A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer

PURPOSE: We developed a preoperative nomogram for prediction of lymph node metastases in patients with clinically localized prostate cancer. MATERIALS AND METHODS: The study was a retrospective, nonrandomized analysis of 7,014 patients treated with radical prostatectomy at 6 institutions between 1985 and 2000. Exclusion criteria consisted of preoperative androgen ablation therapy, salvage radical prostatectomy and pretreatment prostate specific antigen (PSA) greater than 50 ng/ml. Preoperative predictors of lymph node metastases consisted of pretreatment PSA, clinical stage (1992 TNM) and biopsy Gleason sum. These predictors were used in logistic regression analysis based nomograms to predict the probability of lymph node metastases. RESULTS: Overall 5,510 patients with complete clinical and pathological information were included in the study. Lymph nodes metastases were present in 206 patients (3.7%). Pretreatment PSA, biopsy Gleason sum, clinical stage and institution represented predictors of lymph node status (p <0.001). Bootstrap corrected predictive accuracy of the 3-variable nomogram (clinical stage, Gleason sum and PSA) was 0.76. Inclusion of a fourth variable, which accounts for institutional differences in lymph node metastases, yielded an area under the receiver operating characteristics curve of 0.78. The negative predictive value of our nomograms was 0.99 when they predicted 3% or less chance of positive lymph nodes. CONCLUSIONS: Using clinical information, we produced 2 calibrated and validated nomograms, which accurately predict pathologically negative lymph nodes in men with localized prostate cancer who are candidates for radical prostatectomy.     

Immunization of Mice with Formalin-Inactivated Spores from Avirulent Bacillus cereus Strains Provides Significant Protection from Challenge with Bacillus anthracis Ames

Bacillus anthracis spores are the infectious form of the organism for humans and animals. However, the approved human vaccine in the United States is derived from a vegetative culture filtrate of a toxigenic, nonencapsulated B. anthracis strain that primarily contains protective antigen (PA). Immunization of mice with purified spore proteins and formalin-inactivated spores (FIS) from a nonencapsulated, nontoxigenic B. anthracis strain confers protection against B. anthracis challenge when PA is also administered. To investigate the capacity of the spore particle to act as a vaccine without PA, we immunized mice subcutaneously with FIS from nontoxigenic, nonencapsulated B. cereus strain G9241 pBCXO1⁻/pBC210⁻ (dcG9241), dcG9241 ΔbclA, or 569-UM20 or with exosporium isolated from dcG9241. FIS vaccination provided significant protection of mice from intraperitoneal or intranasal challenge with spores of the virulent B. anthracis Ames or Ames ΔbclA strain. Immunization with dcG9241 ΔbclA FIS, which are devoid of the immunodominant spore protein BclA, provided greater protection from challenge with either Ames strain than did immunization with FIS from BclA-producing strains. In addition, we used prechallenge immune antisera to probe a panel of recombinant B. anthracis Sterne spore proteins to identify novel immunogenic vaccine candidates. The antisera were variably reactive with BclA and with 10 other proteins, four of which were previously tested as vaccine candidates. Overall our data show that immunization with FIS from nontoxigenic, nonencapsulated B. cereus strains provides moderate to high levels of protection of mice from B. anthracis Ames challenge and that neither PA nor BclA is required for this protection.     

Prognostic factors in male urethral cancer

BACKGROUND:

Male urethral cancer is a rare neoplasm, with the published literature consisting of small single‐institution retrospective series. As such, there is no objective analysis of prognostic factors and treatment outcome. The author sought to use the population‐based Surveillance, Epidemiology, and End Results (SEER) database to evaluate prognostic factors in male urethral cancer.

METHODS:

From 1988 to 2006, 2065 men were identified in the SEER database as having primary urethral cancer. Median follow‐up was 2.5 years. Cancer‐specific and overall survival was computed using the Kaplan‐Meier method, and Cox proportional hazards analysis was used to evaluate patient age at diagnosis, year of diagnosis, race, histologic type, grade, T stage, nodal status, M stage, extent of surgery, and type of radiation as potential significant independent predictors of survival.

RESULTS:

Overall survival at 5 and 10 years was 46.2% (95% confidence interval [CI], 43.9‐48.6%) and 29.3% (95% CI, 26.6‐32.0%), respectively, whereas cancer‐specific survival at 5 and 10 years was 68.0% (95% CI, 65.5‐70.5%) and 60.1% (95% CI, 57.0‐63.2%), respectively. Advanced age, higher grade, higher T stage, systemic metastases, other histology versus transitional cell carcinoma (TCC), and no surgery versus radical resection were predictors of death and death from disease, whereas adenocarcinoma was associated with a lower likelihood of death and death from disease as compared with TCC. In addition, nodal metastasis was a predictor of death. Surgery had a better outcome than radiation for stage T₂‐T₄ nonmetastatic disease.

CONCLUSIONS:

Age, grade, TNM stage, histology, and extent of surgery were predictive of overall and cancer‐specific survival. Cancer 2011. © 2010 American Cancer Society.     

Mutation in CYP27A1 identified in family with coronary artery disease

Coronary artery disease (CAD) is a leading cause of death worldwide. Myocardial infarction is the most severe outcome of CAD. Despite extensive efforts, the genetics of CAD is poorly understood. We aimed to identify the genetic cause of CAD in a pedigree with several affected individuals. Exome sequencing led to identification of a mutation in CYP27A1 that causes p.Arg225His in the encoded protein sterol 27-hydroxylase as the likely cause of CAD in the pedigree. The enzyme is multifunctional, and several of its functions including its functions in vitamin D metabolism and reverse cholesterol transport (RCT) are relevant to the CAD phenotype. Measurements of vitamin D levels suggested that the mutation does not affect CAD by affecting this parameter. We suggest that the mutation may cause CAD by affecting RCT. Screening of all coding regions of the CYP27A1 in 100 additional patients led to finding four variations (p.Arg14Gly, p.Arg26Lys, p.Ala27Arg, and p.Val86Met) in seven patients that may contribute to their CAD status. CYP27A1 is the known causative gene of cerebrotendinous xanthomatosis, a disorder which is sometimes accompanied by early onset atherosclerosis. This and the observation of potentially harmful variations in unrelated CAD patients provide additional evidence for the suggested causative role of the p.Arg225His mutation in CAD.     

Evaluation of osteogenic cell differentiation in response to bone morphogenetic protein or demineralized bone matrix in a critical sized defect model using GFP reporter mice

We evaluated the osteoprogenitor response to rhBMP‐2 and DBM in a transgenic mouse critical sized defect. The mice expressed Col3.6GFPtopaz (a pre‐osteoblastic marker), Col2.3GFPemerald (an osteoblastic marker) and α‐smooth muscle actin (α‐SMA‐Cherry, a pericyte/myofibroblast marker). We assessed defect healing at various time points using radiographs, frozen, and conventional histologic analyses. GFP signal in regions of interest corresponding to the areas of new bone formation was quantified using a novel computer assisted algorithm. All defects treated with rhBMP‐2 healed. In contrast, the majority of the defects in the DBM (27/30) and control (28/30) groups did not heal. Quantitation of pre‐osteoblasts demonstrated a maximal response (% GFP+ cells/TV) in the Col3.6GFPtopaz mice at day 7 (7.2% ± 6.0, p < 0.05 compared to days 14, 21, 28, and 56). The maximal response of the Col2.3GFP cells was seen at days 14 (8.04% ± 5.0) and 21 (8.31% ± 4.32), p < 0.05. In contrast, DBM and control groups showed a limited osteogenic response at all time points. In conclusion, we demonstrated that the BMP and DBM induce vastly different osteogenic responses which should influence their clinical application as bone graft substitutes. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1120–1128, 2014.     

Complications of lymphadenectomy in urologic surgery

Lymphadenectomy in urologic surgery provides accurate staging and may be therapeutic in some patients with lymph node metastases. In addition to the associated cost, pelvic lymph node dissection (PLND) has the potential for morbidity. This article focuses on the complications associated with PLND, including lymphocele, thromboembolic events, ureteral injury, nerve injury, vascular injury, and lymphedema. With improvements in surgical technique and perioperative care, the morbidity associated with lymphadenectomy may be minimized.