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Simple Summary: This study investigated the circadian rhythm of intracellular protoporphyrin IX (PPIX) accumulation in bladder cancer cells exposed to 5-aminolevulinic acid to understand the variability in red fluorescence intensity observed during photodynamic diagnosis-assisted transurethral resection among different tumors and patients. We identified the circadian rhythm of the clock genes PER2 and BMAL1 and their impact on PPIX accumulation in bladder cancer cell lines UM-UC-3 and J82, as well as in mouse xenograft models. Additionally, enzymes involved in heme synthesis, including coproporphyrinogen oxidase and ferrochelatase, were found to follow circadian rhythms. When red fluorescence intensity was quantified and compared among the four groups based on surgery start times, from 9 a.m. to 5 p.m., it peaked in surgeries performed between 3 and 5 p.m. These findings suggest that optimizing surgery timing based on circadian rhythms may improve the efficacy of photodynamic diagnosis in bladder cancer. Background/Objectives: The standard recommendation for patients with non-muscle invasive bladder cancer is 5-aminolevulinic acid-mediated photodynamic diagnosis. The intensity of the fluorescence caused by the intracellular accumulation of protoporphyrin IX (PPIX) varies among tumors and patients. This study investigated the circadian rhythm of intracellular PPIX accumulation in bladder urothelial cancer cells exposed to 5-aminolevulinic acid. Methods: The expression of two clock genes, PER2 and BMAL1, and their impact on intracellular PPIX accumulation were evaluated in two bladder cancer cell lines, UM-UC-3 and J82, and mouse xenograft models. We evaluated the enzymes involved in the heme synthesis pathway that potentially affect the circadian rhythm of intracellular PPIX accumulation. The red fluorescence intensity of the images captured during photodynamic diagnosis-assisted transurethral resection of bladder tumors was quantified and compared among the four groups according to surgery start time: 9 a.m.–11 a.m., 11 a.m.–1 p.m., 1–3 p.m., and 3–5 p.m. Results: We observed the circadian rhythm of intracellular PPIX accumulation, which was potentially regulated by the clock genes PER2 and BMAL1. Two enzymes involved in the heme synthesis pathway, coproporphyrinogen oxidase and ferrochelatase, exhibit a circadian rhythm. The fluorescence intensity started gradually increasing at 12 p.m., and the highest level was observed in patients who underwent surgery between 3 and 5 p.m. Conclusions: Our findings suggest that it may be possible to optimize the timing of the photodynamic diagnosis in photodynamic diagnosis-assisted transurethral resection of bladder cancer based on the circadian rhythm to improve tumor detection and treatment outcomes. [ABSTRACT FROM AUTHOR]

Objectives: In a primary analysis of data from the BRIGHT study (UMIN000035712), photodynamic diagnosis‐assisted transurethral resection of bladder tumor (PDD‐TURBT) using oral 5‐aminolevulinic acid hydrochloride reduced residual tumors in high‐risk non‐muscle invasive bladder cancer (NMIBC). We aimed to evaluate the effectiveness of PDD‐TURBT for intravesical recurrence after a second transurethral resection for high‐risk NMIBC. Methods: High‐risk NMIBC patients initially treated with PDD‐TURBT (PDD group) were prospectively registered between 2018 and 2020. High‐risk patients with NMIBC who were initially treated with white‐light TURBT (WL group) were retrospectively registered. Intravesical recurrence‐free survival after the second transurethral resection was compared between the PDD and WL groups using propensity score matching analysis. Results: In total, 177 patients were enrolled in the PDD group, and 306 patients were registered in the WL group. After propensity score matching (146 cases in each group), intravesical recurrence within 1 year was significantly less frequent in the PDD group than in the WL group (p = 0.004; hazard ratio [HR] 0.44, 95% confidence interval [CI]: 0.25–0.77). In subgroup analysis, PDD‐TURBT showed a particularly high efficacy in reducing intravesical recurrence within 1 year, especially in cases of tumors measuring less than 3 cm (p = 0.003; HR 0.31, 95% CI: 0.14–0.67), absence of residual tumor at second transurethral resection (p = 0.020; HR 0.37, 95% CI: 0.16–0.86), and no postoperative intravesical Bacillus Calmette‐Guérin therapy (p < 0.001; HR 0.27, 95% CI: 0.13–0.58). Conclusions: PDD‐TURBT may reduce short‐term intravesical recurrence in patients with high‐risk NMIBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Bladder cancer (BC) possesses distinct molecular profiles that influence progression depending on its biological nature and delivered treatment intensity. Muscle-invasive BC (MIBC) and non-MIBC (NMIBC) demonstrate great intrinsic heterogeneity regarding different prognoses, survival, progression, and treatment outcomes. Transurethral resection of bladder tumor (TURBT) is the standard treatment for NMIBC. The high risks of disease recurrence from residual tumor and progression after TURBT in NMIBC are well known. A new-generation photosensitizer, 5-Aminolevulinic acid (5-ALA), with a high tumor specificity, has been studied for detecting precise tumor areas. Moreover, it has been applied for treatment by producing its cytotoxic reactive oxygen species, as well as screening for urological carcinomas by excreting porphyrin in the blood and urine. Thus, 5-ALA may contribute to the inclusive treatment of NMIBC. Bladder cancer (BC) possesses distinct molecular profiles that influence progression depending on its biological nature and delivered treatment intensity. Muscle-invasive BC (MIBC) and non-MIBC (NMIBC) demonstrate great intrinsic heterogeneity regarding different prognoses, survival, progression, and treatment outcomes. Transurethral resection of bladder tumor (TURBT) is the standard of care in treating NMIBC and serves both diagnostic and therapeutic purposes despite the prevalent recurrence and progression among many patients. In particular, flat urothelial carcinoma in situ and urothelial carcinoma with lamina propria invasion are the major precursors of MIBC. A new-generation photosensitizer, 5-Aminolevulinic acid (5-ALA), demonstrates high tumor specificity by illuminating the tumor lesion with a specific wavelength of light to produce fluorescence and has been studied for photodynamic diagnosis to detect precise tumor areas by TURBT. Additionally, it has been applied for treatment by producing its cytotoxic reactive oxygen species, as well as screening for urological carcinomas by excreting porphyrin in the blood and urine. Moreover, 5-ALA may contribute to screening before and after TURBT in NMIBC. Here, we summarize the updated evidence and ongoing research on photodynamic technology for NMIBC, providing insight into the potential for improving patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Oral 5-aminolevulinic acid for transurethral resection of bladder tumor reduces bladder cancer recurrence compared with standard white-light transurethral resection of bladder tumor. However, data regarding risks of adverse events with this drug are unclear. The aim of the present study was to identify risk factors associated with oral 5-aminolevulinic acid induced adverse events in photodynamic diagnosis-transurethral resection of bladder tumor. Methods: We studied 104 cases of 5-aminolevulinic acid-photodynamic diagnosis-transurethral resection of bladder tumor from October 2021 to April 2023, administering 20 mg/kg 5-aminolevulinic acid orally at least 2 h pre-surgery. Four major adverse events associated with 5-aminolevulinic acid were selected to identify risk factors for their occurrence, including perioperative hypotension, nausea and/or vomiting, photosensitivity, and liver dysfunction. Univariate and multivariate analyses were conducted to identify the risk factors of those adverse events. Results: Perioperative hypotension (11.5 %), nausea and/or vomiting (37.5 %) photosensitivity (31.7 %), and liver dysfunction (51.9 %) were observed. Multivariate analyses revealed that spinal anesthesia was associated with hypotension (p = 0.02), whereas advanced age (p < 0.01) and higher body mass index (p < 0.01) were associated with nausea and/or vomiting. Also, male sex (p < 0.01) and longer operative time (p = 0.01) were associated with photosensitivity, and renin-angiotensin system inhibitors use was associated with postoperative liver dysfunction (p < 0.01). Conclusions: For elderly male obese patients taking renin-angiotensin system inhibitors, particular attention is needed during the perioperative period of photodynamic diagnosis-transurethral resection of bladder tumor under spinal anesthesia due to the higher risk of onset of the adverse events involved in oral administration of 5-aminolevulinic acid.

Background: Although photodynamic-diagnosed transurethral resection of bladder cancer (PDD-TURBT) and Bacillus Calmette-Guérin (BCG) intravesical instillation are the two representative therapies for non-muscle invasive bladder cancer (NMIBC), no studies directly compare their efficacy. We evaluated the outcome of PDD-TURBT alone compared with white light TURBT with intravesical BCG therapy and analyzed the efficacy of both therapies depending on the characteristics of the tumors. Methods: We retrospectively analyzed intermediate- and high-risk NMIBC patients treated with PDD-TURBT alone (the PDD group) or white light TURBT with BCG therapy (the white light group) using propensity score matched analysis. Results: In the propensity score matched cohort, the 1-, 2-, and 3-year recurrence-free survival rates for the PDD group were 77.6 %, 64.1 %, and 48.1 %, respectively, compared to 84.6 %, 75.1 %, and 75.1 % for the white light group (p = 0.44, 0.27, 0.17, respectively). The difference in recurrence rates between the two groups tended to become more pronounced over time, although there was no significant difference. In the univariate and multivariate analysis, recurrence, multiplicity, and tumor grade were the significant prognostic factors of recurrence in the PDD group (p = 0.010, 0.047, 0.048, respectively). Long-term RFS was similar in the PDD and white light groups when the population was limited to the primary and single tumors, suggesting that PDD-TURBT alone may be sufficient in this spectrum of patients. Conclusions: PDD-TURBT alone is insufficient to control the long-term recurrence of bladder cancer but can be effective in selected cases such as primary and single tumors.

Background and Aim: The diagnostic accuracy for cholangiocarcinoma (CCA) is inadequate, necessitating the exploration of novel diagnostic approaches. Protoporphyrin IX (Pp IX), a metabolic product of 5-aminolevulinic acid (5-ALA), emits red fluorescence upon blue light exposure. Because it accumulates selectively in cancer cells, photodynamic diagnosis using 5-ALA (5-ALA-PDD) has been integrated into clinical practice for diverse cancer types. Nevertheless, there is currently no device capable of capturing Pp IX-derived fluorescence for real-time 5-ALA-PDD within the biliary tract, largely due to challenges in device miniaturization. Methods: To investigate the feasibility of real-time 5ALA-PDD in CCA, we developed two essential components of the cholangioscopy system: a small-diameter flexible camera and a light guide for emitting blue light. We evaluated the detectability of Pp IX fluorescence using these devices in experimental gels and animal models. Results: Our camera and light guide were smoothly inserted into the lumen of existing cholangioscopes. Incorporating a long-pass filter at the camera tip enabled efficient detection of red fluorescence without significantly impacting white-light observation. The integration of these devices facilitated clear visualization of red fluorescence from gels containing Pp IX at concentrations of 5 μM or higher. Additionally, when observing subcutaneous human CCA tumor models in nude mice treated with 5-ALA, we successfully demonstrated distinct red fluorescence from Pp IX accumulation in tumors compared to peritumoral subcutaneous areas. Conclusion: The integration of our device combination holds promise for real-time 5-ALA-PDD in human CCA, potentially enhancing the diagnostic accuracy for this complex condition.

Objectives: To analyze the incidence and risk factors of intraoperative hypotension related to photodynamic diagnosis‐assisted transurethral resection of bladder tumor (PDD‐TURBT) with oral 5‐aminolevulinic acid (5‐ALA). Methods: We retrospectively analyzed 487 patients with bladder tumors who underwent PDD‐TURBT (n = 184) or conventional TURBT (conv‐TURBT) (n = 303) between 2018 and 2021. Intraoperative hypotension was defined as hypotension requiring vasopressors during TURBT, and its incidence was compared between the two groups. Potential risk factors of intraoperative hypotension, including preoperative change in mean arterial pressure (MAP), were further investigated in patients receiving PDD‐TURBT. Results: The median age was 72 years, 392 patients (81%) were male, and 203 (42%) had hypertension. TURBT was performed under general and spinal anesthesia in 76 (16%) and 411 (84%) patients, respectively. The incidence of intraoperative hypotension was significantly higher in PDD‐TURBT compared to conv‐TURBT (43% vs. 17%, respectively). The median change in MAP until the induction of anesthesia was +6.5 mmHg (range: −29.0 to +46.3) in the PDD‐TURBT group and +14.7 mmHg (range: −35.3 to +67.7) in the conv‐TURBT group, showing a significantly smaller increase in the PDD‐TURBT group (p < 0.001). In the multivariable analysis for PDD‐TURBT patients, advanced age, general anesthesia, and lower MAP change (<+6.5 mmHg) until anesthesia induction were significantly associated with intraoperative hypotension (p = 0.0104, <0.001, and <0.001, respectively). Conclusions: Intraoperative hypotension occurred more frequently in patients who underwent PDD‐TURBT than in those who underwent conv‐TURBT. Using oral 5‐ALA decreases preoperative blood pressure elevation and may be responsible for intraoperative hypotension. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to observe the fluorescence characteristics of acne inflammatory skin lesions in 5‐aminolevulinic acid‐based photodynamic diagnosis (ALA‐PDD), and discuss the viability of using ALA‐PDD to evaluate acne inflammatory skin lesions and explore the advantages of predicting subclinical skin lesions. Methods: The OBSERV facial skin detector collected photographs of 20 patients before and after optical intra‐tissue fiber irradiation photodynamic therapy (OFI‐ALA‐PDT) in both ALA‐PDD and white light patterns. The patients were treated once a week for four consecutive weeks in order to analyze the correlation between the two patterns in recognizing inflammatory skin lesions. Results: Before and after treatment, there was no significant difference between the two patterns for recognizing acne inflammatory skin lesions (p > 0.05). Both patterns demonstrated a strong correlation (r > 0.90) for the recognition of various types of inflammatory skin lesions at different treatment stages. Conclusion: ALA‐PDD is a feasible method for evaluating acne inflammatory lesions, guiding treatment and judging efficacy. It has advantages in predicting subclinical skin lesions and deserves further study. [ABSTRACT FROM AUTHOR]

• Oral administration of 5-aminolevulinic acid enhances photodynamic diagnosis but increases the risk of specific adverse events during bladder tumor resection. • Significant associations found between spinal anesthesia and perioperative hypotension; advanced age and higher BMI with nausea/vomiting and male sex and longer operative times with increased photosensitivity. • Patients using renin-angiotensin system inhibitors showed a higher incidence of postoperative liver dysfunction, suggesting the need for careful monitoring. • The study identifies critical risk factors that could guide preoperative planning and patient counseling to mitigate potential adverse effects in vulnerable populations. • This research underscores the importance of individualized patient assessments when using 5-aminolevulinic acid in surgical procedures for bladder cancer. Oral 5-aminolevulinic acid for transurethral resection of bladder tumor reduces bladder cancer recurrence compared with standard white-light transurethral resection of bladder tumor. However, data regarding risks of adverse events with this drug are unclear. The aim of the present study was to identify risk factors associated with oral 5-aminolevulinic acid induced adverse events in photodynamic diagnosis-transurethral resection of bladder tumor. We studied 104 cases of 5-aminolevulinic acid-photodynamic diagnosis-transurethral resection of bladder tumor from October 2021 to April 2023, administering 20 mg/kg 5-aminolevulinic acid orally at least 2 h pre-surgery. Four major adverse events associated with 5-aminolevulinic acid were selected to identify risk factors for their occurrence, including perioperative hypotension, nausea and/or vomiting, photosensitivity, and liver dysfunction. Univariate and multivariate analyses were conducted to identify the risk factors of those adverse events. Perioperative hypotension (11.5 %), nausea and/or vomiting (37.5 %) photosensitivity (31.7 %), and liver dysfunction (51.9 %) were observed. Multivariate analyses revealed that spinal anesthesia was associated with hypotension (p = 0.02), whereas advanced age (p < 0.01) and higher body mass index (p < 0.01) were associated with nausea and/or vomiting. Also, male sex (p < 0.01) and longer operative time (p = 0.01) were associated with photosensitivity, and renin-angiotensin system inhibitors use was associated with postoperative liver dysfunction (p < 0.01). For elderly male obese patients taking renin-angiotensin system inhibitors, particular attention is needed during the perioperative period of photodynamic diagnosis-transurethral resection of bladder tumor under spinal anesthesia due to the higher risk of onset of the adverse events involved in oral administration of 5-aminolevulinic acid. [ABSTRACT FROM AUTHOR]

Abstract Background To compare 5-aminolevulinic acid (5-ALA)-mediated photodynamic diagnosis (PDD) with narrow-band imaging (NBI) for cancer detection during transurethral resection of bladder tumour (TURBT). Methods Between June 2018 and October 2020, 114 patients and 282 lesions were included in the analysis. Patients were orally administered 5-ALA (20 mg/kg) 2 h before TURBT. The bladder was inspected with white light (WL), PDD, and NBI for each patient, and all areas positive by at least one method were resected or biopsied. The imaging data were then compared to the pathology results. Results The sensitivities of WL, PDD, and NBI for detecting urothelial carcinoma were 88.1%, 89.6%, and 76.2%, respectively. The specificity, positive predictive value, and negative predictive value for detecting urothelial carcinoma were 47.5%, 80.9%, and 61.3%, respectively, for WL; 22.5%, 74.5%, and 46.2%, respectively, for PDD; and 46.3%, 78.2%, and 43.5%, respectively, for NBI. PDD was significantly more sensitive than NBI for all lesions (p

Abstract Background To investigate risk factors for orally administered 5-aminolevulinic acid (ALA)-induced hypotension for bladder cancer patients receiving photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT). Methods Patients were categorized into two groups intraoperatively: a hypotensive group (minimum systolic blood pressure (SBP) ≤80 mmHg) and a non-hypotensive group (minimum SBP > 80 mmHg). We examined differences between the hypotensive group and non-hypotensive groups to identify clinical risk of ALA-induced hypotension using multivariate logistic regression analysis and decision tree analysis. Results Among 282 cases with ALA-PDD-assisted TURBT from three institutions who were screened, 245 patients were included in the final analysis. In total, 156 patients (63.7%) showed any grade of hypotension during ALA-PDD-assisted TURBT. General anesthesia and spinal anesthesia were induced intraoperatively in 113 patients (46.1%) and 132 patients (53.9%), respectively. Median SBP at baseline (before taking ALA) and at the beginning of anesthesia was 127 mmHg (range, 69–186 mmHg) and 124 mmHg (range, 69–186 mmHg), respectively. Median minimum SBP during ALA-PDD-assisted TURBT was 75 mmHg (range, 43–140 mmHg). Multivariate logistic regression analysis revealed that history of hypertension (odds ratio (OR) 7.568, p

Photodynamic diagnosis (PDD) is more sensitive than white light observation but has reduced specificity. Herein, we investigated whether artificial intelligence technology can be used to discriminate between true-positive and false-positive tissues in PDD to improve its low specificity. The results suggest that specificity can be improved depending on the observation site. [ABSTRACT FROM AUTHOR]

Objectives: Transurethral resection of bladder tumor with photodynamic diagnosis has been reported to result in lower residual tumor and intravesical recurrence rates in non‐muscle invasive bladder cancer. We aimed to evaluate the usefulness of photodynamic diagnosis‐transurethral resection of bladder tumor combined with oral 5‐aminolevulinic acid hydrochloride for high‐risk non‐muscle invasive bladder cancer. Methods: High‐risk non‐muscle invasive bladder cancer patients with an initial photodynamic diagnosis‐transurethral resection of bladder tumor (photodynamic diagnosis group) were prospectively registered between 2018 to 2020. High‐risk non‐muscle invasive bladder cancer cases with a history of initial white‐light transurethral resection of bladder tumor (white‐light group) were retrospectively registered. Propensity score‐matching analysis was used to compare residual tumor rates, and factors that could predict residual tumors at the first transurethral resection of bladder tumor were evaluated. Results: Analyses were conducted with 177 and 306 cases in the photodynamic diagnosis and white‐light groups, respectively. The residual tumor rates in the photodynamic diagnosis and white‐light groups were 25.7% and 47.3%, respectively. Factor analysis for predicting residual tumors in the photodynamic diagnosis group showed that the residual tumor rate was significantly higher in cases with a current/past smoking history, multiple tumors, and pT1/pTis. When each factor was set as a risk level of 1, cases with a total risk score ≤1 showed a significantly lower residual tumor rate than cases with a total risk score ≥2 (8.3% vs 33.3%, odds ratio 5.46 [1.81–22.28]). Conclusions: In high‐risk non‐muscle invasive bladder cancer cases, the odds of a residual tumor after initial photodynamic diagnosis‐transurethral resection of bladder tumor were 0.39‐fold that of the odds of those after initial white‐light transurethral resection of bladder tumor. A risk stratification model could be used to omit the second transurethral resection of bladder tumor in 27% of the cases. [ABSTRACT FROM AUTHOR]

Detecting early-stage oral cancer and precancerous lesions are critical to improving patient prognosis and quality of life after treatment. Photodynamic diagnosis using 5-aminolevulinic acid enables the detection of malignant lesions. This study aimed to improve the diagnostic accuracy of photodynamic diagnosis using an objective chromaticity analysis of fluorescence emitted from oral lesions. Sixty-seven patients with clinically suspicious oral cavity lesions underwent photodynamic diagnosis after topical application of 5-aminolevulinic acid solution, followed by imaging and histological evaluation of the lesions. Chromaticity red and green values were measured from the fluorescence images on the lesion, and the red-to-green ratio was calculated. The photodynamic diagnosis allowed for the visualization of oral cancer and high-risk dysplasia as red fluorescence. Compared to low-risk dysplasia and benign lesions, oral cancer and high-risk dysplasia areas had a significantly higher red value and red-to-green ratio. After setting the cutoff value, sensitivity and specificity were 83.3–88.7% and 83.3–83.9%, respectively, when discriminating between oral cancer or high-risk dysplasia and low-risk dysplasia or benign lesions. Photodynamic diagnosis combined with chromaticity analysis may be a valuable diagnostic tool for detecting oral lesions, with a high likelihood of malignant transformation. [ABSTRACT FROM AUTHOR]

• 5-ALA-PDD for Pp IX fluorescence imaging of cholangiocarcinoma in the biliary tract. • Small-diameter flexible camera and light guide developed for per-oral cholangioscopy (POCS). • Pre-clinical study demonstrates devices efficiently detect Pp IX fluorescence. • This device combination is expected to enhance diagnostic accuracy in POCS. The diagnostic accuracy for cholangiocarcinoma (CCA) is inadequate, necessitating the exploration of novel diagnostic approaches. Protoporphyrin IX (Pp IX), a metabolic product of 5-aminolevulinic acid (5-ALA), emits red fluorescence upon blue light exposure. Because it accumulates selectively in cancer cells, photodynamic diagnosis using 5-ALA (5-ALA-PDD) has been integrated into clinical practice for diverse cancer types. Nevertheless, there is currently no device capable of capturing Pp IX-derived fluorescence for real-time 5-ALA-PDD within the biliary tract, largely due to challenges in device miniaturization. To investigate the feasibility of real-time 5ALA-PDD in CCA, we developed two essential components of the cholangioscopy system: a small-diameter flexible camera and a light guide for emitting blue light. We evaluated the detectability of Pp IX fluorescence using these devices in experimental gels and animal models. Our camera and light guide were smoothly inserted into the lumen of existing cholangioscopes. Incorporating a long-pass filter at the camera tip enabled efficient detection of red fluorescence without significantly impacting white-light observation. The integration of these devices facilitated clear visualization of red fluorescence from gels containing Pp IX at concentrations of 5 μM or higher. Additionally, when observing subcutaneous human CCA tumor models in nude mice treated with 5-ALA, we successfully demonstrated distinct red fluorescence from Pp IX accumulation in tumors compared to peritumoral subcutaneous areas. The integration of our device combination holds promise for real-time 5-ALA-PDD in human CCA, potentially enhancing the diagnostic accuracy for this complex condition. [ABSTRACT FROM AUTHOR]

• We evaluated the outcome of PDD-TURBT alone compared with white light TURBT with intravesical BCG therapy for intermediate- and high-risk NMIBC. • The difference in recurrence rate between PDD-TURBT alone and white light TURBT with intravesical BCG therapy tended to become more pronounced over time. • PDD-TURBT alone is insufficient to control the long-term recurrence of bladder cancer but can be effective in selected cases such as primary and single tumors. Although photodynamic-diagnosed transurethral resection of bladder cancer (PDD-TURBT) and Bacillus Calmette-Guérin (BCG) intravesical instillation are the two representative therapies for non-muscle invasive bladder cancer (NMIBC), no studies directly compare their efficacy. We evaluated the outcome of PDD-TURBT alone compared with white light TURBT with intravesical BCG therapy and analyzed the efficacy of both therapies depending on the characteristics of the tumors. We retrospectively analyzed intermediate- and high-risk NMIBC patients treated with PDD-TURBT alone (the PDD group) or white light TURBT with BCG therapy (the white light group) using propensity score matched analysis. In the propensity score matched cohort, the 1-, 2-, and 3-year recurrence-free survival rates for the PDD group were 77.6 %, 64.1 %, and 48.1 %, respectively, compared to 84.6 %, 75.1 %, and 75.1 % for the white light group (p = 0.44, 0.27, 0.17, respectively). The difference in recurrence rates between the two groups tended to become more pronounced over time, although there was no significant difference. In the univariate and multivariate analysis, recurrence, multiplicity, and tumor grade were the significant prognostic factors of recurrence in the PDD group (p = 0.010, 0.047, 0.048, respectively). Long-term RFS was similar in the PDD and white light groups when the population was limited to the primary and single tumors, suggesting that PDD-TURBT alone may be sufficient in this spectrum of patients. PDD-TURBT alone is insufficient to control the long-term recurrence of bladder cancer but can be effective in selected cases such as primary and single tumors. [ABSTRACT FROM AUTHOR]

5-Aminolevulinic acid (5-ALA) is a natural amino acid and a precursor of heme and chlorophyll. Exogenously administered 5-ALA is metabolized into protoporphyrin IX (PpIX). PpIX accumulates in cancer cells because of the low activity of ferrochelatase, an enzyme that metabolizes PpIX to heme. High expression of 5-ALA influx transporters, such as peptide transporters 1/2, in cancer cells also enhances PpIX production. Because PpIX radiates red fluorescence when excited with blue/violet light, 5-ALA has been used for the visualization of various tumors. 5-ALA photodynamic diagnosis (PDD) has been shown to improve the tumor removal rate in high-grade gliomas and non-muscular invasive bladder cancers. However, 5-ALA PDD remains a challenge as a diagnostic method because tissue autofluorescence interferes with PpIX signals in cases where tumors emit only weak signals, and non-tumorous lesions, such as inflammatory sites, tend to emit PpIX fluorescence. Here, we review the current outline of 5-ALA PDD and strategies for improving its diagnostic applicability for tumor detection, focusing on optical techniques and 5-ALA metabolic pathways in both viable and necrotic tumor tissues. [ABSTRACT FROM AUTHOR]

Clinical evidence regarding risk reduction of bladder cancer recurrence after initial photodynamic diagnosis (PDD)-assisted transurethral resection of a bladder tumor (TURBT) has accumulated. However, evidence regarding over-diagnosis and over-resection is still limited. False-positive results are mainly due to mucosa inflammation and tangential effect. An objective diagnostic tool is required to eliminate false-positive results and over-resection. Moreover, side effects from oral 5-aminolevulinic hydrochloride (5-ALA) cannot be ignored. Well-known side effects include liver dysfunction, hypotension, skin photosensitivity reaction, and vomiting. Given that 5-ALA-PDD is associated with inevitable negative aspects, urologists may not need to use 5-ALA-PDD for all patients with non-muscle invasive bladder cancer. [ABSTRACT FROM AUTHOR]

5aminolevulinic acid (ALA)-photodynamic diagnosis (PDD) using ALAGLIO® (ALA hydrochloride, SBI Pharmaceuticals Co., Ltd., Tokyo, Japan) has been approved for the management of non-muscle invasive bladder cancer (NMIBC) in Japan and has been accepted for funding by the public health insurance system since 2017. The clinical indication of ALAGRIO® is the visualization of NMIBC during transurethral resection of a bladder tumor (TURBT). In addition, ALA-PDD is expected to contribute significantly to NMIBC treatment by increasing the accuracy at which invisible lesions can be detected. [ABSTRACT FROM AUTHOR]

Positive diagnoses of gastric tumors from photodynamic diagnosis (PDD) images after the administration of 5-aminolevulinic acid are subjectively identified by expert endoscopists. Objective methods of tumor identification are needed to reduce potential misidentifications. We developed two methods to identify gastric tumors from PDD images. Method one was applied to segmented regions in the PDD endoscopic image to determine the region in LAB color space to be attributed to tumors using a multi-layer neural network. Method two aimed to diagnose tumors and determine regions in the PDD endoscopic image attributed to tumors using the convoluted neural network method. The efficiencies of diagnosing tumors were 77.8% (7/9) and 93.3% (14/15) for method one and method two, respectively. The efficiencies of determining tumor region defined as the ratio of the area were 35.7% (0.0–78.0) and 48.5% (3.0–89.1) for method one and method two, respectively. False-positive rates defined as the ratio of the area were 0.3% (0.0–2.0) and 3.8% (0.0–17.4) for method one and method two, respectively. Objective methods of determining tumor region in 5-aminolevulinic acid-based endoscopic PDD were developed by identifying regions in LAB color space attributed to tumors or by applying a method of convoluted neural network. [ABSTRACT FROM AUTHOR]

Gastric cancer is the second most common cancer in Japan. The incidence of gastric cancer remains high owing to the increase in the elderly population. Endoscopy outperforms radiography in identifying early gastric cancer (EGC). Furthermore, image-enhanced endoscopy (IEE) has been developed and implemented worldwide in clinical practice. Magnifying IEE images can help to visualize the microvascular pattern and microstructure architecture, which is used for the characterization of EGC. However, accurate endoscopic diagnosis requires the experience and skill of endoscopists, making an objective and simple diagnostic method desirable. In this retrospective study, we investigated the diagnostic yield of 5-aminolevulinic acid (5-ALA)-mediated photodynamic diagnosis (PDD) for identifying gastric cancers and high-grade adenomas. In total, 52 lesions from 43 patients were ultimately included in the study. We detected 5-ALA-mediated protoporphyrin IX fluorescence in 45 of the 52 lesions that were initially intended for PDD, resulting in a detection rate of 86.5%, whereas each signet ring cell carcinoma was negative using 5-ALA PDD. In eight of the patients with multiple lesions, 17 lesions were identified using 5-ALA PDD. Again, we took biopsies from six areas that we suspected as new lesions. While 4 lesions were gastric neoplasms resected by endoscopic submucosal dissection, two other lesions were normal. Preoperative 5-ALA-PDD could provide additional diagnostic yields to detect such multiple lesions simultaneously. No severe adverse events were observed. Prospective multicenter studies are warranted to confirm the usefulness of 5-ALA PDD for EGC identification. [ABSTRACT FROM AUTHOR]

Abstract Background The advantages of photodynamic diagnostic technology using 5-aminolevulinic acid (ALA-PDD) have been established. The aim of this prospective cohort study was to evaluate the usefulness of ALA-PDD to diagnose upper tract urothelial carcinoma (UT-UC) using the Olympus VISERA ELITE video system. Methods We carried out a prospective, interventional, non-randomized, non-contrast and open label cohort pilot study that involved patients who underwent ureterorenoscopy (URS) to detect UT-UC. 5-aminolevulinic acid hydrochloride was orally administered before URS. The observational results and pathological diagnosis with ALA-PDD and traditional white light methods were compared, and the proportion of positive subjects and specimens were calculated. Results A total of 20 patients were enrolled and one patient who had multiple bladder tumors did not undergo URS. Fifteen of 19 patients were pathologically diagnosed with UT-UC and of these 11 (73.3%) were ALA-PDD positive. Fourteen of 19 patients were ALA-PDD positive and of these 11 were pathologically diagnosed with UC. For the 92 biopsy specimens that were malignant or benign, the sensitivity for both traditional white light observation and ALA-PDD was the same at 62.5%, whereas the specificities were 73.1% and 67.3%, respectively. Of the 38 specimens that were randomly biopsied without any abnormality under examination by both white light and ALA-PDD, 11 specimens (28.9%) from 5 patients were diagnosed with high grade UC. In contrast, four specimens from 4 patients, which were negative in traditional white light observation but positive in ALA-PDD, were diagnosed with carcinoma in situ (CIS). Conclusions Our results suggest that ALA-PDD using VISERA ELITE is not sufficiently applicable for UT-UC. Nevertheless, it might be better particularly for CIS than white light and superior results would be obtained using VISERA ELITE II video system. Trial registration: The present clinical study was approved by the Okayama University Institutional Review Board prior to study initiation (Application no.: RIN 1803–002) and was registered with the UMIN Clinical Trials Registry (UMIN-CTR), Japan (Accession no.: UMIN000031205).

Background: Photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) is useful for detecting microperitoneal dissemination in gastric cancer. However, reports on its use in colorectal cancer are sparse. In this study, we performed PDD with 5-ALA to diagnose peritoneal dissemination in colorectal cancer during laparoscopic surgery. Methods: Between January 2018 and March 2019, we examined six patients scheduled laparoscopic surgery for colorectal cancer (cT3 or deeper) with suspected peritoneal dissemination. A solution of 5-ALA (20 mg/kg) in water was orally administered 3 to 4 hours before surgery. Intraoperatively, the peritoneal cavity was observed with white and fluorescent lights. Nodules suspected as dissemination lesions were resected and the presence or absence of seeding was confirmed histopathologically. Results: The median time from oral 5-ALA administration to observation was 226 minutes. Peritoneal nodules found in four of six cases using white light were collected. In Case 5, white nodules were observed in white light and luminescence in fluorescent light. Of the nodules collected, only that of Case 5 was pathologically diagnosed as disseminating. No adverse events were observed. Conclusions: We attempted PDD using 5-ALA during laparoscopic surgery for colorectal cancer. Observing more cases and optimizing observation conditions are required to improve accuracy. This study was registered at the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN Exam ID: UMIN000030531).

Gastric cancer is the second most common cancer in Japan. The incidence of gastric cancer remains high owing to the increase in the elderly population. Endoscopy outperforms radiography in identifying early gastric cancer (EGC). Furthermore, image-enhanced endoscopy (IEE) has been developed and implemented worldwide in clinical practice. Magnifying IEE images can help to visualize the microvascular pattern and microstructure architecture, which is used for the characterization of EGC. However, accurate endoscopic diagnosis requires the experience and skill of endoscopists, making an objective and simple diagnostic method desirable. In this retrospective study, we investigated the diagnostic yield of 5-aminolevulinic acid (5-ALA)-mediated photodynamic diagnosis (PDD) for identifying gastric cancers and high-grade adenomas. In total, 52 lesions from 43 patients were ultimately included in the study. We detected 5-ALA-mediated protoporphyrin IX fluorescence in 45 of the 52 lesions that were initially intended for PDD, resulting in a detection rate of 86.5%, whereas each signet ring cell carcinoma was negative using 5-ALA PDD. In eight of the patients with multiple lesions, 17 lesions were identified using 5-ALA PDD. Again, we took biopsies from six areas that we suspected as new lesions. While 4 lesions were gastric neoplasms resected by endoscopic submucosal dissection, two other lesions were normal. Preoperative 5-ALA-PDD could provide additional diagnostic yields to detect such multiple lesions simultaneously. No severe adverse events were observed. Prospective multicenter studies are warranted to confirm the usefulness of 5-ALA PDD for EGC identification.

Background: Latest guidelines recommend kidney-sparing management as the primary treatment option for selected patients with upper urinary tract urothelial carcinoma (UTUC). One of the biggest issues of ureteroscopic laser ablation (ULA) is a high rate of surgical site recurrence, which is largely attributed to residual lesions at the initial ULA. Another clinical issue is a significant lack of non-invasive reliable detection tools of urinary recurrent tumors in this treatment setting. Methods: The FLUAM trial is a prospective, single-center, single-arm pilot trial to investigate the efficacy of 5-aminolevulinic acid-mediated photodynamic diagnosis (ALA-PDD)-assisted ULA for localized UTUC and the usefulness of the UroVysion® assay (multiprobe fluorescence in situ hybridization) as a monitoring test after the kidney-sparing treatment. After the screening and registration, a total of 20 patients with localized UTUC will undergo the initial ALA-PDD-assisted ULA followed by the second look ALA-PDD-assisted ureteroscopic examination. The primary endpoint is progression-free survival. Secondary endpoints include patient reported outcomes, diagnostic accuracy of UroVysion assay to detect tumor recurrence, adverse events, and safety of the intervention. Conclusion: The goal of this trial is to determine the potential benefit of ALA-PDD assistance in patients who undergo the ULA. The evidence of this novel technique is still limited. The results are expected to change the standard of care and lead to better management of localized UTUC. Trial registration: This clinical trial was prospectively registered with the Japan Registry of Clinical Trials on 23 June 2021. The reference number is jRCTs051210042, nara0023 (Certified Review Board of Nara Medical University).

Background: To compare 5-aminolevulinic acid (5-ALA)-mediated photodynamic diagnosis (PDD) with narrow-band imaging (NBI) for cancer detection during transurethral resection of bladder tumour (TURBT).Methods: Between June 2018 and October 2020, 114 patients and 282 lesions were included in the analysis. Patients were orally administered 5-ALA (20 mg/kg) 2 h before TURBT. The bladder was inspected with white light (WL), PDD, and NBI for each patient, and all areas positive by at least one method were resected or biopsied. The imaging data were then compared to the pathology results.Results: The sensitivities of WL, PDD, and NBI for detecting urothelial carcinoma were 88.1%, 89.6%, and 76.2%, respectively. The specificity, positive predictive value, and negative predictive value for detecting urothelial carcinoma were 47.5%, 80.9%, and 61.3%, respectively, for WL; 22.5%, 74.5%, and 46.2%, respectively, for PDD; and 46.3%, 78.2%, and 43.5%, respectively, for NBI. PDD was significantly more sensitive than NBI for all lesions (p < 0.001) and carcinoma in situ (CIS) lesions (94.6% vs. 54.1%, p < 0.001).Conclusions: PDD can increase the detection rate of bladder cancer, compared to NBI, by greater than 10%. Therefore, 100% of CIS lesions can be detected by adding PDD to WL. [ABSTRACT FROM AUTHOR]

Background: To investigate risk factors for orally administered 5-aminolevulinic acid (ALA)-induced hypotension for bladder cancer patients receiving photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT).Methods: Patients were categorized into two groups intraoperatively: a hypotensive group (minimum systolic blood pressure (SBP) ≤80 mmHg) and a non-hypotensive group (minimum SBP > 80 mmHg). We examined differences between the hypotensive group and non-hypotensive groups to identify clinical risk of ALA-induced hypotension using multivariate logistic regression analysis and decision tree analysis.Results: Among 282 cases with ALA-PDD-assisted TURBT from three institutions who were screened, 245 patients were included in the final analysis. In total, 156 patients (63.7%) showed any grade of hypotension during ALA-PDD-assisted TURBT. General anesthesia and spinal anesthesia were induced intraoperatively in 113 patients (46.1%) and 132 patients (53.9%), respectively. Median SBP at baseline (before taking ALA) and at the beginning of anesthesia was 127 mmHg (range, 69-186 mmHg) and 124 mmHg (range, 69-186 mmHg), respectively. Median minimum SBP during ALA-PDD-assisted TURBT was 75 mmHg (range, 43-140 mmHg). Multivariate logistic regression analysis revealed that history of hypertension (odds ratio (OR) 7.568, p < 0.05) and general anesthesia (OR 14.435, p < 0.05) as significantly associated with an increased risk of hypotension incidence. Use of calcium antagonist showed significant negative associations with hypotension (OR 0.183, p < 0.05). Decision tree analysis showed presence of general anesthesia, age ≥ 74 years and American Society of Anesthesiologists physical status (ASA-PS) ≥2 as the most important discriminators.Conclusions: General anesthesia and hypertension were independent risk factors related to ALA-induced hypotension. In contrast, use of calcium antagonists was identified as a factor associated with reduced risk of ALA-induced hypotension. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the diagnostic performance of fluorescent voided urine cytology (FVUC) using a novel automated detection technology to screen for primary bladder cancer and for surveillance of recurrent bladder tumour. Patients and Methods: We created a rapid, objective, automated, and high‐throughput detection device for hexylaminolevulinate‐mediated FVUC, named the cellular fluorescence analysis unit‐II (CFAU‐II). Two different cohorts were used in this study: (i) screening test for primary bladder cancer (165 patients with bladder cancer and 52 controls), and (ii) surveillance test for detecting intravesical recurrent tumour (192 patients with treated non‐muscle‐invasive bladder cancer and 15 with post‐nephroureterectomy upper urinary tract cancer). Voided urine samples were subjected to urine analysis, conventional VUC (cVUC), and FVUC. Diagnostic performance was compared between cVUC, FVUC, and a combination of the two. Results: A total of 614 urine samples were successfully collected, processed, and analysed. Comparative analysis of the screening test cohort demonstrated that the overall sensitivity of FVUC (63%, P < 0.001) and combination testing (72%, P < 0.001) was significantly higher than that of cVUC (29%). FVUC was found to be superior in most of the subgroups, especially in low‐grade, Ta, and small tumours. Analysis of the surveillance test cohort showed that combination testing achieved a sensitivity of 82% and a negative predictive value of 98%, whereas those of cVUC were 39% and 96%, respectively. According to the pathological finding of recurrent tumours presenting false‐negative result in the FVUC, the majority of the overlooked recurrent diseases were Ta low‐grade tumours. Logistic regression analysis suggested an association between the risk of false‐positive results and high density of urine white blood cells and alkaluria. Conclusion: The present findings clearly demonstrate that FVUC using the newly developed automation technology has superior sensitivity to cVUC for both screening for primary bladder cancer and recurrent tumour detection. It is essential to confirm the clinical usefulness of this method via further large‐scale studies, in addition to ensuring its affordability and availability. [ABSTRACT FROM AUTHOR]

Abstract Background 5-Aminolevulinic acid (5-ALA) is utilized for photodynamic diagnosis-assisted (PDD) surgery. However, it has been associated with vasodilation, hence, occasional hypotension. Case presentation We encountered two patients who had severe postural hypotension following 5-ALA pretreatment prior to an operation. They were scheduled for urological PDD surgery, but upon standing to walk to the operation room, they felt sick because of severe hypotension. One of them underwent the surgery after recovery, but the other surgery was canceled due to a prolonged hypotension that lasted for more than a day. Conclusions Severe postural hypotension may develop as a result of the high concentration of porphyrin precursors, which may affect the nervous system. Severe postural hypotension may be due to 5-ALA-induced autonomic dysfunction as well as vasodilative action of 5-ALA. These observations suggest that in addition to the careful monitoring of patients’ vital signs, standing should be avoided following 5-ALA pretreatment.

Introduction Transurethral resection of bladder tumor is widely used in combination with photodynamic diagnosis to treat non‐muscle invasive bladder cancer. We experienced an intriguing case, in which bladder cancer infiltrated into the right ureteral orifice and was resected via photodynamic diagnosis‐assisted transurethral resection involving the oral administration of 5‐aminolevulinic acid. Case presentation This case was a 71‐year‐old Japanese man. He was diagnosed with bladder carcinoma, which had infiltrated into the right ureter (clinical classification: T1, N0, M0). He underwent transurethral resection involving the oral administration of 5‐aminolevulinic acid. We successfully resected the tumor in the ureteral orifice, which was accomplished by resecting the ureteral orifice until the non‐luminescent lumen was exposed. After the surgery, to prevent recurrence, Bacillus Calmette–Guérin was administered intravesically after right ureteral stent placement. Conclusion Photodynamic diagnosis‐assisted transurethral resection involving the oral administration of 5‐aminolevulinic acid has the potential to treat ureteral tumors derived from bladder tumors.

Abstract Protoporphyrin IX‐fluorescence measurement is a powerful in situ approach for cancer detection after oral/topical administration of 5‐aminolevulinic acid. However, this approach has not been clinically established for breast cancer, probably due to insufficient delivery of 5‐aminolevulinic acid to the mammary glands. In the present study, we directly exposed breast cancer cells to 5‐aminolevulinic acid to assess their discrimination via protoporphyrin IX‐fluorescence. Fluorescence intensity (FI) was measured in the human breast cancer cell lines MCF7 and MDA‐MB‐231 and breast epithelial cell line MCF10A by confocal microscopy and flow cytometry. After 5‐aminolevulinic acid exposure for 2 hours, protoporphyrin IX‐FI in MCF7 and MDA‐MB‐231 cells significantly increased with marked cell‐to‐cell variability, whereas that in MCF10A cells increased moderately. Combined exposure of the cancer cells to 5‐aminolevulinic acid and Ko143, a specific inhibitor of ATP‐binding cassette transporter G2, further increased protoporphyrin IX‐FI and alleviated the cell‐to‐cell variability in MCF7 and MDA‐MB‐231 cells, indicating improvement in the reproducibility and accuracy for fluorescence‐based cancer detection. The increased FI by combined administration of these two drugs was also demonstrated in cells obtained via fine needle aspiration from mouse xenograft models inoculated with MDA‐MB‐231 cells. Furthermore, a cutoff value for increased protoporphyrin IX‐FI ratio, before and after exposure to these drugs, clearly discriminated between cancer and noncancer cells. Taken together, direct exposure to 5‐aminolevulinic acid and Ko143 may be a promising strategy for efficient fluorescence‐based detection of breast cancer cells ex vivo using fine needle aspiration.

Photodynamic diagnosis is a promising method in the treatment of laryngeal papillomatosis, which includes an assessment of the increased visual and spectrometric contrast of papillomatosis masses against the background of the introduction of the photosensitizer. We have developed a method of treatment of laryngeal papillomatosis in two stages: intraoperative diagnosis using the domestic preparation of 5-aminolevulinic acid hydrochloride and subsequent surgical treatment using a carbon dioxide laser. Using the new method, we treated 21 patients, of which 13 (61.9%) had the inter-recurrent period longer than 12 months.

Background/Aim: Non-muscle invasive bladder carcinoma (NMIBC) is highly recurrent. We studied if 5-aminolevulinic acid (5-ALA) instillations before transurethral resection of bladder tumours (TURBT) and cystoscopy extend the time to recurrence during follow-up with NMIBC patients. Patients and Methods: A prospective multicenter study enrolled 328 NMIBC patients. All TURBTs and control cystoscopies during the one-year study period were done with or without 5-ALA instillations. The primary endpoint was time to recurrence. The secondary endpoints were time to recurrence after 7.5, 10.5, and 13.5 months and the number of patients with progressive disease. Results: The overall median follow-up time was 80.4 and 87.0 months for the control and study groups, respectively. There was no statistical difference in time to first recurrence between the two groups. Conclusion: We could not obtain significant differences between the control and 5-ALA groups in tumour recurrence among patients with NMIBC. [ABSTRACT FROM AUTHOR]

Detecting early-stage oral cancer and precancerous lesions are critical to improving patient prognosis and quality of life after treatment. Photodynamic diagnosis using 5-aminolevulinic acid enables the detection of malignant lesions. This study aimed to improve the diagnostic accuracy of photodynamic diagnosis using an objective chromaticity analysis of fluorescence emitted from oral lesions. Sixty-seven patients with clinically suspicious oral cavity lesions underwent photodynamic diagnosis after topical application of 5-aminolevulinic acid solution, followed by imaging and histological evaluation of the lesions. Chromaticity red and green values were measured from the fluorescence images on the lesion, and the red-to-green ratio was calculated. The photodynamic diagnosis allowed for the visualization of oral cancer and high-risk dysplasia as red fluorescence. Compared to low-risk dysplasia and benign lesions, oral cancer and high-risk dysplasia areas had a significantly higher red value and red-to-green ratio. After setting the cutoff value, sensitivity and specificity were 83.3–88.7% and 83.3–83.9%, respectively, when discriminating between oral cancer or high-risk dysplasia and low-risk dysplasia or benign lesions. Photodynamic diagnosis combined with chromaticity analysis may be a valuable diagnostic tool for detecting oral lesions, with a high likelihood of malignant transformation.

Background: The advantages of photodynamic diagnostic technology using 5-aminolevulinic acid (ALA-PDD) have been established. The aim of this prospective cohort study was to evaluate the usefulness of ALA-PDD to diagnose upper tract urothelial carcinoma (UT-UC) using the Olympus VISERA ELITE video system.Methods: We carried out a prospective, interventional, non-randomized, non-contrast and open label cohort pilot study that involved patients who underwent ureterorenoscopy (URS) to detect UT-UC. 5-aminolevulinic acid hydrochloride was orally administered before URS. The observational results and pathological diagnosis with ALA-PDD and traditional white light methods were compared, and the proportion of positive subjects and specimens were calculated.Results: A total of 20 patients were enrolled and one patient who had multiple bladder tumors did not undergo URS. Fifteen of 19 patients were pathologically diagnosed with UT-UC and of these 11 (73.3%) were ALA-PDD positive. Fourteen of 19 patients were ALA-PDD positive and of these 11 were pathologically diagnosed with UC. For the 92 biopsy specimens that were malignant or benign, the sensitivity for both traditional white light observation and ALA-PDD was the same at 62.5%, whereas the specificities were 73.1% and 67.3%, respectively. Of the 38 specimens that were randomly biopsied without any abnormality under examination by both white light and ALA-PDD, 11 specimens (28.9%) from 5 patients were diagnosed with high grade UC. In contrast, four specimens from 4 patients, which were negative in traditional white light observation but positive in ALA-PDD, were diagnosed with carcinoma in situ (CIS).Conclusions: Our results suggest that ALA-PDD using VISERA ELITE is not sufficiently applicable for UT-UC. Nevertheless, it might be better particularly for CIS than white light and superior results would be obtained using VISERA ELITE II video system.Trial Registration: The present clinical study was approved by the Okayama University Institutional Review Board prior to study initiation (Application no.: RIN 1803-002) and was registered with the UMIN Clinical Trials Registry (UMIN-CTR), Japan (Accession no.: UMIN000031205). [ABSTRACT FROM AUTHOR]

Background: Transurethral resection of bladder tumor (TURBT) is an essential procedure both for the treatment and staging of bladder cancer, particularly non-muscle invasive bladder cancer (NMIBC). The dissemination of cancer cells during resection and the consequent seeding into the bladder mucosa is the main cause of post-TURBT intravesical recurrence. Although the tumor dissemination is inevitable during conventional TURBT (cTURBT), this drawback can be overcome by tumor resection in one piece with intact surrounding normal tissues, referred to as en bloc resection. We previously described the photodynamic diagnosis (PDD)-assisted en bloc TURBT (EBTUR) technique and its favorable outcomes. Based on our preliminary studies, this randomized controlled trial was designed to evaluate the superiority of PDD-EBTUR to PDD-cTURBT.Methods: The FLEBER study is a single-center randomized controlled trial in NMIBC patients who require TURBT. The longest diameter of the tumor must be between 6 and 30 mm. A total of 160 eligible patients will be enrolled after screening and randomly allocated to the PDD-EBTUR (experimental) and PDD-cTURBT (control) groups in a 1:1 ratio (80 cases to 80 cases). All patients will be treated using a single, immediate postoperative intravesical chemotherapy with epirubicin. The primary endpoint of this trial is the 2-year recurrence-free survival after surgery in pathologically proven low- or intermediate-risk NMIBC. All patients will be monitored by cystoscopy and urine cytology every 3 months for 2 years. Patient data including adverse events and complications, and data from frequency volume charts, pain scales, and health-related QOL questionnaires will be collected before and after the TURBT at indicated visits.Discussion: The goal of this trial is to determine the potential benefits of PDD-cTURBT and PDD-EBTUR followed by a single immediate postoperative intravesical chemotherapy in patients with low- or intermediate-risk NMIBC who undergo TURBT. Ultimately, our findings will lead to the development of better interventions and potentially change the standard of care.Trial Registration: This clinical trial was prospectively registered with the UMIN Clinical Trials Registry on 1 August 2020. The reference number is UMIN000041273 , and the Ethics Committee of Nara Medical University Approval ID is 2702. [ABSTRACT FROM AUTHOR]

Photodynamic technology using light-sensitive and fluorescent substances has an important role in an accurate diagnosis for a variety of malignancies, including bladder cancer and prostate cancer. Light-sensitive and fluorescent substances accumulate specifically in tumor cells compared to normal tissue, and by light irradiation and excitation at each specific wavelength, tumor lesion, blood flow, lymph node and so on show fluorescence. 5-Aminolevulinic acid (ALA) is converted to protoporphyrin IX (PpIX) into mitochondria. PpIX is excited by blue light, red fluorescence is emitted in the mitochondria. This phenomenon is the mechanism of ALA-mediated photodynamic diagnosis (ALA-PDD). ALA-PDD has made it possible to visualize smaller lesions and flat lesions that were previously difficult to visualize by endoscope using a white-light source. So accurate diagnosis and complete resection become possible during operation. The accumulation of PpIX in the mitochondria also induces direct mitochondrial damage and subsequent cell death by red and green light. This biological reaction is the ALA-mediate photodynamic therapy (ALA-PDT). ALA-PDT has been developed as a modality for minimum invasive cancer treatment that utilizes low-energy light and photosensitizer. Vascular-activated photosensitizer induces rapid tumor ablation by PDT involving direct tumor cell killing as well as damage to the exposed microvasculature. We summarize the clinical outcomes of PDD and PDT for urothelial carcinoma and prostate cancer. [ABSTRACT FROM AUTHOR]

New diagnostic techniques based on photodynamic medicine, such as near-infrared fluorescence using indocyanine green (NIR-ICG) and 5-aminolevulinic acid-mediated photodynamic diagnosis (ALA-PDD), are aiding navigation tasks across various fields of surgery. Specifically, NIR-ICG is being used for the intraoperative identification of sentinel lymph nodes or blood vessels in organ resection and for blood flow evaluation in surgery. These ICG-fluorescent imaging techniques could provide an additional and potentially valuable way to identify vascular and lymphatic structures in surrounding tissue. 5-Aminolevulinic acid is a precursor of a photosensitizing substance with affinity for tumors; thus, diagnostic laparoscopy using ALA-PDD in combination should improve the accuracy of detecting peritoneal dissemination in patients with advanced gastric cancer. The ability to overlay fluorescent imaging with conventional color images in real time using ALA-PDD and NIR with ICG would be of immense benefit to surgeons, providing good visualization and detection of target lesions not seen with the naked eye. A multi-center clinical study examining the safety and efficacy of ALA-PDD during laparoscopic examination for patients with advanced gastric cancer is currently underway in the form of doctor-initiated trials, and further verification studies will be conducted. Such imaging capability could have broad potential across cancer and vascular surgery. [ABSTRACT FROM AUTHOR]

Study Objective: To examine the diagnostic accuracy of hysteroscopic photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5ALA) in patients with endometrial cancer and premalignant atypical endometrial hyperplasia.Design: A single-center, open-label, exploratory intervention study.Setting: University Hospital in Japan.Patients: Thirty-four patients who underwent hysteroscopic resection in the Department of Obstetrics and Gynecology at Keio University Hospital.Interventions: Patients were given 5ALA orally approximately 3 hours before surgery and underwent observation of the uterine cavity and endometrial biopsy using 5ALA-PDD during hysteroscopic resection. Specimens were diagnosed histopathologically and the diagnostic sensitivity and specificity of hysteroscopic 5ALA-PDD for malignancy in the uterine cavity was determined. Red (R), blue (B), and green (G) intensity values were determined from PDD images, and the relationships of histopathological diagnosis with these values were used to develop a model for objective diagnosis of uterine malignancy.Measurements and Main Results: Three patients were excluded from the study because of failure of the endoscope system. A total of 113 specimens were collected endoscopically. The sensitivity and specificity of 5ALA-PDD for diagnosis of malignancy in the uterine cavity were 93.8% and 51.9%, respectively. The R/B ratio in imaging analysis was highest in malignant lesions, followed by benign lesions and normal uterine tissue, with significant differences among these groups (p <.05). The R/B and G/B ratios were used in a formula for prediction of malignancy based on logistic regression and the area under the receiver operating characteristic curve for this formula was 0.838. At a formula cutoff value of 0.220, the sensitivity and specificity for diagnosis of malignant disease were 90.6% and 65.4%, respectively.Conclusion: To our knowledge, this is the first study of the diagnostic accuracy of 5ALA-PDD for malignancies in the uterine cavity. Hysteroscopic 5ALA-PDD had higher sensitivity and identifiability of lesions. These findings suggest that hysteroscopic 5ALA-PDD may be useful for diagnosis of minute lesions. [ABSTRACT FROM AUTHOR]

Background Photodynamic diagnosis (PDD) is an optical imaging technology based on the fundamental biological features of porphyrin metabolized in cancer cells. We reported the usefulness of laser-based photodynamic endoscopic diagnosis (LPDED) with 5-aminolevulinic acid (5-ALA) for early gastric cancers. However, the first-generation prototype endoscope system had the flaw that the images captured were rather dark. To overcome this, we constructed a nextgeneration endoscope system for LPDED. Methods We evaluated the usefulness of the next-generation prototype endoscope system, called Sie-P2, for brighter LPDED to detect early gastric cancer (EGC) and gastric adenoma. The 14 patients diagnosed with EGC and/or gastric adenoma who underwent endoscopic submucosal dissection (ESD) at our hospital between April 2018 and March 2019 were enrolled consecutively in this study. Patients were administered 5-ALA orally and LPDED was performed 3 h later. The primary endpoint was the presence of fluorescence in tumors when we performed LPDED. The secondary endpoint was to assess the adverse events related to each LPDED procedure. Results One patient was excluded because of a contraindication, while the remaining 13 patients (median 72 years, range 56-77; one female) with 16 lesions were assessed. There were 10 elevated lesions and 6 flat/depressed lesions; there were 10 EGCs and 6 adenomas. LPDED-fluorescence was detected in all 16 lesions (sensitivity 100%, 95% confidence interval 79-100%). Two cases showed temporary, though not substantial, elevation in blood liver function tests. Conclusion All lesions examined were LPDED-positive, indicating that the Sie-P2 system could be useful. [ABSTRACT FROM AUTHOR]

Objective: To analyze perioperative blood pressure in patients undergoing transurethral resection of bladder tumor with photodynamic diagnosis. Methods: A total of 109 consecutive patients who underwent photodynamic diagnosis‐assisted transurethral resection of bladder tumor at Kanazawa University, Kanazawa, Ishikawa, Japan, were included in this study and considered as the photodynamic diagnosis group. Clinical data were collected, and perioperative systolic bladder pressure and vasopressor usage were analyzed. In contrast, consecutive patients who previously underwent conventional transurethral resection of bladder tumor (without the use of oral 5‐aminolevulinic acid) were used as the control group. Results: The systolic blood pressure before anesthesia, lowest systolic blood pressure from the anesthesia induction to the start of operation and lowest systolic blood pressure during operation were significantly lower in the photodynamic diagnosis group. The rate of vasopressor use was significantly higher in the photodynamic diagnosis group. On multivariate analysis, we found that general anesthesia and regular use of renin–angiotensin system inhibitor were associated with an increased risk of hypotension (lowest systolic blood pressure from the anesthesia induction to the start of operation <80 mmHg). Conclusions: Oral intake of 5‐aminolevulinic acid can obviously cause a drop in intraoperative blood pressure in patients undergoing transurethral resection of bladder tumor. Therefore, urologists and anesthesiologists should consider withdrawal of renin–angiotensin system inhibitors and monitor the blood pressure during photodynamic diagnosis‐assisted transurethral resection of bladder tumor. [ABSTRACT FROM AUTHOR]

Protoporphyrin IX‐fluorescence measurement is a powerful in situ approach for cancer detection after oral/topical administration of 5‐aminolevulinic acid. However, this approach has not been clinically established for breast cancer, probably due to insufficient delivery of 5‐aminolevulinic acid to the mammary glands. In the present study, we directly exposed breast cancer cells to 5‐aminolevulinic acid to assess their discrimination via protoporphyrin IX‐fluorescence. Fluorescence intensity (FI) was measured in the human breast cancer cell lines MCF7 and MDA‐MB‐231 and breast epithelial cell line MCF10A by confocal microscopy and flow cytometry. After 5‐aminolevulinic acid exposure for 2 hours, protoporphyrin IX‐FI in MCF7 and MDA‐MB‐231 cells significantly increased with marked cell‐to‐cell variability, whereas that in MCF10A cells increased moderately. Combined exposure of the cancer cells to 5‐aminolevulinic acid and Ko143, a specific inhibitor of ATP‐binding cassette transporter G2, further increased protoporphyrin IX‐FI and alleviated the cell‐to‐cell variability in MCF7 and MDA‐MB‐231 cells, indicating improvement in the reproducibility and accuracy for fluorescence‐based cancer detection. The increased FI by combined administration of these two drugs was also demonstrated in cells obtained via fine needle aspiration from mouse xenograft models inoculated with MDA‐MB‐231 cells. Furthermore, a cutoff value for increased protoporphyrin IX‐FI ratio, before and after exposure to these drugs, clearly discriminated between cancer and noncancer cells. Taken together, direct exposure to 5‐aminolevulinic acid and Ko143 may be a promising strategy for efficient fluorescence‐based detection of breast cancer cells ex vivo using fine needle aspiration. [ABSTRACT FROM AUTHOR]

Clinical evidence regarding risk reduction of repeated bladder recurrence after initial photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) is still limited in patients with non-muscle-invasive bladder cancer (NMIBC). We analyzed patients with primary NMIBC undergoing TURBT without any adjuvant treatment to compare the risk of cumulative recurrence between the conventional white-light (WL)-TURBT and PDD-TURBT. Out of 430 patients diagnosed with primary NMIBC from 2010 to 2019, 40 undergoing WL-TURBT and 60 undergoing PDD-TURBT were eligible. Multivariate Cox regression analysis for time to the first recurrence demonstrated that PDD assistance was an independent prognostic factor with better outcome (p = 0.038, hazard ratio = 0.39, and 95% confidence interval 0.16–0.95). While no patient experienced more than one recurrence within 1000 postoperative days in the PDD-TURBT group, five out of 40 patients treated by WL-TURBT experienced repeated recurrence. The comparison of cumulative incidence per 10,000 person-days between the two groups revealed that PDD assistance decreased by 6.6 recurrences per 10,000 person-days (exact p = 0.011; incidence rate ratio 0.37, Clopper–Pearson confidence interval 0.15–0.82). This is the first study addressing PDD assistance-induced risk reduction of repeated bladder recurrence using the person-time method. Our findings could support clinical decision making, especially on adjuvant therapy after TURBT.

The natural amino acid 5-aminolevulinic acid (ALA) is a protoporphyrin IX (PpIX) precursor and a new-generation photosensitive substance that accumulates specifically in cancer cells. When indocyanine green (ICG) is irradiated with near-infrared (NIR) light, it shifts to a higher energy state and emits infrared light with a longer wavelength than the irradiated NIR light. Photodynamic diagnosis (PDD) using ALA and ICG-based NIR fluorescence imaging has emerged as a new diagnostic technique. Specifically, in laparoscopic examinations for serosa-invading advanced gastric cancer, peritoneal metastases could be detected by ALA-PDD, but not by conventional visible-light imaging. The HyperEye Medical System (HEMS) can visualize ICG fluorescence as color images simultaneously projected with visible light in real time. This ICG fluorescence method is widely applicable, including for intraoperative identification of sentinel lymph nodes, visualization of blood vessels in organ resection, and blood flow evaluation during surgery. Fluorescence navigation by ALA-PDD and NIR using ICG imaging provides good visualization and detection of the target lesions that is not possible with the naked eye. We propose that this technique should be used in fundamental research on the relationship among cellular dynamics, metabolic enzymes, and tumor tissues, and to evaluate clinical efficacy and safety in multicenter cooperative clinical trials. [ABSTRACT FROM AUTHOR]

Highlights • Cure rate of PDT for cervical diseases ranged from 31.6% to 100% in 8 articles. • In the only article on PDT for endometrial cancer the cure rate was 75%. • The efficacy of PDD for ovarian cancer was high in 6 articles. Abstract Introduction Several types of photosensitizers such as 5-aminolevulinic acid are progenitors of protoporphyrin IX (PpIX). PpIX accumulates in cancer cells and has photosensitivity. Based on these characteristics, they are used in photodynamic diagnosis (PDD) and photodynamic therapy (PDT). These methods have recently been applied to gynecologic malignant diseases. Here, we review articles on clinical applications of PDD and PDT for these diseases. Materials and Methods A systematic literature search in Pubmed was performed with a combination of keywords to collect the articles. Result There were eight articles on PDT for uterine cervical diseases, including one study that included patients with cervical cancer. The disease remission rate ranged from 31.6% to 100%. PDD under hysteroscopy had positive effects on endometrial cancer, endometrial hyperplasia and secretory endometrial tissue, and 7 of 11 patients were able to become pregnant after PDT for endometrial cancer. For ovarian cancer, the sensitivity and specificity of clinical PDD were high. Discussion There is a need to improve the disease remission rate in uterine cervical diseases, and application of PDT for cervical cancer should be considered. For endometrial cancer, the risks and benefits of PDD that should be compared with those of hysteroscopy using narrow band imaging, which already has been shown to have high efficacy and few side effects. For ovarian cancer, it will be necessary to collect more data to evaluate the effect of PDD on overall survival. Conclusion PDD and PDT can contribute to diagnosis and therapy in clinical practice for gynecologic malignant diseases. [ABSTRACT FROM AUTHOR]

To evaluate the feasibility of photodynamic diagnosis using 5-aminolevulinic acid (PDD-ALA) for detection of prostate cancer (PCa) cells in urine samples after prostate massage in patients who were suspected to have PCa. One hundred and eighty-nine patients with abnormal digital rectal examination and/or an elevated prostate-specific antigen (PSA) level who underwent initial prostate biopsy were recruited. After prostate massage, the first 60 mL of voided urine was collected. For PDD-ALA, 50 mL was used. The rest of collected urine was used for polymerase chain reaction (PCR) of PSA and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). After incubation for 2 h, the intensity was measured at 635 nm under a 405-nm wavelength excitation. The results of PDD-ALA were compared with those of an initial transrectal ultrasound (TRUS)-guided prostate biopsy. Overall, 126/189 (67%) samples that showed bands of both PSA and GAPDH on PCR in urine samples were analyzed. The area under the curve, sensitivity, and specificity of PDD-ALA were 0.74, 77, and 67%, respectively. The value of PDD-ALA was significantly higher in patients with Gleason scores of 6 (p = 0.03), 7 (p = 0.005), and 8-10 (p = 0.0002) than in those with negative biopsy results. In the multivariate analysis, high PSA density, abnormal findings on TRUS, and a high value of PDD-ALA were significant markers for prediction of positive biopsy results. PDD-ALA was useful to predict positive biopsy results in patients who underwent initial prostate biopsy with suspected PCa. This PCa-detection method has potential for clinical use. [ABSTRACT FROM AUTHOR]

Peritoneal metastasis is an important prognostic factor for pancreatic cancer. The present study evaluated the possibility of diagnosing peritoneal metastasis by a photodynamic diagnosis using 5-aminolevulinic acid (5-ALA-PDD). In vitro, protoporphyrin IX (PpIX) accumulation was examined in the AsPC-1-GFP cell line following 5-ALA hydrochloride administration. In vivo, AsPC-1-GFP cells were injected into the peritoneal cavities of mice. Three weeks later 5-ALA hydrochloride was intraperitoneally administered to the mice. The peritoneal nodules were observed under fluorescence excitation. A total of 34 patients were enrolled in the present study who were clinically diagnosed with pancreatic malignancy. 5-ALA hydrochloride was orally administered to the patients prior to surgery. During the operation the abdominal cavity was observed under white light and fluorescence. In vitro and in vivo, it was confirmed that PpIX-induced red fluorescence. In 9 patients peritoneal nodules suspected to be peritoneal metastasis were observed under white light. In 4 of the 9 patients nodules were detected on the basis of the fluorescence images. Fluorescent nodules were histopathologically diagnosed as metastatic. In the present study it was confirmed that 5-ALA-PDD holds promise for the rapid diagnosis of peritoneal metastasis in patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background Oral 5-aminolevulinic acid (ALA) induces biosynthesis/accumulation of the natural photo-sensitizer protoporphyrin IX (PpIX) in cancer cells. ALA is used widely in photodynamic diagnosis (PDD) and therapy (PDT) during malignant glioma surgery, but few studies have examined the effects of photodynamics plus ALA on normal brain tissue in vivo. We investigated the effects of ALA-mediated PDD and PDT on normal brain tissue. Methods We established a rat model in which the brain surface was irradiated through the skull by light-emitting diode (635 nm) after ALA administration. Using this model, we investigated the effects of various amounts of light irradiation with various ALA doses on brain tissue. Results Neurological symptoms developed with administration of ALA at 240 or 120 mg/kg accompanied by irradiation at 100 or 400 J/cm 2 , respectively. Dye leakage occurred due to disruption of the blood–brain barrier (BBB) at 90 mg/kg and 100 J/cm 2 , respectively. Thickness of the cortex increased significantly at 240 mg/kg and 400 J/cm 2 , respectively. The number of neurons appeared to decrease at 200 mg/kg plus 400 J/cm 2 , respectively, and there was an increase in the number of cells that were positive for terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling (TUNEL) staining. Conclusions ALA-mediated PDT is safe at doses of 90 mg/kg or less followed by light irradiation of 100 J/cm 2 in rat brains. At doses above this threshold, ALA-PDT led to irreversible BBB and brain damage in rats. [ABSTRACT FROM AUTHOR]