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.

Development and (pre-) clinical assessment of a novel surgical tool for primary and secondary tracheoesophageal puncture with immediate voice prosthesis insertion, the Provox Vega Puncture Set.

Development and (pre-) clinical assessment were performed of a novel surgical tool for primary and secondary tracheoesophageal puncture (TEP) with immediate voice prosthesis (VP) insertion in laryngectomized patients, the Provox Vega Puncture Set (PVPS). After preclinical assessment in fresh frozen cadavers, a multicenter prospective clinical feasibility study in two stages was performed. Stage-1 included 20 patients, and stage-2 had 27. Based on observations in stage-1, the PVPS was re-designed (decrease in diameter of the dilator from 23.5 to 18 Fr.) and further used in stage-2. Primary outcome measure was immediate VP insertion without requiring additional instruments. Secondary outcome measures for comparison of the new with the traditional TEP procedure were: appreciation, ease of use, time consumption, estimated surgical risks and overall preference. A mini-max two-stage study design was used to establish the required sample size. In stage-1, dilatation forces were considered too high in patients with a fibrotic TE wall. With the final thinner version of the PVPS, VPs were successfully inserted into the TEP in 'one-go' in 24/27 (89%) of TEPs: 20 primary and 7 secondary. Participating surgeons rated appreciation, ease of use, time consumption and estimated surgical risks as better. Related adverse events were few and minor. The new PVPS appeared to be the preferred device by all participating surgeons. This study shows that the novel, disposable PVPS is a useful TEP instrument allowing quick and easy insertion of the VP in the vast majority of cases without requiring additional instruments.

Dual wavelength tumor targeting for detection of hypopharyngeal cancer using near-infrared optical imaging in an animal model.

Optical imaging is a promising technique to visualize cancer tissue during surgery. In this study, we explored the use of combinations of near-infrared (NIR) fluorescence agents that emit fluorescence signal at different wavelengths and each target specific tumor characteristics. Two combinations of agents (ProSense680 combined with 2DG CW800 and MMPSense680 combined with EGF CW800) were used to detect hypopharyngeal cancer in an animal model. ProSense680 and MMPSense680 detect increased activity of cathepsins and matrix metalloproteinases, respectively. These enzymes are mainly found in the invasive tumor border due to degradation of the extracellular matrix. 2DG CW800 detects tumor cells with high glucose metabolism and EGF CW800 is internalized by the epidermal growth factor receptor of tumor cells. Whole-body imaging revealed clear demarcation of tumor tissue using all four agents. The tumor-to-background ratio (standard deviation, p-value) was 3.69 (0.72, p < 0.001) for ProSense680; 4.26 (1.33, p < 0.001) for MMPSense680; 5.81 (3.59, p = 0.02) for 2DG CW800 and 4.84 (1.56, p < 0.001) for EGF CW800. Fluorescence signal corresponded with histopathology and immunohistochemistry, demonstrating signal of ProSense680 and MMPSense680 in the invasive tumor border, and signal of 2DG CW800 and EGF CW800 in the tumor tissue. In conclusion, we demonstrated the feasibility of dual wavelength tumor detection using different targeting strategies simultaneously in an animal model. Combined targeting at different wavelengths allowed simultaneous imaging of different tumor characteristics. NIR fluorescence optical imaging has the potential to be translated into the clinic in order to improve the complete removal of tumors by real-time image-guided surgery.

Translational optical imaging in diagnosis and treatment of cancer.

In cancer imaging, many different modalities are used that each have their specific features, leading to the combined use of different techniques for the detection, staging and treatment evaluation of cancer. Optical imaging using near-infrared fluorescence light is a new imaging modality that has recently emerged in the field of cancer imaging. After extensive preclinical research, the first steps of translation to the clinical practice are currently being made. In this article, we discuss the preclinical and clinical results of near-infrared optical imaging for non-invasive detection and classification of tumors, therapy monitoring, sentinel lymph node procedures, and image-guided cancer surgery. Widespread availability of imaging systems and optical contrast agents will enable larger studies on their clinical benefit and can help establish a definitive role in clinical practice.

Optical imaging of oral squamous cell carcinoma and cervical lymph node metastasis.

BACKGROUND: In oral cancer surgery, intraoperative optical imaging could help the surgeon to determine adequate tumor-free margins. METHODS: Tumor-specific near-infrared fluorescence agents targeting epidermal growth factor receptor (CW800 EGF) or glucose transporter system (CW800 2-DG) were administered to mice with tongue carcinoma and cervical lymph node metastases. Tumor growth was followed by bioluminescence imaging. Fluorescence signals were compared with a control group of healthy animals. RESULTS: Significantly higher fluorescence was found in tongue tumors and cervical lymph node metastases compared with that in control animals. Fluorescence correlated with histopathology. Tumor-to-background ratio of CW800 EGF in the tongue was 13.8 (SD = 6.1) and in the lymph nodes 15.7 (SD = 8.8). For CW800 2-DG, the tumor-to-background ratio in the tongue was 4.6 (SD = 2.1) and in the lymph nodes 33.9 (SD = 18.4). CONCLUSIONS: Optical imaging can be used to detect oral cancer and cervical lymph node metastases and could potentially improve complete surgical resection by real-time image-guided surgery.

Chemoradiation for advanced hypopharyngeal carcinoma: a retrospective study on efficacy, morbidity and quality of life.

Chemoradiation (CRT) is a valuable treatment option for advanced hypopharyngeal squamous cell cancer (HSCC). However, long-term toxicity and quality of life (QOL) is scarcely reported. Therefore, efficacy, acute and long-term toxic effects, and long-term QOL of CRT for advanced HSCC were evaluated,using retrospective study and post-treatment quality of life questionnaires. in a tertiary hospital setting. Analysis was performed of 73 patients that had been treated with CRT. Toxicity was rated using the CTCAE score list. QOL questionnaires EORTC QLQ-C30, QLQ-H&N35, and VHI were analyzed. The most common acute toxic effects were dysphagia and mucositis. Dysphagia and xerostomia remained problematic during long-term follow-up. After 3 years, the disease-specific survival was 41%, local disease control was 71%, and regional disease control was 97%. The results indicated that CRT for advanced HSCC is associated with high locoregional control and disease-specific survival. However, significant acute and long-term toxic effects occur, and organ preservation appears not necessarily equivalent to preservation of function and better QOL.

High complication risk of salvage surgery after chemoradiation failures.

CONCLUSIONS: Although organ preservation can be achieved with chemoradiation protocols for laryngeal or pharyngeal cancers, salvage surgery is accompanied by high complication rates. OBJECTIVES: To determine the rate of complications associated with salvage surgery after chemoradiation for laryngeal and pharyngeal cancers. METHODS: A multicenter retrospective study was performed of 24 patients treated with total laryngectomy combined with total or partial pharyngectomy between 1995 and 2004 who had previously been treated with chemoradiation. The main outcome measures were early and late complication rates. Quality of life analysis was determined by two questionnaires. RESULTS: The complication rate after salvage surgery was 92% in the direct postoperative period. The most frequent complication was pharyngocutaneous fistula formation. Narrowing of the esophagus and tracheostoma were the most common late sequelae. The quality of life, measured at least 2 years after salvage surgery, showed a social dysfunctioning.

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

BACKGROUND AND OBJECTIVES: 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 αvß3 integrins or the enhanced permeability and retention (EPR) effect in an orthotopic mouse model of oral cancer. METHODS: Binding of the integrin-targeted agent to tumor cells was assessed in vitro. Oral cancer was induced in 6 BALB/c nu/nu mice by submucosal inoculation of human OSC19-luc cells into the tongue. Tumor growth was followed with bioluminescence imaging. A combination of agents targeting integrins or EPR effect was injected followed by fluorescence imaging in vivo and ex vivo after resection of the tongues. RESULTS: Oral cancer was clearly demarcated in vitro; in vivo; and on histological analysis with sufficient tumor-to-background ratios of the contrast agents. CONCLUSION: This study demonstrates the feasibility of optical imaging of oral squamous cell carcinoma based on targeting of αvß3 integrins and the EPR effect. Once these NIR fluorescence agents become available for clinical testing, optical image-guided surgery could reduce residual disease after oral cancer surgery.

Detection of oral squamous cell carcinoma and cervical lymph node metastasis using activatable near-infrared fluorescence agents.

OBJECTIVE: To assess the feasibility of optical imaging using activatable near-infrared fluorescence (NIRF) agents to detect oral cancer and cervical lymph node metastasis in vivo. DESIGN: In vivo study. SETTING: University medical center. SUBJECTS: Female nude mice aged 4 to 6 weeks. INTERVENTION: Luciferase-expressing OSC-19-luc cells were injected into the tongues of nude mice. A control group of nude mice was injected in the tongue with a physiologic saline solution. Tumor growth was followed by bioluminescence imaging. After 3 weeks, animals were randomly allocated to intravenous administration of 1 of 2 activatable NIRF agents: ProSense680 or MMPSense680. Fluorescence imaging of the mice was performed, and the tumor to background ratio (TBR) was determined on histologic sections of the tongue and cervical lymph nodes after resection at necropsy. MAIN OUTCOME MEASURE: Fluorescence signals. RESULTS: The fluorescence signals in tongue tumor and cervical lymph node metastases were significantly higher than those in control animals. The mean (SD) TBR of ProSense680 in the tongue was 15.8 (8.1) and in the lymph nodes was 11.8 (3.6). For MMPSense680, the mean (SD) TBR in the tongue was 18.6 (9.4) and in the lymph nodes was 10.5 (4.0). CONCLUSIONS: Oral cancer and cervical lymph node metastases can be detected by targeting increased proteolytic activity at the tumor borders using NIRF optical imaging. These NIRF agents could be used for real-time image-guided surgery, which has the potential to improve the complete surgical resection of oral cancer.

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.

Diagnostic accuracy of fine-needle aspiration cytology in Warthin tumors.

BACKGROUND: Our aim was to evaluate the diagnostic accuracy of fine-needle aspiration cytology (FNAC) for Warthin tumors of the parotid gland. METHODS: All cytologic diagnoses of Warthin tumor between 1990 and 2007 were correlated with available histology. In addition, our results were compared to current literature. RESULTS: In 310 cases, Warthin tumor was diagnosed by FNAC. In 133 cases, (43%) both cytology and histology were available. In 127 of these 133 cases (95.5%), the diagnosis Warthin tumor was confirmed by histology. In 4 cases (3%), a benign lesion was diagnosed and 2 (1.5%) revealed a malignant lesion. On review, those cytologic diagnoses were not certain. In the literature, 11 missed malignancies (5.4%) in 202 cases were reported. CONCLUSION: The diagnostic accuracy of FNAC for the diagnosis of Warthin tumor is high and the percentage of missed malignant tumors is very low. Our results imply that a cytologic diagnosis of Warthin tumor may justify conservative treatment.

Early and long-term morbidity after total laryngopharyngectomy.

To determine the early and long-term morbidity of patients treated with a total laryngopharyngectomy and reconstruction using a jejunum interposition or gastric pull-up procedure. It is a retrospective study; and it is conducted in tertiairy referral center. Sixty-three patients were included in whom 70 reconstructions were performed (51 jejunum interpositions and 19 gastric pull-up procedures) between 1990 and 2007. The studied parameters were success rate of the reconstruction, early and long-term complication rate, and functional outcome including quality of life. Subjective quality of life analysis was determined by two questionnaires: the EORTC Quality of Life Questionnaire (QLQ)-C30 Dutch version 3.0, and the EORTC-Head and Neck (H & N 35). The success rates were 84 and 74%, respectively. The procedures were associated with a high complication rate (63% after jejunum interposition and 89% after gastric pull-up), and a lengthy rehabilitation. Surviving patients were found to have a good long-term quality of life. Complete oral intake was achieved in 97%, and speech rehabilitation in 95%. These procedures are associated with significant morbidity, high complication rates, lengthy rehabilitation, but a good long-term quality of life.

Prognostic value of plasminogen activator inhibitor-1 in head and neck squamous cell carcinoma.

BACKGROUND: Tumor cell biological factors, such as urokinase plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor-1 (PAI-1), cathepsin D, and c-myc play a role in tumor invasion, metastasis, and proliferation. In this study, the prognostic importance of these factors in patients with primary head and neck squamous cell carcinoma (HNSCC) was evaluated and correlated with clinicopathologic variables. METHODS: In 46 paired primary tumors and normal tissues, levels of uPA, PAI-1, cathepsin D, and c-myc amplification were determined. The clinical follow-up was over 10 years. Relationships between cell biological factors and patient and tumor characteristics were studied by the Mann-Whitney test. The Cox proportional hazard model was used for univariate and multivariate analysis. RESULTS: In this study, only a high level of PAI-1 was associated with a significantly shorter disease-free survival (p < .01). PAI-1 levels were higher in tumors with perineural invasion (p < .01). Both PAI-1 and uPA levels were higher in patients who smoked (p < .01 and p = .02). In univariate analysis, smoking (p= .04), excessive alcohol intake (p = .02), perineural invasion (p = .001), and vaso-invasion (p = .009) were associated with a shorter disease-free survival. The only factor related to overall survival was perineural invasion (p = .045). The combination of a high PAI-1 level and perineural invasion appeared to be a significant predictor of a shorter disease-free interval (p = .01). CONCLUSION: PAI-1 may present a novel prognostic factor for patients with HNSCC. Perineural invasion and PAI-1 level combined seemed to be prognostic for disease-free survival.

Supracricoid partial laryngectomy with cricohyoidoepiglottopexy for recurrent laryngeal cancer.

OBJECTIVES: Recurrent laryngeal cancer can be treated either with total laryngectomy or in selected cases with supracricoid laryngectomy with cricohyoidoepiglottopexy (CHEP). We performed a retrospective study to analyze the functional and oncological results of supracricoid laryngectomy with CHEP. METHODS: Fourteen patients were treated with supracricoid laryngectomy with CHEP. In 8 patients, flexible endoscopic evaluation of swallowing was performed. Preoperative and postoperative voice evaluation was performed in 5 patients. Oncological and functional follow-up, postoperative complications, and data concerning rehabilitation were recorded on standard forms. RESULTS: After the supracricoid laryngectomy with CHEP, 11 of the 14 patients were alive and disease-free. No local recurrences were found, but 2 patients had regional recurrences. The voice was worse after the operation; however, most patients were satisfied. Swallowing was uncompromised. CONCLUSIONS: Supracricoid laryngectomy with CHEP for recurrent glottic laryngeal cancer after radiotherapy appears to be oncologically safe and functional.

Osteoblastoma of the larynx: a case report.

We describe a unique case of an osteoblastoma in the cricoid cartilage of a 50-year-old man who presented with hoarseness and progressive dyspnea. Panendoscopic examination revealed a reddish tumor at the left side of the cricoid cartilage. Computed tomography (CT) imaging showed a sclerotic lesion involving the cricoid cartilage, protruding in the airway lumen. The tumor was removed via an external procedure. Histology confirmed the diagnosis of osteoblastoma.

Surgery for recurrent laryngeal carcinoma after radiotherapy: partial laryngectomy or total laryngectomy for a better quality of life?

OBJECTIVE: To investigate the quality of life after partial laryngectomy versus total laryngectomy for recurrent laryngeal carcinomas after radiotherapy. STUDY DESIGN AND SETTING: A retrospective study performed at least one year after treatment. This study was performed in a university hospital. RESULTS: Twenty-three patients (N = 12 partial laryngectomy, N = 11 total laryngectomy) with recurrent laryngeal cancer after radiotherapy were included in the study. Three different questionnaires, 1) EORTC Quality of Life Questionnaire (QLQ)-C30 Dutch version 3.0, 2) EORTC-H & N 35, and 3) the Voice Handicap Index, were sent to all patients. The only major difference in quality of life of patients after partial laryngectomy versus total laryngectomy was found to be smell and taste related. No other differences were found. CONCLUSION: We did not find much difference in quality of life after treatment with a partial laryngectomy or a total laryngectomy in patients with recurrent laryngeal cancer after radiotherapy.

Partial laryngectomy for recurrent glottic carcinoma after radiotherapy.

BACKGROUND: Early laryngeal cancer is treated with surgery or radiotherapy. A partial laryngectomy instead of a total laryngectomy can be used for treating patients with radiation failures. METHODS: Patients were grouped by the two types of partial laryngectomies we performed: group I, endoscopic laser surgery (n = 42); and group II, frontolateral partial laryngectomy (n = 21). RESULTS: With CO2 laser treatment, 14 of 24 patients (no involvement of the anterior commissure) and eight of 18 patients (involvement of the anterior commissure) were cured. With the frontolateral partial laryngectomy, we achieved local control in 15 of 21 patients. CONCLUSIONS: If the surgeon is familiar with the different techniques of, and indications for, partial laryngectomy, this can be a good and satisfying treatment in selected patients with radiation failure for glottic cancer

An extra letter, care gets better? Informing general practitioners about planned surgery for head and neck cancer.

OBJECTIVE: To investigate how general practitioners (GPs) value an additional letter from the hospital. This so-called preadmission letter informs the GP about planned surgery for head and neck cancer in one of their patients. DESIGN: Prospective survey among GPs by means of a questionnaire attached to the preadmission letter. SETTING: Department of Otolaryngology and Head and Neck Surgery of a tertiary care centre in the Netherlands and 104 different GPs in primary care. PARTICIPANTS: All GPs of patients undergoing surgery for head and neck cancer received the preadmission letter during a 1-year study period. MAIN OUTCOME MEASURES: GPs' appreciation of the received preadmission letter, GPs' opinion on the content of the preadmission letter, and GPs' general opinion on information provided by our hospital. RESULTS: Of the 145 preadmission letters sent during the study year, 115 questionnaires were returned (response rate of 79%). All GPs positively appreciated receiving the preadmission letter and considered its content relevant. They valued the letter, with a mean mark of 8.3 on a 10-point scale. The majority of the GPs agreed that the preadmission letter allows them to provide better care. CONCLUSIONS: GPs highly appreciate an extra letter informing them about intended surgery for head and neck cancer in one of their patients. Despite the basic content of the preadmission letter (five items only), the majority of GPs consider the information sufficient. The results of this study have led to the implementation of the preadmission letter to GPs of head and neck cancer patients on a permanent basis in our institution.