A 25-year perspective on advances in an understanding of the biology, evaluation, treatment and future directions/challenges of urothelial cancer.

The Urologic Oncology Journal was founded 25 years ago and we reviewed the literature since that time in the area of urothelial cancer to see the progress and pitfalls we have made over this time period. A comprehensive literature search was conducted by the authors involved who are all actively involved in research, clinical trials, and treatment for urothelial cancer and the results were summarized over the past 25 years. The field of urothelial cancer has evolved tremendously in the last 25 years with the incorporation of molecular subtyping, novel imaging, immunotherapy, and robotic surgery. However, treatments such as BCG and radical cystectomy have remained steadfast over the last 25 years. Although we have a better understanding of the biology of bladder cancer, we still have a long way from being able to cure patients with bladder cancer and eliminate morbidity from treatments. Nevertheless, considerable progress has been made since the founding of the Urologic Oncology Journal 25 years ago.

A 25-year perspective on evaluation and understanding of biomarkers in urologic cancers.

The past 25 years have witnessed an explosion of investigative attempts to identify clinically useful biomarkers which can have meaningful impacts for patients with urologic cancers. However, in spite of the enormous amount of research aiming to identify markers with the hope of impacting patient care, only a handful have proven to have true clinical utility. Improvements in targeted imaging, pan-omics evaluation, and genetic sequencing at the tissue and single-cell levels have yielded many potential targets for continued biomarker investigation. This article, as one in this series for the 25th Anniversary Issue of Urologic Oncology: Seminars and Original Investigations, serves to give a perspective on our progress and failures over the past quarter-century in our highest volume urologic cancers: prostate, bladder, and kidney cancers.

BCG turns 100: its nontraditional uses against viruses, cancer, and immunologic diseases.

First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called "trained immunity." In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG.

Trends in the incidence and mortality of transitional cell carcinoma of the bladder for the last four decades in the USA: a SEER-based analysis.

BACKGROUND: Transitional cell carcinoma (TCC) accounts for around 95% of bladder cancers and is the 4th most common cancer among men and the tenth most common in women, in the US. There is a constant need to clarify current TCC incidence and mortality rates among different population groups for better clinical practice guidelines. We aimed to describe the TCC incidence and incidence-based mortality by demographic and tumor-related characteristics over the last 40 years in the US. METHODS: We obtained data from the SEER 18 registries to study TCC cases that were diagnosed between the years 1973 and 2014. We calculated incidence rates and incidence-based mortality rates in different demographic and tumor-related characteristics and expressed rates by 100,000 person-years. We then calculated the annual changes in incidence and incidence-based mortality rates and displayed them as annual percent changes (APCs). RESULTS: There were 182,114 patients with TCC between 1973 and 2014 in the United States. Overall incidence rates of TCC increased 0.16% (95% CI, 0.02-0.30, p = .02) per year over the study period. However, the incidence declined significantly since 2007; (95%CI,-1.89- -0.77, p < .001), except among the elderly and African Americans, which increased significantly over the study period. Overall TCC mortality rates did not change over the study period. However, since 2000 it started to decrease significantly. CONCLUSION: TCC incidence and incidence-based mortality rates had been showing significant increases over the previous decades. However, significant declines in both incidence and incidence-based mortality rates have been observed over the recent years, except in some patients with certain racial groups. Improved understanding of the etiological and ecological factors of TCC could lead to further declines in incidence and incidence-based mortality rates.

The overlooked primary: bladder cancer metastases on dry bone. A study of the 20th century CAL Milano Cemetery Skeletal Collection.

OBJECTIVE: The aim of this article is to provide additional documentation of bone metastases to help anthropologists recognize the condition and potentially suggest the diagnosis of bladder carcinoma in differential diagnosis. MATERIALS AND METHODS: Thirteen individuals clinically diagnosed with bladder carcinoma from the 20th century Milano Cemetery Skeletal Collection were macroscopically studied to document bone metastases in bladder cancer. RESULTS: Bone metastases were found through macroscopic observation in three individuals or 23% of the study sample. Metastases were mostly of a mixed nature (45%), although both osteoblastic (13%) and osteolytic (9%) also occurred. In particular, mixed and osteoblastic metastases exhibited different distribution patterns, even when affecting the same bones. The vertebrae (24.7%), skull (12.9%), ribs (11.7%), proximal humeri (7.8%), pelvis (5.2%), proximal femora (2.6%), sacrum (1.3%) and sternum (1.3%) were the most commonly affected. Osteolytic lesions included coalescing superficial pits or lesions perforating the bone cortex. Proliferative lesions manifested as spongiosclerosis or periosteal new bone. Mixed metastases were osteolytic lesions exposing a thickened trabecular bone or coalescent porosity with reactive new bone. CONCLUSIONS: Bladder carcinoma metastases were mostly mixed, exhibiting periosteal reactions, perforations of bone cortex, spongiosclerosis and coalescing porosity. SIGNIFICANCE: Bladder carcinoma is rarely considered in the differential diagnosis of the primary organ. This study reports the macroscopic aspect of bone metastases in bladder carcinoma and may help anthropologists diagnose the condition in skeletons. LIMITATIONS: Absence of evidence is not evidence of absence; some lesions may have been hidden from macroscopic observation and therefore missed. FURTHER RESEARCH: Radiographic analysis and comparison with other neoplasms should provide additional details for the diagnosis of bladder cancer bone metastases.

Incidence and Survival of urothelial carcinoma of the urinary bladder in Norway 1981-2014.

BACKGROUND: Urothelial carcinoma of the urinary bladder (UCB) is the 4th most common cancer type in men in developed countries, and tumor recurrence or progression occurs in more than half of the patients. Previous studies report contradictory trends in incidence and survival over the past decades. This article describes the trends of UCB incidence and survival from 1981 to 2014, including both invasive and non-invasive UCB using data from the Cancer Registry of Norway. METHODS: In Norway, 33,761 patients were diagnosed with UCB between 1981 and 2014. Incidence and 5-year relative survival were calculated, stratified by sex, morphology, stage, age and diagnostic period. Age-period-cohort models were used to distinguish period- and cohort effects. Temporal trends were summarized by calculating the average absolute annual change in incidence and relative survival allowing for breaks in this trend by incorporating a joinpoint analysis. Excess mortality rate ratios (EMRR) quantify the relative risks by using a proportional excess hazard model. RESULTS: The incidence of UCB in men increased from 18.5 (1981-85) to 21.1 (1991-95) per 100 000 person-years and was rather stable thereafter (1996-2014). The incidence rates of UCB were lower in women increasing linearly from 4.7 to 6.2 over the past 34 years (p = 5.9 · 10-7). These trends could be explained by an increase of the incidence rates of non-invasive tumors. Furthermore, the observed pattern seemed to represent a birth cohort effect. Five-year relative survival increased annually with 0.004 in men (p = 1.3 · 10-6) and 0.003 in women (p = 4.5 · 10-6). There is a significant increase over the past 34 years in survival of UCB in both genders for local tumors but not for advanced stages. CONCLUSIONS: Increasing and stable incidence trends mirror little improvement in primary and secondary prevention of UCB for more than three decades. Survival proportions increased only marginally. Thus, any changes in treatment and follow-up care did not lead to notable improvement with respect to survival of the patients. High estimates of preventable cases together with large recurrence rates of this particular cancer type, demand more research on prevention guidelines, diagnostic tools and treatment for UCB.

[From "Karzinos" to modern urologic oncology : A long way from the first surgical procedures to targeted therapy]. / Von "Karzinos" zur modernen Uroonkologie : Der lange Weg von den ersten Operationen zur "targeted therapy".

Cancer can be traced back to the Iron Age. Both the ancient Egyptians and Hippocrates dealt with the disease. Urological tumor treatment is an integral part of urology and has undergone interesting developments. Today, it comprises all possible forms of treatment-from radical surgery to the most modern radiological therapies, including antihormal therapy, chemotherapy, and modern targeted therapy.

Survival trends in metastatic bladder cancer in the United States: a population based study.

BACKGROUND: To evaluate the relative survival rates for patients with metastatic bladder cancer (MBC) over the last two decades in the United States: 1991-2000 and 2001-2010. MATERIALS AND METHODS: We used the Surveillance, Epidemiology, and End Results (SEER*Stat) Program to analyze 6-month and 12-month relative survival rates of American Joint Committee on Cancer (AJCC) Stage IV bladder cancer patients included in the SEER database. We used Z-test in the SEER*Stat Program to compare relative survival rates among cohorts of patients categorized by race, gender, and age groups (<60 and ≥ 60 years). RESULTS: The dataset comprised 4195 and 7629 patients with AJCC Stage IV bladder cancer in the periods 1991-2000 and 2001-2010, respectively. There were statistically significant decreases in relative survival rates for pooled data across all races (67.8 ± 0.7% in 1991-2000 vs. 64.7 ± 0.5% in 2001-2010, P < 0.01), among Caucasian (CC) and other races (Oth) men + women, among CC and Oth men, and several cohorts among men and 60 + Oth-women when categorized by age. African American patients did not show significant changes in survival. CONCLUSIONS: This population-based study shows that decreases in 6-month and 12-month relative survival rates among patients with MBC in 2001-2010 compared to 1991-2000, specifically, more pronounced among CC men and Oth men.

Incidence trends of urinary bladder and kidney cancers in urban Shanghai, 1973-2005.

OBJECTIVES: We examined the incidence trends of bladder and kidney cancers using a population-based cancer registration data. METHODS: Age-standardized incidence rates were analyzed using data from the Shanghai Cancer Registry during 1973 to 2005. Annual percentage changes and 95% confidence intervals were calculated to evaluate the incidence changes. Age-period-cohort analysis was further implemented to assess the contributions of age, period and cohort effects to the trends using the intrinsic estimator method. RESULTS: In total, 12,676 bladder and 5,811 kidney cancer patients were registered in urban Shanghai. The age-standardized rates of bladder cancer in males increased from 6.39 to 7.66 per 100,000, or 0.62% per year, whereas the rates in females increased from 1.95 to 2.09 per 100,000, or 0.33% per year. For kidney cancer, the age-standardized rates in males increased from 1.20 to 5.64 per 100,000, or 6.98% per year. Similarly in females, the rates increased from 0.85 to 3.33 per 100,000, or 5.93% per year. Age-period-cohort analysis showed increasing curves of age and period effects but generally decreasing cohort effects for bladder and kidney cancers. CONCLUSIONS: Our results show increasing incidence trends of bladder and kidney cancers in Chinese men and women, especially for kidney cancer.

[The history and the present conditions of the occupational bladder cancer in our country].

PURPOSE: We examined the history and the present conditions of the occupational bladder cancer of our country and a chemical carcinogenesis study career of the bladder cancer. OBJECT AND METHOD: We performed consideration from literatures mainly on document and Ministry of Health, Labor and Welfare, Labor Standards Bureau, Accident compensation element document and documents of Association of Formation Product Industry. RESULT: Production of aromatic amine was started in about 1920 in our country, and the first occupational bladder cancer case was reported in 1940. It arrived at the greatest amount of production time of aromatic amine caused by Communist China Trade in 1955. The production, the import of benzidine and 2-naphthylamine were prohibited in 1972 by Safe Hygiene Method Official Announcement. During this time, 3,310 people were exposed by these materials, and the occupational bladder cancer of 357 people was registered by 1985. A number authorized from 1976 through 2006 that Workmen's comp was started is 341 cases of urinary tract system tumors by duties exposed to benzidine, 150 cases of urinary tract system tumors by duties exposed to 2-naphthylamine and one case of urinary tract tumors by o-dianisidine in total 492 cases. The occupational urinary tract cancer patient almost reaches a retirement age, and it is thought that they reach the end in about 2025. CONCLUSION: We reported the history and the present conditions of the occupational bladder cancer which occurred from 3,310 people of aromatic amine revelation in our country and we commented on a trend of the recent occupational bladder cancer for consideration from literatures.

From Leonardo to da Vinci: the history of robot-assisted surgery in urology.

What's known on the subject? and What does the study add? Numerous urological procedures can now be performed with robotic assistance. Though not definitely proven to be superior to conventional laparoscopy or traditional open surgery in the setting of a randomised trial, in experienced centres robot-assisted surgery allows for excellent surgical outcomes and is a valuable tool to augment modern surgical practice. Our review highlights the depth of history that underpins the robotic surgical platform we utilise today, whilst also detailing the current place of robot-assisted surgery in urology in 2011. The evolution of robots in general and as platforms to augment surgical practice is an intriguing story that spans cultures, continents and centuries. A timeline from Yan Shi (1023-957 bc), Archytas of Tarentum (400 bc), Aristotle (322 bc), Heron of Alexandria (10-70 ad), Leonardo da Vinci (1495), the Industrial Revolution (1790), 'telepresence' (1950) and to the da Vinci(®) Surgical System (1999), shows the incredible depth of history and development that underpins the modern surgical robot we use to treat our patients. Robot-assisted surgery is now well-established in Urology and although not currently regarded as a 'gold standard' approach for any urological procedure, it is being increasingly used for index operations of the prostate, kidney and bladder. We perceive that robotic evolution will continue infinitely, securing the place of robots in the history of Urological surgery. Herein, we detail the history of robots in general, in surgery and in Urology, highlighting the current place of robot-assisted surgery in radical prostatectomy, partial nephrectomy, pyeloplasty and radical cystectomy.

[Baltasar Llopis Mínguez (1934-1990). A pioneer in research on bladder cancer and introduction of computing in Urology]. / Baltasar Llopis Mínguez (1934-1990). Pionero en la investigación del cáncer vesical y en la introducción de la informática en Urología.

OBJECTIVE: To recall the figure of a great Valencian urologist, to emphasize his great personality and humanity, and to draw particular attention to his significant contribution to the study of prognostic factors in urology and estimation of individual oncological risk, as well as to introduction of computing in urology. METHOD: His work, the testimony of colleagues who treated him, and data obtained from his close relatives, as well as our own personal knowledge, are reviewed. Result. Baltasar Llopis was born in Valencia, and obtained his degree and doctorate in Medicine at the Valencia University. He specialized in urology with Dr. Tramoyeres Cases, for whom he acted as assistant surgeon and with whom he shared work at La Fe Hospital, where he carried out his complete urological activity, since its inception. Dr. Llopis opted for oncological research, with a special focus on urothelial tumors. He pioneered diagnosis of these tumors using tumor markers and the study of prognostic factors to assess the individual risk of relapse and to implement a specific chemotherapeutic treatment, which he introduced in clinical practice at La Fe Hospital. He thus demonstrated the two essential components of his personality, his investigative and human sides. CONCLUSION: A multi-faceted person with great skills and intelligence, Dr. Llopis eagerly devoted himself to research aimed at understanding the biological behavior of cancer, particularly urothelial tumors. In the early 80s he pioneered worldwide the development of specific markers, estimations of individual oncological risk, and prognostic factors useful for planning treatment. He was 20 years ahead of the era of predictive nomograms and their clinical INTRODUCTION: In addition to being a forerunner of computing applications in Urology, he designed a database for registration of superficial bladder tumors, which allowed him to perform statistical and multivariate analyses using multiple regression models to predict the risk of relapse.

Errors and difficulties in the diagnosis of bladder cancer in the 19th century: about an uncommon case reported by Professor Claude-François Lallemand (1790-1854).

Before the official foundation of the specialty of urology in 1870 from Félix Guyon, its exercise was in the hands of general surgeons. One of the most distinguished surgeons interested in urology was Claude-François Lallemand, Professor of Surgery in Montpellier. Despite his enormous experience in the diagnosis and treatment of urinary tract diseases as well as the invention of various surgical instruments for the lower urinary system, Lallemand, however, did not avoid serious diagnostic errors because of the lack of diagnostic tools. Characteristically in the present article we present a serious diagnostic mistake in a patient with bladder cancer with fatal outcome.