Laser interstitial thermotherapy (LITT) for breast cancer: dosimetry optimization and numerical simulation.

Surgical treatment is standard for the treatment of small breast cancers. Due to the pain and esthetic sequelae that can follow surgery, minimally invasive treatments are under investigation. Our aim was to conduct a dosimetry study of laser interstitial thermotherapy. Turkey tissue was used as an ex vivo model, and mammary glands from ewes were used as in vivo models. We used two different wavelength lasers (805 nm and 980 nm). Two types of fiber from two different manufacturers were used: bare fibers with a diameter of 600 µm and diffusing fiber. The diffusing fibers were 5 mm and 10 mm in length. We also used a computerized model to predict thermal damage and to correlate with the ex vivo and in vivo procedures using a constant and variable coefficient. The mathematical model was based on the finite element method for solving light distribution, bio-heat, and thermal damage equations. Based on our ex vivo and in vivo experiments, we found that the optimal configuration for this treatment was the use of the 980-nm laser at 4 W with bare fibers for a minimum treatment time of 150 s. We also developed a predictive mathematical model that showed good predictability of necrosis in line with the experimental data. Laser treatment is a promising therapy for small breast lesions. However, further development of treatment guidance is necessary to support its use in clinical practice.

A Warp-Knitted Light-Emitting Fabric-Based Device for In Vitro Photodynamic Therapy: Description, Characterization, and Application on Human Cancer Cell Lines.

Photodynamic therapy (PDT) appears to be a promising strategy in biomedical applications. However, the complexity of its parameters prevents wide acceptance. This work presents and characterizes a novel optical device based on knitted light-emitting fabrics and dedicated to in vitro PDT involving low irradiance over a long illumination period. Technical characterization of this device, called CELL-LEF, is performed. A cytotoxic study of 5-ALA-mediated PDT on human cancer cell lines is provided as a proof of concept. The target of delivering an irradiance of 1 mW/cm2 over 750 cm2 is achieved (mean: 0.99 mW/cm2; standard deviation: 0.13 mW/cm2). The device can maintain a stable temperature with the mean thermal distribution of 35.1 °C (min: 30.7 °C; max: 38.4 °C). In vitro outcomes show that 5-ALA PDT using CELL-LEF consistently and effectively induced a decrease in tumor cell viability: Almost all the HepG2 cells died after 80 min of illumination, while less than 60% of U87 cell viability remained. CELL-LEF is suitable for in vitro PDT involving low irradiance over a long illumination period.

Phototherapy Using a Light-Emitting Fabric (BUBOLight) Device in the Treatment of Newborn Jaundice: Protocol for an Interventional Feasibility and Safety Study.

BACKGROUND: Neonatal jaundice is a common condition occurring in 60%-80% of all healthy-term and late-preterm neonates. In the majority of cases, neonatal jaundice resolves spontaneously and causes no harm; however, in some neonates, significant hyperbilirubinemia can develop and lead to kernicterus jaundice, a serious neurological disease. Phototherapy (PT) is the preferred treatment for jaundice; however, to be effective, PT devices need to have a broad light emission surface to generate no or little heat and to provide an optimal wavelength and light intensity (420-490 nm and ≥30 µW/cm²/nm, respectively). OBJECTIVE: This study aimed to investigate the feasibility, safety, and level of satisfaction of parents and health care teams with the BUBOlight device, an innovative alternative to conventional hospital PT, in which luminous textiles have been incorporated in a sleeping bag. METHODS: This interventional, exploratory, simple group, nonrandomized, single-center trial will be conducted at Lille Hospital. In total, 10-15 neonates and their parents will be included to obtain evaluable data from 10 parent-neonate pairs. Neonates weighing more than 2500 g at birth and born with ≥37 weeks of amenorrhea that required PT in accordance with the guidelines of the National Institute For Health and Clinical Excellence will receive one 4-hour session of illumination. Total serum bilirubin and transcutaneous bilirubin levels were obtained at the start and 2 hours after the end of PT. Cutaneous and rectal temperatures, heart rate, and oxygen saturation will be measured at the beginning and during PT. The number of subjects is therefore not calculated on the basis of statistical assumptions. We aim to obtain a minimum proportion of 90% (ie, 9 of 10) of the neonates included, who have been able to undergo 4-hour PT without unacceptable and unexpected toxicities. We will calculate the mean, median, quartiles, minimum and maximum values of the quantitative parameters, and the frequency of the qualitative parameters. The rate of patients with no unacceptable and unexpected toxicities (ie, the primary endpoint) will be calculated. RESULTS: The first patient is expected to be enrolled at the end of 2020, and clinical investigations are intended for up to June 2021. The final results of this study are expected to be available at the end of 2021. CONCLUSIONS: Our findings will provide insights into the safety and feasibility of a new PT device based on light-emitting fabrics for the treatment of newborn jaundice. This new system, if proven effective, will improve the humanization of neonatal care and help avoid mother-child separation. TRIAL REGISTRATION: ClinicalTrials.gov NCT04365998; https://clinicaltrials.gov/ct2/show/NCT04365998. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/24808.

Photodynamic Therapy Using a New Painless Light-Emitting Fabrics Device in the Treatment of Extramammary Paget Disease of the Vulva (the PAGETEX Study): Protocol for an Interventional Efficacy and Safety Trial.

BACKGROUND: Extramammary Paget disease of the vulva (EMPV) is a rare skin disorder commonly seen in postmenopausal Caucasian females that appears clinically as red, eczematous, pruriginous, and sometimes painful lesions. Although most cases are noninvasive, EMPV may be associated with an underlying or distant adenocarcinoma. EMPV has a chronic and relapsing course. The reference treatment is based on local surgical excision with negative margins. However, disease frequently extends far from the visible lesion, and surgical margins are frequently positive. Topical photodynamic therapy (PDT) is an established treatment modality for various dermatooncologic conditions. For example, red light irradiation with the Aktilite CL 128 and Metvixia (Galderma SA) as a photosensitizing molecule is a conventional protocol approved and widely used in Europe for PDT treatment of actinic keratosis, but this treatment is not yet widely used for EMPV because it has never clearly been demonstrated and is very painful. OBJECTIVE: The aim of the study is to investigate the efficacy and safety relating to the medical device PAGETEX as a new painless PDT device using Metvixia in the treatment of vulvar Paget disease. The primary end point is the disease control rate at 3 months in 30% of the patients included, defined as stability, partial response, or total response, considering the extent of the lesion. Secondary end points are the disease control rate at 6 months, patient quality of life, level of pain experienced by the patient at each PDT session, severity of erythema, presence of protoporphyrin IX in Paget cells after each PDT session, and overall satisfaction level of the patient. METHODS: The trial is an interventional, exploratory, simple group, nonrandomized, and single center (Lille University Hospital) study. Twenty-four patients will be included according to Simon's optimal plan. Therapeutic procedure is based on a cycle of two PDT sessions with the PAGETEX medical device at 15-day intervals (Metvixia incubation during 30 minutes and 635 nm red light illumination with a low irradiance for 2 hours and 30 minutes for a total fluence of 12 J/cm²). At the assessment session, 3 months after inclusion, if the control of the disease is partial or null, the patient will complete another cycle of two PDT sessions. A final evaluation will be performed in all patients at 6 months. Analyses will be performed using SAS version 9.4 software (SAS Institute Inc). The characteristics of the patients at baseline will be described; qualitative variables will be described by numbers and percentages, and quantitative variables will be described either by the mean and standard deviation for Gaussian distribution or by the median and interquartile range (ie, 25th and 75th percentiles). The normality of the distributions will be tested by a Shapiro-Wilk test and checked graphically by histograms. RESULTS: First patient was included in September 2019 and clinical investigations are planned until August 2022. The final results of this study are expected to be available in January 2023. CONCLUSIONS: This clinical trial aims to evaluate the efficacy and safety of a new PDT protocol for the treatment of EMPV. The PAGETEX device could become the treatment of choice if it is effective, painless, and easy to implement and use in hospitals. TRIAL REGISTRATION: ClinicalTrials.gov NCT03713203; https://clinicaltrials.gov/ct2/show/NCT03713203. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/15026.

Evaluating the Noninferiority of a New Photodynamic Therapy (Flexitheralight) Compared With Conventional Treatment for Actinic Keratosis: Protocol for a Phase 2 Study.

BACKGROUND: Actinic keratosis (AK) is characterized by preinvasive, cancerous lesions on sun-exposed skin that negatively affect patient quality of life and may progress to invasive squamous cell carcinoma (SCC). If untreated, AK may either regress or progress to SCC, with significant morbidity and possible lethal outcomes. The most commonly used treatments for AK are cryotherapy, topical chemotherapy and, more recently, photodynamic therapy (PDT). This clinical study is part of a project that aims to create specific light-emitting fabrics (LEFs) that strongly improve the efficiency and reliability of PDT as a treatment for AK. OBJECTIVE: This study aims to compare the efficacy and tolerability of a new PDT protocol involving the Flexitheralight device (N-PDT) with the classical protocol involving the Aktilite CL 128 device (C-PDT; Galderma Laboratories) for the treatment of AK. All participants receive both protocols. The primary objective of this study is to compare the lesion response rate after 3 months of N-PDT with C-PDT. Secondary objectives are evaluations of pain and local tolerance during treatment, clinical evolution of the subject's skin, and evaluations of patient quality of life and satisfaction. METHODS: The study is a split-face, intraindividual comparison of two PDT protocols. The total number of patients recruited was 42. Patients were exposed to a continuous red light with the Aktilite CL 128 device on one side of the face and to fractionated red illumination with the new device, Flexitheralight, on the other side of the face. Males or females over the age of 18 years with a clinical diagnosis of at least 10 previously untreated, nonpigmented, nonhyperkeratotic grade I and II AK lesions of the forehead and/or scalp were included and were recruited from the Department of Dermatology of the Centre Hospitalier Universitaire de Lille. The patients came to the investigational center for one treatment session (day 1), and they were followed up after 7 days, 3 months and 6 months. A second treatment session was performed on day 111 in cases in which an incomplete response was observed at the 3-month follow-up. Data will be analyzed using SAS software version 9.4 (SAS Institute Inc). Continuous variables will be reported as means and standard deviations, and categorical variables will be reported as frequencies and percentages. The Shapiro-Wilk test will be used to assess the normality of the distribution. RESULTS: The clinical investigation was performed by July 2018. Data analysis was performed at the end of 2018, and results are expected to be published in early 2019. CONCLUSIONS: This phase II clinical trial aims to evaluate the noninferior efficacy and superior tolerability of N-PDT compared to that of C-PDT. If N-PDT is both efficacious and tolerable, N-PDT could become the treatment of choice for AK due to its ease of implementation in hospitals. TRIAL REGISTRATION: ClinicalTrials.gov NCT03076918; https://clinicaltrials.gov/ct2/show/NCT03076918 (archived by WebCite at http://www.webcitation.org/771KA0SSK). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11530.

A New Light-Emitting, Fabric-Based Device for Photodynamic Therapy of Actinic Keratosis: Protocol for a Randomized, Controlled, Multicenter, Intra-Individual, Phase II Noninferiority Study (the Phosistos Study).

BACKGROUND: Actinic keratosis (AK) is a common early in situ skin carcinoma caused by long-term sun exposure and usually develops on sun-exposed skin areas. Left untreated, AK may progress to squamous cell carcinoma. To prevent such risk, most clinicians routinely treat AK. Therapy options for AK include cryotherapy, topical treatments, curettage, excision surgery, and photodynamic therapy (PDT). OBJECTIVE: The aim of this study is to assess the noninferiority, in terms of efficacy at 3 months, of a PDT protocol involving a new light-emitting device (PDT using the Phosistos protocol [P-PDT]) compared with the conventional protocol (PDT using the conventional protocol [C-PDT]) in the treatment of AK. METHODS: In this randomized, controlled, multicenter, intra-individual, phase II noninferiority clinical study, subjects with AK of the forehead and scalp are treated with P-PDT on one area and with C-PDT on the contralateral area. In both areas, lesions are prepared and methyl aminolevulinate (MAL) is applied. Thirty minutes after MAL application, the P-PDT area is exposed to red light at low irradiance (1.3 mW/cm2) for 2.5 hours so that a light dose of 12 J/cm2 is achieved. In the control area (C-PDT area), a 37 J/cm2 red light irradiation is performed 3 hours after MAL application. Recurrent AK at 3 months is retreated. The primary end point is the lesion complete response rate at 3 months. Secondary end points include pain scores at 1 day, local tolerance at 7 days, lesion complete response rate at 6 months, cosmetic outcome at 3 and 6 months, and patient-reported quality of life and satisfaction throughout the study. A total of 45 patients needs to be recruited. RESULTS: Clinical investigations are complete: 46 patients were treated with P-PDT on one area (n=285 AK) and with C-PDT on the contralateral area (n=285 AK). Data analysis is ongoing, and statistical results will be available in the first half of 2019. CONCLUSIONS: In case of noninferiority in efficacy and superiority in tolerability of P-PDT compared with C-PDT, P-PDT could become the treatment of choice for AK. TRIAL REGISTRATION: ClinicalTrials.gov NCT03076892; https://clinicaltrials.gov/ct2/show/NCT03076892 (Archived by WebCite at http://www.webcitation.org/779qqVKek). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12990.

Can daylight-PDT be performed indoor?

Natural DayLight-mediated PhotoDynamic Therapy (NDL-PDT) is an efficacious treatment option for thin actinic keratosis that offers advantages over conventional PDT in terms of tolerability and cost. It is now accepted that the minimum criteria required for effective NDL-PDT is a dose of 4 J/cm² with a treatment time of 2 hours and a minimum temperature of 10 °C, corresponding to a minimum illuminance of 11,000 lux. This value is easily achievable: 20,000 lux can be obtained during a typical overcast day at midday. It can reach 110,000 lux with a bright sunlight. However, it is limited to certain times of the year at our latitude. However rain and cold temperatures appear the main limitations of NDL-PDT. Greenhouses make possible to perform the illumination even in harsh weather conditions. Furthermore, it is difficult to install a greenhouse everywhere. Several solutions are now proposed to carry out indoor illumination so-called artificial white light or simulated daylight (SDL-PDT). Illumination sources installed at the ceiling of the treatment room is one option. Several lamp pairs can be combined to illuminate groups of patients simultaneously. A surgical theatre light can be used or dedicated systems using white LEDs can be used to deliver the required illumination dose. In conclusion, Indoor lightning (or simulated daylight: SDL-PDT or Artificial White Light: AWL) could offer an interesting alternative to NDL-PDT.

A novel device for intraoperative photodynamic therapy dedicated to glioblastoma treatment.

AIM: Photodynamic therapy (PDT) appears to be a valuable new treatment modality for cancer therapy. Studies have reported successful application of PDT for glioblastoma. Here, we introduce a new device dedicated to intraoperative PDT delivered early after fluoro-guided resection combined with a transfer function that determines the treatment time based on the size of the surgical resection cavity. MATERIALS & METHODS: First, we describe the device, which is composed of a trocar, a balloon filled with a diffusing solution, and a fiber guide in which a cylindrical light diffuser is inserted. Ex vivo experiments were performed to measure the fluence rate inside biological tissues. A calibration factor was defined to convert power measurements into fluence rate values. Calf brains were used to simulate light propagation in human brain tissue, and the photosensitizer administration effect on optical properties was discussed. The temperature elevation during illumination was evaluated. RESULTS: Light power was measured in tissues surrounding the device during ex vivo experiments. Using the previously characterized calibration factor, power measurements were converted to fluence rate values to obtain the transfer function. No thermal elevation was observed during a 2-h temperature test, and the impact of protoporphyrin IX on brain optical properties was considered negligible. CONCLUSION: A discussion of experimental precision is presented. The light duration determined by the abacus had a standard deviation of <1 min. This value is weak compared with the total illumination time necessary to treat one patient. The main advantage of our device lies in its straightforward implementation of intraoperative PDT for neurosurgery with acceptable dosimetry and easy treatment time.