Impact of paraaortic lymphadenectomy for endometrial cancer with positive pelvic lymph nodes: A Korean Radiation Oncology Group study (KROG 13-17).

AIM: We investigated the role of paraaortic lymph node dissection (PALND) in patients with stage IIIC1 endometrial carcinoma after surgery followed by adjuvant radiotherapy (RT) alone or chemoradiotherapy (CTRT). METHODS: We performed a subgroup analysis in 151 patients treated with adjuvant pelvic RT. Paraaortic-recurrence free survival, disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: In adjuvant RT alone, PALND was significantly related to reduced risk of paraaortic recurrence (0% vs. 17.1%) and distant metastasis (4.5% vs. 19.5%) compared with the no PALND group. PALND affected 5-year DFS (90.2% vs. 58.9%, p = 0.016) and OS (100% vs. 83.1%, p = 0.022). For the CTRT group, the paraaortic recurrence rate was 19.5% for the no PALND group and 12.8% for the PALND group (p = 0.682). Of patients who underwent PALND in the CTRT group, less extensive PALND was significantly related to increased paraaortic recurrence (≤10 vs. >10 dissected LNs, 17.1% vs. 0%). In the no PALND group (n = 82), 5-year paraaortic-recurrence free survival was 79.4% for the CTRT group and 76.2% for the RT alone group (p = 0.941). In multivariate analysis, PALND was significantly associated with reduced risk of disease-specific death (HR, 0.50; 95% CI, 0.26-0.96; p = 0.037). CONCLUSION: PALND provided excellent paraaortic control and improved outcome in stage IIIC1 endometrial cancer with favorable tumor features treated with adjuvant RT alone. Less extensive PALND was associated with significantly increased paraaortic recurrence in patients with advanced tumor features treated with adjuvant CTRT. Combined CTRT did not affect disease control in the paraaortic region compared with RT alone.

Arteriovenous access creation defers chronic hemodialysis initiation.

AIMS: This study evaluated whether arteriovenous access (AVA) creation before hemodialysis might affect the rate of decline of renal function. METHODS: This was a retrospective, case-control study comparing two groups of 80 patients each. The AVA group underwent AVA creation more than 2 months before initiation of chronic hemodialysis (CHD). The catheter group (i.e., the control group) commenced CHD through a temporary catheter. The catheter group patients were matched with AVA group patients in terms of age, gender, nature of underlying disease, and rate of decline in estimated glomerular filtration rate (eGFR) before AVA creation. The zero point (Z-point) was defined as the date of AVA creation for AVA patients, or the date on which the same eGFR was attained by each catheter group patient compared with a matched AVA patient. Time-to-dialysis was defined as the interval from the Z-point to the date of initiation of dialysis. The rates of change in eGFR before and after the Z-point were also measured. RESULTS: The AVA and catheter groups were similar in terms of baseline characteristics. The Z-point eGFR (ml/min/1.73 m2) was 11.4±3.1 in the AVA group and 11.3±3.2 in the catheter group. The eGFR at the time of dialysis was 6.4±2.0 in the AVA group and 6.1±1.9 in the catheter group. The mean and median dialysis-free time was longer in the AVA than in the catheter group (14.2±9.4 vs. 5.9±4.1 months, 13.1 (3-41) vs. 5.0 (2-17) months, p<0.001). Multivariate proportional Cox's hazard modeling showed that the AVA group and the Z-point eGFR were each independent predictors of the time to initiation of CHD. The mean changes in eGFR per month (delta eGFR) before the Z-point were similar for the two groups. For the AVA group, the mean delta eGFR was lower after the Z-point compared to before (-0.63 vs. -0.21 ml/min/1.73 m2, p=0.002). For the catheter group, the mean delta eGFR was similar before and after the Z-point (-0.63 vs. -0.67 ml/min/1.73 m2). The mean delta eGFR after the Z-point was less in the AVA group compared to the catheter group (-0.67 vs. -0.21 ml/min/1.73 m2, p=0.002). CONCLUSION: In this retrospective observational study, AVA creation appears to retard the rate of decline in eGFR and to defer CHD initiation.

Nutritional markers, not markers of bone turnover, are related predictors of bone mineral density in chronic peritoneal dialysis patients.

BACKGROUND AND AIMS: this study evaluated the factors associated with bone mineral density (BMD) in chronic peritoneal dialysis (CPD) patients. METHODS: in this cross-sectional study in 91 stable CPD patients, BMD was measured using dual-energy X-ray absorptiometry. Markers of bone turnover (iPTH, osteocalcin, bone alkaline phosphatase, serum C-telopeptide), 25-hydroxy (OH) vitamin D3 and nutritional markers (prealbumin, nPNA, BMI) were measured by standard techniques. RESULTS: of the 91 patients, 48 were female and 22 (24%) had Type 2 diabetes. Mean age of the patients was 52.7, and patients had been on PD for about 44 months. For the lumbar spine (LS) and femoral neck (FN), the mean T-scores were -1.19 ± 1.53 and -1.24 ± 1.01, respectively, and the mean Z-scores were -0.78 ± 1.33 and -0.40 ± 0.92, respectively. Using the WHO-based criteria, osteopenia (-2.5 < T-score < -1.0) at the LS and FN was observed in 37 (41%) and 48 (53%) patients, respectively, and osteoporosis (T-score <= -2.5) at the LS and FN was observed in 15 (17%) and 6 (7%) patients, respectively. LS T-score was positively correlated with BMI (r = 0.40, p < 0.001) and albumin (r = 0.29, p = 0.005), and FN T-score was positively correlated with albumin (r = 0.40, p < 0.001), prealbumin (r = 0.38, p < 0.001), age (r = -0.32, p = 0.002) and BMI (r = 0.29, p < 0.006). Markers of bone turnover were not associated with BMD. In multiple linear regression models, independent predictors of FN T-score were age, BMI, albumin and prealbumin (r(2) = 0.259, F = 6.23, p < 0.001), whereas BMI was the only independent predictor of LS T-score (r(2) = 0.24, F = 6.63, p < 0.001). CONCLUSION: nutritional markers, not markers of bone turnover, are correlated predictors of BMD in CPD patients.

A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys.

Cathepsin K is an osteoclast-derived cysteine protease that has been implicated as playing a major role in bone resorption. A substantial body of evidence indicates that cathepsin K is critical in osteoclast-mediated bone resorption and suggests that its pharmacological inhibition should result in inhibition of bone resorption in vivo. Here we report the pharmacological characterization of SB-462795 (relacatib) as a potent and orally bioavailable small molecule inhibitor of cathepsin K that inhibits bone resorption both in vitro in human tissue and in vivo in cynomolgus monkeys. SB-462795 is a potent inhibitor of human cathepsins K, L, and V (K(i, app)=41, 68, and 53 pM, respectively) that exhibits 39-300-fold selectivity over other cathepsins. SB-462795 inhibited endogenous cathepsin K in situ in human osteoclasts and human osteoclast-mediated bone resorption with IC50 values of approximately 45 nM and approximately 70 nM, respectively. The anti-resorptive potential of SB-462795 was evaluated in normal as well as medically ovariectomized (Ovx) female cynomolgus monkeys. Serum levels of the C- and N-terminal telopeptides of Type I collagen (CTx and NTx, respectively) and urinary levels of NTx were monitored as biomarkers of bone resorption. Administration of SB-462795 to medically ovariectomized or normal monkeys resulted in an acute reduction in both serum and urinary markers of bone resorption within 1.5 h after dosing, and this effect lasted up to 48 h depending on the dose administered. Our data indicate that SB-462795 potently inhibits human cathepsin K in osteoclasts, resulting in a rapid inhibition of bone resorption both in vitro and in vivo in the monkey. These studies also demonstrate the therapeutic potential of relacatib in the treatment of postmenopausal osteoporosis and serves to model the planned clinical trials in human subjects.

On topography and functionality in the B-D rings of cephalostatin cytotoxins.

Analogues 12'beta-hydroxycephalostatin 1 (9), 7'-deoxyritterazine G (10), and 14-epi-7'-deoxyritterazine B (11) were prepared via our protocol for unsymmetrical pyrazine synthesis. Cytotoxicity against human tumors was also determined for the first time for ritterazines, with femtomolar potency and a high correlation to cephalostatins observed. The SAR of these and related compounds provide insight into the importance of topography and certain chemical functionality in the B-D and B'-D' rings of cephalostatin type antineoplastics.