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Few cancers can be targeted efficiently by engineered T cell strategies. Here, we show that γδ T cell antigen receptor (γδ TCR)-mediated cancer metabolome targeting can be combined with targeting of cancer-associated stress antigens (such as NKG2D ligands or CD277) through the addition of chimeric co-receptors. This strategy overcomes suboptimal γ9δ2 TCR engagement of αβ T cells engineered to express a defined γδ TCR (TEGs) and improves serial killing, proliferation and persistence of TEGs. In vivo, the NKG2D-CD28WTchimera enabled control only of liquid tumors, whereas the NKG2D-4-1BBCD28TMchimera prolonged persistence of TEGs and improved control of liquid and solid tumors. The CD277-targeting chimera (103-4-1BB) was the most optimal co-stimulation format, eradicating both liquid and solid tumors. Single-cell transcriptomic analysis revealed that NKG2D-4-1BBCD28TMand 103-4-1BB chimeras reprogram TEGs through NF-κB. Owing to competition with naturally expressed NKG2D in CD8+TEGs, the NKG2D-4-1BBCD28TMchimera mainly skewed CD4+TEGs toward adhesion, proliferation, cytotoxicity and less exhausted signatures, whereas the 103-4-1BB chimera additionally shaped the CD8+subset toward a proliferative state.

AimTreatment options for head and neck adenoid cystic carcinoma (AdCC) are limited in advanced disease. Chemokine receptor type 4 (CXCR4) is present in various tumour types, including AdCC. Upregulation is associated with tumour recurrence and metastasis. New CXCR4-specific diagnostic and therapeutic target agents have recently been available. This study aimed to analyse CXCR4 expression in a cohort of primary head and neck AdCC.MethodsAfter histopathological revision, tumour tissues of 73 consecutive patients with AdCC over 1990–2016 were sampled on a tissue microarray. Slides were immunohistochemically stained for CXCR4 and semiquantitatively scored. Associations between protein expression and cliniopathological parameters were tested. HRs were calculated using a Cox proportional hazard model.ResultsSixty-six tumours could be analysed. CXCR4 expression was present in 81% of the tumours with a median of 29% (IQR 1–70) positive cells. Expression was univariately correlated to perineural growth (Spearman ρ .26, p=0.04) and bone invasion (Spearman ρ .32, p=0.01), but not with tumour grade.CXCR4 expression in the primary tumour was significantly higher in tumours that recurred as compared with those that did not recur (median 60%, IQR 33–72 vs 12%, IQR 1–70, Kruskal-Wallis p=0.01). After dichotomisation, >25% of CXCR4 expressions proved an independent prognosticator for a reduced recurrence-free survival (RFS) (HR 7.2, 95% CI 1.5 to 72.4, p=0.04).ConclusionCXCR4 is expressed in the majority of primary AdCCs and independently correlated to worse RFS, suggesting CXCR4 as a target for imaging and therapy purposes in patients with advanced AdCC.

The objective of this review is to discuss factors related to the risk of osteoradionecrosis (ORN) and how to minimize the likelihood of this complication. A PubMed search for publications pertaining to ORN within the last 3 years was conducted revealing 44 publications. The bibliographies of these publications were reviewed to identify additional references spanning a longer time period. The incidence of ORN is 5% to 10% with a median latency period of 1 to 2 years or less. The likelihood of ORN depends on a number of factors including primary site and extent of disease, dental status, treatment modality, radiotherapy (RT) dose, volume of mandible included in the planning target volume, RT fractionation schedule and technique, and teeth extractions. The risk of ORN may be reduced by limiting the RT dose and volume of mandible irradiated without increasing the risk of a local-regional recurrence due to a marginal miss.

AimsTumour-associated macrophages (TAMs) and regulatory T cells (Tregs) form a special niche supporting tumour progression, and both correlate with worse survival in head and neck cancers. However, the prognostic role of TAM and Tregs in nasopharyngeal carcinoma (NPC) is still unknown. Therefore, we determined differences in TAMs and Tregs in different NPC subtypes, and their prognostic significance.MethodsTissue of 91 NPCs was assessed for TAMs and Tregs by determination of CD68, CD163, CD206 and FOXP3 expression in the tumour microenvironment. Clinicopathological correlations were assessed using Pearson X2test, Fisher’s exact test, analysis of variance and Mann-Whitney U test. Survival was analysed using Kaplan-Meier curves and Cox regression.ResultsCD68 and FOXP3 counts were higher in Epstein-Barr virus (EBV)-positive NPC, while CD68−/FOXP3−, CD163+/FOXP3− and CD206+/FOXP3− infiltrates were more common in EBV-negative NPC. In the whole NPC group, CD68−/FOXP3− correlated with worse overall survival (OS), and after multivariate analysis high FOXP3 count showed better OS (HR 0.352, 95% CI 0.128 to 0.968). No difference in M2 counts existed between EBV-positive and negative NPC.ConclusionsFOXP3, a Treg marker, seems to be an independent prognostic factor for better OS in the whole NPC group. Therefore, immune-based therapies targeting Tregs should be carefully evaluated. M2 spectrum macrophages are probably more prominent in EBV-negative NPC with also functional differences compared with EBV-positive NPC.

AimsTo assess differences in methylation profiles, and thus pathogenesis, between Epstein-Barr virus (EBV)-positive and negative nasopharyngeal carcinomas (NPCs). Also, promoter hypermethylation is a common phenomenon in early carcinogenesis to inactivate tumour suppressor genes. Since epigenetic changes are reversible, the therapeutic application of methylation inhibitors could provide treatment options.MethodsWe evaluated promoter hypermethylation profiles of 22 common tumour suppressor genes in 108 NPCs using methylation-specific multiplex ligation-dependent probe amplification. Correlation between methylation, clinicopathological features (including EBV) and survival was examined. Cluster analysis was also performed.ResultsHypermethylation of RASSF1A and ESR1 was significantly more frequent in EBV-positive NPC, while hypermethylation of DAPK1 was more frequent in EBV-negative NPC. In logistic regression, age, with EBV-positive NPC occurring at earlier age, and RASSF1, with RASSF1 hypermethylation being more frequent in EBV-positive NPC, remained significant. In EBV-positive NPC, hypermethylation of RASSF1A predicted worse overall survival (OS) (HR 3.058,95% CI 1.027 to 9.107). In EBV-negative NPC, hypermethylated adenomatous polyposis coli (APC) was a predictor of poor disease-free survival (DFS) (HR 6.868, 95% CI 2.142 to 22.022).ConclusionThere are important epigenetic differences between EBV-negative and EBV-positive NPCs, with EBV-negative NPC having a more similar hypermethylation profile to other head and neck squamous cell carcinomas than EBV-positive NPC. Hypermethylation of RASSF1A might contribute to worse OS in EBV-positive NPC, and may be an important event in the pathogenesis of EBV-infected NPC. Hypermethylation of APC might contribute to worse DFS in EBV-negative NPC.

Organoids are in vitrothree-dimensional structures that can be grown from patient tissue. Head and neck cancer (HNC) is a collective term used for multiple tumor types including squamous cell carcinomas and salivary gland adenocarcinomas.

Background. Sinonasal teratocarcinosarcoma is a rare, aggressive malignancy located almost exclusively in the nasal cavity, paranasal sinuses, or anterior skull base. Histopathological diagnosis can be challenging due to the heterogeneous composition. Methods. Retrospective analysis of 3 patients with sinonasal teratocarcinosarcoma diagnosed and treated at the University Medical Center Utrecht was conducted. Results. Patients presented with nasal obstruction, epistaxis, headaches, or behavioral changes. All three patients had locally advanced disease, and one had lymph node metastases. Two patients underwent surgery followed by radiotherapy, and one underwent neoadjuvant chemotherapy followed by surgery. The follow-up duration ranged from 3 to 32 months. All three patients died due to progression of their disease. Conclusion. Sinonasal teratocarcinosarcoma is characterized by rapid, aggressive local expansion. The prognosis is poor due to a high risk of metastases and locally recurrent disease. Multimodality treatment consisting of surgery, followed by (chemo)‐radiotherapy, is essential for optimizing outcomes. Neoadjuvant therapy offers a promising treatment option.

IMPORTANCE: The surgical dictum of en bloc resection without violating cancer tissue has been challenged by novel treatments in head and neck cancer. OBSERVATIONS: An analysis of treatment outcomes involving piecemeal removal of sinonasal, laryngeal, oropharyngeal, and hypopharyngeal cancer shows that it did not compromise tumor control. The rationale for the evolution toward use of this technique is outlined. CONCLUSIONS AND RELEVANCE: While complete resection with clear margins remains a key end point in surgical oncology, we believe it is time to acknowledge that this time-honored dictum of avoiding tumor violation is no longer valid in selected situations.

Various lymphoscintigraphic imaging protocols exist for sentinel node (SN) identification in early-stage oral cancer. This study aimed to evaluate the clinical value of performing additional late lymphoscintigraphic imaging.

This paper reviews the advances in surgery in head and neck cancer patients.

OBJECTIVE To determine the effectiveness of repeated intracutaneous injections of botulinum toxin A to treat Frey syndrome. PATIENTS Between January 6, 1999, and July 1, 2005, 22 patients with Frey syndrome (12 men and 10 women) received repeated intracutaneous injections of botulinum toxin type A. MAIN OUTCOME MEASURES Before each treatment, the time since the previous treatment; the size of the affected area, as determined by a starch-iodine test; and subjective quantification of symptoms, as assessed by the previously used Frey Questionnaire Card, were recorded. RESULTS All patients underwent at least 3 treatments. Univariate analysis of variance showed a significant difference (P <.001) in the between-treatment interval. Univariate analysis of variance showed a significant difference in the size of the affected area in accordance with the number of treatments received (P <.001). The mean Frey Questionnaire Card score also decreased with repeated treatments. CONCLUSIONS In patients with Frey syndrome, repeated treatment with intracutaneous injection of botulinum toxin type A lowered subjective symptom scores, decreased the size of the affected area, and increased the duration of the effect.Arch Otolaryngol Head Neck Surg. 2009;135(3):287-290--

A great disappointment in head and neck cancer surgery is that 10–30% of head and neck squamous cell carcinoma (HNSCC) patients develop local recurrences despite histopathologically tumor-free surgical margins. These recurrences result from either minimal residual cancer (MRC) or preneoplastic lesions that remain behind after tumor resection. Distinguishing MRC from preneoplasic lesions is important to tailor postoperative radiotherapy more adequately. Here we investigated the suitability of quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) using human Ly-6D (hLy-6D) transcripts as molecular marker to detect MRC in surgical margins.Submucosal samples of deep surgical margins were collected from 18 non-cancer control patients and 67 HNSCC patients of whom eight had tumor-positive surgical margins. The samples were analyzed with hLy-6D qRT-PCR, and the data were analyzed in relation to the clinicohistological parameters.A significant difference was shown between the group of patients with histopathological tumor-positive surgical margins and the non-cancer control group (p<0.001), and the group of patients with histopathological tumor-free surgical margins (p=0.001).This study shows a novel approach for molecular analysis of deep surgical margins in head and neck cancer surgery. The preliminary data of this approach for detection of MRC in deep margins of HNSCC patients are promising.

The aim of this article is to examine the need for screening of endocrine dysfunction following treatment of head and neck cancer.

In subtotal nose reconstruction, different tissues have to be reconstructed. We report the case of a 51-year-old man with a severe deformity of the nose (shortening and collapse of the nose, retraction of the right alar area, and a total septal defect after surgery and radiotherapy for a septum nasi carcinoma). Reconstruction with good results was performed with a “gangplank” flap technique (using a U-shaped skin flap for inner lining and for lengthening), rib cartilage for the nasal skeleton, and skin coverage with a paramedian forehead flap.

Background:The objective of this study is to obtain insight into distress in spouses and patients treated for head and neck cancer.

In this prospective study, the effects of a second course of postoperative radiation therapy on locoregional control, survival, toxicity, and quality of life were investigated in patients who underwent resection of a second primary or locoregional recurrent head and neck tumor in a previously irradiated area.In total, 39 patients who underwent surgery for second primary tumors (n = 19 patients) or for recurrent locoregional tumors (n = 20 patients) were retreated with postoperative radiotherapy (RE‐PORT). Indications for RE‐PORT were extranodal spread (49%), positive surgical margins (44%), and/or other risk factors (8%). The target volume for RE‐PORT was confined to the high‐risk area. No elective radiotherapy was applied in regions that were situated in the formerly high‐dose area. A total dose of 46 grays (Gy) was given to elective areas with boosts from 60 Gy to 66 Gy to the high‐risk region with conventional fractionation. The results of RE‐PORT were compared with the results from patients who were treated in the same period with primary adjuvant radiotherapy (PRI‐PORT) at the authors' institution.The mean follow‐up was 32 months (range, 3‐84 mos). The locoregional control rate after 3 years in the RE‐PORT group was 74%, and the 3‐year overall survival rate was 44%. This did not differ significantly compared with survival rates in the PRI‐PORT group. Although a higher rate of late radiation‐induced morbidity and more head and neck symptoms were observed in the RE‐PORT group compared with the PRI‐PORT group, no differences were observed with regard to the more general dimensions of quality of life.RE‐PORT after surgery for recurrent locoregional tumors and/or second primary tumors should be considered in patients who have high‐risk histopathologic features. Cancer 2006. © 2006 American Cancer Society.

Objectives/Hypothesis:The detection of distant metastases during screening influences the choice of treatment in patients with head and neck squamous cell carcinoma. A previous study in the authors' institution showed that chest computed tomography (CT) scan was the most important screening technique. Different clinical risk factors in patients with head and neck squamous cell carcinoma for the development of distant metastases were identified.

Introduction Sinusitis is a well recognised but insufficiently understood complication of critical illness. It has been linked to nasotracheal intubation, but its occurrence after orotracheal intubation is less clear. We studied the incidence of sinusitis in patients with fever of unknown origin (FUO) in our intensive care unit with the aim of establishing a protocol that would be applicable in everyday clinical practice.Methods Sinus X-rays (SXRs) were performed in all patients with fever for which an initial screening (physical examination, microbiological cultures and chest X-ray) revealed no obvious cause. All patients were followed with a predefined protocol, including antral drainage in all patients with abnormal or equivocal results on their SXR.Results Initial screening revealed probable causes of fever in 153 of 351 patients (46.4%). SXRs were taken in the other 198 patients (56.4%); 129 had obvious or equivocal abnormalities. Sinus drainage revealed purulent material and positive cultures (predominantly Pseudomonas and Klebsiella species) in 84 patients. Final diagnosis for the cause of fever in all 351 patients based on X-ray results, microbiological cultures, and clinical response to sinus drainage indicated sinusitis as the sole cause of fever in 57 (16.2%) and as contributing factor in 48 (13.8%) patients with FUO. This will underestimate the actual incidence because SXR and drainage were not performed in all patients.Conclusion Physicians treating critically ill patients should be aware of the high risk of sinusitis and take appropriate preventive measures, including the removal of nasogastric tubes in patients requiring long-term mechanical ventilation. Routine investigation of FUO should include computed tomography scan, SXR or sinus ultrasonography, and drainage should be performed if any abnormalities are found.

Objectives:The aim of this retrospective study was to evaluate the prognostic significance of paratracheal lymph node (PTLN) metastases for tumor recurrence and survival for patients treated with total laryngectomy (TL) and PTLN dissection.

Objective:To assess the results of the use of the free radial forearm flap in terms of objective morbidity and subjective patient response.

Neonatal tracheal or laryngeal rupture is a rare but life-threatening condition that is attributable to traumatic endotracheal intubation or traumatic delivery. We present a review of the literature and 6 new cases of laryngeal or tracheal rupture following complicated delivery. High-risk groups were identified as 1) low-birth weight neonates, for intubation trauma, and 2) extremely high-birth weight neonates with shoulder dystocia, for trauma due to delivery. Two specific types of ruptures can be distinguished. The less-rare type involves a partial anterior rupture in the subglottic area, which can occur after traumatic intubation or traumatic delivery. The rarer type involves a distal circumferential tracheal rupture that gives rise to ventilatory problems, usually after a delay of several days. This type of rupture was only observed following traumatic delivery. Early diagnosis, optically guided orotracheal intubation, and timely treatment can reduce the risks of mortality and morbidity.

The objective of this study was to assess patency of the internal jugular vein following modified radical or selective neck dissection and microvascular flap reconstruction by power Doppler ultrasound and its impact on free flap survival. In 23 patients who underwent selective or modified radical neck dissection and microvascular flap reconstruction the patency of the internal jugular vein was examined by power Doppler ultrasound on the first post-operative day and after follow-up of at least four months. On the first post-operative day in one patient partial thrombosis was found, while in the other 22 patients the internal jugular vein was normal patent. During follow-up in 17 (74 per cent) patients a normal patent internal jugular vein was found, while partial and complete thrombosis were found in three (13 per cent) patients each. On the first post-operative day 22 of the 23 (96 per cent) free flap veins were visualized. There was no free flap loss during follow-up. Power Doppler ultrasound is a valuable diagnostic technique for determination of internal jugular vein patency and may be useful as screening method or in case of clinical suspicion of thrombosis to determine internal jugular vein patency. Late internal jugular vein thrombosis may probably not effect free flap survival due to neovascularization.

ObjectivesThe detection of distant metastases at initial evaluation may alter the selection of therapy in patients with head and neck squamous cell carcinoma (HNSCC). In this study the value of screening for distant metastases is evaluated.

Abstract.: Radioimmunotherapy (RIT) seems to be a realistic option for eradication of minimal residual squamous cell carcinoma of the head and neck (HNSCC), although uptake levels of radiolabelled monoclonal antibodies (MAbs) in tumour tissue vary strongly. The aim of this study was to obtain greater insight into the factors influencing the accumulation of MAbs in HNSCC. Twenty-seven HNSCC patients were injected with radiolabelled MAb E48 or U36 and underwent surgery 2 days after injection. Radioactivity was measured in tumour biopsies taken from the surgical specimen. Uptake levels were correlated with various patient, tumour and MAb characteristics, including age, sex, site, TNM stage, volume as assesssed by computed tomography or magnetic resonance imaging, degree of differentiation, antigen expression of the tumour, the particular MAb that had been injected and the MAb dose. A stepwise regression multivariate analysis showed that tumour volume is the most significant prognostic factor (P=0.01) for MAb uptake. In conclusion, a significantly higher MAb uptake is found in small tumours as compared to larger tumours. Therefore, RIT may be particularly effective in head and neck cancer patients when used in an adjuvant setting.