Light and energy-based therapeutics for genitourinary applications: Consensus on protocols and best practices.

BACKGROUND: Lasers and energy-based technologies have been developed for genitourinary applications over the past several decades. AIMS: This consensus article aims to categorize the published articles and clinical trial data that culminated in protocol development of technology for genitourinary applications, and to develop consistent parameters in future clinical trials. MATERIALS AND METHODS: The published articles and clinical trials data on lasers and energy-based devices applied to genitourinary conditions were categorized according to device and condition and consensus developed on protocols and parameters. RESULTS: The devices in genitourinary applications were classified as fractional lasers, radiofrequency and high-intensity focused electromagnetic field therapy. The consensus of the protocols and parameters based upon the published clinical trials of their application to the vaginal and urologic conditions associated with genitourinary syndrome of menopause was developed and organized according to device and condition. DISCUSSION: The status of FDA clearances and future pathways are discussed. CONCLUSIONS: This consensus article categorizes and presents the protocols and practices for the main classes of lasers and energy-based devices for genitourinary applications in future clinical trials.

Light and energy based therapeutics for genitourinary syndrome of menopause: Consensus and controversies.

Gynecologist and plastic surgeons pioneered the application of lasers in medicine and surgery almost 5 decades ago, initially used to treat cervical and vaginal pathologies. Ever since, energy-based devices have been deployed to treat pelvic pathologies and improve fertility. Recent technological developments triggered an unprecedented wave of publications, assessing the efficacy of fractional laser, and radiofrequency on the vaginal wall in reversing natural aging processes. Studies have shown that a certain degree of thermal energy deposited on the vaginal wall stimulates proliferation of the glycogen-enriched epithelium, neovascularization, and collagen formation in the lamina propria, and improves natural lubrication and control of urination. This review aimed to review such data and to guide future research. A unique assembly of experts from around the globe, compiled and edited this manuscript based on a thorough literature review and personal experience. Lasers Surg. Med. 49:137-159, 2017. © 2017 Wiley Periodicals, Inc.

Lasers in Gynecology.

The first published reports on the use of laser for cervical pathology date back to 1973. Technical advancements in flexible and rigid laser fibers revolutionized video laser laparoscopy in the 1990s. Fractionated lasers have been used to treat vulvovaginal symptoms associated with genitourinary syndrome of menopause, lichen sclerosus, and urinary incontinence. Review of available data suggests that fractionated lasers can improve both subjective and objective signs of vaginal atrophy and lichen sclerosus, but the evidence is weak because most of the trials are underpowered, are at risk for bias, and lack long-term follow-up. There is no strong evidence to support fractionated laser therapy for urinary incontinence or low-level laser therapy for chronic pelvic pain. Although short-term, single-arm trials suggest benefit of fractionated laser therapy for genitourinary syndrome of menopause, lichen sclerosus, and urinary incontinence, additional adequately powered, prospective, randomized, and longer-term comparative trials are needed before lasers can be recommended for these specific conditions. The purpose of this Clinical Expert Series is to review basic laser biophysics and the mechanism of action for modern fractionated lasers as relevant to the gynecologist. We also summarize safety and effectiveness data for lasers used for some of the most commonly studied gynecologic conditions: the vulvovaginal atrophy component of genitourinary syndrome of menopause, lichen sclerosus, and urinary incontinence.

OCT angiography in the monitoring of vaginal health.

Fractional-pixel CO2 laser therapy shows promise for treating the genitourinary syndrome of menopause (GSM). Nevertheless, it remains controversial in the field of female pelvic medicine. This is due to the inherent difficulties in obtaining noninvasive biopsies to evaluate the treatment's efficacy and safety objectively. To address this challenge, we developed a noninvasive intravaginal optical coherence tomography (OCT)/OCT angiography (OCTA) endoscopic system, whose probe features a shape identical to the laser treatment probe. This system can provide high-resolution OCT images to identify the microstructure of vaginal tissue and visualize the vasculature network in vivo. We conducted clinical research on 25 post-menopausal patients with GSM. OCT/OCTA scans were acquired at four different locations of the vagina (distal anterior, distal posterior, proximal anterior, and proximal posterior) during the whole laser treatment session. A U-Net deep learning model was applied to segment the vaginal epithelium for assessing vaginal epithelial thickness (VET). Blood vessel density and VET were quantified to monitor the efficacy of fractional-pixel CO2 laser therapy. Statistical correlation analyses between these metrics and other clinical scores were conducted, validating the utility of our system. This OCT/OCTA endoscopic system has great potential to serve as a noninvasive biopsy tool in gynecological studies to screen, evaluate, and guide laser treatment for GSM.

Optical coherence tomography evaluation of vaginal epithelial thickness during CO2 laser treatment: A pilot study.

Genitourinary syndrome of menopause (GSM) negatively affects more than half of postmenopausal women. Energy-based therapy has been explored as a minimally invasive treatment for GSM; however, its mechanism of action and efficacy is controversial. Here, we report on a pilot imaging study conducted on a small group of menopause patients undergoing laser treatment. Intravaginal optical coherence tomography (OCT) endoscope was used to quantitatively monitor the changes in the vaginal epithelial thickness (VET) during fractional-pixel CO2 laser treatment. Eleven patients with natural menopause and one surgically induced menopause patient were recruited in this clinical study. Following the laser treatment, 6 out of 11 natural menopause patient showed increase in both proximal and distal VET, while two natural menopause patient showed increase in VET in only one side of vaginal tract. Furthermore, the patient group that showed increased VET had thinner baseline VET compared to the patients that showed decrease in VET after laser treatment. These results demonstrate the potential utility of intravaginal OCT endoscope in evaluating the vaginal tissue integrity and tailoring vaginal laser treatment on a per-person basis, with the potential to monitor other treatment procedures.

Optical Vaginal Biopsy Using Optical Coherence Tomography.

OBJECTIVE: Optical coherence tomography is a noninvasive technology that visualizes tissue microstructure with high spatial resolution. We designed a novel vaginal system that demonstrates a clear distinction between vaginal tissues planes. In this study, we sought to compare vaginal tomographic images of premenopausal, perimenopausal, and postmenopausal women, demonstrate feasibility of tracking vaginal tissue changes after treatment with fractional-pixel CO2 laser therapy, and obtain a histologic correlation of these findings. METHODS: Enrolled subjects underwent imaging and were divided into 3 groups based on menopausal status. Women with genitourinary syndrome of menopause who received fractional-pixel CO2 laser therapy were assessed before and after treatment. A cadaveric vagina was used to obtain tomographic and histologic images to assess for accuracy. Our primary outcome was mean vaginal epithelial thickness. Statistical analysis was performed using analysis of variance and t tests, respectively. RESULTS: Among 6 women, the mean vaginal epithelial thickness decreased with menopause (P < 0.01). Although change in epithelial thickness after fractional-pixel CO2 laser treatment varied between the 2 subjects evaluated, it increased significantly for the subject who reported improvement of vaginal symptoms (P < 0.01). Using a cadaveric specimen, optical biopsy was correlated to an hematoxylin and eosin-stained biopsy of the same vaginal site. CONCLUSIONS: This study establishes feasibility of optical coherence tomography in providing an optical biopsy of the vaginal epithelium and lamina propria. In addition, it demonstrates vaginal changes as women enter menopause. This report is the initial phase of a longitudinal cohort study to evaluate changes in vaginal microstructure after energy-based treatment.

[Laparoscopic surgery training system in gynecology].

With the increasing demand of Laparoscopic surgery, many departments are considering the development of surgical skills centers. The authors describe their hospitaLs endoscopic training program which includes a theoretical curriculum and an inexpensive laparoscopic simulator The system is designed in order to improve basic skills of laparoscopic surgery. Other systems available elsewhere are discussed.

[Uterine fibroids].

Uterine fibroids (leiomyoma) are the most common benign tumors in women. Better understanding of the pathophysiology, as well as recent technical advancements opened the gates for new options for women who suffer from symptomatic uterine fibroids. Treatments are categorized in four groups: surgical removal, minimally invasive or noninvasive approach causing damage to cellular viability, medical treatments to reduce volume and relieve symptoms, and complementary medicine. This review may assist in tailoring the type of treatment according to age, desire for future fertility, size and location of the fibroids.

Vaginal mifepristone for the treatment of symptomatic uterine leiomyomata: an open-label study.

OBJECTIVE: To evaluate the efficacy and safety of 3 months of vaginal mifepristone treatment on leiomyoma volume and related symptoms. DESIGN: Prospective, open-label, two tertiary centers, phase II clinical trial. SETTING: Two tertiary medical centers in Israel. PATIENT(S): Thirty-three enrolled women, ages 30-53 years, diagnosed with symptomatic uterine fibroids. INTERVENTION(S): Patients received 10 mg mifepristone vaginally daily for 3 months. MAIN OUTCOME MEASURE(S): Reduction in uterine leiomyoma volume. Improvement in symptoms related to uterine fibroids was assessed with the use of the "Uterine Fibroid Symptoms Quality of Life Questionnaire" (UFS-QoL). The number of bleeding days, safety, and tolerability were secondary measures. RESULT(S): Mifepristone treatment significantly reduced leiomyoma volume from 135.3 ± 22.9 cc at enrollment to 101.2 ± 22.4 cc after 3 months of treatment. The UFS-QoL Score significantly decreased from 20.7 ± 0.7 at enrollment to 14.0 ± 0.8 after 3 months of treatment. The number of bleeding days significantly decreased by 3.5 days. Endometrial biopsies showed no evidence of endometrial hyperplasia or cellular atypia. There were no major side effects during the course of the study, and treatment was well tolerated. CONCLUSION(S): Vaginal mifepristone may offer an effective treatment option for women with symptomatic uterine leiomyoma and can improve the patients' quality of life. CLINICAL TRIAL REGISTRATION NUMBER: NCT00881140.

Laser effects in the manipulation of human eggs and embryos for in vitro fertilization.

Gamete manipulations using laser micro beams were introduced in 1991 and testing its application for assisted hatching occurred shortly thereafter. This procedure has now become an accepted modality of penetrating or reducing the thickness of the zona pellucida in human in vitro fertilization (IVF). Lasers used in earlier work are summarized. Although the earliest lasers used pulses as long as 15 ms, the simplest and safest laser presently used in this application is the high-power 1480-nm In GaAsP diode, used in pulses with duration typically < 1 ms. Since prevention of damage to the blastomeres is essential, we specifically discuss this system with particular attention to safety considerations. The laser operates by its thermal effect on the zona pellucida, and the implications for embryo safety are discussed in detail. A thermal model is derived using numerical analysis and the effect on the embryo of laser beam power and pulse duration is indicated. Typical recommended protocols and operating values for various applications in the human IVF laboratory are given.

Photodynamic therapy of high-grade cervical intraepithelial neoplasia with 5-aminolevulinic acid.

BACKGROUND AND OBJECTIVES: To determine the safety and efficacy of 5-aminolevulinic acid (ALA) as a topically applied photosensitizer for photodynamic therapy (PDT) of cervical intraepithelial neoplasia (CIN). STUDY DESIGNS/MATERIALS AND METHODS: Forty women, who were at least 18 years old with persistent biopsy-proven CIN 2 and CIN 3 within the previous 3 months of enrollment, underwent PDT in a phase I and II design. Five escalating radiant energies (increments of 25 J/cm(2), beginning at 50-150 J/cm(2)) using a Coherent Dye Model 920 argon pumped dye laser providing light at 630 nm (maximum output 0.8 W) were used to perform PDT with a fixed dose of ALA (200 mg/ml). ALA was placed in a cervical cap fitted to the cervix. After 90 minutes, the cap was removed and the ectocervix was illuminated for 5-16 minutes, depending on the irradiance. Success was defined as the absence of CIN on Pap smear or colposcopic examination at 12-months. Patients were monitored for toxicity. RESULTS: Thirty-two women (80%) completed the study with 1 year of follow-up. Sixty percent had CIN 3 and 40% CIN 2. Success rates at 4, 8, and 12 months were 51, 46, and 31%, respectively, and were not light-dose dependent. Three patients progressed from CIN 2 to CIN 3. Toxicity was tolerable and only consisted of spotting, vaginal discharge, mild cramping, and vaginal warmth. There was no apparent dose relationship to toxicity. CONCLUSIONS: PDT at this light and ALA dose is well tolerated but has minimal activity in the treatment of CIN 2 and CIN 3. Other doses and schedules of light and ALA or novel photosensitizers may improve efficacy.

Photodynamic endometrial ablation: morphological study.

BACKGROUND AND OBJECTIVES: Endometriumablation provides an alternative treatment modality to hysterectomy for dysfunctional uterine bleeding (DUB). Its feasibility was demonstrated in animal studies. The purpose of this study was the evaluation of histological changes following photodynamic endometrial ablation in patients. STUDY DESIGN/MATERIALS AND METHODS: 5-Aminolevulinic acid (ALA) was topically applied in three premenopausal and one postmenopausal patient 4-6 hours before laser-illumination. ALA-concentration: 100-400 g/ml, NaOH-titration (pH 5.5). Volume applied, 1.5-2.0 ml; intrauterine balloon-lightdiffuser; wavelength, 635 nm; lightdose, 160 J/cm(2). Hysterectomy was performed 3-152 days after photodynamic ablation. Histological examination was carried out on endometrium sections stained with hematoxylin and eosin (H&E). RESULTS: Necrosis including the full thickness of the endometrium was found 3 days after photodynamic endometrial ablation. Specimens collected after 35 and 152 days did not exhibit fibrosis or adhesions. Foci of preserved endometrium were detected in all patients. CONCLUSIONS: Photodynamic endometrial ablation is selective and does not cause endometrial fibrosis or adhesions.

Photodynamic endometrial ablation for the treatment of dysfunctional uterine bleeding: a preliminary report.

BACKGROUND AND OBJECTIVES: To evaluate feasibility and functional effects of photodynamic endometrial ablation (PEA) in patients. STUDY DESIGN/PATIENTS AND METHODS: A total of 15 PEAs has been performed in 11 patients using topically applied 5-aminolevulinic acid (ALA) solutions and a balloon-light diffuser (160 J/cm(2), 635 nm). Uterine bleeding intensity has been determined on a daily basis 3 months prior to and up to 6 months after endometrial ablation using an analogous scale scoring from 1 (spotting) to 6 U (severe bleeding). Statistical analysis by unpaired Student's t-test. RESULTS: The mean number of bleeding units per cycle (n = 44) was 35.7 prior to PEA. The decrease in bleeding units was significant for the months 1-3 (24.4 U per cycle; P = 0.03), but not for the months 4-6 (25.9 U; P = 0.11) following PEA. CONCLUSIONS: PEA is feasible and provides a significant short-term reduction of uterine bleeding.

Laparoscopic photodynamic diagnosis of ovarian cancer using 5-aminolevulinic acid in a rat model.

OBJECTIVE: The objective of this study was to determine the efficacy and sensitivity of laparoscopic photodynamic diagnosis to detect 5-aminolevulinic acid (ALA)-induced fluorescent tumors in an animal model. METHODS: Cancer cells were injected into the peritoneum of rats to induce peritoneal carcinomatosis. After 3-4 weeks, ALA was administered to establish fluorescence in tumor nodules. All intraperitoneal surfaces were inspected using fluorescence and white light laparoscopy. Suspicious lesions were then biopsied in vivo under either fluorescence or white light laparoscopic guidance. Fluorescence intensities of the cancerous lesions compared to normal tissues were determined. A pathologist blinded to our clinical impression analyzed all biopsied specimens. We compared the sensitivity of fluorescence and white light laparoscopic-guided detection of cancerous lesions and determined the clinical utility of fluorescent photodynamic diagnosis in detecting metastatic ovarian cancer. RESULTS: Forty-three biopsies were performed in vivo under laparoscopic fluorescent guidance and 42 biopsies were taken using white light in various regions of the peritoneal surface from nine rats. Ten biopsies were also removed from nonfluorescent regions as nontumor controls. Cancerous lesions showed significantly higher fluorescent intensity compared to noncancerous lesions. Cancerous lesions that were difficult to differentiate from normal surrounding tissue under white light conditions were clearly detected by ALA-induced fluorescence. The average size of these metastatic lesions biopsied under fluorescent light was 1.0 mm (range: 0.3-2.5) compared to 1.5 mm (range: 0.5-2.9) with white light illumination (P < 0.05). CONCLUSIONS: Fluorescent laparoscopic detection of micrometastatic ovarian cancer using ALA is significantly more sensitive than white-light laparoscopy in detecting smaller cancerous lesions in an ovarian cancer rat model. Human trials are indicated.