Citations

Purpose An increasing serum prostate-specific antigen (PSA) level is the initial sign of recurrent prostate cancer among patients treated with radical prostatectomy. Salvage radiation therapy (SRT) may eradicate locally recurrent cancer, but studies to distinguish local from systemic recurrence lack adequate sensitivity and specificity. We developed a nomogram to predict the probability of cancer control at 6 years after SRT for PSA-defined recurrence. Patients and Methods Using multivariable Cox regression analysis, we constructed a model to predict the probability of disease progression after SRT in a multi-institutional cohort of 1,540 patients. Results The 6-year progression-free probability was 32% (95% CI, 28% to 35%) overall. Forty-eight percent (95% CI, 40% to 56%) of patients treated with SRT alone at PSA levels of 0.50 ng/mL or lower were disease free at 6 years, including 41% (95% CI, 31% to 51%) who also had a PSA doubling time of 10 months or less or poorly differentiated (Gleason grade 8 to 10) cancer. Significant variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSA doubling time (P < .001), surgical margins (P < .001), androgen-deprivation therapy before or during SRT (P < .001), and lymph node metastasis (P = .019). The resultant nomogram was internally validated and had a concordance index of 0.69. Conclusion Nearly half of patients with recurrent prostate cancer after radical prostatectomy have a long-term PSA response to SRT when treatment is administered at the earliest sign of recurrence. The nomogram we developed predicts the outcome of SRT and should prove valuable for medical decision making for patients with a rising PSA level.

AbstractTLRs are usually thought to recognize substances produced by microorganisms and thus, to initiate host defenses. This concept, however, fails to explain some functions of this family of receptors. Recognition of endogenous substances may explain the broader functions of TLRs in physiology and disease. Activation of TLRs by endogenous substances necessitates vigorous control of the function of the receptors. This communication will summarize a line of research, which points to an endogenous agonist for TLR4 and a putative mechanism for controlling the function of that receptor.

Purpose Controversy exists regarding estrogen (ER) and progesterone (PgR) receptor expression on efficacy of adjuvant endocrine therapy. In the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, the benefit of anastrozole over tamoxifen was substantially greater in ER+/PgR–than ER+/PgR+ tumors. In BIG 1-98 (Breast International Group), the benefits of letrozole over tamoxifen were the same in ER+ tumors irrespective of PgR. MA.17 randomized postmenopausal women after 5 years of tamoxifen, to letrozole or placebo. We present outcomes according to tumor receptor status. Patients and Methods Disease-free survival (DFS) and other outcomes were assessed in subgroups by ER and PgR status using Cox's proportional hazards model, adjusting for nodal status and prior adjuvant chemotherapy. Results The DFS hazard ratio (HR) for letrozole versus placebo in ER+/PgR+ tumors (N = 3,809) was 0.49 (95% CI, 0.36 to 0.67) versus 1.21 (95% CI, 0.63 to 2.34) in ER+/PgR–tumors (n = 636). ER+/PgR+ letrozole patients experienced significant benefit in distant DFS (DDFS; HR = 0.53; 95% CI, 0.35 to 0.80) and overall survival (OS; HR = 0.58; 95% CI, 0.37 to 0.90). A statistically significant difference in treatment effect between ER+/PgR+ and ER+/PgR–subgroups for DFS was observed (P = .02), but not for DDFS (P = .06) or OS (P = .09). Conclusion These results suggest greater benefit for letrozole in DFS, DDFS, and OS in patients with ER+/PgR+ tumors, implying greater activity of letrozole in tumors with a functional ER. However, because this is a subset analysis and receptors were not measured centrally, we caution against using these results for clinical decision making.

Abstract Estrogen-induced Syrian hamster tumors in the kidney represent a useful model to gain insight into the role of estrogens in oncogenic processes. We provided evidence that early tumor foci in the kidney arise from interstitial ectopic uterine-like germinal stem cells, and that early tumor foci and well-established tumors are highly aneuploid (92–94%). The molecular mechanisms whereby estrogens mediate this process are unclear. Here, we report that estrogen treatment induced significant increases in Aurora A protein expression (8.7-fold), activity (2.6-fold), mRNA (6.0-fold), and Aurora B protein expression (4.6-fold) in tumors, compared with age-matched cholesterol-treated kidneys. Immunohistochemistry revealed that this increase in Aurora A and B protein expression was essentially confined to cells within early and large tumor foci at 3.5 and 6 months of estrogen treatment, respectively. Upon estrogen withdrawal or coadministration of tamoxifen for 10 days, a 78% to 79% and 81% to 64% reduction in Aurora A and B expression, respectively, were observed in primary tumors compared with tumors continuously exposed to estrogens. These data indicate that overexpressed Aurora A and B in these tumors are under estrogen control via estrogen receptor α. Aurora A coenriched with the centrosome fraction isolated from tumors in the kidney. Centrosome amplification (number and area/cell) was detected in early tumor foci and large tumors but not in adjacent uninvolved or age-matched control kidneys. Taken together, these data indicate that persistent overexpression of Aurora A and B is under estrogen control, and is coincident with centrosome amplification, chromosomal instability, and aneuploidy, and represent an important mechanism driving tumorigenesis. [Cancer Res 2007;67(7):2957–63]

Abstract High-risk susceptibility genes explain &lt;40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)–tagging approach to evaluate common variants in 13 genes involved in cell cycle control—CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D—and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark (∼1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States (∼2,000 cases and ∼3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85–0.98) for rs3731257; and OR, 0.93 (0.87–0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies. [Cancer Res 2007;67(7):3027–35]

The peripheral nerve of experimental diabetic neuropathy (EDN) is reported to be ischemic and hypoxic, with an increased dependence on anaerobic metabolism, requiring increased energy substrate stores. When glucose stores become reduced, fiber degeneration has been reported. We evaluated glucose uptake, nerve energy metabolism, the polyol pathway, and protein kinase C (PKC) activity in EDN induced by streptozotocin. Control and diabetic rats received lipoic acid (0, 10, 25, 50, 100 mg/kg). Duration of diabetes was 1 month, and alpha-lipoic acid was administered intraperitoneally 5 times per week for the final week of the experiment. Nerve glucose uptake was reduced to 60, s 37, and 30% of control values in the sciatic nerve, L5 dorsal root ganglion, and superior cervical ganglion (SCG), respectively, in rats with EDN. Alpha-lipoic acid supplementation had no effect on glucose uptake in normal nerves at any dose, but reversed the deficit in EDN, with a threshold between 10 and 25 mg/kg. Endoneurial glucose, fructose, sorbitol, and myo-inositol were measured in sciatic nerve. Alpha-lipoic acid had no significant effect on either energy metabolism or polyol pathway of normal nerves. In EDN, endoneurial glucose, fructose, and sorbitol were significantly increased, while myo-inositol was significantly reduced. Alpha-lipoic acid had a biphasic effect: it dose-dependently increased fructose, glucose, and sorbitol, peaking at 25 mg/kg, and then fell beyond that dose, and it dose-dependently increased myo-inositol. Sciatic nerve cytosolic PKC was increased in EDN. ATP, creatine phosphate, and lactate were measured in sciatic nerve and SCG. Alpha-lipoic acid prevented the reduction in SCG creatine phosphate. We conclude that glucose uptake is reduced in EDN and that this deficit is dose-dependently reversed by alpha-lipoic acid, a change associated with an improvement in peripheral nerve function.