Robert J. Baatenburg de Jong

Optical Image-guided Surgery—Where Do We Stand?

In cancer surgery, intra-operative assessment of the tumor-free margin, which is critical for the prognosis of the patient, relies on the visual appearance and palpation of the tumor. Optical imaging techniques provide real-time visualization of the tumor, warranting intra-operative image-guided surgery. Within this field, imaging in the near-infrared light spectrum offers two essential advantages: increased tissue penetration of light and an increased signal-to-background-ratio of contrast agents. In this article, we review the various techniques, contrast agents, and camera systems that are currently used for image-guided surgery. Furthermore, we provide an overview of the wide range of molecular contrast agents targeting specific hallmarks of cancer and we describe perspectives on its future use in cancer surgery.

Increasing prevalence rates of HPV attributable oropharyngeal squamous cell carcinomas in the Netherlands as assessed by a validated test algorithm

Human papillomavirus (HPV) infection has been etiologically linked to oropharyngeal squamous cell carcinoma (OPSCC). The prevalence of HPV‐positive OPSCC varies between studies, ranging from 20 to 90%. This may be related to the lack of a standardized HPV detection assay as well as to the time period in which HPV prevalence is investigated, as rising incidence rates are reported over the last decades. Here, we validated our previously defined test algorithm for HPV detection in formalin‐fixed paraffin‐embedded (FFPE) tumor specimen consisting of p16INK4A immunostaining followed by high‐risk HPV DNA detection by GP5+/6+ PCR on the positive cases (Smeets et al., Int J Cancer 2007;121:2465–72). In addition, we analyzed HPV prevalence rates in OPSCCs in the years 1990–2010. The test algorithm was validated on a consecutive series of 86 OPSCCs collected during 2008–2011, of which both fresh frozen and FFPE samples were available. We performed HPV‐E6 RT‐PCR on the frozen samples as gold standard and applied the algorithm to the corresponding FFPE samples. The test algorithm showed an accuracy of 98%. Using the validated algorithm, we determined the presence of an oncogenic HPV infection in 240 OPSCCs of patients diagnosed in the years 1990–2010 at our center. A significant increase in the proportion of HPV‐positive samples was observed, from 5.1% in 1990 to 29.0% in 2010 (p = 0.001). In conclusion, we confirmed the accuracy of the test algorithm for HPV detection in FFPE tumor specimen and we found a significant increase in the prevalence of HPV in OPSCC over the last two decades at our center.

Optical Image-Guided Cancer Surgery: Challenges and Limitations

Optical image-guided cancer surgery is a promising technique to adequately determine tumor margins by tumor-specific targeting, potentially resulting in complete resection of tumor tissue with improved survival. However, identification of the photons coming from the fluorescent contrast agent is complicated by autofluorescence, optical tissue properties, and accurate fluorescent targeting agents and imaging systems. All these factors have an important influence on the image that is presented to the surgeon. Considering the clinical consequences at stake, it is a prerequisite to answer the questions that are essential for the surgeon. What is optical image-guided surgery and how can it improve patient care? What should the oncologic surgeon know about the fundamental principles of optical imaging to understand which conclusions can be drawn from the images? And how do the limitations influence clinical decision making? This article discusses these questions and provides a clear overview of the basic principles and practical applications. Although there are limitations to the intrinsic capacity of the technique, when practical and technical surgical possibilities are considered, optical imaging can be a very powerful intraoperative tool in guiding the future oncologic surgeon toward radical resection and optimal clinical results. Clin Cancer Res; 19(14); 3745–54. ©2013 AACR.

Impact of comorbidity on short-term mortality and overall survival of head and neck cancer patients.

In 2001, we presented a Cox regression model that is able to predict survival of the newly diagnosed patient with head and neck squamous cell carcinoma (HNSCC). This model is based on the TNM classification and other important clinical variables such as age at diagnosis, sex, primary tumor site, and prior malignancies. We aim to improve this model by including comorbidity as an extra prognostic variable. Accurate prediction of the prognosis of the newly diagnosed patient with head and neck cancer can assist the physician in patient counseling, clinical decision‐making, and quality maintenance.

Staging and prognosis in head and neck cancer

Head and neck malignant tumors are classified according to the TNM staging system. The TNM system is a universally accepted, widely used, staging method. Its goals are to help clinicians and researchers to choose from treatment options, to give patients an estimate of their prognosis and to compare results of treatment. In this paper we discuss the history and daily usage of the TNM system and some pros and cons. In the field of prognostic estimations, particularly for the individual patient, the TNM system could be upgraded with other prognostic indicators. We discuss insights into enhanced usage of the TNM system and the possibilities of comprehensive and dynamic staging models.

Impact of severe malnutrition on short-term mortality and overall survival in head and neck cancer

BACKGROUND Basic patient and tumor characteristics impact overall survival of head and neck squamous cell carcinoma patients. Severe malnutrition, defined as weight loss > 10% in 6 months preceding primary tumor diagnosis, impacts overall survival as well. Little attention has been paid to the interaction between severe malnutrition and other relevant prognostic covariables. This study investigates the impact of malnutrition on short-term mortality and overall survival, together with the covariables age, tumor site, gender, TNM-classification, comorbidity and prior tumors. METHODS 383 consecutive primary HNSCC patients, diagnosed and treated between 1995 and 1999 were followed until January 2010. Impact of covariables on short-term mortality and overall survival was studied univariately with Kaplan-Meier curves and the log-rank test. Cox-regression and binary logistic regression were used for multivariate analyses. RESULTS 28 (7.3%) patients were severely malnourished. All covariables, except gender and prior tumors had significant impact on overall survival. The relative risk of severe malnutrition was 1.8 and is comparable to the impact of a T2 tumor, a N1 neck or moderate comorbidity. A univariate relationship between severe malnutrition and short-term mortality was established. CONCLUSIONS Severe malnutrition has an independent impact on overall survival of primary HNSCC patients. There is a clear distinction between patients with and without severe malnutrition from moment of diagnosis until 10 years after. This emphasizes the importance of identification and optimal treatment of malnutrition before, during and after cancer treatment.

INCIDENCE AND PREDICTION OF MAJOR CARDIOVASCULAR COMPLICATIONS IN HEAD AND NECK SURGERY

Patients with head and neck squamous cell carcinoma (HNSCC) usually have a history of tobacco and alcohol abuse. These 2 intoxications not only are main oncologic risk factors but also show a strong causal relationship with certain comorbid conditions. Examples are coronary artery disease, stroke, renal dysfunction, and heart failure, which are all proven major risk factors for an adverse postoperative outcome after stressful noncardiac surgery. Preoperative identification of these conditions could lead to preventive measures in patients with HNSCC that undergo extensive surgery. Preventing morbidity and mortality is of medical and economical importance.

Validation of a Gene Expression Signature for Assessment of Lymph Node Metastasis in Oral Squamous Cell Carcinoma

PURPOSE Current assessment of lymph node metastasis in patients with head and neck squamous cell carcinoma is not accurate enough to prevent overtreatment. The aim of this study was validation of a gene expression signature for distinguishing metastasizing (N+) from nonmetastasizing (N0) squamous cell carcinoma of the oral cavity (OSCC) and oropharynx (OPSCC) in a large multicenter cohort, using a diagnostic DNA microarray in a Clinical Laboratory Improvement Amendments/International Organization for Standardization-approved laboratory. METHODS A multigene signature, previously reported as predictive for the presence of lymph node metastases in OSCC and OPSCC, was first re-evaluated and trained on 94 samples using generic, whole-genome, DNA microarrays. Signature genes were then transferred to a dedicated diagnostic microarray using the same technology platform. Additional samples (n=222) were collected from all head and neck oncologic centers in the Netherlands and analyzed with the diagnostic microarray. Human papillomavirus status was determined by real-time quantitative polymerase chain reaction. RESULTS The negative predictive value (NPV) of the diagnostic signature on the entire validation cohort (n=222) was 72%. The signature performed well on the most relevant subset of early-stage (cT1-T2N0) OSCC (n=101), with an NPV of 89%. CONCLUSION Combining current clinical assessment with the expression signature would decrease the rate of undetected nodal metastases from 28% to 11% in early-stage OSCC. This should be sufficient to enable clinicians to refrain from elective neck treatment. A new clinical decision model that incorporates the expression signature is therefore proposed for testing in a prospective study, which could substantially improve treatment for this group of patients.

Hypofractionated radiotherapy denoted as the "Christie scheme": an effective means of palliating patients with head and neck cancers not suitable for curative treatment.

Objectives. A prospective study of the efficacy and toxicity profile of patients with squamous cell carcinoma of the head and neck (HNSCC) without curative treatment options treated consistently with hypofractionated radiotherapy schedule. Patients and methods. Between 1995 and 2006, 158 patients with HNSCC, unsuitable for curative treatment, were treated with a hypofractionated scheme of radiotherapy consisting of 16 fractions of 3.125 Gy. Endpoints of the study were response rates, loco-regional control, disease-free survival, overall survival, acute and late toxicity, and quality of life (QoL). Results. Seventy four percent of patients were male, 31% had oropharyngeal cancer and 81% stage IV disease. With 45% complete response and 28% partial response an overall response rate of 73% was achieved, 6% had stable disease, and 21% progressed during or directly after completion of treatment. Median survival time was 17 months and 62 patients (40%) survived ≥1 year after RT. The actuarial rates of loco-regional control, disease-free survival and overall survival were 62%, 32% and 40% at 1-year, respectively and 32%, 14% and 17% at 3-years, respectively. Acute grade ≥3 skin and mucosal toxicities were observed in 45% and 65% of patients, respectively. Severe late toxicity was reported in 4.5% of patients. Of patients surviving ≥1 year after RT, retrospective chart review showed that 50% gained weight, pain improved in 77%, performance status in 47% and only 29% of them was still feeding-tube dependent. Conclusions. Our hypofractionated radiotherapy scheme is an effective, well-tolerated and safe palliative schedule in HNSCC who are unsuitable for curative treatment options. Using 3.125 Gy per fraction (Christie scheme), excellent palliation was achieved resulting in acceptable response rates, excellent symptom control, acceptable toxicity profile, and good QoL of patients surviving ≥1 year after completion of treatment.

Targeting integrins and enhanced permeability and retention (EPR) effect for optical imaging of oral cancer.

Near‐infrared (NIR) fluorescence optical imaging is a promising technique to assess the tumor margins during cancer surgery. This technique requires targeting by specific fluorescence agents to differentiate tumor from normal surrounding tissue. We assessed the feasibility of cancer detection using NIR fluorescence agents that target either αvβ3 integrins or the enhanced permeability and retention (EPR) effect in an orthotopic mouse model of oral cancer.