ABSTRACT
Objectives
Although photodynamic diagnosis (PDD) using 5‐aminolevulinic acid (ALA) is a highly a sensitive and excellent method for detecting nonmuscle‐invasive bladder cancer, false‐positive rates should not be overlooked. One of the factors causing false‐positive results is inflammation. Currently, the relationship between pyuria and PDD accuracy remains unclear. Therefore, this study aimed to clarify the influence of preoperative pyuria on the diagnostic accuracy of PDD.
Methods
This study retrospectively analyzed 101 patients who underwent PDD‐assisted transurethral resection of bladder tumors at Kochi Medical School Hospital between January 2018 and December 2020. After dividing the patients into two groups according to the presence or absence of preoperative pyuria, the diagnostic accuracy of each group was analyzed.
Results
A total of 616 specimens from 101 patients were analyzed, among which 460 specimens from 75 patients belonged to the no pyuria group and 156 specimens from 26 patients belonged to the pyuria group. The sensitivity, specificity, positive predictive value, and negative predictive value of PDD were 90.2%, 64.1%, 38.6%, and 96.3% for the no pyuria group and 92.9%, 45.6%, 38.6%, and 94.5% for the pyuria group, respectively. The pyuria group had a lower specificity than did the no pyuria group, indicating a significantly higher false positive rate in the former.
Conclusions
Our findings suggest that the presence of preoperative pyuria did not affect the ability of PDD to detect cancer but may increase its false‐positive rate and that preoperative pyuria is a useful predictor of false‐positive PDD rates.
Keywords: 5‐aminolevulinic acid, inflammation, nonmuscle‐invasive bladder cancer, pyuria, transurethral resection of bladder
1. Introduction
Bladder cancer is the tenth most commonly diagnosed cancer worldwide, with approximately 573 000 new cases and 213 000 deaths in 2020 [1]. The initial treatment for nonmuscle‐invasive bladder cancer (NMIBC) is essentially transurethral resection of bladder tumor (TURBT). However, given the high postoperative recurrence rates associated with TURBT with white light cystoscopy (WL‐TURBT) [2, 3], studies on TURBT using photodynamic diagnosis (PDD) or narrow‐band imaging have emerged [4, 5, 6, 7]. In particular, after oral ALA had been recognized as a photosensitizer in Japan, the Japanese national health insurance system began covering PDD using ALA (ALA‐PDD) starting in December 2017, with its use continuing to spread throughout the country [8, 9, 10, 11, 12].
ALA‐PDD is a highly sensitive diagnostic approach that has been considered better than WL for detecting cancer, especially in the presence of tiny lesions, flat lesions, residual cancer, and carcinoma in situ [4, 8]. However, concerns regarding its false‐positive rates have remained. Several causes for false‐positive results have been proposed, among which some are noninflammatory factors, such as the tangent effect or genomic alterations [13, 14], whereas others are inflammatory factors, such as post‐Bacillus Calmette Guerin (BCG) therapy [15]. Assuming that inflammatory factors do exist and affect diagnostic accuracy, we hypothesized that the presence of preoperative pyuria could be an indicator of the expected diagnostic accuracy of ALA‐PDD. However, only a few reports have investigated the impact of the presence or absence of preoperative pyuria on the diagnostic accuracy of TURBT using ALA‐PDD.
The current study has been the first to analyze whether the presence of preoperative pyuria could predict the diagnostic accuracy of ALA‐PDD.
2. Methods
2.1. Patients
We retrospectively analyzed 616 specimens from 101 patients who underwent PDD‐TURBT for NMIBC at Kochi Medical School Hospital from January 2018 to December 2020. This single‐center retrospective study was approved by the Institutional Review Board of Kochi University Medical School (approval no. 2021‐093). Informed consent was obtained from the patients or deceased patients' families through websites using the opt‐out method. This study was conducted according to the ethical principles for medical research involving human subjects (including research on identifiable human material and data) described in the Declaration of Helsinki (64th World Medical Association General Assembly, Fortaleza, Brazil, October 2013).
2.2. Surgical Procedure and Device
ALA hydrochloride was dissolved in 50 mL of saline. ALA hydrochloride solution (20 mg/kg) was then administered orally prior to PDD cystoscopy. Intraoperative fluorescence observation was performed using an IMAGE1S OPAL1 PDD system (Karl Storz GmbH & Co., Tuttlingen, Germany). Red fluorescence was detected through a telescope (HOPKINS II PDD telescope, 4 mm, 30°) using a d‐LIGHT C/AF (300w xenon bulb) with a band pass filter transmitting blue light (excitation wavelength: 375–445 nm). The same lesion was observed in both modes by quickly turning on and off the white light mode for normal observation and blue light mode for PDD observation.
2.3. Urine Sample Analysis and Preoperative Pyuria Definition
Urine samples were analyzed via the visual field method of urinary sediment or using the Sysmex UF‐5000 Fully Automated Urine Particle Analyzer. When urine samples were analyzed via the visual field method of urinary sediment, positive pyuria was defined as five or more leukocytes per visual field. Given the lack of an adequate clinically useful definition of pyuria based on the visual field method [16, 17, 18], we used the definition proposed by Hooker JB et al. [16]. After analyzing urine samples using the Sysmex UF‐5000 Fully Automated Urine Particle Analyzer, preoperative pyuria was defined as positive when the urinary leukocyte count was ≥ 10/μL and negative when the urinary leukocyte count was < 10/μL [17]. Preoperative pyuria results were based on the data obtained on the examination date closest to the date of PDD‐TURBT. None of the patients underwent urinalysis after cystoscopy.
2.4. Statistical Analysis
All statistical analyses were performed using EZR [19], a graphical user interface for R. More precisely, this tool is a modified version of R commander designed to add statistical functions frequently used in biostatistics. Statistical processing was performed using the McNemar test or Fisher's exact test for diagnostic accuracy, after which univariate and multivariate logistic regression analyses were performed to identify factors that could predict false‐positive rates.
3. Results
The overall patient background and diagnostic accuracy of the cases that underwent PDD‐TURBT are summarized in Tables 1 and 2. The total sensitivity, specificity, positive predictive value, and negative predictive value were 73.9%, 85.3%, 58.2%, and 92.2% for white light and 91.0%, 59.8%, 38.6%, and 96.0% for PDD, respectively (Table 2). Next, the background characteristics of patients who underwent PDD were presented according to positivity and negativity for preoperative pyuria. Notably, the positive preoperative pyuria group had a higher proportion of women (p = 0.003) than the negative preoperative pyuria group (Table 1).
TABLE 1.
Patient characteristics.
| Total (n = 101) | Pre‐operative pyuria | p | ||
|---|---|---|---|---|
| Negative (n = 75) | Positive (n = 26) | |||
| Age, years (range) | ||||
| Average | 73.7 (25–89) | 72.6 (25–89) | 76.9 (60–88) | 0.0548† |
| Sex (%) | ||||
| Male | 81 (80.2) | 66 (88.0) | 15 (57.5) | 0.003*‡ |
| Female | 20 (19.8) | 9 (12.0) | 11 (42.3) | |
| Medical history (%) | ||||
| Primary | 55 (54.4) | 40 (53.3) | 15 (57.5) | 0.820‡ |
| Recurrence | 46 (45.5) | 35 (46.7) | 11 (42.3) | |
| Previous BCG therapy (%) | ||||
| Yes | 14 (13.9) | 10 (13.3) | 4 (15.4) | 0.752‡ |
| No | 87 (86.1) | 65 (86.7) | 22 (84.6) | |
| Pathological T stage | ||||
| T0 | 14 | 11 | 3 | |
| Ta | 57 | 45 | 12 | |
| T1 | 13 | 7 | 6 | |
| T2–T4 | 9 | 5 | 4 | |
| Tis only | 7 | 6 | 1 | |
| Tx | 1 | 1 | 0 | |
Note: p values were calculated using Student's t test (†) or Fisher's exact test (‡), *p < 0.05 indicates statistical significance.
Abbreviation: BCG, bacillus Calmette‐Guérin.
TABLE 2.
Diagnostic accuracy of white and blue light in total lesions.
| WL (+) or BL (+)/total positive lesion | Sensitivity (%) (95% CI) | WL (−) or BL (−)/total negative lesion | Specificity (%) (95% CI) | Positive lesion/WL (+) or BL (+) | Positive predictive value (%) (95% CI) | Negative lesion/WL (−) or BL (−) | Negative predictive value (%) (95% CI) | |
|---|---|---|---|---|---|---|---|---|
| WL | 99/134 | 73.9 (65.6–88.2) | 411/482 | 85.3 (81.8–88.3) | 99/170 | 58.2 (50.5–65.7) | 411/446 | 92.2 (89.3–94.5) |
| BL | 122/134 | 91.0 (84.9–95.3) | 288/482 | 59.8 (55.2–64.2) | 122/316 | 38.6 (33.2–44.2) | 288/300 | 96.0 (93.1–97.9) |
| p | 0.00004*† | 0.00000*† | 0.00004*‡ | 0.0447*‡ | ||||
Note: p values were calculated using McNemar test (†) or Fisher's exact test (‡), *p < 0.05 indicates statistical significance.
Abbreviations: BL, blue light; CI, confidence interval; WL, white light.
In both the negative and positive preoperative pyuria groups, diagnostic sensitivity was significantly higher with PDD than with white light diagnosis, whereas specificity was lower with PDD than with white light diagnosis (Table 3). Thereafter, the sensitivity and specificity of PDD were compared between the negative and positive preoperative pyuria groups. Accordingly, we found that PDD had a sensitivity of 90.2% and 92.9% in the negative and positive preoperative pyuria groups, respectively, with no significant difference in sensitivity between the two groups (p = 0.7527). However, PDD had a specificity of 45.6% and 64.1% in the positive and negative preoperative pyuria groups, respectively (Table 4), with the difference being significant (p = 0.00066).
TABLE 3.
Diagnostic accuracy of white and blue light in negative/positive preoperative pyuria groups.
| WL (+) or BL (+)/total positive lesion | Sensitivity (%) (95% CI) | WL (−) or BL (−)/total negative lesion | Specificity (%) (95% CI) | Positive lesion/WL (+) or BL (+) | Positive predictive value (%) (95% CI) | Negative lesion/WL (−) or BL (−) | Negative predictive value (%) (95% CI) | |
|---|---|---|---|---|---|---|---|---|
| Negative preoperative pyuria | ||||||||
| WL | 67/92 | 72.8 (62.6–81.6) | 315/368 | 85.6 (81.6–89.0) | 67/120 | 55.8 (46.5–64.9) | 315/340 | 92.6 (89.3–95.2) |
| BL | 83/92 | 90.2 (82.2–95.4) | 236/368 | 64.1 (59.0–69.0) | 83/215 | 38.6 (32.1–45.5) | 236/245 | 96.3 (93.1–98.3) |
| p | 0.00138*† | 0.00000*† | 0.00286*‡ | 0.073 ‡ | ||||
| Positive preoperative pyuria | ||||||||
| WL | 32/42 | 76.2 (60.5–87.9) | 96/114 | 84.2 (76.2–90.4) | 32/50 | 64.0 (49.2–77.1) | 96/106 | 90.6 (83.3–95.4) |
| BL | 39/42 | 92.9 (80.5–98.5) | 52/114 | 45.6 (36.3–55.2) | 39/101 | 38.6 (29.1–48.8) | 52/55 | 94.5 (84.9–98.9) |
| p | 0.0233*† | 0.00000*† | 0.00531*‡ | 0.545‡ | ||||
Note: p values were calculated using McNemar test (†) or Fisher's exact test (‡), *p < 0.05 indicates statistical significance.
Abbreviations: BL, blue light; CI, confidence interval; WL, white light.
TABLE 4.
Comparison of blue light diagnostic accuracy in negative/positive preoperative pyuria groups.
| BL (+)/total positive lesion | Sensitivity (%) (95% CI) | BL (−)/total negative lesion | Specificity (%) (95% CI) | |
|---|---|---|---|---|
| Negative preoperative pyuria | 83/92 | 90.2 (82.2–95.4) | 236/368 | 64.1 (59.0–69.0) |
| Positive preoperative pyuria | 39/42 | 92.9 (80.5–98.5) | 52/114 | 45.6 (36.3–55.2) |
| p | 0.7527 | 0.00066* |
Note: p values were calculated using Fisher's exact test, *p < 0.05 indicates statistical significance.
Abbreviations: BL, blue light; CI, confidence interval.
The lack of a significant difference in sensitivity but the presence of a significant difference in specificity indicates no difference in cancer detection performance or a difference in false‐positive rates. Therefore, we next performed univariate and multivariate analyses on tissue samples (n = 616) to determine whether age (≥ 75 or < 75 years), gender (male or female), medical history (primary or recurrence), previous BCG therapy (yes or no), and preoperative pyuria (yes or no) could be factors predicting false‐positive rates. Notably, our results showed that previous BCG intravesical infusion therapy (odds ratio: 2.230, 95% CI: 1.370–3.620) and positive preoperative pyuria (odds ratio: 1.680, 95% CI: 1.150–2.460) were significant predictors of false‐positive rate (Table 5).
TABLE 5.
Multiple logistic regression models of factors associated with PDD false positives for specimen (n = 616).
| Variable | Univariate | Multivariate | ||
|---|---|---|---|---|
| Odds ratio (95% CI) | p | Odds ratio (95% CI) | p | |
| Age | ||||
| ≥ 75 Years | 0.976 (0.693–1.370) | 0.891 | 0.812 (0.563–1.1170) | 0.265 |
| < 75 Years | Reference | Reference | ||
| Sex | ||||
| Female | 0.612 (0.408–0.918) | 0.018* | 0.713 (0.462–1.100) | 0.127 |
| Male | Reference | Reference | ||
| Medical history | ||||
| Reccurence | 1.570 (1.110–2.220) | 0.0114* | 1.26 (0.837–1.910) | 0.264 |
| Primary | Reference | Reference | ||
| Previous BCG therapy | ||||
| Yes | 2.230 (1.370–3.620) | 0.00116* | 1.90 (1.070–3.360) | 0.027* |
| No | Reference | Reference | ||
| Preoperative pyuria | ||||
| Positive | 1.680 (1.150–2.460) | 0.00697* | 1.65 (1.090–2.520) | 0.019* |
| Negative | Reference | Reference | ||
Note: p values were calculated using logistic regression analysis. *p < 0.05 indicates statistical significance.
Abbreviations: BCG, Bacillus Calmette‐Guérin; CI, confidence interval; PDD, photodynamic diagnosis.
We additionally investigated the impact of the degree of pyuria on diagnostic accuracy. Accordingly, the 26 cases with positive preoperative pyuria were divided into two groups, namely, those with preoperative pyuria having ≥ 100 leukocytes/μL (13 cases) and those with preoperative pyuria having < 100 leukocytes/μL (13 cases), after which the diagnostic accuracy of blue light was compared. Specificity was 51.5% (95% CI: 38.9–64.0) in the group with preoperative pyuria having ≥ 100 leukocytes/μL and 37.5% (95% CI: 24.0–52.6) in the group with preoperative pyuria having < 100 leukocytes/μL (Table 6).
TABLE 6.
Comparison of blue light diagnostic accuracy in pre‐operative pyuria having < 100 leukocytes/μL or ≥ 100 leukocytes/μL groups.
| BL (+)/total positive lesion | Sensitivity (%) (95% CI) | BL (−)/total negative lesion | Specificity (%) (95% CI) | |
|---|---|---|---|---|
| Pre‐operative pyuria having < 100 leukocytes/μL group | 13/16 | 81.2 (54.4–96.0) | 34/66 | 51.5 (38.9–64.0) |
| Pre‐operative pyuria having ≥ 100 leukocytes/μL group | 26/26 | 100 (81.0–100) | 18/48 | 37.5 (24.0–52.6) |
Abbreviations: BL, blue light; CI, confidence interval.
4. Discussion
Studies have shown that PDD‐TURBT with oral ALA has certain therapeutic effects, such as reduced residual tumor rate, reduced postoperative recurrence rate, and reduced cumulative recurrence rate due to improved cancer detection; unfortunately, some side effects, such as liver dysfunction, photosensitivity, and ALA‐induced hypotension, have also been documented [8, 9, 10, 11, 12, 20, 21, 22, 23]. In particular, ALA‐induced hypotension has been considered one of the most important perioperative safety risks. Therefore, urologists need to account for the benefits and risks when making decisions on the indications for the use of PDD [24].
Despite its high sensitivity for cancer detection, PDD has been associated with decreased specificity (i.e., increased false‐positive rates). Some causes for the increased false‐positive rates with PDD include tangent effects, scarring after TURBT, inflammation (e.g., follicular cystitis, after bladder infusion therapy with BCG or anticancer drugs) [25, 26, 27], pathological changes, and chromosomal abnormalities [27, 28].
Draga et al. reported that being female (p = 0.005; odds ratio = 0.41) and undergoing TURBT within 90 days (p = 0.01; odds ratio = 2.38) were risk factors for a false‐positive PDD [23]. They also reported that multiple BCG instillations within 3 months most certainly reduced the specificity of PDD (odds ratios > 1) [22]. Meanwhile, Grimbergen et al. reported that the rates of false‐positive biopsies were 25.7% and 30.6% in the “no intravesical therapy (IVT)” and “PDD‐IVT > 6 months” groups, respectively, whereas the rate in the “within 6 months after intravesical therapy” group was 39.6% (p < 0.025) [24]. Matsuyama et al. reported the results of multicolor fluorescence in situ hybridization for detecting copy number abnormalities in the bladder mucosa of 20 patients suspected of having in situ carcinoma based on fluorescent cystoscopy using 5‐aminolevulinic acid. They assessed mutation rates and chromosomal instability in chromosomes 7, 9, and 17 and reported that the variant fraction of chromosome 9 was significantly higher in fluorescent mucosa than in nonfluorescent mucosa for all tissues (33% vs. 17%; p = 0.0069) as well as nonmalignant tissues (28% vs. 15%; p = 0.0225) [25]. Our previous report showed that the group who underwent false‐positive tissue removal had a significantly lower postoperative recurrence rate than did the group who did not undergo the same (p < 0.05) [20]. This finding suggests that residual false‐positive tissues may play a role in recurrence. Studies have reported that some false‐positive tissues in bladder cancer PDD have chromosome 9 copy number abnormalities (particularly 9p24.1) [14, 15]. Chromosome 9 has also been associated with p53, which is involved in the carcinogenesis of bladder cancer [15]. This finding suggests that PDD may detect chromosomal or genetic abnormalities and that the resection of false‐positive tissues may also have a suppressive effect on novel cancer lesions. Therefore, excluding false‐positive tissues due to the tangent effect or inflammation and properly resecting other false‐positive tissues may be necessary.
The present study showed that the overall diagnostic accuracy of preoperative pyuria was significantly lower in terms of specificity and positive predictive value than that reported in the Phase III study conducted by Nakai et al. [11]. Notably, among 616 specimens included in the present study, 134 (21.8%) were pathologically malignant, whereas 482 (78.2%) were nonmalignant. In contrast, among 511 specimens included in the study by Nakai et al., 181 (35.4%) were pathologically malignant, whereas 330 (64.6%) were nonmalignant [11]. In the present study, random or targeted biopsies were performed, with an average of 6.1 biopsy specimens per case. Given that the number of random biopsies was not changed according to the presence or absence of preoperative pyuria, the number of tissue specimens per case in both groups was similar. In contrast, even after excluding the two specimens in which no mucosa was removed, the average number of biopsy specimens per case in the study by Nakai et al. was 8.5. Hence, the specificity and positive predictive value of PDD could have been affected by the higher proportion of nonmalignant specimens and lower number of biopsies per case in the present study than in the study by Nakai et al.
The current study found that PDD false‐positive rates differed significantly between patients with and without preoperative pyuria. The degree of pyuria also tended to affect the false‐positive rates. However, this analysis was based on a very small number of cases and should be validated in studies with a larger number of cases. The etiology of pyuria can be divided into infection‐related and ‐unrelated causes [29, 30]. One of the many causes of positive preoperative pyuria is bacterial infection. In fact, one study reported the incidence of bacteriuria to be 25.4%, 28.2%, 33%, and 53.8% in cases with 0–5, 5–10, 10–25, and > 25 leukemic cells/hpf on microscopic examination of urine, respectively [30]. Bacterial cystitis and PDD false‐positive rates may be associated with iron. In normal cells, protoporphyrin IX is originally metabolized as heme by binding to ferrous iron (Figure 1A). However, in cancer cells, metabolic abnormalities result in abnormal intracellular accumulation of PpIX (Figure 1B). However, owing to the large amounts of exogenous ALA, PpIX could accumulate intracellularly in a state of local intracellular iron deficiency for some reason, causing PDD false‐positive findings. Bacteria have been known to need iron for their survival and often deplete iron from cells. In fact, researchers have hypothesized that when Escherichia coli infects the bladder, it forms iron chelates called siderophores, which deplete iron from the bladder mucosa, causing localized iron deficiency in the normal bladder mucosa [31, 32]. Therefore, assuming that local iron deficiency due to bladder bacterial infection does indeed cause PDD false‐positive findings (Figure 1C), preoperative antibiotic therapy for the positive pyuria group may decrease inflammatory false‐positive findings due to infection. Bacteriuria is defined as a threshold of ≥ 105 colony‐forming units/mL detected through culture of intermediate urine. Given that preoperative urine culture for PDD‐TURBT is not routinely performed at our institution, our inability to assess the impact of the presence or absence of bacteriuria on the diagnostic accuracy of PDD can be considered a limitation of this study and is a matter that needs to be addressed in future studies [33].
FIGURE 1.
Images depicting PpIX metabolism. (A) Images depicting PpIX metabolism in normal cells. (B) Images depicting PpIX metabolism in cancer cells. Abnormal accumulation of PpIX in cancer cells. (C) Image showing the PpIX metabolism hypothesis in urothelial cells with cystitis. The hypothesis states that when E. coli infects the bladder, it forms iron chelates called siderophores, which deplete iron from the bladder mucosa, causing localized iron deficiency in the normal bladder mucosa. ALA, 5‐aminolevulinic acid; FECH, Ferrochelatase; PpIX, Protoporphyrin IX.
In conclusion, our results suggest that preoperative pyuria is a useful predictor of false‐positive PDD rates. Patients positive for preoperative pyuria may have high false‐positive PDD rates, potentially including instances in which bacteriuria is present. Therefore, preoperative antibacterial therapy for patients positive for preoperative pyuria may be effective in reducing false‐positive PDD rates and should be validated in further studies.
Author Contributions
Shinkuro Yamamoto: conceptualization, data curation, investigation, writing – original draft, writing – review and editing. Hideo Fukuhara: writing – review and editing. Hajime Kuroiwa: formal analysis. Ryu Shigehisa: supervision. Hiroto Osakabe: supervision. Tomoya Nao: supervision. Tsutomu Shimamoto: supervision. Nobutaka Shimizu: supervision. Satoshi Fukata: supervision. Shingo Ashida: supervision. Takashi Karashima: supervision. Keiji Inoue: conceptualization, writing – review and editing.
Disclosure
Approval of the Research Protocol by an Institutional Review Board: This study was approved by the Institutional Review Board of Kochi University Medical School (approval no. 2021–093).
Registry and the Registration No. of the Study/Trial: Not applicable.
Animal Studies: Not applicable.
Consent
Informed consent was obtained from all patients or deceased patients' families through websites using the opt‐out method.
Conflicts of Interest
Keiji Inoue is an Editorial Board member of the International Journal of Urology and a co‐author of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication.
Acknowledgments
The authors have nothing to report.
Funding: The authors received no specific funding for this work.
References
- 1. Sung H., Ferlay J., Siegel R. L., et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 71 (2021): 209–249. [DOI] [PubMed] [Google Scholar]
- 2. Sylvester R. J., van der Meijden A. P., Oosterlinck W., et al., “Predicting Recurrence and Progression in Individual Patients With Stage ta T1 Bladder Cancer Using EORTC Risk Tables: A Combined Analysis of 2596 Patients From Seven EORTC Trials,” European Urology 49 (2006): 466–477, discussion 75–7. [DOI] [PubMed] [Google Scholar]
- 3. Divrik R. T., Sahin A. F., Yildirim U., Altok M., and Zorlu F., “Impact of Routine Second Transurethral Resection on the Long‐Term Outcome of Patients With Newly Diagnosed pT1 Urothelial Carcinoma With Respect to Recurrence, Progression Rate, and Disease‐Specific Survival: A Prospective Randomised Clinical Trial,” European Urology 58 (2010): 185–190. [DOI] [PubMed] [Google Scholar]
- 4. Mowatt G., N'Dow J., Vale L., et al., “Photodynamic Diagnosis of Bladder Cancer Compared With White Light Cystoscopy: Systematic Review and Meta‐Analysis,” International Journal of Technology Assessment in Health Care 27 (2011): 3–10. [DOI] [PubMed] [Google Scholar]
- 5. Maisch P., Koziarz A., Vajgrt J., Narayan V., Kim M. H., and Dahm P., “Blue vs White Light for Transurethral Resection of Non‐Muscle‐Invasive Bladder Cancer: An Abridged Cochrane Review,” BJU International 130 (2022): 730–740. [DOI] [PubMed] [Google Scholar]
- 6. Naito S., Algaba F., Babjuk M., et al., “The Clinical Research Office of the Endourological Society (CROES) Multicentre Randomised Trial of Narrow Band Imaging‐Assisted Transurethral Resection of Bladder Tumour (TURBT) Versus Conventional White Light Imaging‐Assisted TURBT in Primary Non‐Muscle‐Invasive Bladder Cancer Patients: Trial Protocol and 1‐Year Results,” European Urology 70 (2016): 506–515. [DOI] [PubMed] [Google Scholar]
- 7. Hagimoto H., Makita N., Mine Y., et al., “Comparison Between 5‐Aminolevulinic Acid Photodynamic Diagnosis and Narrow‐Band Imaging for Bladder Cancer Detection,” BMC Urology 21 (2021): 180. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Inoue K., Anai S., Fujimoto K., et al., “Oral 5‐Aminolevulinic Acid Mediated Photodynamic Diagnosis Using Fluorescence Cystoscopy for Non‐Muscle‐Invasive Bladder Cancer: A Randomized, Double‐Blind, Multicentre Phase II/III Study,” Photodiagnosis and Photodynamic Therapy 12 (2015): 193–200. [DOI] [PubMed] [Google Scholar]
- 9. Inoue K., Matsuyama H., Fujimoto K., et al., “The Clinical Trial on the Safety and Effectiveness of the Photodynamic Diagnosis of Non‐Muscle‐Invasive Bladder Cancer Using Fluorescent Light‐Guided Cystoscopy After Oral Administration of 5‐Aminolevulinic Acid (5‐ALA),” Photodiagnosis and Photodynamic Therapy 13 (2016): 91–96. [DOI] [PubMed] [Google Scholar]
- 10. Yamamoto S., Fukuhara H., Karashima T., and Inoue K., “Real‐World Experience With 5‐Aminolevulinic Acid for the Photodynamic Diagnosis of Bladder Cancer: Diagnostic Accuracy and Safety,” Photodiagnosis and Photodynamic Therapy 32 (2020): 101999. [DOI] [PubMed] [Google Scholar]
- 11. Nakai Y., Inoue K., Tsuzuki T., et al., “Oral 5‐Aminolevulinic Acid‐Mediated Photodynamic Diagnosis Using Fluorescence Cystoscopy for Non‐Muscle‐Invasive Bladder Cancer: A Multicenter Phase III Study,” International Journal of Urology 25 (2018): 723–729. [DOI] [PubMed] [Google Scholar]
- 12. Fukuhara H., Yamamoto S., Lai H. W., et al., “Real‐World Experience With 5‐Aminolevulinic Acid for Photodynamic Diagnosis of Bladder Cancer (2nd Report): Reduced Bladder Recurrence After PDD‐TURBT,” Photodiagnosis and Photodynamic Therapy 38 (2022): 102757. [DOI] [PubMed] [Google Scholar]
- 13. Fukuhara H., Kureishi M., Khoda T., et al., “The Utility of a Flexible Fluorescence‐Cystoscope With a Twin Mode Monitor for the 5‐Aminolevulinic Acid‐Mediated Photodynamic Diagnosis of Bladder Cancer,” PLoS One 10 (2015): e0136416. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Matsuyama H., Yamamoto Y., Nagao K., Ohmi C., Sakano S., and Sasaki K., “Cytogenetic Analysis of False‐Positive Mucosa by Photodynamic Diagnosis Using 5‐Aminolevulinic Acid ‐ Possible Existence of Premalignant Genomic Alterations Examined by In Vitro Experiment,” Oncology 76 (2009): 118–125. [DOI] [PubMed] [Google Scholar]
- 15. Hartmann A., Schlake G., Zaak D., et al., “Occurrence of Chromosome 9 and p53 Alterations in Multifocal Dysplasia and Carcinoma In Situ of Human Urinary Bladder,” Cancer Research 62 (2002): 809–818. [PubMed] [Google Scholar]
- 16. Hooker J. B., Mold J. W., and Kumar S., “Sterile Pyuria in Patients Admitted to the Hospital With Infections Outside of the Urinary Tract,” Journal of American Board of Family Medicine 27 (2014): 97–103. [DOI] [PubMed] [Google Scholar]
- 17. Horan T. C., Andrus M., and Dudeck M. A., “CDC/NHSN Surveillance Definition of Health Care‐Associated Infection and Criteria for Specific Types of Infections in the Acute Care Setting,” American Journal of Infection Control 36 (2008): 309–332. [DOI] [PubMed] [Google Scholar]
- 18. Satake N., Ohno Y., Nakashima J., Ohori M., and Tachibana M., “Prognostic Value of Preoperative Pyuria in Patients With Non‐Muscle‐Invasive Bladder Cancer,” International Journal of Urology 22 (2015): 645–649. [DOI] [PubMed] [Google Scholar]
- 19. Kanda Y., “Investigation of the Freely Available Easy‐To‐Use Software ‘EZR’ for Medical Statistics,” Bone Marrow Transplantation 48 (2013): 452–458. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Fukuhara H., Nohara T., Nishimoto K., et al., “Identification of Risk Factors Associated With Oral 5‐Aminolevulinic Acid‐Induced Hypotension in Photodynamic Diagnosis for Non‐Muscle Invasive Bladder Cancer: A Multicenter Retrospective Study,” BMC Cancer 21 (2021): 1223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Nohara T., Kato Y., Nakano T., et al., “Intraoperative Hypotension Caused by Oral Administration of 5‐Aminolevulinic Acid for Photodynamic Diagnosis in Patients With Bladder Cancer,” International Journal of Urology 26 (2019): 1064–1068. [DOI] [PubMed] [Google Scholar]
- 22. Miyake M., Nakai Y., Hori S., Morizawa Y., Hirao Y., and Fujimoto K., “Transient Liver Toxicity as a Result of the Oral Administration of 5‐Aminolevulinic Acid for Photodynamic Diagnosis in Patients With Bladder Cancer,” International Journal of Urology 26 (2019): 315–317. [DOI] [PubMed] [Google Scholar]
- 23. Ishikawa Y., Tanaka H., Fujiwara M., et al., “Incidence and Predictors of Intraoperative Hypotension During Transurethral Bladder Tumor Resection With Oral 5‐Aminolevulinic Acid,” International Journal of Urology 31 (2024): 238–244. [DOI] [PubMed] [Google Scholar]
- 24. Kobayashi K., Matsuyama H., Oka S., et al., “Risks and Benefits of Transurethral Resection of the Bladder Tumor Using Photodynamic Diagnosis With Oral 5‐Aminolevulinic Acid Hydrochloride According to Age and History of Recurrence in Patients With Non‐Muscle Invasive Bladder Cancer,” Photodiagnosis and Photodynamic Therapy 41 (2023): 103294. [DOI] [PubMed] [Google Scholar]
- 25. Draga R. O., Grimbergen M. C., Kok E. T., Jonges T. N., van Swol C. F., and Bosch J. L., “Photodynamic Diagnosis (5‐Aminolevulinic Acid) of Transitional Cell Carcinoma After Bacillus Calmette‐Guerin Immunotherapy and Mitomycin C Intravesical Therapy,” European Urology 57 (2010): 655–660. [DOI] [PubMed] [Google Scholar]
- 26. Draga R. O., Grimbergen M. C. M., Kok E. T., Jonges T. N., and Bosch J. L. H. R., “Predictors of False Positives in 5‐Aminolevulinic Acid‐Induced Photodynamic Diagnosis of Bladder Carcinoma: Identification of Patient Groups That May Benefit Most From Highly Specific Optical Diagnostics,” Urology 74 (2009): 851–856. [DOI] [PubMed] [Google Scholar]
- 27. Grimbergen M. C., van Swol C. F., Jonges T. G., Boon T. A., and van Moorselaar R. J., “Reduced Specificity of 5‐ALA Induced Fluorescence in Photodynamic Diagnosis of Transitional Cell Carcinoma After Previous Intravesical Therapy,” European Urology 44 (2003): 51–56. [DOI] [PubMed] [Google Scholar]
- 28. Matsuyama H., “Could Basic Research Shed Light on False Positivity in Photodynamic Diagnosis?,” International Journal of Urology 19 (2012): 695–696. [DOI] [PubMed] [Google Scholar]
- 29. Wise G. J. and Schlegel P. N., “Sterile Pyuria,” New England Journal of Medicine 372 (2015): 1048–1054. [DOI] [PubMed] [Google Scholar]
- 30. Cheng B., Zaman M., and Cox W., “Correlation of Pyuria and Bacteriuria in Acute Care,” American Journal of Medicine 135 (2022): e353–e358. [DOI] [PubMed] [Google Scholar]
- 31. Steigedal M., Marstad A., Haug M., et al., “Lipocalin 2 Imparts Selective Pressure on Bacterial Growth in the Bladder and Is Elevated in Women With Urinary Tract Infection,” Journal of Immunology 193 (2014): 6081–6089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Flo T. H., Smith K. D., Sato S., et al., “Lipocalin 2 Mediates an Innate Immune Response to Bacterial Infection by Sequestrating Iron,” Nature 432 (2004): 917–921. [DOI] [PubMed] [Google Scholar]
- 33. Bilsen M. P., Jongeneel R. M. H., Schneeberger C., et al., “Definitions of Urinary Tract Infection in Current Research: A Systematic Review,” Open Forum Infectious Diseases 10 (2023): ofad332. [DOI] [PMC free article] [PubMed] [Google Scholar]