, first and second assistant surgeons, and scrub nurse respectively. Droplet count was highest and most widespread during osteotomies. No droplet splash was noted for transoral robotic surgery. CONCLUSION: Face shield is not a mandatory adjunctive PPE for all head and neck surgical procedures and health care providers. Judicious use helps to conserve resources during such difficult times.

Transoral robotic total laryngopharyngectomy and free jejunal flap reconstruction for hypopharyngeal cancer.

BACKGROUND: To report on the feasibility of total laryngopharyngectomy and free jejunal flap transfer for patient with hypopharyngeal cancer via the transoral robotic surgery (TORS) approach. MATERIAL AND METHODS: A patient with hypopharyngeal cancer involving the post-cricoid region is used for demonstration of the TORS total laryngopharyngectomy and free jejunal flap reconstruction. RESULTS: The procedure starts with a cruciate incision for terminal tracheostomy. The trachea and cervical esophagus is exposed and transected, making sure that the resection margins are adequate. This is followed by the transoral dissection using the robotic surgical system. The laryngopharyngectomy specimen is delivered and the free jejunal flap is replaced transorally. Jejuno-oesophageal suturing and the microvascular anastomosis are performed through the tracheostomy wound. The remaining pharyngo-jejunal anastomosis is performed transorally via the TORS approach. CONCLUSION: TORS total laryngopharyngectomy and free jejunal flap reconstruction is feasible and provides and alternative option to the traditional transcervical approach.

Multivariate analysis of prognostic factors for salvage nasopharyngectomy via the maxillary swing approach.

BACKGROUND: The purpose of this study was to investigate the prognostic factors for salvage nasopharyngectomy. METHODS: A retrospective review was conducted on maxillary swing nasopharyngectomy performed between 1998 and 2010. Univariate and multivariate analyses identified prognostic factors affecting actuarial local tumor control and overall survival. RESULTS: The median follow-up duration was 52 months. Among the 268 patients, 79.1% had clear resection margins. The 5-year actuarial local tumor control and overall survival was 74% and 62.1%, respectively. On multivariate analysis, tumor size, resection margin status, and gross tumor in the sphenoid sinus were independent prognostic factors for local tumor control. For overall survival, resection margin status, synchronous cervical nodal recurrence, and cavernous sinus invasion had a negative influence on overall survival after surgery. CONCLUSION: Extent of nasopharyngectomy should be tailored to the individual tumor to achieve clear resection margins. Cavernous sinus invasion is associated with poor survival outcome, and detailed counseling and meticulous surgical planning is crucial in such circumstances.

Safety of intra-operative vasopressor in free jejunal flap reconstruction.

BACKGROUND: Microvascular surgeons always hold strong belief against the use of vasopressors during free flap surgery. Our aim is to study the safety of intra-operative vasopressors on free jejunal flap reconstruction. METHODS: A retrospective chart review was performed on patients undergoing free jejunal flap reconstruction, aiming at investigating the intra-operative use of vasopressors and the potential complications associated. RESULTS: Between 1984 and 2012, 110 free jejunal flaps were performed for reconstruction of circumferential pharyngeal defects created after resection of cancers of the hypopharynx. Intra-operative vasopressor was given in 81 (73.6%) patients. The most common vasopressors used were ephedrine (42.7%), phenylephrine (14.5%) or both (42.8%). They were administered to the patients before the start of flap harvesting (n = 32, 29.1%), during the flap harvesting (n = 30, 27.3%), during microvascular anastomosis (n = 20, 18.2%), or they were given more than once during the whole operation (n = 28, 25.4%). The incidence of intra-operative re-anastomosis due to thrombosis was 4.5% and the post-operative flap failure rate was 5.4%. There was no significant relationship between the administration of vasopressor during surgery and the need for intra-operative re-anastomosis, post-operative flap failure and the timing of flap failure. Similarly, there was also no relationship between the timing of vasopressor administration and the above variables. The long-term stricture rate was 2.7%, the risk of which was not increased by the intra-operative use of vasopressors. CONCLUSION: The intra-operative use of vasopressors is safe in free jejunal flap reconstruction.

Surgical salvage for recurrent retropharyngeal lymph node metastasis in nasopharyngeal carcinoma.

BACKGROUND: The purpose of this study was to analyze the surgical management of recurrent retropharyngeal lymph node metastasis after radiotherapy for nasopharyngeal carcinoma (NPC). METHODS: We conducted a prospective analysis of preoperative imaging, surgical approach, and oncological results. RESULTS: Between 1990 and 2011, 82 patients were included. The mean size of the retropharyngeal lymph node on MRI was 1.6 cm, and the mean standardized uptake value maximum (SUVmax) on positron emission tomography (PET) scan was 6.8. All the retropharyngeal lymph nodes were resected via the maxillary swing approach. Among the resected retropharyngeal lymph nodes, 87.8% contained viable tumor cells. The rate of microscopic extracapsular spread was 30.6%. The mean follow-up duration was 38 months. The 5-year actuarial tumor control and the overall disease-free survival of patients who underwent surgeries for isolated recurrent retropharyngeal lymph node metastasis was 79.6% and 59%, respectively. CONCLUSION: A PET scan is potentially useful in diagnosing persistent or recurrent retropharyngeal lymph node after previous radiotherapy for NPC. The maxillary swing approach allows surgical resection with clear margins in order to achieve the best oncological outcome.

Efficacy of fine-needle aspiration in diagnosing cervical nodal metastasis from nasopharyngeal carcinoma after radiotherapy.

OBJECTIVES/HYPOTHESIS: Our purpose was to study the effect of previous radiotherapy (RT) on the efficacy of fine-needle aspiration (FNA) in diagnosing cervical nodal metastasis in nasopharyngeal carcinoma (NPC). STUDY DESIGN: Case-control study. METHODS: The diagnostic efficacy of FNA in a group of patients with residual or recurrent cervical lymphadenopathy after previous RT for NPC was compared with a cohort of patients with primary NPC before RT during the same period. RESULTS: Between 2008 and 2010, 50 patients were included for each group in the study. The specificity (100% vs. 88%, P = .12) and positive predictive value (100% vs. 89%, P = .12) was comparable in the two groups. However, the sensitivity (82% vs. 40%, P = .04), negative predictive value (NPV; 74% vs. 36%, P = .03), and accuracy (88% vs. 54%, P = .05) were significantly worse after previous RT. Previous RT was the only factor that was significantly associated with worse diagnostic efficacy (P = .001). When used together with plasma Epstein-Barr virus (pEBV)-DNA level and magnetic resonance imaging (MRI) findings (triple assessment), the diagnostic efficacy was significantly improved, especially regarding sensitivity (40% vs. 98%, P = .01), NPV (36% vs. 96%, P = .02), and accuracy (54% vs. 97%, P = .03). CONCLUSIONS: Diagnostic efficacy of FNA for residual or recurrent cervical lymph node metastasis in NPC is significantly reduced after previous RT. To ensure that the proper diagnosis is made early, triple assessment using FNA, pEBV-DNA, and MRI should be adopted in this scenario.

Extramammary Paget's Disease: 20 Years of Experience in Chinese Population.

Background. To examine the results of treatment of Extramammary Paget's disease (EMPD) in ethnic Chinese. Method. Between 1990 and 2010, patients treated for EMPD were reviewed. Data were analyzed retrospectively. Results. Forty-eight patients were treated by surgical resection. Local recurrence rate was 14.6%. The postresection defects were repaired by primary closure (8.3%), partial thickness skin graft (72.9%), or local/regional flaps (18.8%). Dermal invasion was found in 9 patients (18.8%). Seven patients (14.6%) developed regional lymph node metastasis (concurrent with surgery, n = 1; subsequent to surgery, n = 6), and 3 patients (6.3%) had systemic metastasis after surgery. The presence of dermal invasion was associated with significantly higher incidence of regional lymph nodes and systemic metastasis. The incidence of associated internal malignancy was 8.3%. Conclusion. The mainstay of treatment for EMPD is surgery. Pathological dermal invasion increases the chance of regional lymph node as well as systemic metastasis. The association with internal malignancy warrants preoperative endoscopic examination in all patients.

Prediction of surgical outcome using plasma Epstein-Barr virus dna and (18)F-FDG PET-CT scan in recurrent nasopharyngeal carcinoma.

BACKGROUND: This study was carried out to determine the role of plasma Epstein-Barr virus (pEBV)-DNA and positron-emission tomography (PET)-CT scan in predicting the outcome of nasopharyngectomy and cervical lymphadenectomy for recurrent nasopharyngeal carcinoma (NPC). METHODS: Between 2007 and 2009, we recruited patients who had local or regional recurrent NPC after radiotherapy. The relationship between preoperative pEBV-DNA level, maximal standard uptake value (SUVmax), and surgical outcome was analyzed. RESULTS: Forty-two patients had local tumor recurrence. Their median pEBV-DNA level and SUVmax were 348 copies and 4.7, respectively. Both values were significantly lower than those with palliative nasopharyngectomy. Twenty-two patients had regional failure. Their mean pEBV-DNA level and tumor SUVmax were 626 copies and 7.6, respectively. The metastatic lymph nodes with extracapsular spread had a significantly higher mean SUVmax. CONCLUSIONS: Preoperative pEBV-DNA and PET-CT predict the surgical outcome of nasopharyngectomy for recurrent NPC. Similarly, PET-CT scan predicts the presence of extracapsular spread of metastatic lymph nodes. These patients may warrant further postoperative adjuvant therapy.