Merrill A. Biel

Photodynamic therapy of head and neck cancers

Over 1,500 patients have been treated with PDT using Photofrin, HPD, ALA, or Foscan for head and neck cancers. These patients include a mixture of presentations including primary, recurrent, and metastatic lesions. The predominant histology is squamous cell carcinoma, but other histologies treated include mucosal melanoma, Kaposis sarcoma, adenocarcinoma, metastatic breast carcinoma, and adenoid cystic carcinoma. Several multi-institutional phase II clinical trials evaluating PDT treatment of head and neck cancers have demonstrated the efficacy of this minimally invasive therapy in the treatment of early oropharyngeal primary and recurrent cancers as well as the palliative treatment of refractory head and neck cancers. Patients with early stage cancers or early recurrences in the oral cavity and larynx (Cis, T1, T2) tend to have an excellent response to PDT. Of 518 patients treated with Cis, T1, or T2 cancers of the oral cavity, larynx, pharynx, and nasopharynx, 462 (89.1%) obtained a complete clinical response after one PDT treatment. Laryngeal cancers, comprising 171 patients in this group, obtained a durable complete response rate of 89% with up to a 16-year follow-up. Photodynamic therapy is as effective as conventional therapies for the treatment of early (Cis, T1, T2) squamous cell cancers of the head and neck. It is also a promising therapy to be used in association with surgery to increase tumor-free margins and therefore increase cure rates.

Photodynamic therapy of bacterial and fungal biofilm infections

Biofilms have been found to be involved in a wide variety of microbial infections in the body, by one estimate 80% of all infections. Infectious processes in which biofilms have been implicated include common problems such as urinary tract infections, catheter infections, middle-ear infections, sinusitis, formation of dental plaque, gingivitis, coating contact lenses, endocarditis, infections in cystic fibrosis, and infections of permanent indwelling devices such as joint prostheses and heart valves. Bacteria living in a biofilm usually have significantly different properties from free-floating bacteria of the same species, as the dense and protected environment of the film allows them to cooperate and interact in various ways. One benefit of this environment is increased resistance to detergents and antibiotics, as the dense extracellular matrix and the outer layer of cells protect the interior of the community. In some cases antibiotic resistance can be increased 1000-fold. Also, the biofilm bacteria excrete toxins that reversibly block important processes such as translation and protecting the cell from bactericidal antibiotics that are ineffective against inactive targets. In the head and neck area, biofilms are a major etiologic factor in periodontitis, wound infections, oral candidiasis, and sinus and ear infections. For the past several decades, photodynamic treatment has been reported in the literature to be effective in eradicating various microorganisms using different photosensitizers, different wavelengths of light, and different light sources. PDT has been further studied to demonstrate its effectiveness for the eradication of both Gram-negative and Gram-positive antibiotic-resistant bacteria. This chapter will focus on the use of PDT in the treatment of antibiotic-resistant biofilms, antibiotic-resistant wound infections, and azole-resistant oral candidiasis using methylene blue-based photodynamic therapy.

Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report

Navigation with fluorescence guidance has emerged in the last decade as a promising strategy to improve the efficacy of oncologic surgery. To achieve routine clinical use, the onus is on the surgical community to objectively assess the value of this technique. This assessment may facilitate both Food and Drug Administration approval of new optical imaging agents and reimbursement for the imaging procedures. It is critical to characterize fluorescence-guided procedural benefits over existing practices and to elucidate both the costs and the safety risks. This report is the result of a meeting of the International Society of Image Guided Surgery (www.isigs.org) on February 6, 2015, in Miami, Florida, and reflects a consensus of the participants’ opinions. Our objective was to critically evaluate the imaging platform technology and optical imaging agents and to make recommendations for successful clinical trial development of this highly promising approach in oncologic surgery.

Indications for performing hemithyroidectomy for tumors requiring total laryngectomy.

To determine the necessity of performing a hemithyroidectomy in patients who require a total laryngectomy, the pathologic reports and clinical courses of 261 patients who underwent total laryngectomy were reviewed. Twenty-four percent of the specimens demonstrated transcartilaginous invasion, with the highest incidences occurring in glottic (31 percent) and subglottic (60 percent) tumors. Epidermoid tumor invading the thyroid gland occurred in 5 percent of the specimens. All of these showed invasion by direct extension, were palpable at the time of surgery and were associated with transcartilaginous invasion. Ninety percent of these tumors were primarily glottic or subglottic and 70 percent demonstrated subglottic extension greater than 1.5 cm. Furthermore, the prognosis of patients with tumorous invasion of the thyroid gland was dismal, with local recurrence or distant metastasis occurring within 10 months of curative resection. In patients who had laryngectomies, hypothyroidism was found in 70 percent of those who underwent radiotherapy and hemithyroidectomy, in 38 percent of those who underwent radiotherapy alone, in 23 percent of those who underwent hemithyroidectomy alone, and in 20 percent of those who did not undergo hemithyroidectomy or radiotherapy. Based on these results, we advocate ipsilateral or total thyroidectomy for palpably suspicious thyroid glands seen intraoperatively, subglottic tumors, glottic tumors with more than 1 cm of subglottic extension, T4 endolaryngeal tumors with transcartilaginous invasion, and T4 pyriform sinus tumors.

Free Jejunal Autograft Reconstruction of the Pharyngoesophagus: Review of a 10-year experience

Seventeen patients underwent free jejunal autograft reconstruction of the pharyngoesophagus after ablative surgery for Stage III and IV squamous cell carcinoma of the cervical esophagus and hypopharynx. Postoperative complications included three perioperative deaths, three graft failures, six transient fistulas, and two early and one late fistula. The 5-year survival rate of patients with Stage III and IV hypopharyngeal carcinoma was 20% (one of five). The 4-year survival rate for patients with cervical esophageal carcinoma was 33% (one of three). This method of reconstruction is advocated as a reliable palliative procedure for patients with a dismal long-term survival.

The effect of antimicrobial photodynamic therapy on human ciliated respiratory mucosa

Chronic recurrent sinusitis (CRS) is one of the most common chronic conditions in the United States. There is a significant subpopulation of CRS patients who remain resistant to cure despite rigorous treatment regimens including surgery, allergy therapy, and prolonged antibiotic therapy. Antimicrobial photodynamic therapy (aPDT) is a noninvasive nonantibiotic broad spectrum antimicrobial treatment. Our previous in vitro studies demonstrated that aPDT reduced CRS polymicrobial biofilm and planktonic bacteria and fungi by > 99.9% after a single treatment. Prior to human treatment however, aPDT treatment must be demonstrated to not result in histologic damage to the sinus ciliated respiratory epithelium. The objective of this study was to demonstrate the safety of aPDT treatment on a living human ciliated respiratory mucosal model (EpiAirway™).

Antimicrobial photodynamic therapy for treatment of biofilm-based infections.

Photodynamic therapy (PDT) is the combination of light-absorbing chemicals, light and oxygen leading to the production of reactive oxygen species resulting in the destruction or catastrophic damage to adjacent cells. Antimicrobial PDT (aPDT) is the use of PDT to eradicate pathogenic bacteria, fungus, virus or protozoa. aPDT can be deployed for water purification, air purification and human antimicrobial applications. Antimicrobial PDT has been demonstrated in multiple human case series to be a promising clinical treatment of various bacterial, fungal, viral and protozoan diseases. Although there are to date relatively few regulatory approvals for aPDT treatment of human diseases, a number of controlled multi-institutional clinical trials are underway to assess the effectiveness of aPDT as compared to standard of care therapies of various bacterial biofilm related diseases.

Maintaining long-term vessel patency in microvascular surgery using tissue-type plasminogen activator.

The primary cause of free flap failure remains vascular thrombosis at the micro-anastomosis site. Four-hour local infusion of tissue plasminogen activator (t-PA) has been proved to effectively lyse thromboses in microvascular studies of animals; however, rethrombosis occurs once the infusion of t-PA has been terminated. The present study was designed to examine the efficacy of 48 hours of a continous local t-PA infusion in maintaining long-term venous patency. Our previously described modified arterial inversion graft reanastomosed into the venous system was used in rabbits to form venous thrombi. Three mg of t-PA was infused over 48 hours in eleven rabbits. Seven of eleven grafts were patent at 48 hours and four remained patent at 1 week. In comparing the patency rates in this study with the overall patency rate using the modified arterial inversion graft model (1/22), there are statistically significant differences at both 48 hours (p < 0.001) and 7 days (p < 0.05). We conclude that lengthening the infusion time of t-PA may increase the long-term patency rate in this animal model.

Noninvasive tumor oxygen imaging by photoacoustic lifetime imaging integrated with photodynamic therapy

Oxygen plays a major role in cancer biology and tumor progression. In PDT, the reduction in efficacy is directly related to lack of oxygen because its molecular mechanism relies on oxygen as an energy mediator. Measuring tumor oxygenation can provide physicians with better diagnosis and optimization of treatment plans. However, clinical tools for directly assessing tissue oxygenation are limited. The gold standard is oxygen needle electrode, which is invasive and measures oxygen level at a single location. We present our work on developing a combined treatment-imaging modality that integrates PDT and photoacoustic oxygen imaging. We propose a system designed for clinical treatments of cancer of the oral cavity. Tissue oxygen imaging is performed by applying Photoacoustic Lifetime Imaging (PALI). This technology relies on photoacoustic probing of oxygen-dependent excitation lifetime of Methylene Blue. The dye is excited by the same wavelength of illumination source for PDT. Once excited, the population of photosensitizer molecules at triplet state has a lifetime depending on the oxygen level. The transition from excited triplet state to ground state can be probe by another laser, which generate photoacoustic signal that is used to map the lifetime. The lifetime map is then converted to pO2 distribution. We expect that PDT efficacy can be improved by applying PALI imaging feedback in real-time to determine, and individually optimize, O2-enriched gas breathing parameters and PDT light-dose during treatment. Successful implementation of PALI in PDT can also drive its application in guiding other cancer treatments that are affected by hypoxia.

Photodynamic Therapy for the Management of Laryngeal Malignancies

Carcinoma of the larynx accounts for 25–30 % of all carcinomas of the head and neck [1]. Early carcinomas of the larynx (Cis, T1, T2) and severe dysplasia are presently treated with either radiation therapy or surgery alone. Five-year cure rates achieved with this therapy is 75–90 %. Radiation therapy has the advantage of preserving the physical integrity of the larynx, thereby preserving the voice. Radiation therapy, however, has significant disadvantages even when small laryngeal fields of radiation are used. These disadvantages include discomfort and mucositis during and for potential prolonged periods after therapy, permanently altered voice quality, dysphagia, chondroradionecrosis of the larynx and trachea, and the extensive length of therapy (6–7 weeks) [2, 3]. Surgical therapy for early carcinomas, that is, T1 and T2, of the larynx includes performing a partial cordectomy or hemilaryngectomy. Although cure rates are high, surgical removal of portions of the vocal cord or hemilarynx results in significant alteration of the quality of voice [4].