Outcomes for Young Men With Localized Intermediate-Risk Prostate Cancer: An Analysis of the NCDB.

BACKGROUND: Primary management of localized, intermediate-risk prostate cancer consists of radical prostatectomy (RP), radiotherapy (RT) with short-course androgen deprivation therapy (ADT), or RT alone. The purpose of this study was to determine if these treatment strategies have equivalent overall survival (OS) in patients < 55 years old with intermediate-risk prostate cancer. PATIENTS AND METHODS: We identified 35,134 patients in the National Cancer Data Base with localized intermediate-risk prostate cancer treated with RP, RT + ADT, or RT from 2004 to 2013. Ten-year OS rates were estimated by the Kaplan-Meier method. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were computed by multivariate Cox regression. RESULTS: A total of 29,920 patients (85.2%) underwent RP, 1393 (4.0%) RT + ADT, and 3821 (10.9%) RT. Median patient age was 51 years old, and median follow-up was 59.9 months. Ten-year OS was estimated to be 94.2% for RP, 80.7% for RT + ADT, and 85.2% for RT (P < .0001). On multivariate analysis, treatment with RT + ADT or RT was associated with significantly worse OS compared to treatment with RP (RT + ADT HR = 2.06, 95% CI 1.67-2.54, P < .0001; RT HR = 2.0, 95% CI 1.71-2.33, P < .0001). Patients who met all 3 of the intermediate-risk criteria showed worse OS compared to patients who met only one criterion (HR = 1.80; 95% CI, 1.32-2.44; P = .0002). CONCLUSION: RP is significantly more likely than RT + ADT or RT to be used as a primary treatment for young men with localized intermediate prostate cancer. RP was also associated with improved OS compared to RT + ADT and RT.

Extracellular matrix type modulates cell migration on mechanical gradients.

Extracellular matrix composition and stiffness are known to be critical determinants of cell behavior, modulating processes including differentiation, traction generation, and migration. Recent studies have demonstrated that the ECM composition can modulate how cells migrate in response to gradients in environmental stiffness, altering a cell's ability to undergo durotaxis. These observations were limited to single varieties of extracellular matrix, but typically cells are exposed to environments containing complex mixtures of extracellular matrix proteins. Here, we investigate migration of NIH 3T3 fibroblasts on mechanical gradients coated with one or more type of extracellular matrix protein. Our results show that NIH 3T3 fibroblasts exhibit durotaxis on fibronectin-coated mechanical gradients but not on those coated with laminin, demonstrating that extracellular matrix type can act as a regulator of cell response to mechanical gradients. Interestingly, NIH 3T3 fibroblasts were also observed to migrate randomly on gradients coated with a mixture of both fibronectin and laminin, suggesting that there may be a complex interplay in the cellular response to mechanical gradients in the presence of multiple extracellular matrix signals. These findings indicate that specific composition of available adhesion ligands is a critical determinant of a cell's migratory response to mechanical gradients.

Vascular smooth muscle cell durotaxis depends on extracellular matrix composition.

Mechanical compliance has been demonstrated to be a key determinant of cell behavior, directing processes such as spreading, migration, and differentiation. Durotaxis, directional migration from softer to more stiff regions of a substrate, has been observed for a variety of cell types. Recent stiffness mapping experiments have shown that local changes in tissue stiffness in disease are often accompanied by an altered ECM composition in vivo. However, the importance of ECM composition in durotaxis has not yet been explored. To address this question, we have developed and characterized a polyacrylamide hydrogel culture platform featuring highly tunable gradients in mechanical stiffness. This feature, together with the ability to control ECM composition, allows us to isolate the effects of mechanical and biological signals on cell migratory behavior. Using this system, we have tracked vascular smooth muscle cell migration in vitro and quantitatively analyzed differences in cell migration as a function of ECM composition. Our results show that vascular smooth muscle cells undergo durotaxis on mechanical gradients coated with fibronectin but not on those coated with laminin. These findings indicate that the composition of the adhesion ligand is a critical determinant of a cell's migratory response to mechanical gradients.

Waiting Time Between Failure of First Graft and Second Kidney Transplant and Graft and Patient Survival.

BACKGROUND: The number of patients with end-stage renal disease being relisted for a second kidney transplant is increasing worldwide. The aim of this study was to determine the relationship between waiting time for a second transplant and outcomes after that second transplant. METHODS: Using Australia and New Zealand Dialysis and Transplant registry, patients who have received second kidney transplants between 1997 and 2009 were included. The associations between waiting time, defined as duration of dialysis between first allograft failure and second transplantation, and clinical outcomes including acute rejection, graft and patient survival were examined using adjusted logistic and Cox regression models. RESULTS: Of the 911 recipients, the median follow-up time was 4.7 years resulting in 4825 person-years of follow-up. Increasing waiting time before second transplants was associated with an increased risk of early acute rejection occurring within the first 6 months after transplant (adjusted odds ratio, 1.11; 95% confidence interval [95% CI], 1.06-1.16; P < 0.001), severe vascular and/or humoral rejection (adjusted odds ratio, 1.06; 95% CI, 1.01-1.11; P = 0.011), overall graft failure (adjusted hazard ratio [HR], 1.06; 95% CI, 1.02-1.10; P = 0.001), all-cause mortality (adjusted HR, 1.13; 95% CI, 1.07-1.19; P < 0.001), and death with a functioning graft (adjusted HR, 1.12; 95% CI, 1.06-1.18; P < 0.001), independent of donor, recipient, and immunological factors. CONCLUSIONS: Prolonged waiting time for a second transplant was associated with inferior patient and graft outcomes.

The importance of genetic mutation screening to determine retransplantation following failed kidney allograft from recurrent atypical haemolytic ureamic syndrome.

We report the case of a patient with familial atypical haemolytic uraemic syndrome (aHUS) who underwent successful retransplantation 30 months following his failed first kidney allograft from recurrent aHUS. He achieved excellent graft function (creatinine 90 µmol/L), with no evidence of disease recurrence on standard maintenance immunosuppression 9 months after his second deceased donor kidney transplantation. Genetic mutation testing was not available prior to first transplant but screening prior to retransplant identified the patient as having a newly discovered mutation, c.T3566A, within exon 23 of the complement factor H (CFH) gene. Currently, public financing and subsidisation for eculizumab, a costly but effect complement (C5) inhibitor for the treatment of aHUS is not available in Australia. The decision for retransplantation must balance between the risk of disease recurrence and greater risk of death on dialysis. The absence of a more severe CFH genotype assisted in the decision for retransplantation and suggests the importance of genetic mutation screening in order to stratify the risk of disease recurrence and graft loss versus the benefit of transplantation.