and 47% had invasive disease ( ≥ pT2). Lowgrade 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 muscleinvasive 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 highgrade 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 muscleinvasive or high-grade disease.• Improved surrogate markers for pathological grade and stage are necessary, particularly when considering endoscopic modalities for UTUC. KEYWORDS transitional cell carcinoma, radical nephroureterectomy, urothelial carcinoma, cytologyWhat's known on the subject? and What does the study add? Accurate preoperative staging for upper-tract urothelial carcinoma (UTUC) lesions is presently limited. Urinary cytology has shown promise for characterizing pathological features of bladder cancer. The role of cytology for UTUC is at present poorly defined.In this large multi-institutional cohort of patients, urinary cytology was limited in its ability to accurately predict the grade and stage of upper-tract lesions. Selective ureteral sampling improved the diagnostic accuracy of cytology when compared to bladder specimens. Improved preoperative surrogate markers for staging UTUC remain necessary.Study Type -Therapy (case series) Level of Evidence 4 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)
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.
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 (Pϭ0.042) than those without calcification. Stroke and transient ischemic attack occurred less frequently in patients with plaques with large calcific granules (Pϭ0.021). Of the patients, 13% had lamellar bone formation, which directly correlated with the presence of sheetlike calcifications (Pϭ0.0001) and inversely correlated with ulcerated lesions (Pϭ0.048). The presence of bone also correlated with diabetes (PϽ0.01) and coronary artery disease (PϽ0.01). Of the 20 patients with bone, 6 had a history of stoke and transient ischemic attack (Pϭ0.5). 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.
The X-linked inhibitor of apoptosis (XIAP), the most potent member of the inhibitor of apoptosis protein (IAP) family of endogenous caspase inhibitors, blocks the initiation and execution phases of the apoptotic cascade. As such, XIAP represents an attractive target for treating apoptosis-resistant forms of cancer. Here, we demonstrate that treatment with the membranepermeable zinc chelator, N,N,N 0 ,N 0 ,-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces a rapid depletion of XIAP at the post-translational level in human PC-3 prostate cancer cells and several non-prostate cell lines. The depletion of XIAP is selective, as TPEN has no effect on the expression of other zinc-binding members of the IAP family, including cIAP1, cIAP2 and survivin. The downregulation of XIAP in TPEN-treated cells occurs via proteasome-and caspase-independent mechanisms and is completely prevented by the serine protease inhibitor, Pefabloc. Finally, our studies demonstrate that TPEN promotes activation of caspases-3 and -9 and sensitizes PC-3 prostate cancer cells to TRAIL-mediated apoptosis. Taken together, our findings indicate that zinc-chelating agents may be used to sensitize malignant cells to established cytotoxic agents via downregulation of XIAP. Inhibitor of apoptosis proteins (IAPs) are a family of caspase inhibitors that selectively bind and inhibit caspases at both the initiation phase and the execution phase of apoptosis.1 All IAPs contain 1-3 baculoviral IAP repeat (BIR) motifs. Each BIR domain folds into a functionally independent structure that binds a zinc ion. Additionally, many IAPs contain another zincbinding motif, the RING domain, which has E3 ubiquitin ligase activity. 2Of all the members of the IAP family, XIAP has received the most attention, possibly because it is the only member of this family that is able to directly inhibit both the initiation and execution phases of the caspase cascade.3 The BIR2 domain of XIAP binds and inhibits caspases-3 and -7. Overexpression of cDNA corresponding to the BIR2 domain inhibits apoptosis from both death receptor and mitochondrial pathway stimuli, consistent with its ability to inhibit effector caspases.4,5 The BIR3 domain of XIAP binds and inhibits caspase-9, an apical caspase in the mitochondrial arm of the apoptotic pathway. 5,6Overexpression of cDNA corresponding to the BIR3 domain inhibits apoptosis in response to stimuli of the mitochondrial pathway of caspase activation, such as Bax, but not stimuli of the death receptor pathway. 4 XIAP levels are elevated in many cancer cell lines and suppression of XIAP protein levels sensitizes cancer cells to chemotherapeutic agents. Here, we demonstrate that treatment of PC-3 prostate cancer cells with the zinc-specific chelator N,N,N 0 ,N 0 ,-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces rapid and selective depletion of XIAP at the post-translational level. XIAP depletion coincides with increased activation of caspases-3 and -9 and sensitization of PC-3 cells to apoptosis in response to subsequent treatment ...
Objectives-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. We report experience with 100 robot assisted partial nephrectomy (RAPN) operations performed at our institution.Methods-100 RAPN operations were performed for suspicious solid renal lesions over 21 months. 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 to 8). Nephrometry scores of resected lesions were low in 47.9% of patients, medium in 45.7%, and high in 6.4% patients. 46.8% of patients had tumors > 50% intraparenchymal, and 61.7% had tumors <7mm from the renal sinus or collecting system. 17.0% were touching a first order vessel in the renal hilum. Mean warm ischemia time was 25.5 minutes (range 0 to 53). Mean change in postoperative GFR improved 6.32 ml/min/1.73m 2 (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 appears 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.
High URS biopsy grade, but not stage, is associated with adverse tumor pathology. This information may play a valuable role for risk stratification and in the appropriate selection of endoscopic management vs surgical extirpation for UTUC.
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 cancerfree 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. Keywords kidney neoplasms; mortalityLike most malignancies RCC is a heterogeneous disease and its clinical course ranges from indolent to highly aggressive. Accurate risk stratification at diagnosis is imperative to determine individualized followup strategies and to identify appropriate candidates for adjuvant therapy trials. Although the TNM staging system developed by the International Union Against Cancer has been shown to stratify cancer related outcomes effectively, several * Correspondence: Department of Urologic Oncology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, Pennsylvania 19111 (telephone: 215-728-3501; FAX: 215-214-1734 This study uses patient data from the SEER cancer database to examine the relationship between age and outcome in a large cohort of patients with surgically treated localized RCC.To avoid the limitations of cause of death reporting we evaluated survival in terms of relative survival-the ratio of observed survival in the cancer population to expected survival in an age, sex and race matched cancer-free population. Materials and MethodsWe used data from the SEER 13 Public Use Registry to create a cohort of patients with kidney cancer diagnosed between 1988 and 1...
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