Photodynamic Diagnosis Research Articles

Positive Predictive Values of Procedure Codes on the Treatment of Non-Muscle Invasive Bladder Cancer in the Danish National Patient Registry.

Globally non-muscle invasive bladder cancer (NMIBC) is a high-incidence disease. There is a large heterogeneity within NMIBC regarding recurrence- and progression risks, and large-scale studies of treatment patterns and prognoses in an everyday setting could result in NMIBC-subgroup treatment optimization, benefiting both patients and the economy. The Danish national registries provide such an opportunity if the registered procedure codes are valid. Therefore, the aim of the study was to validate the International Classification of Diseases, 10th Edition (ICD-10) codes of NMIBC treatment used in the Danish National Patient Registry (DNPR). From the DNPR, we randomly selected 200 NMIBC treatment courses identified by the dates of the course and the codes of transurethral resection of the bladder ((TURB), n = 125), photodynamic diagnosis ((PDD), n = 25), bladder instillation with Bacillus Calmette vaccine ((BCG), n = 25), or bladder instillation with chemotherapy/Mitomycin C ((MMC), n = 25). We used medical record reviews as the reference standard and estimated positive predictive values (PPVs) of all procedure codes and negative predictive values (NPVs) of PDD- and the perioperative single-shot MMC codes. We identified the medical records in 150 (75%) of the 200 treatment courses (149 individual patients). The overall PPVs were TURB: 98.9% (95% confidence interval: 93.8; 100.0%), PDD: 95.8% (78.9; 99.9%), adjuvant BCG: 90.0% (68.3; 98.8%), perioperative single-shot MMC 1/5, and adjuvant MMC: 69.2% (38.6; 90.9%). The overall NPVs were PDD: 64.8% (54.4; 73.9%) and perioperative single-shot MMC: 97.7% (92.1; 99.4%). The ICD-10 NMIBC procedure codes recorded in the DNPR are generally valid with high PPVs. The NPV of the PPD code is acceptable. However, the code for perioperative single-shot MMC is uncertain with low PPV, but a high NPV.

Photodynamic Therapy for Bladder Cancers, A Focused Review†.

Bladder cancer is the first cancer for which PDT was clinically approved in 1993. Unfortunately, it was unsuccessful due to side effects like bladder contraction. Here, we summarized the recent progress of PDT for bladder cancers, focusing on photosensitizers and formulations. General strategies to minimize side effects are intravesical administration of photosensitizers, use of targeting strategies for photosensitizers and better control of light. Non-muscle invasive bladder cancers are more suitable for PDT than muscle invasive and metastatic bladder cancers. In 2010, the FDA approved blue light cystoscopy, using PpIX fluorescence, for photodynamic diagnosis of non-muscle invasive bladder cancer. PpIX produced from HAL was also used in PDT but was not successful due to low therapeutic efficacy. To enhance the efficacy of PpIX-PDT, we have been working on combining it with singlet oxygen-activatable prodrugs. The use of these prodrugs increases the therapeutic efficacy of the PpIX-PDT. It also improves tumor selectivity of the prodrugs due to the preferential formation of PpIX in cancer cells resulting in decreased off-target toxicity. Future challenges include improving prodrugs and light delivery across the bladder barrier to deeper tumor tissue and generating an effective therapeutic response in an In vivo setting without causing collateral damage to bladder function.

Water soluble octa-imidazolium zinc phthalocyanine for nucleus/nucleolus cell fluorescence microscopy and photodynamic therapy.

A poly-cationic theranostic macrocycle was developed to perform confocal microscopy imaging and photodynamic therapy studies on a model of melanoma cancer, one of the most aggressive cancer. Hence, an octa-imidazolium zinc phthalocyanine was conveniently synthesized in large amount in three steps in a 44% overall yield: upon double nucleophilic aromatic substitution, cyclo-tetramerization and quaternization reactions. Such an octa-cationic molecule was readily soluble in physiological media, reaching concentrations beyond 1mM. It showed fluorescence properties in aqueous medium (ΦF = 0.31) with no noticeable aggregation, spectroscopy studies showed. In vitro confocal fluorescence microscopy studies carried out on murine melanoma model (B16F10 cells) showed that the fluorophore was mainly located in the cell nucleolus, an organelle of interest for the treatment of cancer. The anticancer photodynamic potential of the octa-cationic photosensitizer could be measured (IC50 = 5.4µM) using the MTS viability assay. Both fluorescence microscopy studies and photodynamic studies demonstrate the octa-cationic molecule is theranostic and could be further developed for future photodynamic diagnosis (PDD) and photodynamic inactivation of micro-organisms (PDI).

Hypericin, a potential new BH3 mimetic.

Many types of cancer such as prostate cancer, myeloid leukemia, breast cancer, glioblastoma display strong chemo resistance, which is supported by enhanced expression of multiple anti-apoptotic Bcl-2, Bcl-XL and Mcl-1 proteins. The viable anti-cancer strategies are based on developing anti-apoptotic Bcl-2 proteins inhibitors, BH3 mimetics. Our focus in past years has been on the investigating a new potential BH3 mimetic, Hypericin (Hyp). Hyp is a naturally occurring photosensitive compound used in photodynamic therapy and diagnosis. We have demonstrated that Hyp can cause substantial effects in cellular ultrastructure, mitochondria function and metabolism, and distribution of Bcl2 proteins in malignant and non-malignant cells. One of the possible mechanisms of Hyp action could be the direct interactions between Bcl-2 proteins and Hyp. We investigated this assumption by in silico computer modelling and in vitro fluorescent spectroscopy experiments with the small Bcl2 peptide segments designed to correspond to Bcl2 BH3 and BH1 domains. We show here that Hyp interacts with BH3 and BH1 peptides in concentration dependent manner, and shows the stronger interactions than known BH3 mimetics, Gossypol (Goss) and ABT-263. In addition, interactions of Hyp, Goss and ABT263, with whole purified proteins Bcl-2 and Mcl-1 by fluorescence spectroscopy show that Hyp interacts stronger with the Bcl-2 and less with Mcl-1 protein than Goss or ABT-263. This suggest that Hyp is comparable to other BH3 mimetics and could be explore as such. Hyp cytotoxicity was low in human U87 MG glioma, similar to that of ABT263, where Goss exerted sufficient cytotoxicity, suggesting that Hyp acts primarily on Bcl-2, but not on Mcl-1 protein. In combination therapy, low doses of Hyp with Goss effectively decreased U87 MG viability, suggesting a possible synergy effect. Overall, we can conclude that Hyp as BH3 mimetic acts primarily on Bcl-2 protein and can be explored to target cells with Bcl-2 over-expression, or in combination with other BH3 mimetics, that target Mcl-1 or Bcl-XL proteins, in dual therapy.

Poly(Styrene-Co-Maleic Acid)-Conjugated 6-Aminofluorescein and Rhodamine Micelle as Macromolecular Fluorescent Probes for Micro-Tumors Detection and Imaging.

Styrene-co-maleic acid (SMA) copolymer was evaluated as a polymer platform to conjugate with two fluorescent dyes, i.e., 6-aminofluorescein (AF) and Rhodamine (Rho); which spontaneously self-assembles in an aqueous medium and forms a micelle through a non-covalent interaction. These SMA-dye conjugates showed the nanosized micelle formation through dynamic light scattering (DLS) with discrete distributions having mean particle sizes of 135.3 nm, and 190.9 nm for SMA-AF, and SMA-Rho, respectively. The apparent molecular weight of the micelle was evaluated using Sephadex G-100 gel chromatography and it was found that the 49.3 kDa, and 28.7 kDa for SMA-AF, and SMA-Rho, respectively. Moreover, the biodistribution study showed the selective accumulation of the SMA-dye conjugates in the tumor of mice. Taken together, the SMA-dye conjugated micelles appear in high concentrations in the tumor by utilizing the enhanced permeability and retention (EPR) effect of the tumor-targeted delivery. These results indicate that SMA-dye conjugates have the advanced potential as macromolecular fluorescent probes for microtumor imaging by means of a photodynamic diagnosis.

C5α secreted by tumor mesenchymal stem-like cells mediates resistance to 5-aminolevulinic acid-based photodynamic therapy against glioblastoma tumorspheres.

Advancements in photodynamic diagnosis (PDD) and photodynamic therapy (PDT) as a standard care in cancer therapy have been limited. This study is aimed to investigate the clinical availability of 5-aminolevulinic acid (5-ALA)-based PDD and PDT in glioblastoma (GBM) patient-derived tumorspheres (TSs) and mouse orthotopic xenograft model. PDT was performed using a 635nm light-emitting diode (LED). Transcriptome profiles were obtained from microarray data. For knockdown of C5α, siRNA was transfected into tumor mesenchymal stem-like cells (tMSLCs). The invasiveness of TSs was quantified using collagen-based 3D invasion assays. Treatment with 1mM 5ALA induced distinct protoporphyrin IX (PpIX) fluorescence in GBM TSs, but not in non-tumor cells or tissues, including tMSLCs. These observations were negatively correlated with the expression levels of FECH, which catalyzes the conversion of accumulated PpIX to heme. Furthermore, the 5-ALA-treated GBM TSs were sensitive to PDT, thereby significantly decreasing cell viability and invasiveness. Notably, the effects of PDT were abolished by culturing TSs with tMSLC-conditioned media. Transcriptome analysis revealed diverse tMSLC-secreted chemokines, including C5α, and their correlations with the expression of stemness- or mesenchymal transition-associated genes. By adding or inhibiting C5α, we confirmed that acquired resistance to PDT was induced via tMSLC-secreted C5α. Our results show substantial therapeutic effects of 5-ALA-based PDT on GBM TSs, suggesting C5α as a key molecule responsible for PDT resistance. These findings could trigger PDT as a standard clinical modality for the treatment of GBM.

A Randomized Trial of PHOTOdynamic Surgery in Non–Muscle-Invasive Bladder Cancer

BackgroundRecurrence of non–muscle-invasive bladder cancer (NMIBC) is common after transurethral resection of bladder tumor (TURBT). Photodynamic diagnosis (PDD) provides better diagnostic accuracy and more complete tumor resection and may reduce recurrence. However, there is limited evidence on the longer-term clinical effectiveness and cost-effectiveness of PDD-guided resection.MethodsIn this pragmatic, open-label, parallel-group randomized trial conducted in 22 U.K. National Health Service hospitals, we recruited participants with a suspected first diagnosis of NMIBC at intermediate or high risk for recurrence on the basis of routine visual assessment before being listed for TURBT. Participants were assigned (1:1) to PDD-guided TURBT or to standard white light (WL)–guided TURBT. The primary clinical outcome was time to recurrence at 3 years of follow-up, analyzed by modified intention to treat.ResultsA total of 538 participants were enrolled (269 in each group), and 112 participants without histologic confirmation of NMIBC or who had had cystectomy were excluded. After 44 months’ median follow-up, 86 of 209 in the PDD group and 84 of 217 in the WL group had recurrences. The hazard ratio for recurrence was 0.94 (95% confidence interval [CI], 0.69 to 1.28; P=0.70). Three-year recurrence-free rates were 57.8% (95% CI, 50.7 to 64.2) and 61.6% (95% CI, 54.7 to 67.8) in the PDD and WL groups, respectively, with an absolute difference of −3.8 percentage points (95% CI, −13.37 to 5.59) favoring PDD. Adverse events occurred in less than 2% of participants, and rates were similar in both groups, as was health-related quality of life. PDD-guided TURBT was £876 (95% CI, −766 to 2518; P=0.591) more costly than WL-guided TURBT over a 3-year follow-up, with no evidence of a difference in quality-adjusted life years (−0.007; 95% CI, −0.133 to 0.119; P=0.444).ConclusionsPDD-guided TURBT did not reduce recurrence rates, nor was it cost-effective compared with WL at 3 years. (Funded by the National Institute for Health and Care Research Health Technology Assessment program; ISRCTN number, ISRCTN84013636.)

Outpatient Photodynamic Diagnosis–guided Laser Destruction of Bladder Tumors Is as Good as Conventional Inpatient Photodynamic Diagnosis–guided Transurethral Tumor Resection in Patients with Recurrent Intermediate-risk Low-grade Ta Bladder Tumors. A Prospective Randomized Noninferiority Clinical Trial

BackgroundTransurethral resection of recurrent low-grade intermediate-risk Ta bladder tumor (BT) in general anesthesia (GA) is burdensome to patients and health care system. Laser technologies enable treatment in office-based settings, reducing morbidity and costs. ObjectiveTo compare 4-mo recurrence-free survival after outpatient department (OPD) diode laser coagulation of BT in local anesthesia and gold standard transurethral resection of BT (TUR-BT) in GA in intermediate-risk Ta low-grade BT, and to evaluate treatment-related morbidity. Design, setting, and participantsA prospective randomized noninferiority trial with 4-mo follow-up, in the hospital setting, was conducted in Capital Region of Denmark from 2016 to 2020. Participants were patients with histologically verified Ta low-grade BT recurrence. A total of 206 patients were randomized; 176 finished treatment and follow-up as per protocol. InterventionLaser photocoagulation of bladder tumor (PC-BT) in OPD using a 980 nm diode laser compared with gold standard TUR-BT in GA, both performed with photodynamic diagnosis (PDD) guidance. Outcome measurements and statistical analysisFour-month recurrence-free survival was assessed; predefined inferiority criterion was set at 15%. The secondary outcomes were pain during PC-BT, postoperative morbidity, postoperative complications, and patient’s preference. Results and limitationsFour-month recurrence-free survival was 8% higher after PC-BT (95% confidence interval [CI]: –8% to 24%). The predefined noninferiority criterion was met. Pain score (1–10) during PC-BT was 2.4 (interquartile range 0.8–3.3). Postoperative lower urinary tract symptom score (0–100) was 13.9 points higher (95% CI: 6.9–21.0, p < 0.001) in the group with transurethral resection of the bladder. The frequency of minor complications was 8.1% higher after TUR-BT (95% CI: 1.0–14.6%, p = 0.026). Of the patients, 98% (95% CI: 92–100%) preferred PC-BT. ConclusionsPDD-guided PC-BT in OPD is as good as TUR-BT in GA to remove recurrent low-grade Ta BT. Postoperative quality of life is better after PC-BT and the frequency of minor complications was lower. Patient summaryThis study evaluates the efficacy of outpatient laser removal of low-grade noninvasive bladder tumor. Outpatient tumor removal with laser was as good as transurethral resection in general anesthesia and less burdensome to patients.

Synthesis of conjugates of 5,15-disubstituted aminoporphyrins and terpyridine derivatives with potential chelating properties

meso-Arylporphyrin containing two external chelating 2,2':6',2'-terpyridine fragments and its zinc complex were synthesized. The key step comprised the amide bond formation between the porphyrin diamine derivative and 4'-(4-carboxyphenyl)-2,2':6',2'-terpyridine. The compounds obtained seem to be potent for photodynamic therapy and diagnosis.

5-Aminolevulinic acid-based photodynamic diagnosis for detection of urothelial carcinoma cells in bladder washing sediment suspension: A pilot study

BackgroundBladder cancer is a common malignant disease in developed countries. Early detection of malignancy is important using urine cytology. The 5-aminolevulinic acid (ALA)-based photodynamic diagnosis (ALA-PDD) has not been routinely applied in urine cytology analysis yet, although it has been well accepted for tumor lesion marking in cystoscopy. MethodsA total of eight volunteers were enrolled in this study. The cells of sediment suspension from bladder washing fluid and random urine were stained by ALA-induced protoporphyrin IX (ALA-PpIX) and the fluorescent intensity of ALA-PpIX was analyzed by ImageJ. ResultsThe cutoff value of fluorescent intensity was 90.260 per pixel. The proposed protocol provided an objective fluorescent intensity for evaluation. Sensitivity was 0.931 and specificity was 1.000. ConclusionsThe staining procedure applied was ALA-PpIX for suspicious cells in the cellular suspension from bladder wash fluid and random urine. ImageJ was applied to the objective measurement for the fluorescent intensity of the stained cells. The cutoff value for the positive result was 90.260 per pixel. Therefore, the protocol proposed in this study provides a potential means to enhance accuracy for urine cytology analysis.

Phototherapy with Cancer-Specific Nanoporphyrin Potentiates Immunotherapy in Bladder Cancer.

Immune checkpoint inhibitors (ICI) in general have shown poor efficacy in bladder cancer. The purpose of this project was to determine whether photodynamic therapy (PDT) with bladder cancer-specific porphyrin-based PLZ4-nanoparticles (PNP) potentiated ICI. SV40 T/Ras double-transgenic mice bearing spontaneous bladder cancer and C57BL/6 mice carrying syngeneic bladder cancer models were used to determine the efficacy and conduct molecular correlative studies. PDT with PNP generated reactive oxygen species, and induced protein carbonylation and dendritic cell maturation. In SV40 T/Ras double-transgenic mice carrying spontaneous bladder cancer, the median survival was 33.7 days in the control, compared with 44.8 (P = 0.0123), 52.6 (P = 0.0054), and over 75 (P = 0.0001) days in the anti-programmed cell death-1 antibody (anti-PD-1), PNP PDT, and combination groups, respectively. At Day 75 when all mice in other groups died, only 1 in 7 mice in the combination group died. For the direct anti-tumor activity, compared with the control, the anti-PD-1, PNP PDT, and combination groups induced a 40.25% (P = 0.0003), 80.72% (P < 0.0001), and 93.03% (P < 0.0001) tumor reduction, respectively. For the abscopal anticancer immunity, the anti-PD-1, PNP PDT, and combination groups induced tumor reduction of 45.73% (P = 0.0001), 54.92% (P < 0.0001), and 75.96% (P < 0.0001), respectively. The combination treatment also diminished spontaneous and induced lung metastasis. Potential of immunotherapy by PNP PDT is multifactorial. In addition to its potential for photodynamic diagnosis and therapy, PNP PDT can synergize immunotherapy in treating locally advanced and metastatic bladder cancer. Clinical trials are warranted to determine the efficacy and toxicity of this combination.

The Japanese quail chorioallantoic membrane as a model to study an amphiphilic gradient copoly(2-oxazoline)s- based drug delivery system for photodynamic diagnosis and therapy research

Amphiphilic gradient copoly(2-oxazoline)s are widely researched in the field of drug delivery. They could be used as a transport system for hydrophobic drugs such as hypericin (HYP). We prepared six gradient copolymers (EtOx)-grad-(ROPhOx) by living cationic ring-opening polymerization of a hydrophilic comonomer 2-ethyl-2-oxazoline (EtOx) and a hydrophobic comonomer 2-(4-alkyloxyphenyl)-2-oxazoline (ROPhOx), with different composition ratio (88:12 and 85:15) and three different alkyl chain lengths of alkyl (R) substituents. As an experimental model, Japanese quail chorioallantoic membrane (CAM) was used. The effect of nanoparticles loaded with HYP was evaluated by the changes of fluorescence intensity during photodynamic diagnosis (PDD) monitored under 405 nm LED light before administration, and 0,1,3 and 24 h after topical administration. The effectiveness of photodynamic therapy (PDT) (405 nm, 285 mW/cm2) applied 1h after the administration of HYP-loaded nanoparticles was evaluated using vascular damage score and histological sections. Molecular analysis was done by measuring angiogenesis-related gene expression by qPCR. The application of nanoparticles unloaded or loaded with HYP proved to be biocompatible, non-toxic, and undamaging to the CAM tissue, while they successfully altered the HYP fluorescence. We observed a possible anti-angiogenic potential of prepared nanoparticles, which could present an advantage for PDT used for tumour treatment.

5-Aminolevulinic acid fluorescence-guided endoscopic surgery for intraventricular tumors

Background: In recent years, the efficacy of 5-aminolevulinic acid photodynamic diagnosis (5-ALA PDD) has been reported for various types of brain tumors, including malignant glioma. In addition, many reports have been published on the usefulness of neuroendoscopic surgery for intraventricular lesions. However, no systematic report is available on the combined use of 5-ALA PDD and neuroendoscopy for various intraventricular tumors.Methods: We report 17 consecutive patients with intraventricular tumors. All patients received oral 5-ALA preoperatively and underwent endoscopic surgical treatment (resection or biopsy). We use a rigid endoscope with a built-in PDD system for intraoperative observation.Results: Seven resections and 10 biopsies were performed. Histopathological diagnosis was confirmed in all 17 cases. Gross total resection was achieved in six of seven cases. The fluorescence positivity rates for each tumor were glioblastoma 100% (2/2), low-grade glioma 67% (2/3), subependymoma 0% (0/1), medulloblastoma 100% (1/1), pineoblastoma 0% (0/1), germ cell tumor 75% (3/4), diffuse large B-cell lymphoma 33% (1/3), and metastatic tumor 100% (2/2).Conclusion: Our method has the potential to improve detection of residual tumors in blind spots and deep areas, as well as the accuracy and safety of biopsy procedures for intraventricular lesions that are difficult to view and treat under a microscope.

Increasing the efficiency of hyperthermic intraperitoneal chemotherapy (HIPEC) by combination with a photosensitive drug in pediatric rhabdomyosarcoma in an animal model.

Cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is an option in advanced peritoneal sarcomatosis. Nevertheless, CRS and HIPEC are not successful in all patients. An enhancement of HIPEC using photodynamic therapy (PDT) might be beneficial. Therefore, a combination of the photosensitizer hypericin (HYP) with HIPEC was evaluated in an animal model. An established HIPEC animal model for rhabdomyosarcoma (NOD/LtSz-scid IL2Rγnullmice, n=80) was used. All groups received HYP (100μg/200μl) intraperitoneally with and without cisplatin-based (30 or 60mg/m2 ) HIPEC (37°C or 42°C, for 60minutes) (five groups, each n=16). Peritoneal cancer index (PCI) was documented visually and by HYP-based photodynamic diagnosis (PDD). HYP-based PDT of the tumor was performed. Tissue samples were evaluated regarding proliferation (Ki-67) and apoptosis (TUNEL). HYP uptake was detected even in smallest tumor nodes (<1mm) with improved tumor detection during PDD (PCI with PDD vs. PCI without PDD: 8.5 vs. 7, p<.001***). Apoptotic effects after PDT without HIPEC were limited to the tumor surface, whereas PDT after HIPEC (60mg/m2 , 42°C) showed additional reduction of tumor proliferation in the top nine to 11 cell layers (50μm). HYP as fluorescent photosensitizer offers an intraoperative diagnostic advantage detecting intraperitoneal tumor dissemination. The combination of HYP and cisplatin-based HIPEC was feasible in vivo, showing enhanced effects on tumor proliferation and apoptosis induction across the tumor surface. Further studies combining HYP and HIPEC will follow to establish a clinical application.

Automatic Diagnosis of Early-Stage Oral Cancer and Precancerous Lesions from ALA-PDD Images Using GAN and CNN.

A screening system for early-stage oral cancer and precancerous lesions should be established because it is difficult to detect them even for specialists and they are often detected too late. In this paper, we propose a method for automatically classifying fluorescence images acquired by ALA-PDD (Photodynamic Diagnosis using 5-Aminolevulinic Acid) into three classes: Normal, Low-Risk, High-Risk. We augment a small image dataset by training GAN (Generative adversarial networks) with Differentiable Augmentation, and then train CNN (Convolutional Neural Network) for the classification by the augmented dataset. Experimental results show good classification results, which suggest that the combination of ALA-PDD and CNN classification is a promising method for oral cancer screening. Clinical Relevance- The method proposed in this paper has a potential to be used as a screening method for early-stage oral cancer and precancerous lesions, that is non-invasive, accurate, easy to use, and does not require specialization.

Photodynamic Diagnosis Using 5-Aminolevulinic Acid with a Novel Compact System and Chromaticity Analysis for the Detection of Oral Cancer and High-Risk Potentially Malignant Oral Disorders.

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.

Efficacy of photodynamic diagnosis-assisted transurethral resection of bladder tumor for T1 bladder cancer: Novel second transurethral resection initiatives utilizing photodynamic diagnosis.

Efficacy of photodynamic diagnosis-assisted transurethral resection of bladder tumor for T1 bladder cancer: Novel second transurethral resection initiatives utilizing photodynamic diagnosis.

5-Aminolevulinic Acid-Induced Protoporphyrin IX Fluorescence Imaging for Tumor Detection: Recent Advances and Challenges

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.

Objective Methods of 5-Aminolevulinic Acid-Based Endoscopic Photodynamic Diagnosis Using Artificial Intelligence for Identification of Gastric Tumors.

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.

Artificial Intelligence for Segmentation of Bladder Tumor Cystoscopic Images Performed by U-Net with Dilated Convolution.

Background: Early intravesical recurrence after transurethral resection of bladder tumors (TURBT) is often caused by overlooking of tumors during TURBT. Although narrow-band imaging and photodynamic diagnosis were developed to detect more tumors than conventional white-light imaging, the accuracy of these systems has been subjective, along with poor reproducibility due to their dependence on the physician's experience and skills. To create an objective and reproducible diagnosing system, we aimed at assessing the utility of artificial intelligence (AI) with Dilated U-Net to reduce the risk of overlooked bladder tumors when compared with the conventional AI system, termed U-Net. Materials and Methods: We retrospectively obtained cystoscopic images by converting videos obtained from 120 patients who underwent TURBT into 1790 cystoscopic images. The Dilated U-Net, which is an extension of the conventional U-Net, analyzed these image datasets. The diagnostic accuracy of the Dilated U-Net and conventional U-Net were compared by using the following four measurements: pixel-wise sensitivity (PWSe); pixel-wise specificity (PWSp); pixel-wise positive predictive value (PWPPV), representing the AI diagnostic accuracy per pixel; and dice similarity coefficient (DSC), representing the overlap area between the bladder tumors in the ground truth images and segmentation maps. Results: The cystoscopic images were divided as follows, according to the pathological T-stage: 944, Ta; 412, T1; 329, T2; and 116, carcinoma in situ. The PWSe, PWSp, PWPPV, and DSC of the Dilated U-Net were 84.9%, 88.5%, 86.7%, and 83.0%, respectively, which had improved when compared to that with the conventional U-Net by 1.7%, 1.3%, 2.1%, and 2.3%, respectively. The DSC values were high for elevated lesions and low for flat lesions for both Dilated and conventional U-Net. Conclusions: Dilated U-Net, with higher DSC values than conventional U-Net, might reduce the risk of overlooking bladder tumors during cystoscopy and TURBT.