The Predictive Value of C-reactive Protein for Prognosis in Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy: A Multi-institutional Study

Background

Few studies have discussed the prognostic impact of serum C-reactive protein (CRP) level in upper tract urothelial carcinoma (UTUC).

Objective

To investigate whether the perioperative level of CRP provides additional prognostic information following radical nephroureterectomy (RNU).

Design, setting, and participants

A total of 564 patients with UTUC from a retrospective multi-institutional cohort were included. The median follow-up was 32 mo.

Intervention

All patients underwent RNU without neoadjuvant chemotherapy, while 106 patients (18.8%) received adjuvant chemotherapy.

Outcome measurements and statistical analysis

Associations between perioperative CRP level and outcome were assessed using multivariate analysis. A serum CRP level >0.50 mg/dl was defined as elevated.

Results and limitations

Preoperative CRP (pre-CRP) level was elevated in 136 patients (24.1%). Multivariate analysis showed that pre-CRP elevation was an independent predictor of subsequent disease recurrence (hazard ratio [HR]: 1.47 for CRP 0.51–2.00; HR: 1.89 for CRP >2.00). Five-year recurrence-free survival rates were 69.2% in patients with pre-CRP levels ≤0.50 mg/dl, 54.3% in patients with pre-CRP levels between 0.51 and 2.00 mg/dl, and 35.4% in patients with pre-CRP levels >2.00 mg/dl (p < 0.001). Similar results were found in cancer-specific mortality, showing that pre-CRP elevation was an independent predictor of worse outcome (HR: 1.74 for CRP 0.51–2.00; HR: 2.31 for CRP >2.00). In a subgroup analysis of the elevated pre-CRP group, postoperative normalisation of CRP level was an independent predictor of better outcome. This study is limited by its retrospective nature as well as its heterogeneous group of patients and variable follow-up protocols resulting from the multi-institution design.

Conclusions

Serum CRP may become a possible biomarker in UTUC, suggesting that patients with an elevated pre-CRP level could be predicted to have subsequent disease recurrence and cancer-specific mortality, while postoperative normalisation of CRP level was an independent predictor for prognosis.     

The Effect of Tumor Location on Prognosis in Patients Treated with Radical Nephroureterectomy at Memorial Sloan-Kettering Cancer Center

Background

The prognostic impact of primary tumor location on outcomes for patients with upper-tract urothelial carcinoma (UTUC) is still contentious.

Objective

To test the association between tumor location and disease recurrence and cancer-specific survival (CSS) in patients treated with radical nephroureterectomy (RNU) for UTUC.

Design, setting, and participants

Prospectively collected data were retrospectively reviewed from 324 consecutive patients treated with RNU between 1995 and 2008 at a single tertiary referral center. Patients who had previous radical cystectomy, preoperative chemotherapy, previous contralateral UTUC, or metastatic disease at presentation were excluded. This left 253 patients for analysis. Tumor location was categorized as renal pelvis or ureter based on the location of the dominant tumor. Recurrences in the bladder only, in nonbladder sites, and in any site were analyzed.

Intervention

All patients were treated with RNU.

Measurements

Recurrence-free survival and CSS probabilities were estimated using Kaplan-Meier and Cox regression analyses.

Results and limitations

Median follow-up for survivors was 48 mo. The 5-yr recurrence-free probability (including bladder recurrence) and CSS estimates were 32% and 78%, respectively. On multivariable analysis, pathologic stage was the only predictor for disease recurrence (p = 0.01). Tumor location was not an independent predictor for recurrence (hazard ratio: 1.19; p = 0.3), and there was no difference in the probability of disease recurrence between ureteral and renal pelvic tumors (p = 0.18). On survival analysis, we also found no differences between ureteral and renal pelvic tumors on probability of CSS (p = 0.2). On multivariate analysis, pathologic stage (p < 0.0001) and nodal status (p = 0.01) were associated with worse CSS. This study is limited by its retrospective nature.

Conclusions

Our study did not show any differences in recurrence and CSS rates between patients with ureteral and renal pelvic tumors treated with RNU.     

Prognostic Role of Lymphovascular Invasion in Patients with Urothelial Carcinoma of the Upper Urinary Tract: An International Validation Study

Background

Lymphovascular invasion (LVI) identified following pathologic slide review has been shown to be an independent predictor of recurrence-free survival (RFS) and cancer-specific survival (CSS) in a multicenter series of patients undergoing radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). However, the validity of LVI in everyday practice, where pathologic re-review of all slides is uncommon, has not been assessed.

Objective

Our aim was to evaluate the prognostic role of LVI in an international cohort of patients treated with RNU for UTUC without pathologic slide review.

Design, setting, and participants

Data from 762 patients treated with RNU for UTUC without neoadjuvant chemotherapy were collected at nine centers located in Europe, Asia, and Canada.

Measurements

We evaluated patients’ characteristics, RFS, and CSS.

Results and limitations

LVI was present in 148 patients (19.4%). At a median follow-up of 34 mo, 23.5% of the patients developed disease recurrence and 19.8% died of UTUC. The 5-yr RFS and CSS rates were 79.3% and 82.1%, respectively, in the absence of LVI compared with 45.1% and 45.8%, respectively, in the presence of LVI (p values <0.0001). On multivariable Cox regression analyses, LVI was an independent predictor of RFS (hazard ratio [HR]: 3.3; p = 0.005) and CSS (HR: 5.9; p < 0.0001). Similarly, among patients with pN0/Nx disease, LVI was an independent predictor of RFS (HR: 2.1; p = 0.001) and CSS (HR: 2.3; p < 0.0001).

Conclusions

In a large multicenter series of patients treated with RNU for UTUC and for which no pathologic slide review was performed, LVI was present in approximately 20% and was an independent predictor of both RFS and CSS. LVI status should always be included in the pathologic report of RNU specimens, and patients with LVI should be considered for adjuvant therapy studies.     

Future Direction in Pharmacotherapy for Non-neurogenic Male Lower Urinary Tract Symptoms

Background

The pathophysiology of male lower urinary tract symptoms (LUTS) is highly complex and multifactorial. The shift in perception that LUTS are not sex or organ specific has not been followed by significant innovations regarding the available drug classes.

Objective

To review pathophysiologic mechanisms and clinical and experimental data related to the development of new pharmacologic treatments for male LUTS.

Evidence acquisition

The PubMed database was used to identify articles describing experimental and clinical studies of pathophysiologic mechanisms contributing to male LUTS and, supported by them, new pharmacotherapies with clinical or experimental evidence in the field.

Evidence synthesis

Several pathologic processes (eg, androgen signaling, inflammation, and metabolic factors) and targets (eg, the urothelium, prostate, interstitial cells, detrusor, neurotransmitters, neuromodulators, and receptors) have been implicated in male LUTS. Some newly introduced drugs, such as phosphodiesterase type 5 inhibitors and β3-adrenergic agonists, have just started broad use in clinical practice. Drugs with potential benefit, such as vitamin D3 receptor analogs, gonadotropin-releasing hormone antagonists, cannabinoids, and drugs injected into the prostate, have been evaluated in experimental studies and have progressed to clinical trials. However, safety and efficacy data for these drugs are still scarce. Some compounds with interesting profiles have only been tested in experimental settings (eg, transient receptor potential channel blockers, Rho-kinase inhibitors, purinergic receptor blockers, and endothelin-converting enzyme inhibitors).

Conclusions

New pathophysiologic mechanisms of male LUTS are described that lead to the continuous development of new pharmacotherapies. To date, few drugs have been added to the current armamentarium, and several are in various phases of clinical or experimental investigation.     

Photodynamic Diagnosis in Urology: State-of-the-Art

Objectives

To provide an overview on the methodology and clinical relevance of fluorescence diagnosis with exogenous fluorochromes or fluorochrome prodrugs in urology.

Methods

The methodology is summarised on the basis of our experience and the relevant literature. Clinical results and perspectives are reported and concluded after we scanned and evaluated sources from PubMed. Search items were “aminolev*” or “hypericin” or “photodyn*” or “porphyrin” or “fluorescence” or “autofluorescence” and “bladder” or “prostate” or “kidney” or “peni*” or “condylo*”. Some literature was also obtained from journals not indexed.

Results

A large number of clinical trials have shown that photodynamic diagnosis (PDD) improves the ability to detect inconspicuous urothelial carcinoma of the bladder. Fluorescence diagnosis has recently been approved in Europe for the detection of bladder cancer after instillation of a hexaminolevulinate (Hexvix^®) solution. PDD is recommended by the European Association of Urology for the diagnosis of carcinoma in situ of the bladder. To date, the major weakness of PDD for the detection of bladder cancer is its relatively low specificity. Initial results with PDD for the detection of penile carcinoma, prostate cancer, kidney tumours, and urethral condylomata are promising.

Conclusions

To determine the actual impact of PDD on recurrence and progression rates of bladder cancer, further long-term observational studies are necessary. These studies also will clarify whether PDD is cost efficient.     

Survival Outcome and Treatment Response of Patients with Late Relapse from Renal Cell Carcinoma in the Era of Targeted Therapy

Background

A subset of primarily localized renal cell carcinoma (RCC) patients will experience disease recurrence ≥5 yr after initial nephrectomy.

Objective

To characterize the clinical outcome of patients with late recurrence beyond 5 yr.

Design, setting, and participants

Patients with metastatic RCC (mRCC) treated with targeted therapy were retrospectively characterized according to time to relapse. Relapse was defined as the diagnosis of recurrent metastatic disease >3 mo after initial curative-intent nephrectomy. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as early relapsers (ERs) if they recurred within 5 yr; late relapsers (LRs) recurred after 5 yr.

Outcome measurements and statistical analysis

Demographics were compared with the Student t test, the chi-square test, or the Fisher exact test. The survival time was estimated with the Kaplan-Meier method, and associations with survival outcome were assessed with univariable and multivariable Cox regression analyses.

Results and limitations

Among 1210 mRCC patients treated with targeted therapy after surgery for localized disease, 897 (74%) relapsed within the first 5 yr and 313 (26%) (range: 5–35 yr) after 5 yr. LRs presented with younger age (p < 0.0001), fewer with sarcomatoid features (p < 0.0001), more clear cell histology (p = 0.001), and lower Fuhrman grade (p < 0.0001). Overall objective response rates to targeted therapy were better in LRs versus ERs (31.8% vs 26.5%; p = 0.004). LRs had significantly longer progression-free survival (10.7 mo vs 8.5 mo; p = 0.005) and overall survival (OS; 34.0 mo vs 27.4 mo; p = 0.004). The study is limited by its retrospective design, noncentralized imaging and pathology review, missing information on metastatectomy, and nonstandardized follow-up protocols.

Conclusions

A quarter of patients who eventually developed metastatic disease and were treated with targeted therapy relapsed over 5 yr from initial nephrectomy. LRs have more favorable prognostic features and consequently better treatment response and OS.     

Prospective Randomized Controlled Trial of Robotic versus Open Radical Cystectomy for Bladder Cancer: Perioperative and Pathologic Results

Background

In recent years, surgeons have begun to report case series of minimally invasive approaches to radical cystectomy, including robotic-assisted techniques demonstrating the surgical feasibility of this procedure with the potential of lower blood loss and more rapid return of bowel function and hospital discharge. Despite these experiences and observations, at this point high levels of clinical evidence with regard to the benefits of robotic cystectomy are absent, and the current experiences represent case series with limited comparisons to historical controls at best.

Objective

We report our results on a prospective randomized trial of open versus robotic-assisted laparoscopic radical cystectomy with regard to perioperative outcomes, complications, and short-term narcotic usage.

Design, setting, and participants

A prospective randomized single-center noninferiority study comparing open versus robotic approaches to cystectomy in patients who are candidates for radical cystectomy for urothelial carcinoma of the bladder. Of the 41 patients who underwent surgery, 21 were randomized to the robotic approach and 20 to the open technique.

Intervention

Radical cystectomy, bilateral pelvic lymphadenectomy, and urinary diversion by either an open approach or by a robotic-assisted laparoscopic technique.

Measurements

The primary end point was lymph node (LN) yield with a noninferiority margin of four LNs. Secondary end points included demographic characteristics, perioperative outcomes, pathologic results, and short-term narcotic use.

Results and limitations

On univariate analysis, no significant differences were found between the two groups with regard to age, sex, body mass index, American Society of Anesthesiologists classification, anticoagulation regimen of aspirin, clinical stage, or diversion type. Significant differences were noted in operating room time, estimated blood loss, time to flatus, time to bowel movement, and use of inpatient morphine sulfate equivalents. There was no significant difference in regard to overall complication rate or hospital stay. On surgical pathology, in the robotic group 14 patients had pT2 disease or higher; 3 patients had pT3/T4 disease; and 4 patients had node-positive disease. In the open group, eight patients had pT2 disease or higher; five patients had pT3/T4 disease; and seven patients had node-positive disease. The mean number of LNs removed was 19 in the robotic group versus18 in the open group. Potential study limitations include the limited clinical and oncologic follow-up and the relatively small and single-institution nature of the study.

Conclusions

We present the results of a prospective randomized controlled noninferiority study with a primary end point of LN yield, demonstrating the robotic approach to be noninferior to the open approach. The robotic approach also compares favorably with the open approach in several perioperative parameters.     

Bacillus Calmette-Guérin Osteomyelitis Mimicking Spinal Metastasis from Urothelial Cell Carcinoma of the Bladder

A 66-yr-old male presented with progressively worsening back pain 5 mo after undergoing radical cystectomy and bilateral extended pelvic lymph node dissection for bacillus Calmette-Guérin–refractory pTisN0M0 urothelial carcinoma of the bladder. Imaging revealed lytic lesions in the 10th and 11th vertebral bodies of the thoracic spine that were suspicious for metastasis and cord compression. The patient underwent computed tomography–guided biopsy of the abnormalities, which showed no evidence of malignancy but revealed chronic inflammatory infiltrate with cultures positive for Mycobacterium bovis. The patient was treated with isoniazid, rifampin, ethambutol, and pyrazinamide.     

Systematic Review of Combination Drug Therapy for Non-neurogenic Male Lower Urinary Tract Symptoms

Background

Several drugs are approved for the treatment of lower urinary tract symptoms (LUTS) in men, but these are mostly used by clinicians as monotherapies. The combination of different compounds, each of which targets a different aspect of LUTS, seems appealing. However, only few clinical trials have evaluated the effects of combination therapies.

Objective

This systematic review analyzes the efficacy and adverse events of combination therapies for male LUTS.

Evidence acquisition

PubMed and Cochrane databases were used to identify clinical trials and meta-analyses on male LUTS combination therapy. The search was restricted to studies of level of evidence ≥1b. A total of 49 papers published between January 1988 and March 2012 were identified.

Evidence synthesis

The α₁-adrenoceptor antagonist (α₁-blocker)/5α-reductase inhibitor (5-ARI) combination provides the most data. This combination seems to be more efficacious in terms of several outcome variables in patients whose prostate volume is between 30 ml and 40 ml when treatment is maintained for >1 yr; when given for <1 yr, α₁-blockers alone are just as effective. The combination of α₁-blocker/5-ARI shows a slightly increased rate of adverse events. It remains unknown whether its safety and superiority over either drug as monotherapy are sustained after >6 yr. The α₁-blocker/muscarinic receptor antagonist (antimuscarinic) combination was most frequently assessed as an add-on therapy to already existing α₁-blocker therapy. Inconsistent data derive from heterogeneous study populations and different study designs. Currently, the α₁-blocker/antimuscarinic combination appears to be a second-line add-on for patients with insufficient symptom relief after monotherapy. The combination seems to be safe in men with postvoid residual <200 ml. However, there are no trials >4 mo concerning safety and efficacy of this combination. The α₁-blocker/phosphodiesterase type 5 inhibitor combination is a new treatment option with only preliminary reports. More studies are needed before definitive conclusions can be drawn.

Conclusions

An α₁-blocker/5-ARI combination is beneficial for patients whose prostate volume is between 30 ml and 40 ml when medical treatment is intended for >1 yr. Based on short-term follow-up studies, add-on of antimuscarinics to α₁-blockers is an option when postvoid residual is <200 ml.     

A Proposal for Reclassification of the Fuhrman Grading System in Patients with Clear Cell Renal Cell Carcinoma

Background

The conventional Fuhrman grading system, which categorizes renal cell carcinoma (RCC) with grades I, II, III, and IV, is the most widely used predictor assessment of RCC cancer-specific mortality (CSM).

Objectives

The aim of this study was to test the prognostic ability of simplified Fuhrman grading schemes (FGSs) that rely on two- or three-tiered classifications.

Design, setting, and participants

The current study addressed a population of 14 064 patients with clear cell RCC who were treated with partial or radical nephrectomy between 1988–2004, within nine Surveillance, Epidemiology, and End Results (SEER) cancer registries.

Measurements

Univariable and multivariable analyses as well as prognostic accuracy analyses were performed for various FGSs to test their ability to predict CSM rates. The conventional four-tiered FGS was compared to a modified two-tiered FGS in which grades I and II and grades III and IV were combined. A second simplified three-tiered FGS in which grades I and II were combined but grades III and IV were kept separate was also tested.

Results and limitations

The overall 5-yr CSM-free rate was 81.5%. All three FGSs achieved independent predictor status in multivariable analyses. Prognostic accuracy of multivariable models that relied on various FGSs was 83.6% for the modified two-tiered FGS and 83.8% for both the conventional four-tiered and the modified three-tiered FGS.

Conclusions

Our findings indicate that the simplified FGSs perform equally as well as the conventional four-tiered FGS. The use of simplified grading schemes may represent an advantage for pathologists as well as for clinicians caring for patients with RCC.     

EAU Penile Cancer Guidelines 2009

Context

Squamous cell carcinoma (SCC) of the penis is a relatively rare but ominous disease.

Objective

To present a condensed version of the updated 2009 European Association of Urology (EAU) guidelines on penile SCC.

Evidence acquisition

We performed a literature search of new data available up to December 2009. No randomized study was found; consequently, level of evidence (LE) and grade of recommendations (GR) are low.

Evidence synthesis

More insight was gained into the etiology of SCC of the penis, together with improved staging and treatment: Human papillomavirus 16 plays an etiologic role in approximately 40–50% of cases. Similarities in etiology with SCC of the head and neck, the female genitalia, and the anal canal have been found. Improved diagnostics allowed earlier diagnosis, leading to more conservative treatments. Adjuvant and neoadjuvant chemotherapy showed promising results in patients with advanced or recurrent disease. Centralization of the disease contributed to standardization and rapid diffusion of new treatments with improved results and increased organ preservation.

Conclusions

Improvements in the management of SCC of the penis are reflected in changes in the guidelines, but the rarity of the disease precluded randomized studies, leading to low level of evidence and grade of recommendation.     

ClearCode34: A Prognostic Risk Predictor for Localized Clear Cell Renal Cell Carcinoma

Background

Gene expression signatures have proven to be useful tools in many cancers to identify distinct subtypes of disease based on molecular features that drive pathogenesis, and to aid in predicting clinical outcomes. However, there are no current signatures for kidney cancer that are applicable in a clinical setting.

Objective

To generate a signature biomarker for the clear cell renal cell carcinoma (ccRCC) good risk (ccA) and poor risk (ccB) subtype classification that could be readily applied to clinical samples to develop an integrated model for biologically defined risk stratification.

Design, setting, and participants

A set of 72 ccRCC sample standards was used to develop a 34-gene classifier (ClearCode34) for assigning ccRCC tumors to subtypes. The classifier was applied to RNA-sequencing data from 380 nonmetastatic ccRCC samples from the Cancer Genome Atlas (TCGA), and to 157 formalin-fixed clinical samples collected at the University of North Carolina.

Outcome measurements and statistical analysis

Kaplan-Meier analyses were performed on the individual cohorts to calculate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Training and test sets were randomly selected from the combined cohorts to assemble a risk prediction model for disease recurrence.

Results and limitations

The subtypes were significantly associated with RFS (p < 0.01), CSS (p < 0.01), and OS (p < 0.01). Hazard ratios for subtype classification were similar to those of stage and grade in association with recurrence risk, and remained significant in multivariate analyses. An integrated molecular/clinical model for RFS to assign patients to risk groups was able to accurately predict CSS above established, clinical risk-prediction algorithms.

Conclusions

The ClearCode34-based model provides prognostic stratification that improves upon established algorithms to assess risk for recurrence and death for nonmetastatic ccRCC patients.

Patient summary

We developed a 34-gene subtype predictor to classify clear cell renal cell carcinoma tumors according to ccA or ccB subtypes and built a subtype-inclusive model to analyze patient survival outcomes.     

Systematic Review and Meta-analysis of Candidate Gene Association Studies of Lower Urinary Tract Symptoms in Men

Context

Although family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS.

Objective

To systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations.

Evidence acquisition

A systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies.

Evidence synthesis

We identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49–0.83) with moderate heterogeneity (I² = 27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes.

Conclusions

Few putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses.

Patient summary

Combining the results from all previous studies of genetic variants that may cause urinary symptoms in men, we found significant variants in five genes. Only one, a variant of the vitamin D receptor, was consistently protective across different populations.     

Lymphadenectomy in the Surgical Management of Penile Cancer

Context

Uncertainty remains about the extent and indications for inguinal lymphadenectomy in penile cancer, a procedure known for relatively high morbidity. Several attempts have been made to develop strategies which can improve the diagnostic quality and reduce the morbidity of the management of inguinal lymph nodes in penile cancer.

Objective

To analyse the existing published data on the surgical management of inguinal nodes in penile cancer regarding morbidity and survival.

Evidence acquisition

A Medline search was performed of the English-language literature (1966–September 2008) using the MeSH terms penile carcinoma, lymph node dissection, lymphadenectomy, and complications.

Evidence synthesis

Lymph node metastases are frequent in penile cancer, even in early pT1G2 stages. Since the results of systemic treatment of advanced penile cancer are disappointing, complete dissection of all involved lymph nodes is highly recommended. The extent of lymph node dissection should be adapted to clinical stage, as this corresponds to metastatic spread. For low-risk patients (pTis, pTa, and pT1G1) without palpable lymph nodes and with good compliance, a surveillance strategy may be chosen. For all other patients without palpable lymph nodes (including intermediate risk pT1G2 disease), a modified bilateral lymphadenectomy is recommended. An alternative to this is a dynamic sentinel lymph node biopsy in specialised centres. All patients with histologically proven lymph node metastases should undergo radical inguinal lymphadenectomy. Pelvic lymph node dissection should be done in all patients with more than two metastatic inguinal lymph nodes. In case of fixed inguinal lymph nodes, neoadjuvant chemotherapy is recommended, followed by node resection.

Conclusions

Lymphadenectomy is an integral part of the management of penile cancer, since early dissection of involved lymph nodes improves survival.     

European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update

Context

The European Association of Urology (EAU) Guidelines Panel on Upper Urinary Tract Urothelial Carcinoma (UTUC) has prepared updated guidelines to aid clinicians in the current evidence-based management of UTUC and to incorporate recommendations into clinical practice.

Insulin-like Growth Factor Messenger RNA-binding Protein 3 Expression Helps Prognostication in Patients with Upper Tract Urothelial Carcinoma

Background

Upper tract urothelial carcinoma (UTUC) is a clinically heterogeneous disease that lacks high-quality trials that provide definitive prognostic markers. Insulin-like growth factor messenger RNA binding protein 3 (IMP3) has been associated with outcomes in urothelial carcinoma of the bladder but was not yet studied in UTUC.

Objective

To evaluate the association of the oncofetal protein IMP3 with oncologic outcomes in patients with UTUC treated with radical nephroureterectomy (RNU).

Design, setting, and participants

We investigated the expression of IMP3 and its association with clinical outcomes using tissue microarrays constructed from 622 patients treated with RNU at seven international institutions between 1991 and 2008.

Intervention

All patients were diagnosed with UTUC and underwent RNU.

Outcome measurement and statistical analysis

Uni- and multivariable Cox regression analyses evaluated the association of IMP3 protein expression with disease recurrence, cancer-specific mortality, and all-cause mortality.

Results and limitations

IMP3 was expressed in 12.2% of patients with UTUC (n = 76). The expression was tumor specific and correlated with higher stages/grades. Within a median follow-up of 27 mo (interquartile range [IQR]: 12–53), 191 patients (25.4%) experienced disease recurrence, and 165 (21.9%) died of the disease. Patients with IMP3 demonstrated significantly worse recurrence-free survival (27.4% vs 75.1%; p < 0.01), cancer-specific survival (34.5% vs 78.9%; p < 0.01), and overall survival (15.6% vs 64.8%; p < 0.01) at 5 yr compared with those without IMP3. In multivariable Cox regression analyses, which adjusted for the effects of standard clinicopathologic features, IMP3expression was independently associated with disease recurrence (hazard ratio [HR]: 1.87; p < 0.01), cancer-specific mortality (HR: 2.15; p < 0.01), and all-cause mortality (HR: 2.07; p < 0.01). Major limitations include the retrospective design and relatively short follow-up time.

Conclusions

IMP3 expression is independently associated with disease recurrence, cancer-specific mortality, and all-cause mortality in UTUC. IMP3 may help improve risk stratification and prognostication of UTUC patients treated with RNU.     

Predicting Occult Multifocality of Renal Cell Carcinoma

Background

Multifocal renal cell carcinoma (RCC) has been reported in up to 25% of all radical nephrectomy specimens. Modern imaging tends to underestimate the rate of multifocality. Recognition of multifocality before treatment may guide physicians and patients to the type of intervention and tailor long-term follow-up.

Objective

Our aim was to develop and assess preoperative nomograms to predict occult multifocal RCC.

Design, setting, and participants

We evaluated 560 consecutive patients undergoing radical nephrectomy for clinically localized suspected sporadic RCC between 2000 and 2008 in a tertiary center. Clinically manifest multifocal lesions were excluded. Logistic regression models were used to assess the potential risk factors of occult multifocality with and without pathologic variables that may be available with preoperative biopsy. Nomograms were developed and assessed for diagnostic properties.

Interventions

All patients underwent radical nephrectomy.

Measurements

Assessments of risk factors for occult multifocal RCC were obtained using regression models and nomograms.

Results and limitations

The incidence of occult multifocality was 7.9%. Significantly associated predictors of multifocality were male gender, family history of malignancy other than RCC, radiographic size of the lesion, histologic subtype other than clear cell, and Fuhrman grade IV. The two designed nomograms had 0.75 and 0.82 concordance indices, respectively.

Conclusions

Our data suggest that occult multifocal RCC is more frequently associated with small (2–4 cm) renal lesions. Male gender, family history of kidney cancer, histologic subtype, and grade are strongly associated with an increased risk of occult multifocal RCC. The developed nomograms had good predictive accuracy that was enhanced when combined with pathologic variables.     

Pelvic Lymph Node Dissection in Prostate Cancer

Context

Pelvic lymph node dissection (PLND) is considered the most reliable procedure for the detection of lymph node metastases in prostate cancer (PCa); however, the therapeutic benefit of PLND in PCa management is currently under debate.

Objective

To systematically review the available literature concerning the role of PLND and its extent in PCa staging and outcome. All of the existing recommendations and staging tools determining the need for PLND were also assessed. Moreover, a systematic review was performed of the long-term outcome of node-positive patients stratified according to the extent of nodal invasion.

Evidence acquisition

A Medline search was conducted to identify original and review articles as well as editorials addressing the significance of PLND in PCa. Keywords included prostate cancer, pelvic lymph node dissection, radical prostatectomy, imaging, and complications. Data from the selected studies focussing on the role of PLND in PCa staging and outcome were reviewed and discussed by all of the contributing authors.

Evidence synthesis

Despite recent advances in imaging techniques, PLND remains the most accurate staging procedure for the detection of lymph node invasion (LNI) in PCa. The rate of LNI increases with the extent of PLND. Extended PLND (ePLND; ie, removal of obturator, external iliac, hypogastric with or without presacral and common iliac nodes) significantly improves the detection of lymph node metastases compared with limited PLND (lPLND; ie, removal of obturator with or without external iliac nodes), which is associated with poor staging accuracy. Because not all patients with PCa are at the same risk of harbouring nodal metastases, several nomograms and tables have been developed and validated to identify candidates for PLND. These tools, however, are based mostly on findings derived from lPLND dissections performed in older patient series. According to these prediction models, a staging PLND might be omitted in low-risk PCa patients because of the low rate of lymph node metastases found, even after extended dissections (<8%). The outcome for patients with positive nodes is not necessarily poor. Indeed, patients with low-volume nodal metastases experience excellent survival rates, regardless of adjuvant treatment. But despite few retrospective studies reporting an association between PLND and PCa progression and survival, the exact impact of PLND on patient outcomes has not yet been clearly proven because of the lack of prospective randomised trials.

Conclusions

On the basis of current data, we suggest that if a PLND is indicated, then it should be extended. Conversely, in view of the low rate of LNI among patients with low-risk PCa, a staging ePLND might be spared in this patient category. Whether this approach is also safe from oncologic perspectives is still unknown. Patients with low-volume nodal metastases have a good long-term prognosis; to what extent this prognosis is the result of a positive impact of PLND on PCa outcomes is still to be determined.     

Partial Nephrectomy Is Associated with Improved Overall Survival Compared to Radical Nephrectomy in Patients with Unanticipated Benign Renal Tumours

Background

Partial nephrectomy (PN) has been associated with improved overall survival (OS) in select cohorts with localised renal masses when compared to radical nephrectomy (RN). The driving forces behind these differences have been difficult to elucidate given the heterogeneity of previously compared cohorts.

Objective

Compare OS in a subset of patients with unanticipated benign renal masses to minimise the confounding effect of cancer.

Design, setting, and participants

We retrospectively evaluated 2608 consecutive clinical T1 enhancing renal masses that were treated with extirpative surgery at our institution between 1999 and 2006. Of these, 499 tumours (19%) were found to be benign on final pathology. Preoperative data and renal functional data were used to generate a propensity model that was then plugged into a multivariate model of survival. Median follow-up for the entire cohort was 50 mo (interquartile range [IQR]: 32–73).

Intervention

All patients underwent PN or RN.

Measurements

We measured OS and cardiac-specific survival.

Results and limitations

Five-year OS estimates for the PN (n = 388) and RN (n = 111) cohorts were 95% (95% confidence interval [CI], 93–98) versus 83% (95% CI, 74–90), respectively (P < 0.0001). On multivariate analysis, controlling for both comorbidity and age, RN was associated with a 2.5-fold increased risk of death compared to PN (hazard ratio [HR]: 2.5; 95% CI, 1.3–5.1). Postoperative estimated glomerular filtration rate (eGFR) was also an independent predictor of OS and cardiac-specific survival (HR: 0.97; 95% CI, 0.95–0.99 and HR: 0.96; 95% CI, 0.93–0.99, respectively). The retrospective nature of this analysis limits the strength of the conclusions.

Conclusions

PN was associated with better OS when compared to RN in patients with unanticipated benign tumours. This observed survival advantage appears partly to be the result of better preservation of eGFR, but other kidney functions or unmeasured factors may also play a role. These data indicate that PN should be aggressively pursued in any patient where PN is technically feasible.