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Simple Summary: The 5-year survival of patients with early-stage oral cancer remains at 80% despite advances in treatment. We have previously shown that the proximity between CD20 B cells and CD4 T cells in the invasive margin acts as an independent prognosticator in OSCC, represented by the so-called CD20 cluster score. However, its exact underlying cellular contexture is unknown. In this study, we demonstrated that the abundance of follicular helper T cells as well as the proximity between these cells and B cells were important hallmarks for patients with a high CD20 cluster score and long survival. In early oral squamous cell carcinoma (OSCC), the occurrence of clusters between CD20 B cells and CD4 T cells in the invasive margin (IM) can be captured by using the CD20 cluster score, and is positively associated with patient survival. However, the exact contribution of different CD4 T cell subsets, as well as B cell subsets toward patient prognosis is largely unknown. To this end, we studied regulatory T cells ((Treg cells) FOXP3 and CD4), T helper-type 1 cells ((Th1 cells) Tbet and CD4), follicular helper T cells ((Tfh cells) Bcl6 and CD4), B cells (CD20), germinal center B cells ((GC B cells) BCL6 and CD20), and follicular dendritic cells ((fDCs) CD21) for their density, location, and interspacing using multiplex in situ immunofluorescence of 75 treatment-naïve, primary OSCC patients. We observed that Treg, Th1-, Tfh-, and GC B cells, but not fDCs, were abundantly present in the stroma as compared with the tumor, and in the IM as compared with in the center of the tumor. Patients with high CD20 cluster scores had a high density of all three CD4 T cell subsets and GC B cells in the stromal IM as compared with patients with low CD20 cluster scores. Notably, enriched abundance of Tfh cells (HR 0.20, p = 0.04), and diminished abundance of Treg cells (HR 0.10, p = 0.03), together with an overall short distance between Tfh and B cells (HR:0.08, p < 0.01), but not between Treg and B cells (HR 0.43, p = 0.28), were significantly associated with overall survival of patients with OSCC. Our study identified the prognostic value of clusters between CD20 B cells and Tfh cells in the stromal IM of OSCC patients, and enabled an improved understanding of the clinical value of a high CD20 cluster score, which requires validation in larger clinical cohorts. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to identify risk factors for the development of second primary tumors (SPTs) in the head and neck region, lungs, and esophagus in patients with head and neck cancer. Methods: We collected data from 1581 patients. A cause‐specific Cox model for the development of an SPT was fitted, accounting for the competing risks residual/recurrent tumor and mortality. Results: Of all patients, 246 (15.6%) developed SPTs. Analysis showed that tobacco and alcohol use, comorbidity, and the oral cavity subsite were risk factors for SPTs. The C‐index, the discriminative accuracy, of the model for SPT was 0.65 (95% confidence interval, 0.61–0.68). Conclusions: Our results show that there is potential to identify patients who have an increased risk to develop an SPT. This might increase their survival chances and quality of life. More research is needed to provide head and neck clinicians with definitive recommendations. [ABSTRACT FROM AUTHOR]

Background: Total laryngectomy with or without adjuvant (chemo)radiation often induces speech, swallowing and neck and shoulder problems. Speech, swallowing and shoulder exercises may prevent or diminish these problems. The aim of the present paper is to describe the study, which is designed to investigate the effectiveness and cost-utility of a guided self-help exercise program built into the application "In Tune without Cords" among patients treated with total laryngectomy.Methods/design: Patients, up to 5 years earlier treated with total laryngectomy with or without (chemo)radiation will be recruited for participation in this study. Patients willing to participate will be randomized to the intervention or control group (1:1). Patients in the intervention group will be provided access to a guided self-help exercise program and a self-care education program built into the application "In Tune without Cords". Patients in the control group will only be provided access to the self-care education program. The primary outcome is the difference in swallowing quality (SWAL-QOL) between the intervention and control group. Secondary outcome measures address speech problems (SHI), shoulder disability (SDQ), quality of life (EORTC QLQ-C30, QLQ-H&N35 and EQ-5D), direct and indirect costs (adjusted iMCQ and iPCQ measures) and self-management (PAM). Patients will be asked to complete these outcome measures at baseline, immediately after the intervention or control period (i.e. at 3 months follow-up) and at 6 months follow-up.Discussion: This randomized controlled trial will provide knowledge on the effectiveness of a guided self-help exercise program for patients treated with total laryngectomy. In addition, information on the value for money of such an exercise program will be provided. If this guided self-help program is (cost)effective for patients treated with total laryngectomy, the next step will be to implement this exercise program in current clinical practice.Trial Registration: NTR5255 Protocol version 4 date September 2015. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether porous titanium can provide a better support for revascularization of a mucosal graft ideal for tracheal reconstruction. In patients with laryngotracheal stenosis or tumor, the mucosa with supporting structures can be damaged, resulting in a defect that has to be reconstructed. Autologous tissues like cartilage and mucosa have been used for reconstruction. The main problem has been incomplete mucosal reepithelialization. Design: In the first experiment, porous titanium or ear cartilage was combined with mucosa and implanted subcutaneously in athymic mice for different periods of time. In the second experiment, using rabbits, surgically created defects were reconstructed with porous titanium and mucosa on a pedicled fascia flap using a 2-stage procedure. The implants were analyzed with emphasis on angiogenesis and mucosal survival. Subjects: Male New Zealand white rabbits and nude athymic mice (BALB-c nu/nu). Results: Normal mucosa having a submucosal layer with vital cells was noted on top of the titanium. Multiple blood vessels were observed extending from the muscle layer through the titanium. Cytokeratin expressionwasdetected in the suprabasalandbasal layers of themucosalepithelium. In contrast, the mucosa on cartilage showed no vital cells andnocytokeratin expression. In the rabbit experiment, all animals survived the reconstruction.Thetitaniumwaswell integrated to the adjacent tracheal cartilage and surrounding tissues, supporting a fully vital mucosa. Conclusions: Porous titanium is an inert biomaterial that provides supportandallows easy revascularization of amucosal graft.Titanium,incombinationwithviableautologous tissues, is a good alternative for tracheal reconstruction. [ABSTRACT FROM AUTHOR]

Simple Summary: Laryngeal cancer is a prevalent head and neck malignancy, with poor prognosis and low survival rates for patients with advanced disease. The recurrence rate for advanced laryngeal cancer is between 25 and 50%. In order to improve surgical resection of laryngeal cancer and reduce local recurrence rates, various intraoperative optical imaging techniques have been investigated. In this systematic review we identify these technologies, evaluating the current state and future directions of optical imaging for this indication. Evidently, the investigated imaging modalities are generally unsuitable for deep margin assessment, and, therefore, inadequate to guide resection in advanced laryngeal disease. We discuss two optical imaging techniques that can overcome these limitations and suggest how they can be used to achieve adequate margins in laryngeal cancer at all stages. Laryngeal cancer is a prevalent head and neck malignancy, with poor prognosis and low survival rates for patients with advanced disease. Treatment consists of unimodal therapy through surgery or radiotherapy in early staged tumors, while advanced stage tumors are generally treated with multimodal chemoradiotherapy or (total) laryngectomy followed by radiotherapy. Still, the recurrence rate for advanced laryngeal cancer is between 25 and 50%. In order to improve surgical resection of laryngeal cancer and reduce local recurrence rates, various intraoperative optical imaging techniques have been investigated. In this systematic review, we identify these technologies, evaluating the current state and future directions of optical imaging for this indication. Narrow-band imaging (NBI) and autofluorescence (AF) are established tools for early detection of laryngeal cancer. Nonetheless, their intraoperative utility is limited by an intrinsic inability to image beyond the (sub-)mucosa. Likewise, contact endoscopy (CE) and optical coherence tomography (OCT) are technically cumbersome and only useful for mucosal margin assessment. Research on fluorescence imaging (FLI) for this application is sparse, dealing solely with nonspecific fluorescent agents. Evidently, the imaging modalities that have been investigated thus far are generally unsuitable for deep margin assessment. We discuss two optical imaging techniques that can overcome these limitations and suggest how they can be used to achieve adequate margins in laryngeal cancer at all stages. [ABSTRACT FROM AUTHOR]

Objectives: The guided self-help exercise program called In Tune without Cords (ITwC) is effective in improving swallowing problems and communication among patients treated with a total laryngectomy (TL). This study investigated the cost-utility and cost-effectiveness of ITwC., Materials and Methods: Patients within 5 years after TL were included in this randomized controlled trial. Patients in the intervention group (n = 46) received access to the self-help exercise program with flexibility, range-of-motion and lymphedema exercises, and a self-care education program. Patients in the control group (n = 46) received access to the self-care education program only. Healthcare utilization (iMCQ), productivity losses (iPCQ), health status (EQ-5D-3L, EORTC QLU-C10D) and swallowing problems (SwalQol) were measured at baseline, 3- and 6-months follow-up. Hospital costs were extracted from medical files. Mean total costs and effects (quality-adjusted life-years (QALYs) or SwalQol score) were compared with regression analyses using bias-corrected accelerated bootstrapping., Results: Mean total costs were non-significantly lower (-€685) and QALYs were significantly higher (+0.06) in the intervention compared to the control group. The probability that the intervention is less costly and more effective was 73%. Sensitivity analyses with adjustment for baseline costs and EQ-5D scores showed non-significantly higher costs (+€119 to +€364) and QALYs (+0.02 to +0.03). A sensitivity analysis using the QLU-C10D to calculate QALYs showed higher costs (+€741) and lower QALYs (-0.01) and an analysis that used the SwalQol showed higher costs (+€232) and higher effects (improvement of 6 points on a 0-100 scale)., Conclusion: ITwC is likely to be effective, but possibly at higher expenses., Trial Registration: NTR5255., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the effectiveness of a guided self-help exercise program on swallowing, speech, and shoulder problems in patients treated with total laryngectomy (TL)., Materials and Methods: This randomized controlled trial included patients treated with TL in the last 5 years. Patients were randomized into the intervention group (self-help exercise program with flexibility, range-of-motion and lymphedema exercises and self-care education program) or control group (self-care education program). Both groups completed measurements before and 3 and 6-months after randomization. The primary outcome was swallowing problems (SWAL-QOL). Secondary outcomes were speech problems (SHI), shoulder problems (SDQ), self-management (patient activation: PAM) and health-related quality of life (HRQOL: EORTC QLQ-C30/H&N35). Adherence was defined as moderate-high in case a patient exercised >1 per day. Linear mixed model analyses were conducted to investigate the effectiveness of the intervention and to investigate whether neck dissection, treatment indication (primary/salvage TL), time since treatment, severity of problems, and preferred format (online/booklet) moderated the effectiveness., Results: Moderate-high adherence to the exercise program was 59%. The intervention group (n = 46) reported less swallowing and communication problems over time compared to the control group (n = 46) (p-value = 0.013 and 0.004). No difference was found on speech, shoulder problems, patient activation and HRQOL. Time since treatment moderated the effectiveness on speech problems (p-value = 0.025): patients within 6 months after surgery benefitted most from the intervention. Being treated with a neck dissection, treatment indication, severity of problems and format did not moderate the effectiveness., Conclusion: The guided self-help exercise program improves swallowing and communication., Trial Registration: NTR5255., Competing Interests: Declaration of Competing Interest IV obtained funding for research related to In Tune without Cords from the Michel Keijzer Fund (institutional funding). The other authors declare that they have no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To investigate whether porous titanium can provide a better support for revascularization of a mucosal graft ideal for tracheal reconstruction. In patients with laryngotracheal stenosis or tumor, the mucosa with supporting structures can be damaged, resulting in a defect that has to be reconstructed. Autologous tissues like cartilage and mucosa have been used for reconstruction. The main problem has been incomplete mucosal reepithelialization., Design: In the first experiment, porous titanium or ear cartilage was combined with mucosa and implanted subcutaneously in athymic mice for different periods of time. In the second experiment, using rabbits, surgically created defects were reconstructed with porous titanium and mucosa on a pedicled fascia flap using a 2-stage procedure. The implants were analyzed with emphasis on angiogenesis and mucosal survival., Subjects: Male New Zealand white rabbits and nude athymic mice (BALB-c nu/nu)., Results: Normal mucosa having a submucosal layer with vital cells was noted on top of the titanium. Multiple blood vessels were observed extending from the muscle layer through the titanium. Cytokeratin expression was detected in the suprabasal and basal layers of the mucosal epithelium. In contrast, the mucosa on cartilage showed no vital cells and no cytokeratin expression. In the rabbit experiment, all animals survived the reconstruction. The titanium was well integrated to the adjacent tracheal cartilage and surrounding tissues, supporting a fully vital mucosa., Conclusions: Porous titanium is an inert biomaterial that provides support and allows easy revascularization of a mucosal graft. Titanium, in combination with viable autologous tissues, is a good alternative for tracheal reconstruction.