Multi-institutional validation of the ability of preoperative hydronephrosis to predict advanced pathologic tumor stage in upper-tract urothelial carcinoma.

OBJECTIVE: The presence of hydronephrosis (HN) has been implicated as a predictor of poor outcomes for patients diagnosed with bladder cancer. Small, single institution preliminary reports suggest a similar negative relationship may exist for upper-tract urothelial carcinoma (UTUC). Herein, we attempt to validate the prognostic value of preoperative HN in a large, multi-institutional cohort of UTUC patients. MATERIALS AND METHODS: Data on 469 patients with localized UTUC from 5 tertiary referral centers who underwent a radical nephroureterectomy (91%) or distal ureterectomy (9%) without neoadjuvant chemotherapy were integrated into a relational database. Preoperative HN data, including presence vs. absence and high vs. low grade, were available in 408 patients. The association of HN with pathologic features was evaluated. RESULTS: A total of 254 men and 154 women with a median age of 69 years (IQR 15) were analyzed. Overall, 192 patients (47%) had ≥pT2 disease, 145 (36%) had non-organ-confined (NOC) cancers (≥pT3 and/or positive lymph nodes), and 298 (73%) had high grade UTUC on final pathology. Forty-six percent of patients had tumors in the renal pelvis, 27% in the ureter, and 27% in both locations. Preoperatively, 223 patients (55%) were noted to have ipsilateral HN (39% low grade and 61% high grade). Hydronephrosis was associated with ≥pT2 stage (P < 0.001), NOC disease (P < 0.001), and high grade cancers (P = 0.04). On multivariate analysis adjusting for gender, age, and tumor location, HN was an independent predictor of muscle invasive (HR 7.4, P < 0.001), NOC (HR 5.5, P < 0.001), and high pathologic grade (HR 1.6, P = 0.03) UTUC disease. CONCLUSION: The presence of preoperative HN was associated with advanced stage UTUC. This readily available imaging modality may improve preoperative risk stratification for UTUC patients thereby guiding use of endoscopic versus extirpative surgery as well as the need for neoadjuvant chemotherapy regimens.

High-grade ureteroscopic biopsy is associated with advanced pathology of upper-tract urothelial carcinoma tumors at definitive surgical resection.

BACKGROUND AND PURPOSE: Accurate assessment of upper-tract urothelial carcinoma (UTUC) pathology may guide use of endoscopic vs extirpative therapy. We present a multi-institutional cohort of patients with UTUC who underwent surgical resection to characterize the association of ureteroscopic (URS) biopsy features with final pathology results. PATIENTS AND METHODS: URS biopsy data were available in 238 patients who underwent surgical resection of UTUC. Biopsies were performed using a brush biopsy kit, mechanical biopsy device, or basket. Stage was classified as a positive brush, nonmuscle-invasive (

Urinary cytology has a poor performance for predicting invasive or high-grade upper-tract urothelial carcinoma.

OBJECTIVE: • To evaluate the diagnostic accuracy of urine cytology for detecting aggressive disease in a multi-institutional cohort of patients undergoing extirpative surgery for upper-tract urothelial carcinoma (UTUC). METHODS: • We reviewed the records of 326 patients with urinary cytology data who underwent a radical nephroureterectomy or distal ureterectomy without concurrent or previous bladder cancer. • We assessed the association of cytology (positive, negative and atypical) with final pathology. Sensitivity and positive predictive value (PPV) of a positive (± atypical) cytology for high-grade and muscle-invasive UTUC was calculated. RESULTS: • On final pathology, 53% of patients had non-muscle invasive disease (pTa, pTis, pT1) and 47% had invasive disease (≥ pT2). Low-grade and high-grade cancers were present in 33% and 67% of patients, respectively. • Positive, atypical and negative urine cytology was noted in 40%, 40% and 20% of cases. Positive urinary cytology had sensitivity and PPV of 56% and 54% for high-grade and 62% and 44% for muscle-invasive UTUC. • Inclusion of atypical cytology with positive cytology improved the sensitivity and PPV for high-grade (74% and 63%) and muscle-invasive (77% and 45%) UTUC. Restricting analysis to patients with selective ureteral cytologies further improved the diagnostic accuracy when compared with bladder specimens (PPV > 85% for high-grade and muscle-invasive UTUC). CONCLUSIONS: • In this cohort of patients with UTUC treated with radical surgery, urine cytology in isolation lacked performance characteristics to accurately predict muscle-invasive or high-grade disease. • Improved surrogate markers for pathological grade and stage are necessary, particularly when considering endoscopic modalities for UTUC.

Preoperative hydronephrosis, ureteroscopic biopsy grade and urinary cytology can improve prediction of advanced upper tract urothelial carcinoma.

PURPOSE: We evaluated the value of hydronephrosis, ureteroscopic biopsy grade and urinary cytology to predict advanced upper tract urothelial carcinoma. MATERIALS AND METHODS: We reviewed the charts of 469 patients with upper tract urothelial carcinoma treated with radical nephroureterectomy or distal ureterectomy. Complete data on hydronephrosis (present vs absent), ureteroscopic grade (high vs low) and urinary cytology (positive vs negative) were available in 172 patients. The outcome was muscle invasive (pT2-pT4) or nonorgan confined (pT3 or greater, or lymph node metastasis) upper tract urothelial carcinoma. RESULTS: Of the patients 92 (54%) had hydronephrosis, 74 (43%) had high grade disease on ureteroscopic biopsy and 137 (80%) had positive cytology. On univariate analysis hydronephrosis (p <0.001), high ureteroscopic grade (p <0.001) and positive cytology (p = 0.03) were associated with muscle invasive and nonorgan confined disease. On multivariate analysis adjusting for tumor site, gender and age hydronephrosis and high ureteroscopic grade were associated with muscle invasive carcinoma (HR 12.0 and 4.5, respectively, each p <0.001) but cytology was not (HR 2.3, p = 0.17). However, all 3 variables were independently associated with nonorgan confined disease (HR 5.1, p <0.001; HR 3.9, p <0.001; and HR 3.1, p = 0.035, respectively). Combining these 3 tests incrementally improved the prediction of upper tract urothelial carcinoma stage. Abnormality of all 3 tests had 89% and 73% positive predictive value for muscle invasive and nonorgan confined upper tract urothelial carcinoma, respectively, but when all tests were normal, the negative predictive value was 100%. CONCLUSIONS: Preoperative evaluation for hydronephrosis, ureteroscopic grade and cytology can identify patients at risk for advanced upper tract urothelial carcinoma. Such knowledge may impact surgery choice and extent as well as the need for perioperative chemotherapy regimens.

Robot-assisted partial nephrectomy: a large single-institutional experience.

OBJECTIVES: To report experience with 100 robot-assisted partial nephrectomy (RAPN) operations performed at our institution. Nephron-sparing surgery is an established treatment for patients with small renal masses. The laparoscopic approach has emerged as an alternative to open nephron-sparing surgery, but it is recognized to be technically challenging. The robotic surgical system may enable faster and greater technical proficiency, facilitating a minimally invasive approach to more difficult lesions while reducing ischemia time. METHODS: A total of 100 RAPN operations were performed for suspicious solid renal lesions during a 21-month period. Clinicopathologic variables, nephrometry scores, operative parameters, and renal functional outcomes were prospectively recorded and analyzed. RESULTS: Median tumor size was 2.8 cm (range, 1.0-8). Nephrometry scores of resected lesions were low in 47.9% of patients, medium in 45.7%, and high in 6.4% of patients. Forty-seven percent of patients had tumors>50% intraparenchymal, and 61.7% had tumors located less than 7 mm away from the renal sinus or collecting system. In 17% of patients, the tumors were touching a first-order vessel in the renal hilum. Mean warm ischemia time was 25.5 minutes (range, 0-53). Mean change in postoperative glomerular filtration rate improved 6.32 mL/min/1.73 m2 (range, -41.9 to 68.9). Histology was renal cell carcinoma in 81% (87/107) of tumors. There were 5 microscopically positive margins on final pathology (5.7%). Major and minor complication rates were 6% and 5%, respectively. There were 2 conversions to open surgery. CONCLUSIONS: RAPN seems to be a safe and technically feasible minimally invasive approach to nephron-sparing surgery even in more complex cases, with acceptable pathologic and renal function outcomes.

Age, tumor size and relative survival of patients with localized renal cell carcinoma: a surveillance, epidemiology and end results analysis.

PURPOSE: Recent data demonstrate that age may be a significant independent prognostic variable following treatment for renal cell carcinoma. We analyzed data from the SEER (Surveillance, Epidemiology and End Results) database to evaluate the relative survival of patients treated surgically for localized renal cell carcinoma as related to tumor size and patient age. MATERIALS AND METHODS: Patients in the SEER database with localized renal cell carcinoma were stratified into cohorts by age and tumor size. Three and 5-year relative survival, the ratio of observed survival in the cancer population to the expected survival of an age, sex and race matched cancer-free population, was calculated with SEER-Stat. Brown's method was used for hypothesis testing. RESULTS: A total of 8,578 patients with surgically treated, localized renal cell carcinoma were identified. While 3 and 5-year survival for patients with small (less than 4 cm) renal cell carcinoma was no different from that of matched cancer-free controls, patients treated for large (greater than 7 cm) localized renal cell carcinoma experienced decreased 5-year relative survival across all age groups. Therefore, age was not a significant predictor of relative survival for patients with small (less than 4 cm) or large (greater than 7 cm) tumors. However, a statistically significant trend toward lower relative survival with increasing age was demonstrated in patients with medium size tumors (4 to 7 cm). Hypothesis testing confirmed these findings. CONCLUSIONS: These data suggest that relative survival is high in patients with tumors less than 4 cm and lower in patients with tumors larger than 7 cm regardless of age. However, increasing age may be related to worse outcomes in patients with tumors 4 to 7 cm. The cause of this observation warrants further investigation.

Transcriptional regulation of the major zinc uptake protein hZip1 in prostate cancer cells.

hZip1 has been characterized as the major zinc uptake transporter regulating the accumulation of zinc in prostate cells. The mechanisms regulating expression of hZip1 have not been described. To explore the mechanisms of transcriptional regulation of the hZip1 gene, we determined the putative promoter sequence for hZip1 and identified the potential transcription start site within the predicted hZip1 promoter region. To further characterize the promoter region for basal hZip1 transcription, 3' and 5' deletion constructs and constructs with mutated binding sites for putative transcription factors were generated by PCR amplification and assessed for transcriptional activity with a luciferase reporter assay in PC-3 prostate cancer cells. The ability of the specific transcription factors to bind the hZip1 core promoter was confirmed by EMSA, GelSupershift and ChIP assays. Our experiments identified the core promoter region responsible for constitutive expression of hZip1 and demonstrated critical roles for SP1 and CREB1 in transcriptional regulation of the hZip1 gene in prostate cancer cells.

Bone formation in carotid plaques: a clinicopathological study.

BACKGROUND AND PURPOSE: Bone formation and dystrophic calcification are present in carotid endarterectomy plaques. The clinical significance of these findings is unknown. The purpose of this study was to determine whether bone formation and extensive dystrophic calcification are associated with stable plaques and protective against ischemic vascular events. METHODS: Carotid endarterectomy plaques were collected from 142 patients (94 men) with carotid stenosis. The specimens were evaluated for lamellar bone formation, dystrophic calcifications, inflammatory infiltrates, neovascularization, and histological type or grade of plaque according to a standard AHA grading system. Immunohistochemical staining was performed to identify vascular endothelial cells in neovascularization (factor VIII) and lymphocytes. Clinical data, including history of cerebrovascular and cardiovascular events, were recorded at the time of surgery. RESULTS: Patients with calcification of carotid plaques had fewer symptoms of stroke and transient ischemic attack (P=0.042) than those without calcification. Stroke and transient ischemic attack occurred less frequently in patients with plaques with large calcific granules (P=0.021). Of the patients, 13% had lamellar bone formation, which directly correlated with the presence of sheetlike calcifications (P=0.0001) and inversely correlated with ulcerated lesions (P=0.048). The presence of bone also correlated with diabetes (P<0.01) and coronary artery disease (P<0.01). Of the 20 patients with bone, 6 had a history of stoke and transient ischemic attack (P=0.5). CONCLUSIONS: The results indicate that bone formation tends to occur in heavily calcified carotid lesions devoid of ulceration and hemorrhage. Patients with extensive calcification of the carotid plaques are less likely to have symptomatic disease.