Tools of clinical Photodynamic Therapy (PDT): A Mini Compendium.

Unlike surgical instruments and endoscopic equipment, Photodynamic Therapy (PDT) devices are not readily available or accessible to the clinicians who may like to add this form of treatment modality for selected patients and on an ad hock basis. There is in fact a vacuum in finding the "tools" of PDT for those clinicians who are not part of a "Centre" with a built-in knowledge base and contacts for manufacturers. In this compendium the Yorkshire Laser Centre /YLC in the UK, (the Project of the Moghissi Laser Trust - (Charity number 326689) requested three experienced clinicians (RA, ZH, KM) to produce essential information on the use of and equipment for PDT in the clinic. The YLC also sponsored a researcher (ID) to search and compile a detailed but non-exhaustive list of approved photosensitizing agents, pharmaceutical companies, light sources and laser manufacturers with appropriate delivery devices for PDT. Thus, this Mini -Compendium is the end result of what is hoped to be a useful adjunct for practitioners, scientists and students of PDT.

Photodynamic therapy to a primary cancer of the peripheral lung: Case report.

Photodynamic therapy (PDT) is an FDA approved treatment for lung cancer. In the United States the photosensitizer porfimer sodium (Photofrin®, Pinnacle Biologics) is intravenously introduced at 2mg/kg. After approximately 48 h, illumination to activate the photosensitizer is initiated, with 630nm red light at 200J/cm, delivered by fiber-optic catheter, brought to the tumor endo- bronchially, and delivered for 500 s. This will create, in the presence of oxygen, a Type II Photodynamic Reaction (PDR) which generates singlet oxygen species that are tumor ablative. Classically, PDT for lung cancer has been employed for symptomatic central and obstructing tumors with great success. This case report describes an innovative approach to treat a peripheral, early stage lung cancer employing magnetic navigation and endobronchial treatment. We report on a 79 year old male with numerous comorbidities including pulmonary fibrosis, who was found to have a biopsy proven peripheral and solitary non-small cell cancer. Due to prior SBRT (stereotactic body radiation therapy) with dose levels causing radiation fibrosis, he was not a candidate for repeat SBRT, and he was not a surgical candidate due to comorbidities. Tumor control with PDT was achieved without treatment related morbidity. This report details our findings.

Photodynamic therapy for peripheral lung cancer.

Photodynamic therapy (PDT) is an internationally approved ablation technique for endo-bronchial lung cancer. The majority of reported outcomes are for central and obstructing lesions where excellent long term control is possible. With the current trend of screening high risk for lung cancer populations, a larger cohort of patients are now diagnosed with earlier stage disease. When these early tumors are located in the lung periphery the current therapeutic options include surgery or radiation therapy. Still, many patients may not be candidates or amenable for these procedures. As PDT is a well tolerated non-thermal outpatient therapy to treat lung cancer and as newer bronchoscopy techniques allow for treatment of peripheral lesions, PDT may be an option. We report a case of a primary non-small cell lung cancer treated by interstitial PDT through placement of the diffusing fiber via magnetic navigational bronchoscopy. Forty eight hours post 2 mg/kg intravenous (IV) injection of Photofrin®, a single 500 second illumination of 200 J/cm at 630 nm was directed to the solitary peripheral lesion without complication. On day 30, as a part of planned therapy, lobectomy was undertaken. Pathology reported necrosis and no viable remaining tumor. At 90 days follow up, the patient remains well,with no evidence of disease. Additional details follow in the report.

Survival Outcomes with Photodynamic Therapy, Chemotherapy and Radiation in Patients with Stage III or Stage IV Non-Small Cell Lung Cancer.

Data regarding the association between photodynamic therapy (PDT) and mortality in lung cancer patients are limited. We analyzed the association between PDT and mortality in patients with stage III or IV non-small cell lung cancer (NSCLC) using data from the National Cancer Database (NCDB) between 2004 and 2016. From the NCDB, we identified patients receiving laser ablation/cryosurgery or local tumor destruction/excision (which includes PDT). From Medicare and Medicaid claims between 2000 and 2013, we identified NSCLC patients receiving PDT and those receiving bronchoscopy, then used these to confirm the PDT treatment. From NCDB, we extracted NSCLC patients who received radiation with chemotherapy, radiation alone or chemotherapy alone. We used survival analysis to determine the association between PDT and mortality. Between 2004 and 2016, 457,556 NSCLC patients with stage III or stage IV were identified, of which 147 received PDT with radiation and chemotherapy, 227,629 received radiation with chemotherapy, 106,667 had radiation therapy alone and 122,193 received chemotherapy alone. Compared to the radiation alone group, the PDT group and radiation with chemotherapy group had lower hazard of mortality (50% and 53% lower, respectively). Among the NSCLC patients with stage III or stage IV disease, the addition of PDT to radiation therapy offers survival benefit over radiation therapy alone.

Optical techniques for the diagnosis and treatment of lesions induced by the human papillomavirus - A resource letter.

Human papillomaviruses (HPV) are the most common sexually-transmitted virus, and carcinogenic HPV strains are reported to be responsible for virtually all cases of cervical cancer and its precursor, the cervical intraepithelial neoplasia (CIN). About 30% of the sexually active population are considered to be affected by HPV. Around 600 million people are estimated to be infected worldwide. Diseases related to HPV cause significant impact from both the personal welfare point of view and public healthcare perspective. This resource letter collects relevant information regarding HPV-induced lesions and discusses both diagnosis and treatment, with particular attention to optical techniques and the challenges involved to the implementation of those approaches.

PDT and emerging therapies for Actinic Keratosis-A resource letter.

Aktinic Keratosis is common and if left untreated may develop into life threatening squamous cell carcinoma. Therefore early intervention is the standard of care. While many treatments are available PDT continues to move to the for - front for this indication (Brito et al., 2016 [31]). Topical PS is commercially available that are able to reliably ablate these lesions. Innovative protocols including sunlight, large volume LED arrays and maneuvers to improve treatment parameters and cosmesis continue to make this a worldwide treatment of choice for AK.

Fluorescence guided resection (FGR): A primer for oncology.

Curative treatment for most cancer patients requires surgical removal of the tumor. Often though, residual disease is left behind negatively impacting tumor control and survival. Florescent Guided resection (FGR) is one type of Image Guided Surgery that offers the potential to improve outcomes for these patients. Currently, during FGR, a probe is preoperatively applied and allowed to concentrate in the tumor bed. At surgery appropriate light is applied to generate fluorescence which allows the surgeon to better visualize tumor extent. This improved visualization has translated both into enhanced rates for resection but also diminished rates of morbidity as less normal tissue need be removed to achieve negative margins. This paper will summarize the theory and practise of FGR as currently applied in clinical oncology including select outcomes and limitations of technique and technology.

Radiation oncology: physics advances that minimize morbidity.

Radiation therapy has become an ever more successful treatment for many cancer patients. This is due in large part from advances in physics including the expanded use of imaging protocols combined with ever more precise therapy devices such as linear and particle beam accelerators, all contributing to treatments with far fewer side effects. This paper will review current state-of-the-art physics maneuvers that minimize morbidity, such as intensity-modulated radiation therapy, volummetric arc therapy, image-guided radiation, radiosurgery and particle beam treatment. We will also highlight future physics enhancements on the horizon such as MRI during treatment and intensity-modulated hadron therapy, all with the continued goal of improved clinical outcomes.

Radioprotective agents for radiation therapy: future trends.

Only two radioprotective compounds, amifostine and palifermin, currently have the US FDA approval for use in radiation therapy. However, several agents have been reported that show therapeutic promise. Many of these agents are free radical scavengers/antioxidants. Superoxide dismutase and superoxide dismutase mimetics, nitroxides and dietary antioxidants are all being investigated. Recently, alternative strategies of drug development have been evolving, which focus on targeting the series of cellular insult recognition/repair responses initiated following radiation. These agents, which include cytokines/growth factors, angiotensin-converting enzyme inhibitors and apoptotic modulators, show promise of having significant impact on the mitigation of radiation injury. Herein, we review current literature on the development of radioprotectors with emphasis on compounds with proven or potential usefulness in radiation therapy.

Radiobiological modifiers in clinical radiation oncology: current reality and future potential.

Radiation therapy can successfully ablate tumors. However, the same ionization process that destroys a cancer can also permanently damage surrounding organs resulting in unwanted clinical morbidity. Therefore, modern radiation therapy attempts to minimize dose to normal tissue to prevent side effects. Still, as tumors and normal tissues intercalate, the risk of normal tissue injury often may prevent tumoricidal doses of radiation therapy to be delivered. This paper will review current outcomes and limitations of radiobiological modifiers that may selectively enhance the radiosensitivity of tumors as well as parallel techniques that may protect normal tissues from radiation injury. Future endeavors based in part upon newly elucidated genetic pathways will be highlighted.

Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck.

BACKGROUND: The objective of this trial was to determine how a mucoadhesive hydrogel (MuGard), a marketed medical device, would fare when tested with the strictness of a conventional multi-institutional, double-blind, randomized, placebo-controlled study format. METHODS: A total of 120 subjects planned to receive chemoradiation therapy (CRT) for treatment of head and neck cancers were randomized to receive either MuGard or sham control rinse (SC) during CRT. Subjects completed the validated Oral Mucositis Daily Questionnaire. Weight, opiate use, and World Health Organization (WHO) oral mucositis (OM) scores were recorded. Subjects who dosed at least once daily during the first 2.5 weeks of CRT were included in the efficacy analysis. RESULTS: Of 120 subjects enrolled, 78 (SC, N=41; MuGard, N=37) were eligible for efficacy analysis. Both cohorts were similar in demographics, baseline characteristics, primary tumor type, and planned CRT regimen. MuGard effectively mitigated OM symptoms as reflected by area under the curve of daily patient-reported oral soreness (P=.034) and WHO scores on the last day of radiation therapy (P=.038). MuGard was also associated with nonsignificant trends related to therapeutic benefit including opioid use duration, and OM scores (WHO criteria) at CRT week 4. Rinse compliance was identical between cohorts. No significant adverse events were reported, and the adverse event incidence was similar between cohorts. CONCLUSIONS: Testing MuGard, a rinse marketed as a device, in a standard clinical trial format demonstrated its superiority to SC in mitigating OM symptoms, delaying OM progression, and its safety and tolerability.

Photodynamic therapy: oncologic horizons.

Photodynamic therapy (PDT) is a light-based intervention with a long and successful clinical track record for both oncology and non-malignancies. In cancer patients, a photosensitizing agent is intravenously, orally or topically applied and allowed time to preferentially accumulate in the tumor region. Light of the appropriate wavelength and intensity to activate the particular photosensitizer employed is then introduced to the tumor bed. The light energy will activate the photosensitizer, which in the presence of oxygen should allow for creation of the toxic photodynamic reaction generating reactive oxygen species. The photodynamic reaction creates a cascading series of events including initiation of apoptotic and necrotic pathways both in tumor and neovasculature, leading to permanent lesion destruction often with upregulation of the immune system. Cutaneous phototoxicity from unintentional sunlight exposure remains the most common morbidity from PDT. This paper will highlight current research and outcomes from the basic science and clinical applications of oncologic PDT and interpret how these findings may lead to enhanced and refined future PDT.

Modeling of non-small cell lung cancer volume changes during CT-based image guided radiotherapy: patterns observed and clinical implications.

Background. To characterize the lung tumor volume response during conventional and hypofractionated radiotherapy (RT) based on diagnostic quality CT images prior to each treatment fraction. Methods. Out of 26 consecutive patients who had received CT-on-rails IGRT to the lung from 2004 to 2008, 18 were selected because they had lung lesions that could be easily distinguished. The time course of the tumor volume for each patient was individually analyzed using a computer program. Results. The model fits of group L (conventional fractionation) patients were very close to experimental data, with a median Δ% (average percent difference between data and fit) of 5.1% (range 3.5-10.2%). The fits obtained in group S (hypofractionation) patients were generally good, with a median Δ% of 7.2% (range 3.7-23.9%) for the best fitting model. Four types of tumor responses were observed-Type A: "high" kill and "slow" dying rate; Type B: "high" kill and "fast" dying rate; Type C: "low" kill and "slow" dying rate; and Type D: "low" kill and "fast" dying rate. Conclusions. The models used in this study performed well in fitting the available dataset. The models provided useful insights into the possible underlying mechanisms responsible for the RT tumor volume response.

Oncologic photodynamic therapy: clinical strategies that modulate mechanisms of action.

Photodynamic therapy (PDT) is an elegant minimally invasive oncologic therapy. The clinical simplicity of photosensitizer (PS) drug application followed by appropriate illumination of target leading to the oxygen dependent tumor ablative Photodynamic Reaction (PDR) has gained this treatment worldwide acceptance. Yet the true potential of clinical PDT has not yet been achieved. This paper will review current mechanisms of action and treatment paradigms with critical commentary on means to potentially improve outcome using readily available clinical tools.

Diagnostic microRNA markers to screen for sporadic human colon cancer in stool: I. Proof of principle.

To present proof-of-principle application for employing micro(mi)RNAs as diagnostic markers for colon cancer, we carried out global microarray expression studies on stool samples obtained from fifteen individuals (three controls, and three each with TNM stage 0-1, stage 2, stage 3, and stage 4 colon cancer), using Affymetrix GeneChip miRNA 3.0 Array, to select for a panel of miRNA genes for subsequent focused semi-quantitative polymerase chain reaction (PCR) analysis studies. Microarray results showed 202 preferentially expressed miRNA genes that were either increased (141 miRNAs), or reduced (61 miRNAs) in expression. We then conducted a stem-loop reverse transcriptase (RT)-TaqMan® minor groove binding (MGB) probes, followed by a modified qPCR expression study on 20 selected miRNAs. Twelve of the miRNAs exhibited increased and 8 decreased expression in stool from 60 individuals (20 controls, 20 with tumor-lymph node-metastatic (TNM) stage 0-1, 10 with stage 2, five with stage 3, and 5 with stage 4 colon cancer) to quantitatively monitor miRNA changes at various TNM stages of colon cancer progression. We also used laser-capture microdissection (LCM) of colon mucosal epithelial tissue samples (three control samples, and three samples from each of the four stages of colon cancer, for a total of 15 samples) to find concordance or lack thereof with stool findings. The reference housekeeping pseudogene-free ribosomal gene (18S rRNA), which shows little variation in expression, was employed as a normalization standard for relative PCR quantification. Results of the PCR analyses confirmed that twelve miRNAs (miR-7, miR-17, miR-20a, miR-21, miR-92a, miR-96, miR-106a, miR-134, miR-183, miR-196a, miR-199a-3p and miR214) had an increased expression in the stool of patients with colon cancer, and that later TNM carcinoma stages exhibited a more pronounced expression than did adenomas. On the other hand, eight miRNAs (miR-9, miR-29b, miR-127-5p, miR-138, miR-143, miR-146a, miR-222 and miR-938) had decreased expression in the stool of patients with colon cancer, which was also more pronounced from early to later TNM stages. Results from colon mucosal tissues were similar to those from stool samples, although with more apparent changes in expression. Cytological studies on purified stool colonocytes that employed Giemsa staining showed 80% sensitivity for detecting tumor cells in stool smears. The performance characteristics of the test confirmed that stool is a medium well-suited for colon cancer screening, and that the quantitative changes in the expression of few mature miRNA molecules in stool associated with colon cancer progression provided for more sensitive and specific non-invasive diagnostic markers than tests currently available on the market. Thus, a larger prospective and properly randomized validation study of control individuals and patients exhibiting various stages of colon cancer progression (TNM stages 0-IV) is now needed in order to standardize test conditions, and provide a means for determining the true sensitivity and specificity of a miRNA screening approach in stool for the non-invasive detection of colon cancer, particularly at an early stage (0-I). Eventually, we will develop a chip to enhance molecular screening for colon cancer, as has been accomplished for the detection of genetically-modified organisms (GMOs) in foods.

The electromagnetic spectrum: current and future applications in oncology.

The electromagnetic spectrum is composed of waves of various energies that interact with matter. When focused upon and directed at tumors, these energy sources can be employed as a means of lesion ablation. While the use of x-rays is widely known in this regard, a growing body of evidence shows that other members of this family can also achieve oncologic success. This article will review therapeutic application of the electromagnetic spectrum in current interventions and potential future applications.