Long-Term Oncological and Functional Outcomes After Robot-Assisted Partial Nephrectomy for Clinically Localized Renal Cell Carcinoma.

BACKGROUND: To evaluate long-term oncological and renal function outcomes in patients treated with robot-assisted partial nephrectomy (RAPN) for renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients undergoing RAPN for clinically localized RCC between January 2014 and December 2019 at a tertiary robotic reference center were evaluated. Clinical course, pathologic characteristics, and long-term outcomes were obtained from our institutional review board-approved RCC database. RESULTS: A total of 234 patients were available for analysis. Median follow-up was 46 months (10.8-97.8 months), with 77 patients (32.9%) having at least 5-years of follow-up. Pathology revealed clear-cell RCC in 67.5% (n = 158). Among unfavorable factors, nuclear grades 3 or 4 were found in 67 (29.4%), lymphovascular invasion in 10 (4.3%), positive surgical margins in 22 (9.4%), necrosis in 21 (9%), and sarcomatoid pattern in 2 patients (0.9%). At 12 months, mean serum creatinine was 1.04 mg/dL and 12.9% of patients experienced upstaging in chronic kidney disease. Overall recurrence-free survival at 5-years was 97.8%. There were five local (2.1%) and two distant (0.9%) recurrences, none of them resulting in cancer-specific death. Median time to recurrence was 20 months (11-64 months). Warm ischemia time [hazard ratio (HR) = 1.14, p = 0.034] and sarcomatoid pattern (HR = 124.57, p = 0.001) were the only variables associated with local relapse. CONCLUSIONS: Data from this large cohort demonstrate that patients undergoing RAPN have a low incidence of local and distant relapse, resulting in excellent long-term survival while preserving stable renal function in most patients.

[Prostate cancer mortality trends in Chile (1955-2019)]. / Mortalidad por cáncer de próstata en Chile: tendencias del período 1955-2019.

BACKGROUND: Prostate cancer is the tumor with the highest incidence among men and one of Chile's leading causes of death. AIM: To analyze temporal trends in prostate cancer mortality in Chile. MATERIAL AND METHODS: Mortality rates in Chile for the period between 1955 and 2019 were calculated. The number of deaths was obtained from the national demographic yearbooks and the Ministery of Health mortality registries. Population estimates from the demographic center of the Economic Commission for Latin America and the Caribbean of the United Nations were used. Chilean census population of 2017 was used as reference to calculate adjusted rates. Trends were analyzed using a join point regression. RESULTS: Crude mortality rates of prostatic cancer increased between 1995 and 2012 in three different phases, namely between 1955 and 1989 with a 2.7% annual increase, between 1989 and 1996 at a 6.8% annual rate, and between 1996 to 2012 with a 2.8% annual increase. From 2012 the rate remained stable. Adjusted mortality rates increased slowly at a 1.7% rate from 1955 to 1993, accelerating between 1993 and 1996, when they increased 12.1% per year. From 1996 onwards there was a significant decrease in mortality at a 1.2% annual rate. This decrease was significant and observed within all age groups but more importantly at older ages. CONCLUSIONS: Prostate cancer mortality in Chile has decreased significantly during the last two decades, like that observed in developed nations.

A prospective randomized study comparing bipolar plasmakinetic transurethral resection of the prostate and monopolar transurethral resection of the prostate for the treatment of Benign Prostatic Hyperplasia: efficacy, sexual function, Quality of Life, and complications.

OBJECTIVE: To generate high-quality data comparing the clinical efficacy and safety profile between monopolar transurethral resection of the prostate (M-TURP) and bipolar plasmakinetic resection of the prostate (PK-TURP) for benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Prospective, randomized, single-blinded study conducted in a tertiary-care public institution (Dec/2014-Aug/2016). INCLUSION CRITERIA: prostate of <80g in patients with drug-refractory lower urinary tract symptoms (LUTS), complications derived from BPH, or both. EXCLUSION CRITERIA: a history of pelvic surgery/radiotherapy, neurogenic bladder dysfunction or documented/suspected prostate carcinoma. Treatment efficacy evaluated at 1, 3, 6 and 12 months. Efficacy outcomes: international prostate symptom score (IPSS), quality-of-life (QoL) score, international index of erectile function-5 (IIEF-5), maximum urinary flow rate (Qmax), postvoid residual urine (PVRU) volume, and prostate volume (PV). Complications and sequelae also assessed. Comparisons performed with parametric/non-parametric tests. RESULTS: Out of the 100 hundred patients, 84 qualified for the analysis (45 M-TURP/39 PK-TURP). No significant differences found in baseline characteristics or operative data, except for a longer operative time in PK-TURP (MD:7.9min; 95%CI:0.13-15.74; p=0.04). No differences found in IPSS, Qmax or PVRU volume. QoL score at 12 months was higher in PK-TURP (MD:0,9points; 95%CI:0.18-1.64; p=0.01). No differences in sexual function, PV, complications or sequelae were found. This study is "rigorous" (Jadad-scale) and has a low risk of bias (Cochrane-Handbook). CONCLUSIONS: Based on this controlled trial, there is not significant variation in effectiveness and safety between M-TURP and PK-TURP for the treatment of BPH. The small difference in QoL between PK-TURP and M-TURP at the one-year follow-up is not perceivable by the patients and, therefore, not clinically relevant.

Epidemiology, prevention, screening, diagnosis, and evaluation: update of the ICUD-SIU joint consultation on bladder cancer.

PURPOSE: To update current recommendations on prevention, screening, diagnosis, and evaluation of bladder cancer (BC) based on a thorough assessment of the most recent literature on these topics. METHODS: A non-systematic review was performed, including articles until June 2017. A variety of original articles, reviews, and editorials were selected according to their epidemiologic, demographic, and clinical relevance. Assessment of the level of evidence and grade of recommendations was performed according to the International Consultation on Urological Diseases grading system. RESULTS: BC is the ninth most common cancer worldwide with 430,000 new cases in 2012. Currently, approximately 165,000 people die from the disease annually. Absolute incidence and prevalence of BC are expected to rise significantly during the next decades because of population ageing. Tobacco smoking is still the main risk factor, accounting for about 50% of cases. Smoking cessation is, therefore, the most relevant recommendation in terms of prevention, as the risk of developing BC drops almost 40% within 5 years of cessation. BC screening is not recommended for the general population. BC diagnosis remains mainly based on cystoscopy, but development of new endoscopic and imaging technologies may rapidly change the diagnosis algorithm. The same applies for local, regional, and distant staging modalities. CONCLUSIONS: A thorough understanding of epidemiology, risk factors, early detection strategies, diagnosis, and evaluation is essential for correct, evidence-based management of BC patients. Recent developments in endoscopic techniques and imaging raise the hope for providing better risk-adopted approaches and thereby improving clinical outcomes.

Upper Urinary Tract Carcinoma In Situ: Current Knowledge, Future Direction.

PURPOSE: Carcinoma in situ of the urinary tract is a high grade form of nonmuscle invasive urothelial cancer. Our understanding of this entity in the upper tract is poor, and case management remains challenging due to knowledge gaps regarding the definition, diagnosis, treatment options and followup of the disease. We reviewed the available literature for similarities and differences between bladder and upper tract carcinoma in situ, and herein summarize the best available data. MATERIALS AND METHODS: We reviewed PubMed® and MEDLINE™ databases from January 1976 through September 2014. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement was used to screen publications. All authors participated in the development of a consensus definition of disease. RESULTS: A total of 61 publications were found suitable for this review. All studies were retrospective. Compared to bladder carcinoma in situ, upper tract carcinoma in situ appears to have lower progression rates and improved survival. All available studies demonstrate topical therapy to be effective in treating upper tract carcinoma in situ, with decreased recurrence rates compared to bladder carcinoma in situ. Highlighted areas of current knowledge gaps include variable definitions of disease, methods of drug delivery and ideal treatment course. Improving methods for detection may allow easier diagnosis and more effective treatment. CONCLUSIONS: Based on the available data, organ preserving therapy with topical agents is an alternative to radical surgery in select patients with upper tract carcinoma in situ, although this method has not been evaluated in prospective trials. A paradigm shift regarding detection and treatment is needed to improve care and allow better renal preservation. A consensus definition of the disease is offered, and several areas of major knowledge gaps and opportunities for future research are identified.

Clinical risk stratification in patients with surgically resectable micropapillary bladder cancer.

OBJECTIVE: To analyse survival in patients with clinically localised, surgically resectable micropapillary bladder cancer (MPBC) undergoing radical cystectomy (RC) with and without neoadjuvant chemotherapy (NAC) and develop risk strata based on outcome data. PATIENTS AND METHODS: A review of our database identified 103 patients with surgically resectable (≤cT4acN0 cM0) MPBC who underwent RC. Survival estimates were calculated using Kaplan-Meier method and compared using log-rank tests. Classification and regression tree (CART) analysis was performed to identify risk groups for survival. RESULTS: For the entire cohort, estimated 5-year overall survival and disease-specific survival (DSS) rates were 52% and 58%, respectively. CART analysis identified three risk subgroups: low-risk: cT1, no hydronephrosis; high-risk: ≥cT2, no hydronephrosis; and highest-risk: cTany with tumour-associated hydronephrosis. The 5-year DSS for the low-, high-, and highest-risk groups were 92%, 51%, and 17%, respectively (P < 0.001). Patients down-staged at RC

Epidemiology, diagnosis, preoperative evaluation and prognostic assessment of upper-tract urothelial carcinoma (UTUC).

PURPOSE: Upper-tract urothelial carcinoma (UTUC) is a relatively uncommon disease with limited available evidence on specific topics. The purpose of this article was to review the previous literature to summarize the current knowledge about UTUC epidemiology, diagnosis, preoperative evaluation and prognostic assessment. METHODS: Using MEDLINE, a non-systematic review was performed including articles between January 2000 and February 2016. English language original articles, reviews and editorials were selected based on their clinical relevance. RESULTS: UTUC accounts for 5-10 % of all urothelial cancers, with an increasing incidence. UTUC and bladder cancer share some common risk factors, even if they are two different entities regarding practical, biological and clinical characteristics. Aristolochic acid plays an important role in UTUC pathogenesis in certain regions. It is further estimated that approximately 10 % of UTUC are part of the hereditary non-polyposis colorectal cancer spectrum disease. UTUC diagnosis remains mainly based on imaging and endoscopy, but development of new technologies is rapidly changing the diagnosis algorithm. To help the decision-making process regarding surgical treatment, extent of lymphadenectomy and selection of neoadjuvant systemic therapies, predictive tools based on preoperative patient and tumor characteristics have been developed. CONCLUSIONS: Awareness regarding epidemiology, diagnosis, preoperative evaluation and prognostic assessment changes is essential to correctly diagnose and manage UTUC patients, thereby potentially improving their outcomes.

Clinical outcomes of cT1 micropapillary bladder cancer.

PURPOSE: While many urologists recommend radical cystectomy for micropapillary bladder cancer invading the lamina propria (cT1), contradictory small reports exist on the efficacy of conservative management with intravesical bacillus Calmette-Guérin for this disease. We report our updated experience in what to our knowledge is the largest series of patients with cT1 micropapillary bladder cancer. MATERIALS AND METHODS: An institutional review board approved review of our cancer database identified 283 patients with micropapillary bladder cancer, including 72 staged with cT1N0M0 disease at diagnosis and initiation of therapy. Survival analysis was performed using the Kaplan-Meier estimator and compared using the log rank test. RESULTS: In this cohort of 72 patients 40 received primary intravesical bacillus Calmette-Guérin and 26 underwent up-front radical cystectomy. Of patients who received bacillus Calmette-Guérin 75%, 45% and 35% experienced disease recurrence, progression and lymph node metastasis, respectively. Patients treated with up-front cystectomy had improved survival compared to patients treated with primary bacillus Calmette-Guérin (5-year disease specific survival 100% vs 60% p = 0.006) and patients who underwent delayed cystectomy after recurrence (5-year disease specific survival 62%, p = 0.015). Prognosis was especially poor in patients who waited for progression before undergoing radical cystectomy with an estimated 5-year disease specific survival of only 24% and a median survival of 35 months. In patients treated with up-front cystectomy pathological up-staging was found in 27%, including 20% with lymph node metastasis. CONCLUSIONS: While certain patients with T1 micropapillary bladder cancer may respond to intravesical bacillus Calmette-Guérin, survival is improved in those who undergo early radical cystectomy. Further molecular studies are needed to identify subsets of patients in whom the bladder can be safely spared.

[Advances in the treatment of castration-resistant prostate cancer: emphasis in new hormonal therapies]. / Avances en el tratamiento de cáncer de próstata resistente a la castración: énfasis en nuevas terapias hormonales.

Prostate cancer represents the second cancer-related cause of death in North American and Chilean men. The main treatment for incurable stages of disease is surgical or pharmacological castration. However, with time and despite the addition of anti-androgens, the disease progresses to a clinical state that has been commonly referred to as “hormone refractory”. In recent years, the concept of hormone refractoriness has been challenged and replaced by “castration resistance”, acknowledging that further and optimal hormonal manipulation can be attained, beyond achieving testosterone levels at castration range. The purpose of this review is to summarize the recent therapeutic breakthroughs in the management of metastatic castrate resistant prostate cancer (mCRPC), with greater emphasis in the newer hormonal therapy agents such as Abiraterone and Enzalutamide. Future combination and sequential treatment strategies are contextualized in the current era of personalized cancer medicine and genomic characterization of prostate cancer.

γ-H2AX level in peripheral blood lymphocytes as a risk predictor for bladder cancer.

Identification of susceptibility to double-strand breaks (DSBs) may provide valuable information about individual bladder cancer (BC) risk. The formation of γ-H2AX foci is a highly sensitive marker for DNA DSBs induction. We assessed whether levels of γ-H2AX in peripheral blood lymphocytes (PBL) obtained after stimulation by ionizing radiation (IR) are able to predict BC risk. Patients were enrolled from an ongoing BC case-control study. Baseline- and IR-induced H2AX phosphorylation was assessed in PBL from 174 newly diagnosed and untreated BC patients and from 174 matched control subjects by a novel, image-based, high-throughput phenotypic assay. The ratio of γ-H2AX level of IR-treated cells to that of non-treated cells (baseline) was used as the parameter to assess the sensitivity to the mutagen. The mean γ-H2AX ratios were significantly higher for cases than for controls (1.43±0.14 versus 1.35±0.12; P = 8.45×10(-8)). This trend was irrespective of age, sex and smoking status. The risk estimates of BC for induced DSBs by tertile distributions in controls showed also a significant trend for increased risk at the highest tertile for the whole cohort (odds ratio = 5.16; 95% confidence interval = 2.69, 9.89; P = 7.78 × 10(-7)) as well as for each category. Our findings suggest that a higher susceptibility to induction of DSBs as measured by the γ-H2AX assay is significantly associated with an increased risk for BC. This might help to identify individuals at high risk for this cancer, adding new perspectives to established epidemiological and genetic risk factors. Further research of the role of γ-H2AX in biological processes of BC is warranted.

Long-term impact of arsenic in drinking water on bladder cancer health care and mortality rates 20 years after end of exposure.

PURPOSE: In this study we assessed bladder cancer health care and mortality trends in recent decades in a well studied arsenic exposed area in Northern Chile. MATERIALS AND METHODS: Arsenic levels in the affected region were obtained for the last 60 years, and correlated with bladder cancer hospital discharge and mortality rates in recent decades. RESULTS: Bladder cancer hospital discharge rates were significantly higher in the affected region (peak RR 3.6, 95% CI 3.0-4.7). Mortality rates for bladder cancer showed a trend of increase during the period analyzed, reaching peak mortality rates of 28.4 per 100,000 for men and 18.7 per 100,000 for women in the last 10 years. Poisson regression models showed an increased mortality risk in the studied region compared to the rest of the country until the present for men (IRR 5.3, 95% CI 4.8-5.8) and women (IRR 7.8, 95% CI 7.0-8.7). Mean age at cancer specific death was significantly lower in the exposed region (69.6 years, 95% CI 68.4-70.7 vs 73.7 years, 95% CI 73.3-74.2, p <0.01). CONCLUSIONS: Exposure to arsenic is related to a significant need for bladder cancer health care and to high mortality rates even 20 years after having controlled arsenic levels in drinking water. Affected individuals should be aware of the significant impact of this ecological factor. Further research is required to identify strategies for the management of bladder cancer in arsenic exposed populations.

Postoperative morbidity of tubeless versus conventional percutaneous nephrolithotomy: a prospective comparative study.

Percutaneous Nephrolithotomy (PNL) is an established technique for the treatment of renal calculi. Some reports have challenged the need for a nephrostomy tube at the end of the procedure, arguing that it accounts for a longer hospital stay and increased postoperative pain. During the last years, several series have addressed the feasibility and safety of tubeless PNL, where a double-J ureteral stent is left in place after the end of intervention instead of a nephrostomy tube. The aim of our study was to compare conventional versus tubeless PNL in terms of postoperative morbidity. Eighty-five patients who underwent PNL at a single center met the inclusion criteria (complete intraoperative stone clearance, no evidence of active intraoperative bleeding, single percutaneous access, and operative time shorter than 2 h) and were randomized at the end of the procedure to have placed either a nephrostomy tube (group 1) or a double-J ureteral stent (group 2). Outcomes assessed were postoperative pain, bleeding complications, leakage complications, and length of hospital stay. The patients in the tubeless group had a shorter hospital stay (3.7 vs. 5.8 days; P < 0.001), and less postoperative pain at postoperative days 2 and 3 (P < 0.001). No significant difference in bleeding or leakage complications was observed. This study supports the feasibility and safety of tubeless PNL in a selected group of the patients, suggesting some intraoperative criteria to be considered when performing it. However, further controlled studies will have to determine its impact on stone-free rates prior to be considered the standard technique in these selected cases.

Arsenic exposure is associated with significant upper tract urothelial carcinoma health care needs and elevated mortality rates.

PURPOSE: The aim of the study was to assess upper tract urothelial carcinoma (UTUC) health care needs and specific mortality rates in an arsenic-exposed region in Northern Chile and compare them to those of the rest of the country. MATERIAL AND METHODS: Arsenic levels of drinking water were correlated with UTUC hospital discharges and cancer-specific mortality rates. Mortality and hospital admission rate ratios were estimated using a Poisson regression model. RESULTS: There were 257 UTUC-specific deaths in Chile between 1990 and 2016; 81 (34%) of them occurred in Antofagasta, where only 3.5% of the population lives. The peak mortality rate observed in Antofagasta was 2.15/100,000 compared to 0.07/100,000 in the rest of the country. Mortality in the exposed region was significantly higher when compared to the rest of the country (MRR 17.6; 95%CI: 13.5-22.9). The same trend was observed for UTUC hospital discharges (RR 14.8; 95%CI: 11.5-19.1). CONCLUSION: Even stronger than for bladder cancer, exposure to arsenic is related to a significant need for UTUC health care and high mortality rates, even 25 years after having controlled arsenic levels in drinking-water. Awareness of this ecologic factor in these affected regions is therefore mandatory.

Postadmixture Selection on Chileans Targets Haplotype Involved in Pigmentation, Thermogenesis and Immune Defense against Pathogens.

Detection of positive selection signatures in populations around the world is helping to uncover recent human evolutionary history as well as the genetic basis of diseases. Most human evolutionary genomic studies have been performed in European, African, and Asian populations. However, populations with Native American ancestry have been largely underrepresented. Here, we used a genome-wide local ancestry enrichment approach complemented with neutral simulations to identify postadmixture adaptations underwent by admixed Chileans through gene flow from Europeans into local Native Americans. The top significant hits (P = 2.4×10-7) are variants in a region on chromosome 12 comprising multiple regulatory elements. This region includes rs12821256, which regulates the expression of KITLG, a well-known gene involved in lighter hair and skin pigmentation in Europeans as well as in thermogenesis. Another variant from that region is associated with the long noncoding RNA RP11-13A1.1, which has been specifically involved in the innate immune response against infectious pathogens. Our results suggest that these genes were relevant for adaptation in Chileans following the Columbian exchange.

What Is the Significance of Variant Histology in Urothelial Carcinoma?

CONTEXT: Urothelial carcinoma can exhibit a wide range of variant morphologies. Many variants present diagnostic challenges and carry clinical implications that inform prognosis and treatment decisions. OBJECTIVE: To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma. EVIDENCE ACQUISITION: A PubMed/MEDLINE-based literature search was conducted using the key terms "urothelial carcinoma", "variant histology", "nested", "micropapillary", "microcystic", "sarcomatoid", "squamous differentiation", "glandular differentiation", "clear cell", "plasmacytoid", "lymphoepithelioma-like carcinoma", "squamous cell carcinoma", "small cell carcinoma", "adenocarcinoma", "radiotherapy", "neoadjuvant chemotherapy", and "adjuvant chemotherapy". EVIDENCE SYNTHESIS: The incidence of variant histology is increasing due to improved recognition. Nonetheless, diagnosis can pose challenges due to sampling limitations and interobserver variability. Although associated with advanced disease at presentation, survival outcomes for most variants do not differ significantly compared with pure urothelial carcinoma of the same stage. Controversy exists regarding optimal management due to the low quality of available evidence. For most cases, radical cystectomy with pelvic lymph node dissection (with neoadjuvant chemotherapy when appropriate) represents the standard of care. Small cell carcinoma and lymphoepithelioma-like carcinoma appear to be particularly chemosensitive. CONCLUSIONS: Accurate identification of variant histological subtypes is an important part of risk stratification, as these variants exhibit aggressive biological behaviour. Variant histology tumours are associated with advanced disease at presentation, which must be considered when counselling patients regarding survival outcomes. Optimal management remains to be defined but in most cases; neoadjuvant chemotherapy and radical cystectomy with pelvic lymph node dissection remains the mainstay of treatment. PATIENT SUMMARY: It is important to recognise histological variants of urothelial carcinoma as they indicate aggressive disease. When compared with patients with pure urothelial carcinoma of the same disease stage, survival does not appear to be significantly worse. In most cases, patients with invasive variant histology should be treated with neoadjuvant chemotherapy and radical cystectomy. Take Home Messages Accurate identification of variant histology is important as it exhibits aggressive biological behaviour and affects treatment. Although associated with advanced disease at presentation, with appropriate treatment, survival outcomes are not significantly different compared with pure urothelial carcinoma of the same stage.

Impact of arsenic exposure on clinicopathological characteristics of bladder cancer: A comparative study between patients from an arsenic-exposed region and nonexposed reference sites.

BACKGROUND: Beyond exposure to arsenic in drinking-water, there is few information about demographic and clinicopathological features of patients with bladder cancer living in arsenic-exposed regions. The aim of the study was to assess the impact of arsenic exposure on clinicopathological characteristics in patients with bladder cancer from a contaminated region compared to those of 2 reference areas. METHODS: Data of 285 patients with bladder cancer (83 with arsenic exposure from Antofagasta and 202 controls from 2 different sites in Santiago) were obtained through personal interviews and from review of medical records. Demographic, clinicopathological parameters, and information on relevant environmental risk factors were compared with parametric and nonparametric tests as needed. Multivariable analysis was performed to identify independent predictors for high grade and muscle-invasive disease (T2-4). RESULTS: We found no significant differences between groups regarding age at presentation (66.4 vs. 66.5 and 67.2 years; P = 0.69, for exposed vs. the 2 nonexposed groups, respectively) and female gender (28.9% vs. 29.8% and 26.2%; P = 0.84). Proportion of current smokers was significantly lower in the exposed population (10.7% vs. 38.6% and 26.9%; P < 0.001). There was a significantly higher proportion of locally advanced (10.8 vs. 1.8 and 0.7% T3/4; P = 0.002) and high-grade tumors (79.5% vs. 63.2% and 64.1%; P = 0.001) within arsenic-exposed patients. Arsenic exposure was the only significant predictor for the presence of high-grade tumors (adjusted OR: 5.10; 95%CI: 2.03-12.77) on multivariable analysis. CONCLUSIONS: Our study revealed relevant clinical differences in bladder cancer patients with a history of arsenic exposure as compared to nonexposed cases. The more aggressive phenotype associated to arsenic-related bladder cancer should be considered when designing efficient screening strategies for this high-risk population.

Impact of lymph node dissection on cancer specific survival in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy.

PURPOSE: We examined the impact of lymphadenectomy on the clinical outcomes of patients with upper tract urothelial cancer treated with radical nephroureterectomy. MATERIALS AND METHODS: Data were collected on 1,130 consecutive patients with pT1-4 upper tract urothelial cancer treated with radical nephroureterectomy at 13 centers worldwide. Patients were grouped according to nodal status (pN0 vs pNx vs pN+). The choice to perform lymphadenectomy was determined by the treating surgeon. All pathology slides were reevaluated by dedicated genitourinary pathologists. Univariable and multivariable Cox regression models measured the association of nodal status (pN0 vs pNx vs pN+) with cancer specific survival. RESULTS: Overall 412 patients (36.5%) had pN0 disease, 578 had pNx disease (51.1%) and 140 had pN+ disease (12.4%). The 5-year cancer specific survival estimate was lower in patients with pN+ compared to those with pNx disease (35% vs 69%, p <0.001), which in turn was lower than that in those with pN0 disease (69% vs 77%, p = 0.024). In the subgroup of patients with pT1 disease (345) cancer specific survival rates were not different in those with pN0 and pNx. In pT2-4 cases (813) cancer specific survival estimates were lowest in pN+, intermediate in pNx and highest in pN0 (33% vs 58% vs 70%, p = 0.017). When adjusted for the effects of standard clinicopathological features pN+ was an independent predictor of cancer specific survival (p <0.001). pNx was significantly associated with worse prognosis than pN0 in pT2-4 upper tract urothelial cancer only. CONCLUSIONS: Nodal status is a significant predictor of cancer specific survival in upper tract urothelial cancer. pNx is significantly associated with a worse prognosis than pN0 in pT2-4 tumors. Patients expected to have pT2-4 disease should undergo lymphadenectomy to improve staging and thereby help guide decision making regarding adjuvant chemotherapy.

Lymphangiogenesis occurs in upper tract urothelial carcinoma and correlates with lymphatic tumour dissemination and poor prognosis.

OBJECTIVE: To describe the lymphatic vessel density and to determine the functional and prognostic significance of tumoral lymphatic vessels in upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: The study included 65 patients who had a radical nephroureterectomy (RNU) for UTUC between 1997 and 2004. All pathological slides were re-evaluated by one reference pathologist and clinical data were reviewed. Lymphatic endothelial cells (LECs) were stained immunohistochemically using D2-40. The lymphatic vessel density (LVD) was described in representative intratumoral (ITLVD), peritumoral (PTLVD) and non-tumoral (NTLVD) areas. Random samples were selected for double-immunostaining with D2-40 and CD-34 (to distinguish blood and lymphatic vessels) and the proliferation marker Ki-67 to detect lymphangiogenesis. The primary outcome measures were disease-specific survival (DSS) and disease recurrence (urothelial and/or distant). RESULTS: The median (interquartile range) PTLVD was 4.0 (3.0-6.3), and significantly higher than that for ITLVD, of 0.3 (0-1.7) (P < 0.001), and NTLVD, of 3 (2.0-3.7) (P < 0.001). Both a higher ITLVD and PTLVD, the presence of lymphovascular invasion (LVI) (each P < 0.001) and a high tumour grade (P = 0.004) were associated with reduced DSS on univariate analysis. A higher PTLVD (P = 0.028) and the presence of LVI (P = 0.020) independently predicted reduced DSS on multivariate analysis. IT and PT lymphatic vessels showed proliferating LECs in all analysed samples. CONCLUSION: Lymphangiogenesis is present in UTUC, as shown by a significantly increased PTLVD and proliferating LECs. Our findings suggest functional relevance of PT lymphatic vessels during lymphatic tumour spread. PTLVD is a potential novel prognostic factor for DSS in UTUC, and further prospective studies will be needed to determine the effect of its routine evaluation on clinical outcomes of this malignancy.

The role of lymphangiogenesis in lymphatic tumour spread of urological cancers.

Metastases to regional lymph nodes are a common early event in many malignant diseases and have a poor prognosis, including in urological cancers. Molecular pathways contributing to lymphatic tumour dissemination and lymph node metastasis remain poorly understood. Besides the process of lymphovascular invasion (LVI), recent studies suggested de novo lymphatic vessel formation (i.e. lymphangiogenesis) as a potential mechanism of lymphatic tumour spread. Specific markers for lymphatic endothelium have recently been discovered, enabling basic morphological studies on lymphatic vessel density. There is a gap in the knowledge of the functional relationship between tumoral lymphatic vessels, LVI, lymphangiogenesis and the formation of lymph node metastases. The identification of lymph-specific growth factors (e.g. vascular endothelial growth factor-C and -D) as promoters of lymphatic metastasis has resulted in the interesting idea of targeting the pathways involved in lymphatic tumour progression. We summarize preliminary evidence on the role of lymphangiogenesis during the formation of lymphatic metastasis in the most common urological cancers.

Risk stratification of patients with nodal involvement in upper tract urothelial carcinoma: value of lymph-node density.

OBJECTIVE: To determine the risk factors associated with clinical outcome in patients with lymph node (LN)-positive urothelial carcinoma of the upper urinary tract (UTUC) treated with radical nephroureterectomy (RNU) and lymphadenectomy, focusing on the concept of LN density (LND). PATIENTS AND METHODS: Patients undergoing RNU with regional lymphadenectomy were identified through multi-institutional databases. All pathology slides were re-evaluated by genitourinary pathologists unaware of the clinical data. The exposure variable used was LND (continuously coded and that of all possible thresholds) with recurrence-free and disease-specific survival (DSS) serving as the outcome measures. RESULTS: Of 432 patients undergoing RNU with lymphadenectomy, 135 (31%) had LN metastases. Within a median follow-up of 4.1 years, 90 of the 135 patients with LN metastases (68%) had disease recurrence and 76 (58%) died from UTUC. The mean (sem) 5-year recurrence-free and DSS probabilities were 27 (4)% and 33 (5)%, respectively. The median (range) LND was 50 (3-100)%. The most informative threshold for LND in relation to outcome was 30%. In multivariable analyses that adjusted for the effects of tumour stage and grade, patients with a LND of > or =30% were at greater risk of both cancer recurrence, with 5-year rates of 25 (5)% vs 38 (8)% (hazard ratio 1.8, P = 0.021) and mortality, with 5-year rates of 30 (6)% vs 48 (9)% (1.7, P = 0.032) compared to those with a LND of <30%. Our results are primarily limited by a lack of standardization in the lymphadenectomy template. CONCLUSION: We evaluated the concept of LND for the first time in UTUC. LND provides additional prognostic information in patients with node-positive disease after RNU. The use of LND in clinical trials might provide an additional insight into the value of LN dissection in patients undergoing RNU.