Development of a near-infrared Raman spectroscopy setup compatible with fluorescence-guided surgery.

Near-infrared (NIR) fluorescence imaging using exogenous fluorescent agents provides whole-field images in real-time to assist the surgeon in the excision of a tumor. Although the method has high sensitivity, the specificity can sometimes be lower than expected. Raman spectroscopy can detect tumors with high specificity. Therefore, a combination of both techniques can be advantageous. A complication that must be addressed is that the NIR spectral region is favored by both techniques for (in vivo) tissue analysis. When fluorescence and Raman emissions spectrally overlap, it becomes challenging or impossible to detect the Raman signal. In this paper, by avoiding this overlap, we describe a Raman spectroscopy setup capable of recording high-quality Raman spectra from tissue containing NIR exogenous fluorescent agents. We identify an optimal wavelength interval (900-915 nm) for Raman excitation, which avoids both excitation of fluorescent dyes and Raman signal self-absorption by the tissue. In this way, Raman spectroscopy can be combined with the currently most-used NIR fluorescent dyes. This combined novel setup could pave the way for clinical trials benefiting from both fluorescence imaging and Raman spectroscopy to avoid positive margins in cancer surgery.

Detecting head and neck lymph node metastases with white light reflectance spectroscopy; a pilot study.

INTRODUCTION: A challenge in the treatment of patients with head and neck cancer is the management of occult cervical lymph node (LN) metastases. Single-fiber reflectance (SFR) spectroscopy has the potential to detect physiological tissue changes that occur in a positive LN. This pilot study aimed to investigate whether SFR spectroscopy could serve as an alternative or additional technique to detect cervical lymph node metastases. MATERIALS AND METHODS: We performed intraoperative SFR spectroscopy measurements of LNs with and without malignancies. We analyzed if physiological and scattering parameters were significantly altered in positive LNs. RESULTS: Nine patients with a total of nineteen LNs were included. Three parameters, blood volume fraction (BVF), microvascular saturation (StO2), and Rayleigh amplitude, were significantly lower in positive LNs. They were combined into one optical parameter 'delta', using discriminant analysis. Delta was significantly decreased in positive LNs, p = 0,0006. It had a high diagnostic accuracy where the sensitivity, specificity, PPV, and NPV were 90,0%, 88.9%, 90,0%, and 88.9%, respectively. The area under the ROC curve was 96.7% (95% confidence interval 89.7-100.0%). CONCLUSION: This proof of principle study is a first step in the development of an SFR spectroscopy technique to detect LN metastases in real time. A next step towards this goal is replicating these results in LNs with smaller metastases and in a larger cohort of patients. This future study will combine SFR spectroscopy with fine-needle aspiration, using the same needle, to perform preoperative in vivo measurements.

Current Intraoperative Imaging Techniques to Improve Surgical Resection of Laryngeal Cancer: A Systematic Review.

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.

Cost-utility and cost-effectiveness of a guided self-help head and neck exercise program for patients treated with total laryngectomy: Results of a multi-center randomized controlled trial.

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.

Real-time fluorescence imaging in intraoperative decision making for cancer surgery.

Fluorescence-guided surgery is an intraoperative optical imaging method that provides surgeons with real-time guidance for the delineation of tumours. Currently, in phase 1 and 2 clinical trials, evaluation of fluorescence-guided surgery is primarily focused on its diagnostic performance, although the corresponding outcome variables do not inform about the added clinical benefit of fluorescence-guided surgery and are challenging to assess objectively. Nonetheless, the effect of fluorescence-guided surgery on intraoperative decision making is the most objective outcome measurement to assess the clinical value of this imaging method. In this Review, we explore the study designs of existing trials of fluorescence-guided surgery that allow us to extract information on potential changes in intraoperative decision making, such as additional or more conservative resections. On the basis of this analysis, we offer recommendations on how to report changes in intraoperative decision making that result from fluorescence imaging, which is of utmost importance for the widespread clinical implementation of fluorescence-guided surgery.

A cause-specific Cox model for second primary tumors in patients with head and neck cancer: A RONCDOC study.

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.

Head and neck cancer patients' preferences for individualized prognostic information: a focus group study.

BACKGROUND: Head and Neck cancer (HNC) is characterized by significant mortality and morbidity. Treatment is often invasive and interferes with vital functions, resulting in a delicate balance between survival benefit and deterioration in quality of life (QoL). Therefore, including prognostic information during patient counseling can be of great importance. The first aim of this study was to explore HNC patients' preferences for receiving prognostic information: both qualitative (general terms like "curable cancer"), and quantitative information (numbers, percentages). The second aim of this study was to explore patients' views on "OncologIQ", a prognostic model developed to estimate overall survival in newly diagnosed HNC patients. METHODS: We conducted a single center qualitative study by organizing five focus groups with HNC patients (n = 21) and their caregivers (n = 19), categorized in: 1) small laryngeal carcinomas treated with radiotherapy or laser, 2) extensive oral cavity procedures, 3) total laryngectomy, 4) chemoradiation, 5) other treatments. The patients' perspective was the main focus. The interview guide consisted of two main topics: life-expectancy and the prognostic model OncologIQ. All focus groups were recorded, transcribed and coded. Themes were derived using content analysis. RESULTS: While all patients considered it somewhat to very important to receive information about their life-expectancy, only some of them wanted to receive quantitative information. Disclosing qualitative prognostic information like "the cancer is curable" would give enough reassurance for most patients. Overall, patients thought life-expectancy should not be discussed shortly after cancer diagnosis disclosure, as a certain time is needed to process the first shock. They had a stronger preference for receiving prognostic information in case of a poor prognosis. Prognostic information should also include information on the expected QoL. The pie chart was the most preferred chart for discussing survival rates. CONCLUSIONS: The participants found it important to receive information on their life-expectancy. While most patients were enough reassured by qualitative prognostic information, some wanted to receive quantitative information like OncologIQs' estimates. A tailor-made approach is necessary to provide customized prognostic information. A clinical practice guideline was developed to support professionals in sharing prognostic information, aiming to improve shared decision making and patient-centered care.

Effectiveness of a guided self-help exercise program tailored to patients treated with total laryngectomy: Results of a multi-center randomized controlled trial.

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.

Cystic Degeneration of Craniofacial Fibrous Dysplasia.

BACKGROUND: Fibrous dysplasia (FD) is most often a slowly progressive benign disease in which the normal bone structure is replaced by fibrous and osteoid tissue. CASE DESCRIPTION: A 16-year-old adolescent, known with FD in the sphenoid bone, suffered an acute decreased visual acuity with papilledema on the left eye. The radiologic images were best compatible with cystic degeneration of the known FD with optic nerve compression in the optic canal. Decompression of the optic nerve was performed through an endoscopic exploration of the left sphenoid sinus. The visual acuity recovered completely. CONCLUSIONS: In FD with cystic changes, leading to acute signs of optic nerve compression, early aggressive surgical decompression is strongly recommended. Cystic degeneration of the FD, although rare, should be considered.

Nodal response after 46 Gy of intensity-modulated radiotherapy is associated with human papillomavirus-related oropharyngeal carcinoma.

OBJECTIVES/HYPOTHESIS: This study aimed to analyze the effect of human papillomavirus (HPV)-associated T1-2 node-positive oropharyngeal squamous cell carcinoma (OPSCC) on nodal response, recurrent disease, and survival in patients treated according to the Rotterdam protocol. STUDY DESIGN: Retrospective cohort study. METHODS: In total, 77 patients with T1-2 OPSCC with nodal disease, treated between 2000 and 2012, were included in this study. Patients were treated according to the Rotterdam protocol: 46 Gy of IMRT followed by a local boost using cyberknife or brachytherapy (22 Gy) and neck dissection. The presence of HPV was determined by p16INK4A immunostaining. Outcomes were overall survival, disease-free survival, and the extent of nodal response. Nodal stage was determined following the 7th and 8th American Joint Cancer Committee/Union for International Cancer Control classification. RESULTS: Overall, 68.4% of patients had p16-positive disease, and 35.4% of all patients achieved complete nodal response (pN0) after 46 Gy of intensity-modulated radiotherapy (IMRT). Based on the 7th TNM classification, nodal response (partial or complete) was significantly associated with HPV status (P = .002). Patients with p16-positive OPSCC had an odds ratio (OR) of 4.6 to achieve complete nodal response. However, smoking interacted with this effect. Applying the 8th TNM classification, complete or partial response was associated with HPV status but was not significant (OR: 1.7, P = .138). Complete nodal response led to 100% overall survival in p16-positive OPSCC patients. CONCLUSIONS: HPV-related OPSCCs are associated with complete nodal response after 46 Gy of IMRT. Patients with full regional control (pN0) after IMRT and subsequent neck dissection show a significantly better overall survival, but smoking negatively interacts with this effect. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2333-2340, 2018.

Effectiveness and cost-utility of a guided self-help exercise program for patients treated with total laryngectomy: protocol of a multi-center randomized controlled trial.

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.

Highly-conformal intensity-modulated radiotherapy reduced toxicity without jeopardizing outcome in patients with paranasal sinus cancer treated by surgery and radiotherapy or (chemo)radiation.

OBJECTIVES: To report oncologic outcomes of patients with paranasal sinus cancer (PNSC) treated by surgery and radiotherapy or (chemo)radiation and to investigate the impact of improving the radiation technique on outcomes and toxicity. MATERIALS AND METHODS: Between 1999 and 2010, 82 consecutive patients with PNSC were treated by surgery and radiotherapy or by definitive (chemo)radiation. Three-dimensional conformal (3DCRT) or highly-conformal intensity-modulated RT (IMRT) was used. Endpoints were local control (LC), regional control (RC), disease-free (DFS), cause-specific (CSS), and overall survival (OS), late toxicity, and quality-of-life (QoL). RESULTS: After median follow-up of 51 months, the 5-year actuarial rates of LC, RC, DFS, CSS, and OS were 74%, 94%, 56%, 64%, and 54%, respectively. Grade ≥ 2 late toxicity at 5-years was 28%. High T-stage and perineural invasion were significantly associated with poor LC and RT-technique with late toxicity. Late toxicity was significantly lowered using IMRT, compared to 3DCRT (17% vs. 52%, p<0.0001). Visual preservation were significantly improved using IMRT (88% and 65%, respectively, p=0.01). LC-rate was also improved by IMRT (80% vs. 64%, respectively, p=0.2). QoL-scores deteriorated during and shortly after treatment but returned in almost all scales to baseline levels within 3-12 months. CONCLUSIONS: Surgery and radiotherapy or definitive (chemo)radiation resulted in good LC rates but with high rate of late side-effects. However, late toxicity and permanent visual impairment were significantly decreased by using highly-conformal IMRT without jeopardizing outcome. The improvements in the therapeutic ratio achieved by using IMRT would allow dose escalation of RT to further improve outcomes.

Adenoid cystic carcinoma of parotid gland treated with surgery and radiotherapy: long-term outcomes, QoL assessment and review of the literature.

To assess outcomes, toxicity and quality-of-life (QoL) of patients with parotid gland adenoid cystic carcinoma (PGACC) treated by surgery and postoperative radiotherapy. Between 1995 and 2010, 46 patients with PGACC were treated with parotidectomy±neck dissection followed by radiotherapy. Endpoints were loco-regional control (LRC), distant metastasis-free (DMFS), disease-free (DFS), cause-specific (CSS), and overall survival (OS), late toxicity, and QoL. After a median follow-up of 58 months (range 4-171), the 5-year Kaplan-Meier estimates of LRC, DMFS, DFS, CSS, and OS were 88%, 78%, 75%, 80%, and 67%, respectively and the 8-year rates were 88%, 75%, 72%, 77%, and 64%, respectively. On multivariate analysis, T-stage, N-stage, tumor grade, and perineural invasion correlate significantly with DMFS and DFS. The overall 5-year cumulative incidence of grade ≥2 late toxicity was 9%. QoL-scores deteriorate during and shortly after treatment but returned in all scales to almost baseline levels within 6 months. Excellent LRC rates were achieved in patients with PGACC treated by surgery and postoperative radiotherapy with low rate of late side-effects and preservation of good QoL. Despite the effective local therapy, 9 of 46 patients (20%) failed distantly. Because effective treatment strategies for this problem are lacking, prospective trials are needed to determine the role of adjuvant systemic or targeted therapy in patients at high risk of DM.

Laryngotracheal reconstruction with porous titanium in rabbits: are vascular carriers and mucosal grafts really necessary?

Laryngotracheal reconstruction requires a supportive structure with a mucosal lining, which needs a vascular supply in order to regenerate properly. We investigated the necessity of a vascular carrier and mucosal graft when using porous titanium for laryngotracheal reconstruction. Surgical defects of the laryngotracheal complex in 22 rabbits were reconstructed with: (a) porous titanium implanted on a vascularized fascia combined with a buccal mucosal graft (first stage) before transposing to the neck area (second stage); (b) porous titanium implanted on a vascularized fascia (first stage) combined with a mucosal graft (second stage); (c) porous titanium on a pedicled fascia flap; and (d) porous titanium alone. The grafts were tolerated well. Re-epithelialization occurred in all groups. Normal mucosa with a submucosal layer containing vital cells was noted using the titanium implants. Blood vessels were grown in the pores of the titanium scaffold to supply the overlying mucosa. The scaffold was well integrated in the adjacent tracheal cartilage and surrounding tissues, except in the two cases that showed titanium displacement. Inflammation and granulation formation were seen in most rabbits in groups III and IV, initiated probably by the use of buccal mucosal grafts. Reconstruction of a rabbit's trachea using composites of porous titanium, mucosal grafts and a fascia flap is feasible. Titanium seems to meet the requirements needed for closing a small defect of the tracheal wall and allows for re-epithelialization. For larger defects, a vascular carrier with a mucosal graft is probably indispensable to ensure the process of re-epithelialization.

Tracheal reconstruction: mucosal survival on porous titanium.

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.