Effects of obesity on endothelium-dependent reactivity during acute nitric oxide synthase inhibition: modulatory role of endothelin.

This study investigated vascular reactivity in response to acetylcholine, in the presence of acute inhibition of nitric oxide synthase, in the carotid artery and aorta of obese C57Bl6/J mice fed on a high-fat diet for 30 weeks, and of control mice. A subgroup of obese animals was also treated with the ET(A) receptor antagonist darusentan (50 mg x kg(-1) x day(-1)). In vascular rings from control animals, acetylcholine caused endothelium-dependent contractions in the carotid artery, but not in the aorta. In vascular rings from obese mice, contractility to acetylcholine was also evident in the aorta, and that in the carotid artery was increased compared with control mice. ET(A) receptor blockade by darusentan treatment of the obese mice prevented enhanced vasoconstriction to acetylcholine, resulting in mild vasodilatation. Thus obesity increases endothelium-dependent vasoconstriction in the absence of endothelial nitric oxide. This effect can be completely prevented by chronic ET(A) receptor blockade, suggesting that endothelin modulates increased endothelium-dependent vasoconstriction in obesity.

Growth plate alteration precedes cam-type deformity in elite basketball players

BACKGROUND Vigorous sporting activity during the growth years is associated with an increased risk of having a cam-type deformity develop. The underlying cause of this osseous deformity is unclear. One may speculate whether this is caused by reactive bone apposition in the region of the anterosuperior head-neck junction or whether sports activity alters the shape of and growth in the growth plate. If the latter is true, then one would expect athletes to show an abnormal shape of the capital growth plate (specifically, the epiphyseal extension) before and/or after physeal closure. QUESTIONS/PURPOSES We therefore raised three questions: (1) Do adolescent basketball players show abnormal epiphyseal extension? (2) Does the epiphyseal extension differ before and after physeal closure? (3) Is abnormal epiphyseal extension associated with high alpha angles? METHODS We performed a case-control comparative analysis of young (age range, 9-22 years) male elite basketball athletes with age-matched nonathletes, substratified by whether they had open or closed physes. We measured epiphyseal extension on radial-sequence MRI cuts throughout the cranial hemisphere from 9 o'clock (posterior) to 3 o'clock (anterior). Epiphyseal extension was correlated to alpha angle measurements at the same points. RESULTS Epiphyseal extension was increased in all positions in the athletes compared with the control group. On average, athletes showed epiphyseal extension of 0.67 to 0.83 versus 0.53 to 0.71 in control subjects. In the control group epiphyseal extension was increased at all measurement points in hips after physeal closure compared with before physeal closure. In contrast, the subgroup of athletes with a closed growth plate only had increased epiphyseal extension at the 3 o'clock position compared with the athletes with an open [corrected] growth plate (0.64-0.70). We observed a correlation between an alpha angle greater than 55° and greater epiphyseal extension in the anterosuperior femoral head quadrant: the corresponding Spearman r values were 0.387 (all hips) and 0.285 (alpha angle>55°) for the aggregate anterosuperior quadrant. CONCLUSIONS These findings suggest that a cam-type abnormality in athletes is a consequence of an alteration of the growth plate rather than reactive bone formation. High-level sports activity during growth may be a new and distinct risk factor for a cam-type deformity.

Ureteroileal Strictures After Urinary Diversion with an Ileal Segment—Is There a Place for Endourological Treatment at All?

Purpose We compared the long-term results of minimally invasive endourological intervention and open surgical revision in patients with a nonmalignant ureteroileal stricture. Materials and Methods We retrospectively evaluated the records of 74 patients (85 renal units) treated for unilateral or bilateral nonmalignant ureteroileal strictures. Overall, 96 endourological and 35 open surgical procedures were performed. Balloon dilatation and Acucise® or Ho:YAG laser endoureterotomy were used as minimally invasive endourological interventions. Open surgical revision with stricture resection and open ureteroileal end-to-side-reanastomosis was the alternate therapy. Treatment success was defined as radiological normalization or improvement of upper urinary tract morphology combined with absent flank pain, infection, ureteral stents or percutaneous nephrostomies. Results Median followup was 29 months (range 2 to 177). The overall success rate was 26% (25 of 96 cases) for endourological intervention vs 91% (32 of 35) for open surgical revision (p <0.001). Subgroup analysis showed a significant difference in the success rate of minimally invasive endourological interventions vs open surgical revision for strictures greater than 1 cm (3 of 52 cases or 6% vs 19 of 22 or 86%, p <0.001). The success rate of endourological and open surgical procedures for strictures 1 cm or less was 50% (22 of 44 cases) and 100% (13 of 13), respectively. After adjusting for multiple preoperative stricture characteristics, only stricture length was strongly and inversely associated with a successful outcome (p <0.001). Conclusions Open surgical revision produces better results than minimally invasive endourological intervention for ureteroileal strictures, particularly those greater than 1 cm. The success rate of endourological intervention is acceptable only for ureteroileal strictures 1 cm or less. Therefore, ureteroileal strictures greater than 1 cm should be primarily managed by open surgical revision.

CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response

The CCND1 gene encodes the protein CyclinD1, which is an important promoter of the cell cycle and a prognostic and predictive factor in different cancers. CCND1 is amplified to a substantial proportion in various tumors, and this may contribute to CyclinD1 overexpression. In bladder cancer, information about the clinical relevance of CCND1/CyclinD1 alterations is limited. In the present study, amplification status of CCND1 and expression of CyclinD1 were evaluated by fluorescence in situ hybridization and immunohistochemistry on tissue microarrays from 152 lymph node-positive urothelial bladder cancers (one sample each from the center and invasion front of the primary tumors, two samples per corresponding lymph node metastasis) treated by cystectomy and lymphadenectomy. CCND1 amplification status and the percentage of immunostained cancer cells were correlated with histopathological tumor characteristics, cancer-specific survival and response to adjuvant chemotherapy. CCND1 amplification in primary tumors was homogeneous in 15% and heterogeneous in 6% (metastases: 22 and 2%). Median nuclear CyclinD1 expression in amplified samples was similar in all tumor compartments (60-70% immunostained tumor nuclei) and significantly higher than in non-amplified samples (5-20% immunostained tumor nuclei; P<0.05). CCND1 status and CyclinD1 expression were not associated with primary tumor stage or lymph node tumor burden. CCND1 amplification in primary tumors (P=0.001) and metastases (P=0.02) and high nuclear CyclinD1 in metastases (P=0.01) predicted early cancer-related death independently. Subgroup analyses showed that chemotherapy was particularly beneficial in patients with high nuclear CyclinD1 expression in the metastases, whereas expression in primary tumors and CCND1 status did not predict chemotherapeutic response. In conclusion, CCND1 amplification status and CyclinD1 expression are independent risk factors in metastasizing bladder cancer. High nuclear CyclinD1 expression in lymph node metastases predicts favorable response to chemotherapy. This information may help to personalize prognostication and administration of adjuvant chemotherapy.

Unaltered oncological outcomes of radical cystectomy with extended lymphadenectomy over three decades

OBJECTIVE To evaluate oncological outcome trends over the last three decades in patients after radical cystectomy (RC) and extended pelvic lymph node (LN) dissection. PATIENTS AND METHODS Retrospective analysis of the University of Southern California (USC) RC cohort of patients (1488 patients) operated with intent to cure from 1980 to 2005 for biopsy confirmed muscle-invasive urothelial bladder cancer. To focus on outcomes of unexpected (cN0M0) LN-positive patients, the USC subset was extended with unexpected LN-positive patients from the University of Berne (UB) (combined subgroup 521 patients). Patients were grouped and compared according to decade of surgery (1980-1989/1990-1999/≥2000). Survival probabilities were calculated with Kaplan-Meier plots, log-rank tests compared outcomes according to decade of surgery, followed by multivariable verification. RESULTS The 10-year recurrence-free survival was 78-80% in patients with organ-confined, LN-negative disease, 53-60% in patients with extravesical, yet LN-negative disease and ≈30% in LN-positive patients. Although the number of patients receiving systemic chemotherapy increased, no survival improvement was noted in either the entire USC cohort, or in the combined LN-positive USC-UB cohort. In contrast, patient age at surgery increased progressively, suggesting a relative survival benefit. CONCLUSIONS Radical surgery remains the mainstay of therapy for muscle-invasive bladder cancer. Yet, our study reveals predictable outcomes but no survival improvement in patients undergoing RC over the last three decades. Any future survival improvements are likely to result from more effective systemic treatments and/or earlier detection of the disease.

Timing and outcomes for radical cystectomy in nonmuscle invasive bladder cancer

PURPOSE OF REVIEW To provide an overview on the available clinical and pathological factors in high-risk nonmuscle invasive bladder cancer (NMIBC) patients that help to approximate the risk of progression to muscle invasion and identify 'the' patients requiring timely cystectomy. The value of a high-quality transurethral tumor resection is pointed out. Outcomes following radical cystectomy are compared with a primarily bladder preserving strategy. RECENT FINDINGS Carcinoma in situ within the prostatic urethra of NMIBC patients impacts on patient's outcome. Therefore, biopsies taken from the prostatic urethra improve the initial tumor staging accuracy. Lamina propria substaging may provide more detailed prognostic information. Lympho-vascular invasion within the transurethral resection specimen may help to detect patients who benefit from timely cystectomy. Recent findings from patients undergoing radical cystectomy including super-extended lymphadenectomy for clinically NMIBC confirm the substantial rate (25%) of tumor understaging. The fact that almost 10% were found to harbor lymph node metastases underlines the necessity to perform a meticulous lymphadenectomy in NMIBC patients undergoing radical cystectomy. SUMMARY High-quality transurethral bladder tumor resection including underlying muscle fibers is of utmost importance. Nevertheless, tumor understaging remains an issue of concern and warrants the value of a second transurethral resection in high-risk NMIBC patients. There is a persisting lack of rigid therapeutic recommendations in patients with high-risk NMIBC. Instead, treatment strategy is based on individual risk factors. However, irrespective of initial treatment strategy, there is a subgroup of high-risk NMIBC patients with progressive disease, leading almost inevitably to death.