新型内镜成像技术在膀胱癌诊断中的应用进展

白光膀胱镜检查是诊断及监测膀胱癌的传统方法。然而随着科学技术的不断发展,荧光膀胱镜、窄带成像、共聚焦激光内镜、光学相干断层扫描等新型内镜成像技术的出现,能够提高膀胱癌诊断的灵敏度,且其目的是辅助白光膀胱镜检查提高膀胱癌的诊断及优化临床分期,从而改善预后。     

Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy : A multicenter randomized, double-blind, placebo-controlled trial

BACKGROUND:

The medical community lacks results from prospective controlled multicenter studies of the diagnostic efficacy of 5‐aminolevulinic acid (5‐ALA) cystoscopy on tumor recurrence in patients with superficial bladder tumors.

METHODS:

A prospective randomized, double‐blind, placebo‐controlled study was conducted in 370 patients with nonmuscle‐invasive urinary bladder carcinoma who received either 5‐ALA (n = 187) or a placebo (n = 183) intravesically before cystoscopy. Each group underwent cystoscopy under visible white light and under fluorescent light followed by transurethral tumor resection. The primary study objective was to evaluate the 12‐month recurrence‐free survival.

RESULTS:

Slightly more patients with tumors were detected by using 5‐ALA than by using the placebo (88.5% vs 84.7%). The mean numbers of tumor specimens per patient were 1.8 (5‐ALA) and 1.6 (placebo). Intrapatient comparison of fluorescent light versus white light cystoscopy in patients randomized to receive 5‐ALA showed a higher tumor detection rate with fluorescent light than with white light cystoscopy. In patients receiving 5‐ALA cystoscopy, the percentage of lesions that would not have been detected in these patients by white light cystoscopy ranged between 10.9% (pT1) and 55.9% (atypia). Progression‐free survival was 89.4% (5‐ALA) and 89.0% (placebo) (P = .9101), and recurrence‐free survival 12 months after tumor resection was 64.0% (5‐ALA) and 72.8% (placebo) (P = .2216).

CONCLUSIONS:

In comparison to the placebo, 5‐ALA cystoscopy did not increase the rates of recurrence‐free or progression‐free survival 12 months after tumor resection. Although more tumors per patient were detected in the 5‐ALA group, the higher detection rate did not translate into differences in long‐term outcome. Cancer 2011. © 2010 American Cancer Society.     

The role of narrow-band imaging in the management of non-muscle-invasive bladder cancer

Narrow-band imaging is a young optical enhancement technology for endoscopy. It is a filter to the standard white light which increases the contrast between underlying vasculature and epithelial strata of the mucosa, improving the detection of bladder cancer with particular regard to high grade, flat lesions. Narrow band imaging is absolutely safe, may be used any time during a procedure, either during office cystosopy or transurethral resection, and implies a minimal burden for the healthcare provider given the absence of a learning curve and the limited cost of the camera and light source. The ameliorated detection translates into an improved management of the disease and a lower recurrence risk in prospective randomized studies, suggesting the inclusion of the technology in daily clinical practice.     

Hexyl aminolevulinate fluorescence cystoscopy in bladder cancer

Although bladder cancer occurs frequently, early diagnosis and complete removal of malignant lesions usually lead to good clinical outcomes. In the USA, white light cystoscopy (WLC) is commonly used for bladder cancer diagnosis and guidance of the surgical resection. However, with WLC malignant and precancerous lesions may be missed, resulting in a high rate of disease recurrence. Monitoring for and treating these recurrences carry high direct and indirect costs. Because hexyl aminolevulinate (HAL; 5-ALA-hexylester) fluorescence cystoscopy has greater sensitivity than WLC, especially for detecting early stage lesions, and its use provides more complete resection and lower disease recurrence, it has been recommended in European clinical guidelines. This article reports our own HAL experiences and first time recurrence data, describes how HAL was developed, provides key clinical trial results, and discusses how HAL, which has revolutionized fluorescence cystoscopy and bladder cancer care in Europe, may ultimately revolutionize bladder cancer care in the USA.     

荧光膀胱镜在尿路上皮膀胱癌中的诊断价值

目的:评估以5-氨基乙酰丙酸(5-aminolevulinic acid, 5-ALA)作为荧光剂的荧光膀胱镜检查对非肌层浸润性膀胱癌的诊断价值。方法:按照筛除纳入标准,纳入97名研究对象,膀胱灌注50 mL浓度为3%的5-ALA溶液,保留1小时后,排空膀胱后置入膀胱镜,分别在普通白光和荧光下观察,对白光和/或荧光下显示阳性或可疑区域取组织做病理活检,同时行电切术。结果:97例患者中,19例患者普通白光膀胱镜及荧光膀胱镜下检查均为阴性,剩余78例患者取156处组织进行活检,平均每例患者取2块组织。结果显示97处病理报告为尿路上皮癌。经计算得出荧光膀胱镜的敏感性为91.75%(89/97),特异性为64.41%(38/59);普通白光膀胱镜的敏感性为71.13%(69/97),特异性55.93%(33/59);P<0.05,差异具有统计学意义。结论:荧光膀胱镜在诊断尿路上皮膀胱癌上的敏感性和特异性均显著高于普通白光膀胱镜,具有较高的临床应用价值。     

Fluorescent diagnostics of urinary bladder cancer

Introduction of optic markers in screening for cancer of the urinary bladder (UB) raises diagnostic significance of UB cystoscopy. Application of intravesical form of 5-aminolevulinic acid (5-ALA), precursor of photodynamically active protoporphirine IX, prevents complications in systemic use of tetracycline or hepatoprophirines. Fluorescent cystoscopy with 5-ALA (n = 59) was made in 51 patients treated in the Research Institute of Urology. UB cancer was detected in 32 patients. This procedure proved highly sensitive and specific (97.0 and 75.6%, respectively, being much more effective than standard cystoscopy and biopsy in the white light (85.1 and 81.4%, respectively). Specificity of fluorescent cystoscopy is much higher in detection of tumors and pretumor lesions (88.4%). Fluorescent diagnosis is expected to become a gold standard in the program of UB cancer detection.     

Comparison of ImmunoCyt,UroVysion, and urine cytology in detection of recurrent urothelial carcinoma

BACKGROUND:

ImmunoCyt (uCyt) and UroVysion are ancillary studies that may aid in the detection of urothelial carcinoma in urine specimens. We compared ImmunoCyt and UroVysion to urine cytology in the ability to detect recurrent urothelial carcinoma.

METHODS:

Single voided urine samples were obtained from 100 patients who had a previous history of bladder cancer. All patients underwent cystoscopy immediately after urine sample collection. Forty‐one cystoscopically suspicious lesions were biopsied. Urine samples were divided and processed blindly and independently in 3 different laboratories for ImmunoCyt, UroVysion, and urine cytology (ThinPrep method).

RESULTS:

Of the 41 cystoscopically positive cases, most cystoscopy findings showed multiple tumors that were papillary and less than 1 cm. Biopsies showed many low‐grade tumors (54%). Overall sensitivity of cytology for low‐ and high‐grade urothelial cell carcinoma was 15% and 27%, whereas ImmunoCyt was 62% and 91% and UroVysion was 8% and 18%, respectively. Overall specificity of cytology was 97%, whereas ImmunoCyt was 63% and UroVysion was 90%.

CONCLUSIONS:

ImmunoCyt is more sensitive than either cytology or UroVysion in detecting low‐grade tumors. Both cytology and UroVysion have comparable specificity in cystoscopically negative cases. Whereas ImmunoCyt may improve the cytological detection of recurrent bladder cancer, UroVysion may be used as a confirmatory test for either cytology or ImmunoCyt. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

Advances in optical gastrointestinal endoscopy: a technical review

Optical endoscopy is the primary diagnostic and therapeutic tool for management of gastrointestinal (GI) malignancies. Most GI neoplasms arise from precancerous lesions; thus, technical innovations to improve detection and diagnosis of precancerous lesions and early cancers play a pivotal role in improving outcomes. Over the last few decades, the field of GI endoscopy has witnessed enormous and focused efforts to develop and translate accurate, user‐friendly, and minimally invasive optical imaging modalities. From a technical point of view, a wide range of novel optical techniques is now available to probe different aspects of light–tissue interaction at macroscopic and microscopic scales, complementing white light endoscopy. Most of these new modalities have been successfully validated and translated to routine clinical practice. Herein, we provide a technical review of the current status of existing and promising new optical endoscopic imaging technologies for GI cancer screening and surveillance. We summarize the underlying principles of light–tissue interaction, the imaging performance at different scales, and highlight what is known about clinical applicability and effectiveness. Furthermore, we discuss recent discovery and translation of novel molecular probes that have shown promise to augment endoscopists'' ability to diagnose GI lesions with high specificity. We also review and discuss the role and potential clinical integration of artificial intelligence‐based algorithms to provide decision support in real time. Finally, we provide perspectives on future technology development and its potential to transform endoscopic GI cancer detection and diagnosis.     

盐酸吡柔比星荧光膀胱镜对非肌层浸润性膀胱癌的诊断价值

目的:评估以盐酸吡柔比星作为荧光剂的荧光膀胱镜检查对非肌层浸润性膀胱癌的诊断价值。方法:本次研究共63例患者,膀胱灌注盐酸吡柔比星溶液40 mg,保留30 min后排空置入膀胱镜,分别在普通白光及荧光下观察,对白光和/或荧光下显示阳性或可疑区域进行活检,同时行电切术。结果:63例患者中,18例患者普通白光膀胱镜及荧光膀胱镜检查均阴性;其余45例患者共取活检92处,平均每例患者取活检2.04处。其中53处病理报告为尿路上皮癌,荧光膀胱镜敏感性为90.57%（48/53）,特异性为64.10%（25/39）;普通白光膀胱镜敏感性为71.70%（38/53）,特异性为56.41%（22/39）。结论:吡柔比星荧光膀胱镜诊断非肌层浸润性膀胱癌的敏感性和特异性均显著高于普通白光膀胱镜,具有较高的临床应用价值。     

Diagnostic approach for cancer cells in urine sediments by 5‐aminolevulinic acid‐based photodynamic detection in bladder cancer

Bladder urothelial carcinoma is diagnosed and followed up after transurethral resection using a combination of cystoscopy, urine cytology and urine biomarkers at regular intervals. However, cystoscopy can overlook flat lesions like carcinoma in situ, and the sensitivity of urinary tests is poor in low‐grade tumors. There is an emergent need for an objective and easy urinary diagnostic test for the management of bladder cancer. In this study, three different modalities for 5‐aminolevulinic acid (ALA)‐based photodynamic diagnostic tests were used. We developed a compact‐size, desktop‐type device quantifying red fluorescence in cell suspensions, named “Cellular Fluorescence Analysis Unit” (CFAU). Urine samples from 58 patients with bladder cancer were centrifuged, and urine sediments were then treated with ALA. ALA‐treated sediments were subjected to three fluorescence detection assays, including the CFAU assay. The overall sensitivities of conventional cytology, BTA, NMP22, fluorescence cytology, fluorescent spectrophotometric assay and CFAU assay were 48%, 33%, 40%, 86%, 86% and 87%, respectively. Three different ALA‐based assays showed high sensitivity and specificity. The ALA‐based assay detected low‐grade and low‐stage bladder urothelial cells at shigher rate (68–80% sensitivity) than conventional urine cytology, BTA and NMP22 (8–20% sensitivity). Our findings demonstrate that the ALA‐based fluorescence detection assay is promising tool for the management of bladder cancer. Development of a rapid and automated device for ALA‐based photodynamic assay is necessary to avoid the variability induced by troublesome steps and low stability of specimens.     

Past and current trends in endoscopic diagnosis for early stage gastric cancer in Japan

Methodology for the diagnosis and staging of early gastric cancer (EGC) has improved in Japan since the development of the gastro-camera and determination of a definition of EGC. Imaging technology has been steadily evolving in the endoscopy field. Improvements in the resolution of standard endoscopy images used in screening and surveillance provide greater opportunities to find gastric cancer earlier. Image enhancement endoscopy (IEE), such as narrow band imaging (NBI), highlights mucosal structures and vascularity. In particular, when NBI is used with magnifying endoscopy, it reveals fine details of subtle superficial abnormalities of EGC that are difficult to recognize using standard white light endoscopy. IEE-assisted magnifying endoscopy has improved the accuracy of the differentiation of superficial gastric cancer as well as delineation of the diseased mucosa. The advanced imaging technology enables precise assessment of the risk of lymph node metastasis of EGC and is widely used to determine indications for endoscopic treatment. It is not an overstatement to say that this has become the basis for the current development and dissemination of endoscopic treatments. Moreover, the resolution of endoscopic imaging has been upgraded to the microscopy level by the development of endomicroscopy, including endocytoscopy and confocal laser endomicroscopy. Endomicroscopy allows real-time histological analysis of living tissue during routine endoscopy and may reduce the number of biopsies needed to reach the correct diagnosis, minimizing the risk of sampling errors.

     

Precise detection of lymph node metastases in mouse rectal cancer by using 5‐aminolevulinic acid

Accurate diagnosis of metastatic lymph nodes (LNs) is essential in choosing appropriate treatment for gastrointestinal carcinoma. Our aim was to evaluate the diagnostic power of 5‐aminolevulinic acid (5‐ALA) for LN metastasis in mouse rectal cancer. Colorectal cancer cell lines, isolated cells from normal LNs, and orthotopic mouse model incorporating enhanced green fluorescent protein‐tagged and untagged human rectal cancer cells were studied after 5‐ALA administration by using confocal microscopy, fluorescence stereomicroscopy, fluorescence lifetime imaging microscopy (FLIM), multichannel spectrophotometry and macroconfocal imaging system to precisely detect LN metastases. In vitro confocal microscopic analyses showed that all colorectal cancer cell lines tested were positive for 5‐ALA‐induced fluorescence, whereas isolated normal LN cells were negative. 5‐ALA‐induced protoporphyrin IX (PPIX) fluorescence, verified by FLIM and multichannel spectrophotometry, revealed LN metastases in mice‐bearing human rectal cancer cells. Occult LN metastases, unrecognized on white‐light imaging and simplified hematoxylin‐eosin analyses, were readily detectable on 5‐ALA‐induced PPIX fluorescence imaging. In vivo macroconfocal images clearly revealed PPIX‐fluorescence‐positive cancer cells in draining lymph vessels and nodes. Together with specific speckled patterns of PPIX‐fluorescence in metastatic lesions, the PPIX‐fluorescence intensity ratio of metastatic and nonmetastatic lesions discriminated metastasis with 100% sensitivity and 100% specificity in excised whole LN samples. These results show that fluorescence diagnosis with 5‐ALA is very accurate in the detection of LN micrometastases of mouse rectal cancer, suggesting that this feasible diagnostic approach is applicable to target sectioning of metastases of resected fresh whole node samples in pathology laboratories. © 2009 UICC     

Endoscopic Diagnosis for H. pylori Infection: White Light Imaging (WLI) vs. Image-Enhanced Endoscopy (IEE)

Helicobacter pylori infection is a class I carcinogen that can lead to gastric cancer. Early diagnosis and eradication of H. pylori infection are important to eliminate the risk of gastric cancer. Several invasive diagnostic techniques require biopsy samples, resulting in avoidable injury and medical expense. Furthermore, due to the localized distribution of H. pylori, random biopsies are not always reliable in diagnosing H. pylori infection. This article aimed to review endoscopic findings and new endoscopic options for the diagnosis of H. pylori infection. Using conventional white light imaging (WLI) and image-enhanced endoscopy (IEE), the endoscopic features associated with histological changes have increasingly become apparent. Real-time endoscopy is essential to make a diagnosis of H. pylori infection and allow targeted biopsy. Image-enhanced endoscopy (IEE), such as narrow-band imaging (NBI), linked color imaging (LCI), and blue laser imaging (BLI), enhances visualization of the surface vascular pattern and provides accurate diagnostic performance in H. pylori infection, as well as gastric neoplastic lesions, compared to conventional white light endoscopy. In conclusion, the new endoscopic technologies could be used in current practice with conventional white light endoscopy for accurate and real-time diagnosis of H. pylori infection and pre-cancerous lesions.     

Assessing the clinical benefit of nuclear matrix protein 22 in the surveillance of patients with nonmuscle-invasive bladder cancer and negative cytology: a decision-curve analysis

BACKGROUND:

Several studies have demonstrated that abnormal levels of nuclear matrix protein 22 (NMP22) are associated with bladder cancer and have led to the approval of NMP22 as a urinary biomarker by the US Food and Drug Administration. Nonetheless, the clinical significance of NMP22 remains unclear. The objective of this study was to use decision analysis to determine whether NMP22 improves medical decision‐making.

METHODS:

The current study included 2222 patients who had a history of nonmuscle‐invasive bladder cancer and current negative cytology. The authors developed models to predict cancer recurrence or progression to muscle‐invasive disease using voided NMP22 levels, cystoscopy, age, and sex. Clinical net benefit was calculated by summing the benefits (true‐positives), subtracting the harms (false‐positives), and weighting these values by the threshold probability at which a patient or clinician would opt for cytoscopy.

RESULTS:

After cystoscopy, 581 patients (26%) had cancer identified. The NMP22 level was associated significantly with bladder cancer recurrence and progression (P < .001 for both). The use of NMP22 in a model with age and sex was associated with better patient outcomes than performing cystoscopy on everyone and produced threshold probabilities > 8% for recurrence and > 3% for progression. Only offering cystoscopy to those who had a risk > 15% reduced the number of cystoscopies by 229 while missing only 25 cancer recurrences per 1000 men with negative cytology. The current study was limited by its multicenter design.

CONCLUSIONS:

For clinicians who would perform a cystoscopy at a threshold of 5% for recurrence or 1% for progression, NMP22 did not aid clinical decision‐making. For less risk‐averse clinicians who would only perform a cystoscopy at a threshold probability >thinsp;8% for recurrence or > 3% for progression, NMP22 helped to indicate which patients required cystoscopy and which could be spared this procedure. Cancer 2011. © 2011 American Cancer Society.     

The Italian Research Group for Gastric Cancer (GIRCG) guidelines for gastric cancer staging and treatment: 2015

Methodology for the diagnosis and staging of early gastric cancer (EGC) has improved in Japan since the development of the gastro-camera and determination of a definition of EGC. Imaging technology has been steadily evolving in the endoscopy field. Improvements in the resolution of standard endoscopy images used in screening and surveillance provide greater opportunities to find gastric cancer earlier. Image enhancement endoscopy (IEE), such as narrow band imaging (NBI), highlights mucosal structures and vascularity. In particular, when NBI is used with magnifying endoscopy, it reveals fine details of subtle superficial abnormalities of EGC that are difficult to recognize using standard white light endoscopy. IEE-assisted magnifying endoscopy has improved the accuracy of the differentiation of superficial gastric cancer as well as delineation of the diseased mucosa. The advanced imaging technology enables precise assessment of the risk of lymph node metastasis of EGC and is widely used to determine indications for endoscopic treatment. It is not an overstatement to say that this has become the basis for the current development and dissemination of endoscopic treatments. Moreover, the resolution of endoscopic imaging has been upgraded to the microscopy level by the development of endomicroscopy, including endocytoscopy and confocal laser endomicroscopy. Endomicroscopy allows real-time histological analysis of living tissue during routine endoscopy and may reduce the number of biopsies needed to reach the correct diagnosis, minimizing the risk of sampling errors.     

Recent advances in urinary bladder cancer detection

Urinary bladder cancer (BCa) is the most common malignancy of the urinary tract. In recent decades, the overall incidence of BCa appears to be on the increase. Despite the increase in incidence, mortality rates in North America and Europe appear to have declined in the last decade, probably due to improved detection and treatment. The mainstay of diagnosis is by cystoscopy, aided with imaging and urine tests (e.g., cytology). This article reviews the recent advances made in detection of primary and recurrent bladder cancer.     

Recent advances in urinary bladder cancer detection

Urinary bladder cancer (BCa) is the most common malignancy of the urinary tract. In recent decades, the overall incidence of BCa appears to be on the increase. Despite the increase in incidence, mortality rates in North America and Europe appear to have declined in the last decade, probably due to improved detection and treatment. The mainstay of diagnosis is by cystoscopy, aided with imaging and urine tests (e.g., cytology). This article reviews the recent advances made in detection of primary and recurrent bladder cancer.     

Role of 5-aminolevulinic acid in the detection of urothelial premalignant lesions

BACKGROUND: The authors evaluated the role of 5-aminolevulinic acid (5-ALA)-induced fluorescence endoscopy (AFE) in the detection of flat urothelial lesions in light of the suggestions made for flat neoplastic lesions within the 1999 World Health Organization (WHO) classification of urinary bladder tumors. METHODS: From 1995 to 2000, 713 patients underwent 1414 AFE procedures for the detection of transitional cell carcinoma of the bladder (TCCB). Fluorescence imaging was performed with an incoherent light source (D-light; 380-440 nm) that was filtered for efficient protoporphyrin IX excitation and with cystoscopes partially blocking reflected excitation light to enable fluorescence evaluation by a red/blue color contrast 2-3 hours after 50 mL of a 3% solution of 5-ALA was instilled into the bladder. In total, 3834 biopsy specimens (mean, 2.7 specimens per AFE procedure) were taken. RESULTS: Malignant disease was found in 1250 (32.6%) of all biopsies, with 304 biopsies (24.3%) showing carcinoma in situ (cis) and dysplasia II degrees (dys II) according to the previous diagnostic criteria of the WHO. Under prior conventional white-light endoscopy, 30.3% of specimens with dys II and 52.8% of specimens with cis had been missed. CONCLUSIONS: The current results suggest that 5-ALA may be more effective in the detection of flat urothelial lesions than the current diagnostic devices.     

多参数MRI及基于MRI的放射组学在膀胱癌诊断中的价值

膀胱癌发病率居全球恶性肿瘤前列,其诊断和分期主要依靠膀胱镜取病理活检,因其有创性及取材范围局限性,膀胱癌术前分期困难及预后差等问题仍然是临床诊疗的难点。目前,临床缺乏对膀胱癌术前精准分期及术后评估的无创的影像学方法。多模态磁共振技术包括T2加权、动态对比增强（dynamic contrast enhanced,DCE）和弥散加权成像（diffusion weighted imaging,DWI）被探索性地应用于肿瘤分期、阳性淋巴结的检出、复发预测等方面。同时,基于多模态磁共振技术的放射组学能对肿瘤内部信息进行挖掘,为肿瘤诊断提供更多影像学依据。     

Fluorescent imaging of high‐grade bladder cancer using a specific antagonist for chemokine receptor CXCR4

We previously reported that the expression of CXC chemokine receptor‐4 (CXCR4) was upregulated in invasive bladder cancers and that the small peptide T140 was a highly sensitive antagonist for CXCR4. In this study, we identified that CXCR4 expression was induced in high‐grade superficial bladder tumors, including carcinoma in situ and invasive bladder tumors. To visualize the bladder cancer cells using urinary sediments from the patients and chemically induced mouse bladder cancer model, a novel fluorescent CXCR4 antagonist TY14003 was developed, that is a T140 derivative. TY14003 could label bladder cancer cell lines expressing CXCR4, whereas negative‐control fluorescent peptides did not label them. When labeling urinary sediments from patients with invasive bladder cancer, positive‐stained cells were identified in all patients with bladder cancer and positive urine cytology but not in controls. Although white blood cells in urine were also labeled with TY14003, they could be easily discriminated from urothelial cells by their shape and size. Finally, intravesical instillation of TY14003 into mouse bladder, using N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine (BBN)‐induced bladder cancer model, demonstrated that fluorescent signals were detected in the focal areas of bladder of all mice examined at 12 weeks of BBN drinking by confocal microscopy and fluorescent endoscopy. On the contrary, all the normal bladders were found to be negative for TY14003 staining. In conclusion, these results indicate that TY14003 is a promising diagnostic tool to visualize small or flat high‐grade superficial bladder cancer.