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.

A 25 year perspective on the evolution and advances in an understanding of the biology, evaluation and treatment of kidney cancer.

The diagnosis, evaluation and management of patients with renal cell carcinoma has transformed in the 21st century. Utilizing biological discoveries and technological advances, the field has moved from blunt surgical and largely ineffective medical treatments, to nuanced and fine-tuned approaches based on biology, extent of disease and patient preferences. In this review we will summarize the last 25 years of progress in kidney cancer.

Five decades of urologic pathology: the accelerating expansion of knowledge in renal cell neoplasia.

Those who are knowledgeable in cosmology inform us that the expansion of the universe is such that the velocity at which a distant galaxy is receding from the observer is continually increasing with time. We humbly paraphrase that as "The bigger the universe gets, the faster it gets bigger." This is an interesting analogy for the expansion of knowledge in the field of renal tumor pathology over the past 30 to 50 years. It is clear that a multitude of dedicated investigators have devoted incalculable amounts of time and effort to the pursuit of knowledge about renal epithelial neoplasms. As a consequence of the contributions of numerous investigators over many decades, the most recent World Health Organization classification of renal neoplasms includes about 50 well defined and distinctive renal tumors, as well as various miscellaneous and metastatic tumors. In addition, a number of emerging or provisional new entities are under active investigation and may be included in future classifications. In this review, we will focus on a number of these tumors, tracing as accurately as we can the origins of their discovery, relating relevant additions to the overall knowledge base surrounding them, and in some instances addressing changes in nomenclature.

Primary renal lymphoma: A population-based analysis using the SEER program (1973-2015).

OBJECTIVE: Primary renal lymphoma (PRL) is defined as a non-Hodgkin lymphoma (NHL) restricted to kidneys without extensive nodal disease. The literature on epidemiology and outcome in PRL is limited to case reports and small case series. METHODS: We utilized Surveillance, Epidemiology, and End Result database (1984-2015) to study the demographic, clinical, and pathological characteristics of PRL. We conducted analysis to assess factors associated with overall survival (OS) and cause-specific survival (CSS). RESULTS: A total of 599 (0.17% of all NHL) patients were eligible for the study. The age-adjusted incidence was 0.035/100,000 population and is increasing. The median age was 72 years, and most of the patients were Caucasians and were males. Most of the patients had unilateral tumors, and diffuse large B-cell lymphoma (DLBCL) was the most common histologic type. The median OS was 112 months, while median CSS was not reached. Age ≥ 60 years was the strongest independent risk factor for worse OS and CSS, while non-DLBCL histology was associated with better OS and CSS. DISCUSSION: Primary renal lymphoma is a rare lymphoma with increasing incidence in more recent years. In this study, we describe demographic, clinical, and pathological characteristics of PRL and factors affecting survival among these patients.

Ochratoxin A: 50 Years of Research.

Since ochratoxin A (OTA) was discovered, it has been ubiquitous as a natural contaminant of moldy food and feed. The multiple toxic effects of OTA are a real threat for human beings and animal health. For example, OTA can cause porcine nephropathy but can also damage poultries. Humans exposed to OTA can develop (notably by inhalation in the development of acute renal failure within 24 h) a range of chronic disorders such as upper urothelial carcinoma. OTA plays the main role in the pathogenesis of some renal diseases including Balkan endemic nephropathy, kidney tumors occurring in certain endemic regions of the Balkan Peninsula, and chronic interstitial nephropathy occurring in Northern African countries and likely in other parts of the world. OTA leads to DNA adduct formation, which is known for its genotoxicity and carcinogenicity. The present article discusses how renal carcinogenicity and nephrotoxicity cause both oxidative stress and direct genotoxicity. Careful analyses of the data show that OTA carcinogenic effects are due to combined direct and indirect mechanisms (e.g., genotoxicity, oxidative stress, epigenetic factors). Altogether this provides strong evidence that OTA carcinogenicity can also occur in humans.

Relation between kidney cancer and Soil leads in Isfahan Province, Iran between 2007 and 2009.

INTRODUCTION: The present study sets out to investigate the correlation between kidney cancer and the concentration of lead in Isfahan Province, Iran. All cases of kidney cancer recorded between 2007 and 2009 were utilized. In order to calculate the lead concentrations associated with the poll frequency of kidney cancer, the concentrations of lead in province (case study) were examined. MATERIALS AND METHODS: In this study, the first challenge was to collect some relevant information. In this connection, the authors managed to gain access to data concerning kidney cancer in Isfahan province. The data, which had been collected by Isfahan Province Health Centre, provided information from 2007-2009. Besides, Map of Lead Distribution in soil, which had been drawn by the Mineral Exploration Organization. Using GIS (Geographic Information System Software such Arc Gis), the researchers drew the map of the spatial distribution of kidney cancer in the province. In this research, we applied target detection algorithms on MODIS images to detect leads contamination in soil. RESULTS: The results indicated a significantly positive correlation approximately 88% between kidney cancer and the distribution of lead in soil. CONCLUSIONS: The findings of the current study emphasized not only the importance of preventing exposure to lead but also the importance of controlling lead-producing industries.

The History of Multimodal Treatment of Wilms' Tumor.

Multimodal therapy-surgery, radiation therapy, and chemotherapy-the foundation of modern cancer treatment, has led to dramatic improvements in survival. How the three disciplines coalesced to conquer Wilms' tumor is a compelling story that includes two of history's greatest discoveries, X-rays and antibiotics. By the mid-20th century both fields had matured to where dedicated clinicians and creative scientists could apply them to Wilms' tumor and achieve successive improvements in survival. William Ladd was able to achieve a zero operative mortality by 1940, but was left with a 32 per cent survival with surgery alone. Robert Gross and Edwin Neuhauser combined surgery and radiotherapy and achieve 47 per cent survival rate in 1950. Sidney Farber and his colleagues added an antibiotic, dactinomycin, to the treatment regimen and reached 80 per cent survival rate in 1966. The National Wilms' Tumor Study, organized in 1968, was a multidisciplinary effort of surgeons, radiotherapists, and pediatric oncologists across the country. By the 1990s, the National Wilms' Tumor Study achieved survival rates above 95 per cent while minimizing long-term effects through shortening courses of chemotherapy and radiation. The story of Wilms' tumor serves as a paragon for all types of cancer, in both children and adults.

Sarcoma sinovial renal primario: presentación de un caso con estudio molecular / Synovial sarcoma of the kidney: a case report with molecular analysis

El sarcoma sinovial (SS) renal fue descrito por primera vez por Argani et al. en el año 2000. Presentamos un caso de SS renal monofásico de grado intermedio. Se trata de un varón de 42 años que presentaba un tumor renal sólido-quístico de 6 cm bien delimitado, con un nódulo sólido de 1,5 cm. Se realizó nefrectomía parcial. El tumor se caracterizaba por células fusiformes monomorfas y quistes revestidos por células epiteliales en tachuela. Se observó infiltración focal de la grasa perirrenal que rodeaba el nódulo sólido. Las células fusocelulares expresaban CD99, BCL2, EMA y SMA, y eran negativas para S-100, CD34, receptores de estrógenos y progesterona, desmina y WT1. Las células en tachuela expresaban CD10, PAX8, PAX2, EMA, CKAE1-AE3, CK7 y CK19, confirmando que eran epitelio renal atrapado. Se realizó FISH que demostró la translocación t(X;18), específica del SS. El paciente ha recibido 4 ciclos de quimioterapia adyuvante y continúa libre de recurrencia o metástasis 9 meses tras la intervención (AU)

Synovial sarcoma (SS) of the kidney was first reported by Argani et al. in 2000. We report a case of a renal monophasic SS of intermediate grade in 42-year-old man with a solid-cystic, well-circumscribed, 6 cm renal mass containing a solid nodule of 1.5 cm. Partial nephrectomy was performed. The tumour was characterized by monomorphic spindle cells and cysts lined by trapped «hobnail» epithelial cells. Sections showed focal infiltration of perinephric fat surrounding the solid nodule. Spindle cells expressed CD99, BCL2, EMA and SMA and were negative for S-100, CD34, oestrogen and progesterone receptors, desmin and WT1. The 'hobnail epithelium' expressed CD10, PAX8, PAX2, EMA, CKAE1-AE3, CK7 and CK19, confirming its non-neoplastic and renal identity. FISH was performed and t(X;18) translocation, specific of SS, was demonstrated. The patient received 4 cycles of adjuvant chemotherapy and is alive without evidence of disease 9 months after surgery (AU)

[Sunitinib: 10 years after approval for the therapy of metastatic renal cell carcinoma].

Sunitinib is one of first targeted agents and tyrosine kinase inhibitors of vascular endothelial growth factor receptor (VEGFR) that approved for therapy of metastatic renal cell carcinoma. -Moreover it is among the first compounds in oncology registered after Phase 2 of clinical trials. Sunitinib was used in the United States since January 2006. For the past 10 years a wide experience of sunitinib administration has been accumulated both in practice and in clinical trials. This review summarizes the results of sunitinib studies.

Max Wilms and his tumor.

The most common cancer of the kidney in infants and children is named for Max Wilms, a German surgeon. How did this eponym come about? There were excellent reviews of this lesion before Wilms, a second year surgical assistant, published "Die Mischgeschwulste Der Niere" or The Mixed Tumors of the Kidney in 1899. At thirty two years of age, he demonstrated a masterful knowledge of pathology and embryology. Wilms' career was cut short when he became septic after operating on a prisoner of war during WWI. The survival rate for children with Wilms tumor was dismal until William Ladd, at the Boston Children's hospital introduced rational surgical treatment. By mid century, Robert Gross achieved a 47% survival rate with surgery combined with postoperative radiation. Sydney Farber treated Wilms tumors with Actinomycin-d and opened the door to cancer chemotherapy. With protocols developed by the National Wilms Tumor Study Group, the survival rate of children with Wilms tumors reached 90% by the end of the twentieth century.

Development of renal cell carcinoma (RCC) diagnostics and impact on prognosis.

OBJECTIVE: To evaluate imaging methods and prognoses between small renal cell carcinomas (RCCs) and larger tumours according to the era of diagnostics. PATIENTS AND METHODS: In all, 784 consecutive patients diagnosed with RCC between 1964 and 1997 at the Pirkanmaa Hospital District in Finland were included. Patients were divided into two groups: tumours of ≤3.0 and >3.0 cm in diameter. Prognosis was analysed according to the era of diagnostics: (i) pre-computed tomography (CT) and pre-ultrasound (US), (ii) US era and (iii) CT era. RESULTS: Small tumours became more common: in the pre-CT and pre-US era, only 4.4% of tumours were small; however, in the CT era 16% were small tumours. More diagnostic methods were used in studying small tumours. CT proved to be the most reliable method, although it was actually better at diagnosing large tumours. Relapses occurred less frequently among patients with small tumours; more than half of the tumours that developed distant metastases (16.0%) already evinced them at the time of diagnosis. There were no relapses after 14 years of follow-up among small tumours, whereas large tumours relapsed within that time. RCC was the cause of death in 14.9% of patients with small tumours vs 50.7% with large tumours. The best prognosis was among patients with small tumours diagnosed with CT. CONCLUSION: Among patients with small tumours, prognosis has improved along with better diagnostics, although some showed relapse during a surveillance period of up to 14 years.

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.

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.

Changes in the natural history of renal cancer: comparison of Estonian data from the periods 1986-1988 and 1996-1998.

To explain considerable increase in survival of renal cancer patients in Estonia during last decades, we compared the stage distribution, diagnostic and treatment methods for the patient groups diagnosed in the periods 1986-1988 and 1996-1998. A significant difference in stage distribution was detected with an increase for stages I-II and a decrease for stages III-IV in 1996-1998. There was a shift in primary diagnostic methods from intravenous urography and angiography to ultrasonography and computed tomography. In multivariate analysis the independent prognostic factors for overall survival were age, stage, and operation status. In conclusion, the increase in the survival of renal cancer patients has been due to the larger number of cases with the earlier stage, which is associated with the application of ultrasonography and computed tomography. Another factor for better survival was the higher operation rate among patients with stage IV disease, a possible factor was the change in operation techniques.