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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.

5‐Aminolevulinic acid is a new‐generation photosensitizer with high tumor specificity. It has been used successfully in the diagnosis, treatment, and screening of urological cancers including bladder cancer; specifically, it has been used in photodynamic diagnosis to detect tumors by illuminating the lesion with a specific wavelength of light to produce fluorescence in the lesion after administration of 5‐aminolevulinic acid, in photodynamic therapy, which induces tumor cell death via production of cytotoxic reactive oxygen species, and in photodynamic screening, in which porphyrin excretion in the blood and urine is used as a tumor biomarker after administration of 5‐aminolevulinic acid. In addition to these applications in urological cancers, 5‐aminolevulinic acid–based photodynamic technology is expected to be used as a novel strategy for a large number of cancer types because it is based on a property of cancer cells known as the Warburg effect, which is a basic biological property that is common across all cancers. The mechanism of 5‐aminolevulinic acid‐based photodynamic therapy.

Accumulation of protoporphyrin IX (PpIX) in malignant cells is the basis of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy. We studied the expression of proteins that possibly affect ALA-mediated PpIX accumulation, namely oligopeptide transporter-1 and -2, ferrochelatase and ATP-binding cassette transporter G2 (ABCG2), in several tumor cell lines. Among these proteins, only ABCG2 correlated negatively with ALA-mediated PpIX accumulation. Both a subcellular fractionation study and confocal laser microscopic analysis revealed that ABCG2 was distributed not only in the plasma membrane but also intracellular organelles, including mitochondria. In addition, mitochondrial ABCG2 regulated the content of ALA-mediated PpIX in mitochondria, and Ko143, a specific inhibitor of ABCG2, enhanced mitochondrial PpIX accumulation. To clarify the possible roles of mitochondrial ABCG2, we characterized stably transfected-HEK (ST-HEK) cells overexpressing ABCG2. In these ST-HEK cells, functionally active ABCG2 was detected in mitochondria, and treatment with Ko143 increased ALA-mediated mitochondrial PpIX accumulation. Moreover, the mitochondria isolated from ST-HEK cells exported doxorubicin probably through ABCG2, because the export of doxorubicin was inhibited by Ko143. The susceptibility of ABCG2 distributed in mitochondria to proteinase K, endoglycosidase H and peptide-N-glycosidase F suggested that ABCG2 in mitochondrial fraction is modified by N-glycans and trafficked through the endoplasmic reticulum and Golgi apparatus and finally localizes within the mitochondria. Thus, it was found that ABCG2 distributed in mitochondria is a functional transporter and that the mitochondrial ABCG2 regulates ALA-mediated PpIX level through PpIX export from mitochondria to the cytosol.

BackgroundIn clinical practice, various devices are implanted into the body for medical reasons. As X-ray fluoroscopy is necessary to visualize medical devices implanted into the body, the development of a less-invasive visualization method is highly desired. This study aimed to investigate the clinical applicability of our novel solid material that emits near-infrared fluorescence.MethodsWe developed a solid resin material that emits near-infrared fluorescence. This material incorporates a near-infrared fluorescent pigment, with quantum yield ≥ 20 times than that of indocyanine green. It can be sterilized for medical treatment. This resin material is designed to be molded into a catheter and inserted into the body with an endoscope clip. In this preclinical experiment using a swine model, the resin material was embedded into the body of the swine and visualized with a near-infrared fluorescence camera system.ResultsEndoscopic clips were placed in the mucosa of the stomach, esophagus, and large intestine, and the indwelling ureteral catheters were successfully visualized by near-infrared fluorescence laparoscopy.ConclusionsWe confirmed the tissue permeability of the fluorescence emitted by our novel near-infrared fluorescent material and the possibility of its clinical application. This material may allow visualization of devices embedded in the body.

ObjectiveThe objective of this study was to evaluate the early surgical outcomes of robot-assisted partial nephrectomy (RAPN) for small renal masses in a large Japanese multicenter series.MethodsA total of 804 consecutive cases of RAPN were examined at 42 institutes between 2011 and 2016. Medical records for clinical, pathological characteristics and perioperative outcomes were retrospectively reviewed. Univariable and multivariable analyses were performed to determine factors predicting Trifecta achievement.ResultsThe median tumor size was 2.6 cm. The median RENAL score was 7. The median warm ischemia time was 21 min. The median estimated blood loss was 30 mL. Eight patients (1.0%) were converted to radical nephrectomy. The overall and Clavien–Dindo grade ≥ 3 complication rates were 13.0% and 5.8%, respectively. Pathologically, 91.4% of tumors were malignant and the positive surgical margin (PSM) rate was 1.1%. During the median 27.1-month observation period, the recurrence rate was 1.6%. Postoperative preservation rates of eGFR at 1, 6, 12 and 24 months were 90.3, 89.8, 89.4 and 89.2%, respectively. Trifecta was achieved in 62.1%. Multivariable analysis demonstrated that tumor diameter, estimated blood loss and hilar location of the tumor were significant negative factors predicting Trifecta achievement. The rate of Trifecta achievement for T1b tumors and hilar tumors was significantly lower (48.4% and 50.0%, respectively).ConclusionsRAPN was safely performed with acceptable oncological and functional outcomes, but the rate of Trifecta accomplishment for T1b or hilar tumors was significantly lower than that for T1a or non-hilar tumors, respectively.

Cancer can develop into a recurrent metastatic disease with latency periods of years to decades. Dormant cancer cells, which represent a major cause of recurrent cancer, are relatively insensitive to most chemotherapeutic drugs and radiation. We previously demonstrated that cancer cells exhibited dormancy in a cell density-dependent manner. Dormant cancer cells exhibited increased porphyrin metabolism and sensitivity to 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT). However, the metabolic changes in dormant cancer cells or the factors that enhance porphyrin metabolism have not been fully clarified. In this study, we revealed that lipid metabolism was increased in dormant cancer cells, leading to ALA-PDT sensitivity. We performed microarray analysis in non-dormant and dormant cancer cells and revealed that lipid metabolism was remarkably enhanced in dormant cancer cells. In addition, triacsin C, a potent inhibitor of acyl-CoA synthetases (ACSs), reduced protoporphyrin IX (PpIX) accumulation and decreased ALA-PDT sensitivity. We demonstrated that lipid metabolism including ACS expression was positively associated with PpIX accumulation. This research suggested that the enhancement of lipid metabolism in cancer cells induces PpIX accumulation and ALA-PDT sensitivity.

It has been suggested that the tumor microenvironment plays an important role in tumor progression, acquisition of androgen independence, and distant metastasis in prostate cancer (PC). However, little is known about the transcriptional basis of cellular interactions in the human PC microenvironment. To clarify the mechanism of PC progression and metastasis, we investigated the interaction of PC, epithelial, and stromal cells using genome-wide gene expression profiling. We hypothesized that PC cells could induce stromal cells to differentiate into so-called cancer-associated fibroblasts (CAFs), which might contribute to cancer invasion and metastasis. Genes upregulated in normal human prostate stromal cells (PrSC) co-cultured with human PC cells (LNCaP) included the mevalonate pathway enzymes 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Knockdown of endogenous HMGCS1 or HMGCR in PC cells by shRNA resulted in a significant reduction of PC cell viability. Importantly, exogenous overexpression of HMGCS1 or HMGCR in either PC cells or prostate stromal cells stimulated PC cell growth, suggesting a possible autocrine/paracrine mechanism of action. Immunohistochemical analysis confirmed that HMGCS1 and HMGCR were overexpressed in PC stroma, especially in early stage PC. These results provide clues to the molecular mechanisms underlying PC invasion and metastasis, and suggest that HMGCS1 and HMGCR in PC, as well as in PC stroma, might serve as molecular targets for the treatment of PC.

BackgroundIn Japan, the authorized period (2–4 h) between oral administration of 5-aminolevulinic acid hydrochloride (5-ALA) and transurethral resection for non-muscle invasive bladder cancer (NMIBC) may restrict photodynamic diagnosis (PDD) usage. Therefore, this prospective, single-arm, phase III study aimed to evaluate the diagnostic accuracy and safety of PDD at an extended administration period (4–8 h).MethodsFrom January 2022 to May 2023, 161 patients with NMIBC were enrolled from eight hospitals. The primary endpoint was the blue light (BL) sensitivity of pathologically positive biopsies. The secondary endpoints were a comparison of the specificity and positive and negative prediction rates under BL and white light (WL) conditions.ResultsA total of 1242 specimens comprising 337 histological NMIBC specimens were analyzed. BL-sensitivity was 95.3%. Its lower limit of 95% confidence interval (92.4–97.3%) exceeded the threshold (70%) of non-inferiority to authorized usage. Sensitivity and specificity were significantly higher and lower for BL than those for WL (95.3% vs. 61.1%, P < 0.001; 52.7% vs. 95.2%, P < 0.001), respectively. The positive and negative predictive rates were significantly lower and higher for BL than those for WL (42.9% vs. 82.7%, P < 0.001; 96.8% vs. 86.8%, P < 0.001), respectively. Of the 145 patients receiving 5-ALA, 136 (93.8%) and 75 (51.7%) experienced 377 adverse events and 95 adverse reactions, respectively, most of which were grade 1 or 2.ConclusionFor extended period, the efficacy of PDD for NMIBC was similar to that of authorized period, in terms of higher sensitivity and lower specificity compared with WL, and the safety was acceptable.

Photobleaching of the photosensitizer reduces fluorescence observation time and the intensity of fluorescence emitted for tumor detection during 5-aminolevulinic acid-based photodynamic diagnosis. This study aims to utilize the concept of fluorescence photoswitching, which uses the fluorescence emission from photosensitizer excitation followed by the simultaneous excitation of the photosensitizer and its photoproduct to increase the fluorescence detection intensity during PDD of deeply located tumors. The fluorescence photobleaching of protoporphyrin IX (PpIX) and the formation of its photoproduct, photoprotoporhyrin (Ppp), caused by exposure to 505 nm light were investigated in solution, , and , and the fluorescence photoswitching was analyzed. The fluorescence observations of PpIX and Ppp were performed with 505 and 450 or 455 nm excitation, respectively, which is the suited wavelength for the primary excitation of each fluorophore. Fluorescence photoswitching was observed in all forms of PpIX investigated, and the fluorescence photoswitching time, fluorescence intensity relative to the initial PpIX and Ppp intensity, and fluorescence intensity relative to PpIX after photobleaching were obtained. The dependence of the fluorescence photoswitching time and intensity on the irradiation power density was noted. A fluorescence intensity increase between 1.6 and 3.9 times was achieved with simultaneous excitation of PpIX and Ppp after fluorescence photoswitching, compared with the excitation of PpIX alone. We have demonstrated the potential of fluorescence photoswitching for the improvement of the fluorescence observation intensity for the PDD of deeply located tumors.

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.