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Introduction: Esophageal cancer is an increasingly common type of neoplasm with a very poor prognosis. This prognosis could improve with more early tumor detection. We have previously shown that we can use an optical spectroscopy to detect field cancerization in the buccal mucosa of patients with laryngeal cancer. The aim of this prospective study was to investigate whether we could detect field cancerization of buccal mucosa of patients with esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Methods: Optical measurements were performed in vivo using a novel optical technique: multidiameter single-fiber reflectance (MDSFR) spectroscopy. MDSFR spectra were acquired by a handheld probe incorporating three fiber diameters. Multiple absorption and scattering parameters that are related to the physiological and ultrastructural properties of the buccal mucosa were derived from these spectra. A linear discriminant analysis of the parameters was performed to create a combined biomarker σ to discriminate oncologic from non-oncologic patients. Results: Twelve ESCC, 12 EAC, and 24 control patients were included in the study. The median value of our biomarker σ was significantly higher in patients with ESCC (2.07 [1.93-2.10]) than control patients (1.86 [1.73-1.95], p = 0.022). After cross-validation σ was able to identify ESCC patients with a sensitivity of 66.7% and a specificity of 70.8%. There were no significant differences between the EAC group and the control group. Conclusion: Field cancerization in the buccal mucosa can be detected using optical spectroscopy in ESCC patients. This may be the first step towards non-invasive ESCC cancer screening.

Although the receptor tyrosine kinase (RTK) MET is widely expressed in head and neck squamous cell carcinoma (HNSCC), its prognostic value remains unclear. This might be due to the use of a variety of antibodies and scoring systems. Here, the reliability of five commercial C-terminal MET antibodies (D1C2, CVD13, SP44, C-12 and C-28) was evaluated before examining the prognostic value of MET immunoreactivity in HNSCC. Using cancer cell lines, it was shown that D1C2 and CVD13 specifically detect MET under reducing, native and formalin-fixed paraffin-embedded (FFPE) conditions. Immunohistochemical staining of routinely FFPE oral SCC with D1C2 and CVD13 demonstrated that D1C2 is most sensitive in the detection of membranous MET. Examination of membranous D1C2 immunoreactivity with 179 FFPE oral and oropharyngeal SCC - represented in a tissue microarray - illustrated that staining is either uniform (negative or positive) across tumors or differs between a tumor's center and periphery. Ultimately, statistical analysis revealed that D1C2 uniform staining is significantly associated with poor 5-year overall and disease free survival of patients lacking vasoinvasive growth (HR = 3.019, p < 0.001; HR = 2.559, p < 0.001). These findings might contribute to reliable stratification of patients eligible for treatment with biologicals directed against MET.

The purpose of this review was to identify publications on resection margins in oral cancer surgery and compare these with the results from 2 Dutch academic medical centers. Eight publications were considered relevant for this study, reporting 30% to 65% inadequate resection margins (ie, positive and close margins), compared to 85% in Dutch centers. However, clinical outcome in terms of overall survival and recurrence seemed comparable. The misleading difference is caused by lack of unanimous margin definition and differences in surgicopathological approaches. This prevents comparison between the centers. Data from Dutch centers showed that inadequate resection margins have a significantly negative effect on local recurrence, regional recurrence, distant metastasis, and overall survival. These results confirm the need for improvement in oral cancer surgery. We underline the need for consistent protocols and optimization of frozen section procedures. We comment on development of optical techniques for intraoperative assessment of resection margins. (C) 2015 Wiley Periodicals, Inc.

Recent studies have reported that p16 protein overexpression qualifies as a surrogate marker identifying an oncogenic human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC). However, there is still a percentage of OPSCCs that are positive for p16 immunohistochemistry (p16 IHC) but lack HPV DNA. The objective of this study was to characterize this group at the molecular level by performing sensitive HPV DNA- and RNA-based PCR methods and genetic profiling. All patients diagnosed with an OPSCC in the period 2000-2006 in two Dutch university medical centers were included (n = 841). The presence of HPV in a tumor sample was tested by p16 IHC followed by an HPV DNA GP5+/6+ PCR. p16 IHC scored positive in 195 samples, of which 161 were HPV DNA-positive and 34 (17%) HPV DNA-negative. In the latter group, a SPF10-LiPA25 assay, an HPV16 type-specific E7 PCR and an E6 mRNA RT-PCR were performed. Next, ten of these cases were further analyzed for loss of heterozygosity (LOH) of 15 microsatellite markers at chromosome arms 3p, 9p and 17p. Of the 34 p16-positive but PCR-negative OPSCCs, two samples tested positive by SPF10 assay, HPV16 E7 PCR and HPV16 E6 mRNA RT-PCR. Three samples tested positive by SPF10 assay but negative by the HPV16-specific assays. Nine of ten cases that were tested for LOH showed a genetic pattern comparable to that of HPV-negative tumors. This study categorizes p16-positive but HPV DNA-negative OPSCCs as HPV-negative tumors based on genetic profiling. This study highlights the importance of performing HPV testing in addition to p16 IHC for proper identification of HPV-associated OPSCCs. What's new? Besides tobacco and alcohol consumption, high-risk human papillomavirus (HPV) infection is etiologically linked to the development of oropharyngeal squamous cell carcinoma (OPSCC). Knowledge of HPV-status provides prognostic information and may guide treatment decisions. Recent studies have reported that p16-protein overexpression qualifies as a surrogate marker for oncogenic HPV infection in OPSCC. However, there is still a percentage of OPSCCs that are positive for p16-immunohistochemistry (p16-IHC) but lack HPV DNA. This study categorizes p16-positive but HPV DNA-negative OPSCCs as HPV-negative tumors based on genetic profiling, highlighting the importance of HPV testing in addition to p16-IHC for proper identification of HPV-associated OPSCCs.

Background. Literature is scarce on the palliative care experiences of patients with head and neck cancer. We report our experience in this patient population after the establishment of our Expert Center. Methods. We administered a questionnaire to 40 surviving relatives of patients with head and neck cancer after the establishment of our Expert Center and compared the results to a similar group of patients with head and neck cancer before the establishment of our Expert Center. Results. Since the establishment of our Expert Center, we found: an improved evaluation of the psychosocial support offered; better contact between head and neck surgeons, the patients, and families; and improvement in the quantity of information in the palliative phase. Some relatives, however, reported that patients received treatment against their wishes and life was not made as comfortable as possible. Conclusion. Important aspects of palliative care, such as psychosocial support and contact between patient and surgeon, have been improved since the establishment of our Expert Center. (C) 2013 Wiley Periodicals, Inc.

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Objective: To investigate the influence of previous tumours on overall survival in patients with early glottic carcinoma. Design: Retrospective, population-based cohort study. Setting: Cancer registration area in the west Netherlands. Methods: Population-based data on previous and subsequent tumours in patients diagnosed with early glottic carcinoma (Tis and T1) in the west Netherlands between 1982 and 1993 were collected from charts and cancer registries. The impact of previous tumours on survival was tested in multivariate analysis. Main Outcome Measures: Overall survival. Results: Of 359 patients, 22 patients (6%) had a total of 23 previous tumours. Previous tumours had an independent impact on overall survival (hazard ratio 3.4, p

Objective: To compare voice quality after radiotherapy or endoscopic laser surgery in patients with similar Tla midcord glottic carcinomas according to a validated multidimensional protocol. Design: Retrospective cohort study. Setting: University cancer referral center. Patients: Two cohorts of consecutive patients willing to participate after treatment for primary Tla midcord glottic carcinoma with laser surgery (18 of 23 eligible) or radiotherapy (16 of 18 eligible). Main Outcome Measures: Posttreatment voice quality was evaluated according to a multidimensional voice protocol based on validated European Laryngological Society recommendations, including perceptual, acoustic, aerodynamic, and stroboscopic analyses, together with patient self-assessment using the Voice Handicap Index. Results: Approximately half of the patients had mild to moderate voice dysfunction in the perceptual analysis (53% [8 of 15] in the radiotherapy group and 61% [11 of 18] in the laser surgery group) and on the Voice Handicap Index (44% [7 of 16] in the radiotherapy group and 56% [10 of 18] in the laser surgery group). The voice profile in the laser surgery group was mainly breathy; in the radiotherapy group, it was equally breathy and rough, with a trend for more jitter in the acoustic analysis. There was no statistical difference in the severity of voice dysfunction between the groups in any of the variables. Conclusions: Endoscopic laser surgery offers overall voice quality equivalent to that of radiotherapy for patients with Tla midcord glottic carcinoma, although specific voice profiles may ultimately be different for the 2 modalities. We believe that endoscopic laser surgery is the preferred treatment in these patients because it provides oncologic control similar to that of radiotherapy and the additional benefits of lower costs, shorter treatment time, and the possibility of successive procedures.

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During recent decades, many studies have been performed in patients with early glottic cancer, which provide new insight into the two main treatment modalities, TOLMS and radiotherapy, and their outcomes. The aim of this thesis was: (i) What is the role of TOLMS in T2 glottic carcinoma in the Netherlands? (ii) Should more patients with T2 glottic carcinoma be treated with TOLMS? Within this thesis, we found that (i) the laryngeal preservation rate for T2 glottic carcinoma is higher after primary treatment with TOLMS than after primary treatment with radiotherapy; (ii) that the binary use (yes/no) for the involvement of the anterior commissure (AC) as a prognostic factor leads to inconsistent results, whereas studies with a more detailed classification of the AC show that there is a significant impact on oncological outcomes; (iii) that vertical involvement of the AC on imaging has a significant impact on local control not only in patients treated with TOLMS but also in patients receiving primary radiotherapy; and (iv) that patient with T2 glottic carcinoma treated with radiotherapy reported good long-term functional outcomes, although patients with tumors infiltrating the vocal fold muscle show a trend toward a higher degree of voice handicap than patients with tumor with only superficial spread.

During recent decades, many studies have been performed in patients with early glottic cancer, which provide new insight into the two main treatment modalities, TOLMS and radiotherapy, and their outcomes. The aim of this thesis was: (i) What is the role of TOLMS in T2 glottic carcinoma in the Netherlands? (ii) Should more patients with T2 glottic carcinoma be treated with TOLMS? Within this thesis, we found that (i) the laryngeal preservation rate for T2 glottic carcinoma is higher after primary treatment with TOLMS than after primary treatment with radiotherapy; (ii) that the binary use (yes/no) for the involvement of the anterior commissure (AC) as a prognostic factor leads to inconsistent results, whereas studies with a more detailed classification of the AC show that there is a significant impact on oncological outcomes; (iii) that vertical involvement of the AC on imaging has a significant impact on local control not only in patients treated with TOLMS but also in patients receiving primary radiotherapy; and (iv) that patient with T2 glottic carcinoma treated with radiotherapy reported good long-term functional outcomes, although patients with tumors infiltrating the vocal fold muscle show a trend toward a higher degree of voice handicap than patients with tumor with only superficial spread.

Because of the disappointing progress that has been made in the last decades in survival in patients with head and neck cancer, existing therapy needs to be improved and/or new treatment needs to be introduced. This thesis describes a new promising treatment, apoptin gene therapy. The scope of this study was to investigate the applicability of apoptin in head and neck squamous cell carcinoma (HNSCC). First, we assessed its potential in-vitro. Next, a suitable animal model was established, which was used for in-vivo experiments with apoptin. In chapter 2 we describe the results of apoptin treatment in a HNSCC cell line with a mutated p53 and the effect of over-expression of Bcl-xL on the outcome. Chapter 3 describes the synergistic effect of apoptin and irradiation in HNSCC both in radiation sensitive and in more radioresistant HNSCC cell lines. The applicability of an immune competent animal model for in-vivo research is described in chapter 4. The time needed to establish a useful oral squamous cell carcinoma in mice is assessed and immunological comparisons are made with human counterparts. In chapter 5 the tumorigenesis of the same carcinogenic immune competent model is investigated and characteristics are analyzed. The efficacy of the apoptin therapy in-vivo is described in chapter 6. This is done by looking into the effect of intratumoral injection of a constructed adenovirus expressing the apoptin protein. Finally, the data are critically discussed in chapter 7 in view of apoptin as a potential new anti-cancer therapy.

The general aim of this thesis is to determine and compare disease and voice outcome for T1 glottic carcinoma treated with radiotherapy or laser surgery. The findings show similar oncological and functional results for radiotherapy and laser surgery in __superficial midcord T1a glottic carcinoma__. This outcome supports the Dutch national guideline __Treatment of Laryngeal Carcinoma__ which was published during the life-time of this thesis. In this guideline laser surgery is labeled treatment of choice in these lesions because of the shorter treatment duration, lower costs and the possibility for repeated treatments and/or additional radiotherapy. For larger T1 lesions, our literature review concludes that more comparative data, especially on functional results, are needed before definite conclusions can be drawn as to the role of laser surgery in these lesions. These studies are now being perform ed in a collaboration between the Leiden University Medical Center and the Eramus Medical Center, Rotterdam.