Selecting Patients with Favorable Risk, Grade Group 2 Prostate Cancer for Active Surveillance-Does Magnetic Resonance Imaging Have a Role?

PURPOSE: The National Comprehensive Cancer Network® recommends that selected men with grade group 2 prostate cancer be considered for active surveillance. However, selecting which patients with grade group 2 disease can be safely managed by active surveillance remains controversial. The aim of this study was to evaluate the association of multiparametric magnetic resonance imaging with adverse pathology in the radical prostatectomy specimen of men with favorable risk grade group 2 prostate cancer, which could help select patients for active surveillance. MATERIALS AND METHODS: We retrospectively analyzed a cohort of patients with favorable grade group 2 disease who underwent radical prostatectomy between 2010 and 2019. Preoperative multiparametric magnetic resonance imaging was scored as negative (no identifiable lesion), positive (identifiable lesion) or equivocal. We defined a multivariable logistic regression model with multiparametric magnetic resonance imaging score as the predictor and adverse pathology (up staging to T3a/b disease, upgrading to ≥grade group 3 or lymph node invasion) as the outcome, adjusting for preoperative prostate specific antigen, biopsy Gleason grade, clinical stage, and number of negative and positive prostate biopsy cores. Secondary outcomes of biochemical recurrence, grade group upgrading alone and the added value of incorporating multiparametric magnetic resonance imaging data into the nomogram were also investigated. RESULTS: We identified 1,117 patients with favorable risk grade group 2 disease who underwent radical prostatectomy. Positive multiparametric magnetic resonance imaging was associated with higher rates of adverse pathology (OR 2.55, 95% CI 1.75-3.40, p <0.0001) and upgrading (OR 3.89, 95% CI 2.00-7.56, p <0.0001). However, as our study included only grade group 2 patients who underwent radical prostatectomy, our cohort may represent a higher risk group than grade group 2 patients as a whole. Adding multiparametric magnetic resonance imaging results to a standard prediction model led to higher net benefit on decision curve analysis. An identifiable lesion on multiparametric magnetic resonance imaging was associated with an increased risk of aggressive pathological features in the radical prostatectomy specimen of patients with favorable risk grade group 2 prostate cancer who were potential active surveillance candidates. This information could be used to inform biopsy strategy, counsel patients on treatment options and guide strategies for those on active surveillance. CONCLUSIONS: Combining multiple magnetic resonance imaging modalities (multiparametric magnetic resonance imaging) provides a more accurate prediction of the risk presented by prostate cancer than current prediction methods. In this study, positive magnetic resonance imaging results approximately doubled the chances that a patient with favorable risk prostate cancer would be found to have adverse pathology when their prostate was removed. Thus, multiparametric magnetic resonance imaging could help select patients with favorable risk cancer who may be good candidates for active surveillance, and help guide biopsy and surveillance strategies for such patients.

Determining conventional and unconventional oil and gas well brines in natural samples I: Anion analysis with ion chromatography.

Unconventional natural gas extraction by hydraulic fracturing requires millions of gallons of water and generates flowback water, produced water and recycled fluids of varying chemical composition. Ion chromatography (IC) is a relatively low cost and efficient means to determine the anionic composition, however, the wide range in anionic content of these fluids poses a challenge to analytical methods developed for "natural" waters. We report here that the combination of UV and conductivity detectors increased detection sensitivity (e.g., 10-50 ppb) and expanded the number of anions detectable in a single sample run. Samples from four unconventional shale gas wells, two impoundments, nine conventional oil wells, two freshwater streams and mine drainage samples were analyzed in this study. All produced water samples and impoundment samples had high chloride (17,500-103,000 mg L-1, 93,900 to 134,000 mg L-1, 27,700 and 30,700 mg L-1), bromide (178-996 mg L-1, 183-439 mg L-1, 230 and 260 mg L-1) and conductivity (38,500-160,000 µS/cm3, 95,300 to 183,000 µS/cm3, 61,500 and 103,000 µS/cm3), respectively, relative to mine drainage and freshwater stream samples. Molar ratio analysis using Cl-/Br- to Cl- and SO42-/Cl- to Br- revealed significant differences between the samples, providing a simple means for distinguishing water impacted by different sources of contamination.

Evidence for changing nerve growth factor signalling mechanisms during development, maturation and ageing in the rat molar pulp.

AIM: To examine rat molar pulp innervation and identify complex cellular signalling systems involving nerve growth factor (NGF) and its p75 receptors (NGFR) at different stages of development, maturation and ageing. METHODOLOGY: Decalcified mandibular first molar mesial cusps from Wistar rats of ages 0 day; 1, 2, 3, 4, 6, 9, 12 and 24 weeks (n = 5 per group) were sectioned (10 µm) and incubated with antibodies for NGF, NGFR, calcitonin gene-related peptide (CGRP) and neurofilament. Nerve densities in worn and intact regions of 3- to 24-week-old rats were compared by anova, Bonferroni and t-tests. RESULTS: During odontogenesis, differences in NGF and NGFR expression were observed, with no evidence of nerve fibres, suggesting a signalling mechanism controlling cellular differentiation and dentine formation. Tooth wear in 4-week rats was associated with reduced NGF expression and significantly decreased CGRP axons within affected odontoblast regions. The underlying subodontoblasts started expressing NGF which continued until 9 weeks. This may promote a significant increase in CGRP nerve density in affected regions. Nerve density in intact odontoblast regions increased gradually and reached significant levels in 12-week rats. Reduction in nerve densities within worn and intact regions of cusps was observed at 24 weeks. CONCLUSIONS: Age-related changes and responses to tooth wear may be controlled by the NGF signalling mechanism, with roles in odontoblast/subodontoblast communication and control of sensory innervation at different stages of tooth development, maturation and ageing. Greater understanding of cellular and nerve regulation in the injured pulp may promote therapeutic strategies for pulp survival.

The evolution of chemotherapy for the treatment of prostate cancer.

Chemotherapy has been explored as a treatment option for metastatic prostate cancer since the early 1980s. Docetaxel, a taxane chemotherapeutic, was approved for the treatment of men with metastatic castration-resistant prostate cancer in 2004, and is now standard of care for late stage disease. Recent clinical studies demonstrated that patients with metastatic castration-sensitive disease, and possibly those with high-risk localized prostate cancer also benefit from docetaxel administration, expanding the role of chemotherapy in the prostate cancer treatment landscape. Another taxane, cabazitaxel, is approved for post-docetaxel metastatic castration-resistant prostate cancer. Taxanes and other chemotherapeutics, such as carboplatin, are now being tested in combination regimens. This review presents an outline of recent and ongoing clinical studies assessing docetaxel and its derivative cabazitaxel at different stages of the disease, and in various combinations with other agents. We summarize current knowledge on biomarkers predictive of response to chemotherapy, which may in future be used to guide individualized treatment decisions.

An analysis of the association between prostate cancer risk loci, PSA levels, disease aggressiveness and disease-specific mortality.

BACKGROUND: Genome-wide association studies have identified multiple single-nucleotide polymorphsims (SNPs) associated with prostate cancer (PCa). Although these SNPs have been clearly associated with disease risk, their relationship with clinical outcomes is less clear. Our aim was to assess the frequency of known PCa susceptibility alleles within a single institution ascertainment and to correlate risk alleles with disease-specific outcomes. METHODS: We genotyped 1354 individuals treated for localised PCa between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to phenotypic data. We investigated associations between 61 SNPs and disease-specific end points using multivariable analysis and also determined if SNPs were associated with PSA at diagnosis. RESULTS: Seven SNPs showed associations on multivariable analysis (P<0.05), rs13385191 with both biochemical recurrence (BR) and castrate metastasis (CM), rs339331 (BR), rs1894292, rs17178655 and rs11067228 (CM), and rs11902236 and rs4857841 PCa-specific mortality. After applying a Bonferroni correction for number of SNPs (P<0.0008), the only persistent significant association was between rs17632542 (KLK3) and PSA levels at diagnosis (P=1.4 × 10(-5)). CONCLUSIONS: We confirmed that rs17632542 in KLK3 is associated with PSA at diagnosis. No significant association was seen between loci and disease-specific end points when accounting for multiple testing. This provides further evidence that known PCa risk SNPs do not predict likelihood of disease progression.

Keel bone fractures induce a depressive-like state in laying hens.

In commercial flocks of laying hens, keel bone fractures (KBFs) are prevalent and associated with behavioural indicators of pain. However, whether their impact is severe enough to induce a depressive-like state of chronic stress is unknown. As chronic stress downregulates adult hippocampal neurogenesis (AHN) in mammals and birds, we employ this measure as a neural biomarker of subjective welfare state. Radiographs obtained longitudinally from Lohmann Brown laying hens housed in a commercial multi-tier aviary were used to score the severity of naturally-occurring KBFs between the ages of 21-62 weeks. Individual birds' transitions between aviary zones were also recorded. Focal hens with severe KBFs at 3-4 weeks prior to sampling (n = 15) had lower densities of immature doublecortin-positive (DCX+) multipolar and bipolar neurons in the hippocampal formation than focal hens with minimal fractures (n = 9). KBF severity scores at this time also negatively predicted DCX+ cell numbers on an individual level, while hens that acquired fractures earlier in their lives had fewer DCX+ neurons in the caudal hippocampal formation. Activity levels 3-4 weeks prior to sampling were not associated with AHN. KBFs thus lead to a negative affective state lasting at least 3-4 weeks, and management steps to reduce their occurrence are likely to have significant welfare benefits.

Ki-67 and outcome in clinically localised prostate cancer: analysis of conservatively treated prostate cancer patients from the Trans-Atlantic Prostate Group study.

Treatment decisions after diagnosis of clinically localised prostate cancer are difficult due to variability in tumour behaviour. We therefore examined one of the most promising biomarkers in prostate cancer, Ki-67, in a cohort of 808 patients diagnosed with prostate cancer between 1990 and 1996 and treated conservatively. Ki-67 expression was assessed immunohistochemically, in two laboratories, by two different scoring methods and the results compared with cancer-specific and overall survival. The power of the biomarker was compared with Gleason score and initial serum prostate-specific antigen (PSA). Both methods showed that Ki-67 provided additional prognostic information beyond that available from Gleason score and PSA: for the semi-quantitative method, Deltachi(2) (1 d.f.)=24.6 (P<0.0001), overall survival chi(2)=20.5 (P<0.0001), and for the quantitative method, Deltachi(2) (1 d.f.)=15.1 (P=0.0001), overall survival chi(2)=10.85 (P=0.001). Ki-67 is a powerful biomarker in localised prostate cancer and adds to a model predicting the need for radical or conservative therapy. As it is already in widespread use in routine pathology, it is confirmed as the most promising biomarker to be applied into routine practice.

Evidence for programmed odontoblast process retraction after dentine exposure in the rat incisor.

OBJECTIVE: To re-examine the morphology and potential functions of odontoblasts in intact rat incisors and after cavity preparation into dentine. DESIGN: Intact incisors were fixed, decalcified, snap frozen and sectioned (10µm), before staining with rhodamine phalloidin or antibodies for cyto-skeletal proteins: vimentin and actin, ion transporter: NaK-ATPase, and dendritic cell marker: OX6. Samples with cavity were processed similarly and stained for actin and vimentin before comparing the lengths of odontoblast processes (OP) at baseline, 3h and 24h (n=5 for each group). RESULTS: Actin was expressed through the full length of OP, while vimentin immunoreactivity was not uniform, with 4 distinct regions. OP showed morphological complexity with fine branches emanating within different regions of dentine. Novel actin-positive tree-like OP were identified within predentine which reduced in intensity and length toward the incisal portion of the tooth. Specimens with cavities showed time-dependant pulpal retraction of OP. CONCLUSIONS: Differences in structural antibody expression suggest functional variations in OP within different regions of dentine. The role of actin positive OP in predentine is not known, but could be related to dentine deposition, cellular stability or sensing mechanisms. Cavity preparation into dentine was followed by programmed retraction of OP which could be controlled either mechanically by the spatial limitation of the OP within dentinal tubules or structurally by the presence of vimentin, in addition to actin, in the mid-dentine.

Updated postoperative nomogram incorporating the number of positive lymph nodes to predict disease recurrence following radical prostatectomy.

BACKGROUND: A significant number of patients with minimal lymph node disease at radical prostatectomy (RP) and pelvic lymph node dissection (PLND) have better than expected long-term outcomes. We explored whether stratification by number of positive nodes enhances our institutional prediction model for biochemical recurrence after RP. METHODS: A total of 7789 patients underwent RP and pelvic lymph node dissection from 1995 to 2012 at a tertiary referral center. We compared two recurrence prediction models: one incorporated lymph node invasion and the other tracked the number of positive nodes. Existing and updated models' discrimination was assessed using Harrell's c-index and calibration. The 10-fold cross-validation was performed to correct for model overfitting. RESULTS: Of the 491 patients (6.3%) harboring nodal disease, 387 (5.0%) had 1-2 positive nodes and 104 (1.3%) had ⩾3 positive nodes. Data on number of positive nodes did not improve the c-index for the cohort as a whole. When we assessed discrimination for node-positive patients only, c-index for the model with number of positive nodes was 0.01 (95% confidence interval 0.001-0.024) higher than the model with lymph node invasion. Illustrative examples were provided by reclassification tables using number of positive lymph nodes. For instance, 40 of 7789 patients would be reclassified with a cutoff point of 50% for biochemical recurrence at 1 year, and 36 of 7789 patients would be reclassified with a cutoff point of 40% for biochemical recurrence at 10 years. CONCLUSIONS: Stratification by number of positive lymph nodes provided additional discriminative ability for evaluating risk in node-positive patients. Pending external validation, this model could be used for patient counseling and clinical trial stratification in this subpopulation.

Periprostatic adipose inflammation is associated with high-grade prostate cancer.

BACKGROUND: Obesity, a cause of subclinical inflammation, is associated with increased risk of high-grade prostate cancer (PC) and poor outcomes. Whether inflammation occurs in periprostatic white adipose tissue (WAT), and contributes to the negative impact of obesity on PC aggressiveness, is unknown. METHODS: In a single-center, cross-sectional design, men with newly diagnosed PC undergoing radical prostatectomy were eligible for study participation. The primary objective was to examine the prevalence of periprostatic WAT inflammation defined by the presence of crown-like structures (CLS-P) as detected by CD68 immunohistochemistry. Secondary objectives were to explore the clinical and systemic correlates of periprostatic WAT inflammation. Tumor characteristics and host factors including BMI, adipocyte diameter, and circulating levels of lipids, adipokines, and other metabolic factors were measured. Wilcoxon rank-sum, Chi-square, or Fisher's exact tests, and generalized linear regression were used to examine the association between WAT inflammation and tumor and host characteristics. RESULTS: Periprostatic fat was collected from 169 men (median age 62 years; median BMI 28.3). Periprostatic WAT inflammation was identified in 49.7% of patients and associated with higher BMI (P=0.02), larger adipocyte size (P=0.004) and Gleason grade groups IV/V tumors (P=0.02). The relationship between WAT inflammation and high Gleason grade remained significant after adjusting for BMI (P=0.04). WAT inflammation correlated with higher circulating levels of insulin, triglycerides, and leptin/adiponectin ratio, and lower high density lipoprotein cholesterol, compared to those without WAT inflammation (P's <0.05). CONCLUSION: Periprostatic WAT inflammation is common in this cohort of men with PC and is associated with high-grade PC.

Clinical characteristics and biopsy specimen features in African-American and white men without prostate cancer.

BACKGROUND: The reported incidence of prostate cancer is higher among African-American men than among white men. We conducted a study of African-American and white men without prostate cancer to determine whether clinical and histologic findings might be associated with racial differences in serum prostate-specific antigen (PSA) levels. METHODS: From January 1990 through March 1997, 493 (59.5%) of 829 African-American men and 736 (74.1%) of 993 white men who had elevated serum PSA levels (> or = 4.0 ng/mL) and/or abnormal digital rectal examinations and who underwent transrectal ultrasound-guided prostate biopsies were found to be without prostate cancer. Also reviewed were patients' age and race, indication for biopsy, histologic features of the prostate biopsy specimen, ultrasound-measured prostate volume, PSA density (i.e., the PSA level divided by the prostate volume), and (in some cases) serum testosterone levels. RESULTS: Among these men without prostate cancer, there were no statistically significant differences by race in the ages of the patients, their prostate volumes, or their serum testosterone levels; however, the mean serum PSA levels and PSA densities were significantly higher in African-American men than in white men (two-sided P values of .00003 and .000009, respectively). A higher proportion of African-American men than white men had inflammation in their prostate biopsy specimen, and men of both races with prostate inflammation had higher PSA values than those without inflammation. African-American men without inflammation had higher PSA values than white men without inflammation. CONCLUSIONS: In this study, African-American men without histologic evidence of prostate cancer had significantly higher PSA levels and PSA densities than similarly aged white men. This finding was not accounted for by racial differences in patients' age, serum testosterone level, or prostate volume.

A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer.

BACKGROUND: Few published studies have combined clinical prognostic factors into risk profiles that can be used to predict the likelihood of recurrence or metastatic progression in patients following treatment of prostate cancer. We developed a nomogram that allows prediction of disease recurrence through use of preoperative clinical factors for patients with clinically localized prostate cancer who are candidates for treatment with a radical prostatectomy. METHODS: By use of Cox proportional hazards regression analysis, we modeled the clinical data and disease follow-up for 983 men with clinically localized prostate cancer whom we intended to treat with a radical prostatectomy. Clinical data included pretreatment serum prostate-specific antigen levels, biopsy Gleason scores, and clinical stage. Treatment failure was recorded when there was clinical evidence of disease recurrence, a rising serum prostate-specific antigen level (two measurements of 0.4 ng/mL or greater and rising), or initiation of adjuvant therapy. Validation was performed on a separate sample of 168 men, also from our institution. RESULTS: Treatment failure (i.e., cancer recurrence) was noted in 196 of the 983 men, and the patients without failure had a median follow-up of 30 months (range, 1-146 months). The 5-year probability of freedom from failure for the cohort was 73% (95% confidence interval = 69%-76%). The predictions from the nomogram appeared accurate and discriminating, with a validation sample area under the receiver operating characteristic curve (i.e., comparison of the predicted probability with the actual outcome) of 0.79. CONCLUSIONS: A nomogram has been developed that can be used to predict the 5-year probability of treatment failure among men with clinically localized prostate cancer treated with radical prostatectomy.

Prostate-specific antigen (PSA) and PSA density: racial differences in men without prostate cancer.

BACKGROUND: Many physicians now use serum prostate-specific antigen (PSA) to screen for prostate cancer in asymptomatic men. Whether or not a prostate biopsy should also be performed depends on an accurate definition of what constitutes a normal PSA value. Until recently, studies conducted to establish normal serum PSA values have involved study populations that have included few African-American men. PURPOSE: We sought to compare serum PSA levels and PSA density (i.e., serum PSA level/prostate volume ratio) in African-American and white men without histologic evidence of prostate cancer. METHODS: We reviewed the medical records of 826 consecutive men who underwent one or more prostate biopsies at the Veterans Affairs Medical Center in Shreveport, LA, from January 1993 through December 1995. In this retrospective review, we recorded patient's age, race, serum PSA level, digital rectal examination result, ultrasound-determined prostate volume, indications for biopsy, and biopsy results. Data from a total of 752 consecutive men who were either white or African-American and whose indication for biopsy included a serum PSA of greater than 4.0 ng/mL and/or an abnormal digital rectal examination were analyzed. To examine possible differences in serum PSA level, PSA density, prostate volume, and patient age, the two-sided Student's t test was employed. Multivariate linear regression analysis was used to determine if serum PSA levels were associated with the patient's age, race, or prostate volume in men without prostate cancer. RESULTS: Of the 752 men included in this analysis, 254 had histologic evidence of prostate cancer and 498 did not. Of the 498 men without prostate cancer, 367 (74%) men were white and 131 (26%) were black. There were no racial differences in age or calculated prostate volume. Serum PSA levels and calculated PSA density, however, were significantly (both P < .0001) higher in African-American men that in white men. A multivariate linear regression analysis indicated that race and prostate volume were independent variables associated with serum PSA level. For African-American and white men, serum PSA values of greater than 4 ng/mL were associated with prostate cancer with sensitivities of 89.5% and 81.9%, respectively, and specificities of 38.2% and 52.3%, respectively. CONCLUSION: Among biopsied men without histologic evidence of prostate cancer, African-Americans have a significantly higher PSA level and PSA density than similarly aged white men. IMPLICATIONS: Published criteria for normal PSA level and density have been derived primarily from white men and may not be directly applicable to other populations. Race-specific data are needed to fully optimize PSA as a tumor marker in racial populations that are at high risk for prostate cancer death.

In vivo gene therapy with p53 or p21 adenovirus for prostate cancer.

We introduced the gene for wild-type human p53 or p21, a critical downstream mediator of p53-induced growth suppression, into a p53-deficient mouse prostate cancer cell line using a recombinant adenoviral vector (Ad5CMV-p53 or Ad5CMV-p21). Elevated levels of endogenous mouse p21 mRNA provided evidence for the functional activity of virally transduced p53. Functional activity of viral-transduced p21 was demonstrated through immunoprecipitation of cellular protein extracts, which showed that the viral-transduced p21 associates with cyclin-dependent kinase 2 and was sufficient to down-regulate the activity of the cyclin-dependent kinase by approximately 65%. In vitro growth assays revealed significantly higher growth suppression after Ad5CMV-p21 infection compared to Ad5CMV-p53. In vivo studies in syngeneic male mice with established s.c. prostate tumors demonstrated that the rate of growth and final tumor volume were reduced to a much greater extent in mice that received intratumor injection of Ad5CMV-p21 compared to Ad5CMV-p53. In addition, the survival of host animals bearing tumors that were infected with Ad5CMV-p21, but not Ad5CMV-p53, was significantly extended. These data suggest that Ad5CMV-p21 may be effective as a therapeutic agent for prostate cancer.

Androgen receptor mutations in prostate cancer.

We analyzed the frequency and relevance of mutations in the coding region of the androgen receptor (AR) in genomic DNA extracted from 137 specimens of prostate cancer. The specimens were obtained from the primary tumors of patients affected by stage B disease [15 nonmicrodissected (group 1A) and 84 microdissected (group 1B)] and from the metastatic deposits of individuals with stage D1 disease [8 nonmicrodissected (group 2A) and 30 microdissected (group 2B)] who had not undergone androgen ablation therapy. The study was conducted by PCR-single strand conformational polymorphism (SSCP) analysis of exons 2-8 in the four groups and direct sequence analysis of exon 1 in group 1B. As positive and negative controls, we used genomic DNA extracted from genital skin fibroblasts of patients affected by various forms of androgen resistance with known mutations in the AR. To control for genetic instability, PCR-SSCP analysis of exon 2 of the human progesterone receptor was carried out on each specimen. The overall number of mutations detected was 11 (8%). No mutations were detected in any of the 99 patients with stage B disease. Eleven mutations were detected in exons 2-8 in 8 of the 38 patients with stage D1 disease (all in group 2B). Simultaneous analysis of exon 2 of the progesterone receptor was carried out, and no SSCP changes were identified. These data suggest that AR mutations are rare and presumably do not play a role in the initial phase of prostatic carcinogenesis. The presence of a significant number of AR mutations in metastatic disease indicates that mutations of this molecule may play a role in the most advanced phases of the natural history of this disease, either by facilitating growth or acquisition of the metastatic phenotype.

The very-high-risk prostate cancer: a contemporary update.

BACKGROUND: Treatment of high-risk prostate cancer has evolved considerably over the past two decades, yet patients with very-high-risk features may still experience poor outcome despite aggressive therapy. We review the contemporary literature focusing on current definitions, role of modern imaging and treatment alternatives in very-high-risk prostate cancer. METHODS: We searched the MEDLINE database for all clinical trials or practice guidelines published in English between 2000 and 2016, with the following search terms: 'prostatic neoplasms' (MeSH Terms) AND ('high risk' (keyword) OR 'locally advanced' (keyword) OR 'node positive' (keyword)). Abstracts pertaining to very-high-risk prostate cancer were evaluated and 40 pertinent studies served as the basis for this review. RESULTS: The term 'very'-high-risk prostate cancer remains ill defined. The European Association of Urology and National Comprehensive Cancer Network guidelines provide the only available definitions, categorizing those with clinical stage T3-4 or minimal nodal involvement as very high risk irrespective of PSA level or biopsy Gleason score. Modern imaging with multiparametric magnetic resonance imaging and positron emission tomography-prostate-specific membrane antigen scans has a role in pre-treatment assessment. Local definitive therapy by external beam radiation combined with androgen deprivation is supported by several randomized clinical trials, whereas the role of surgery in the very-high-risk setting combined with adjuvant radiation/androgen deprivation therapy is emerging. Growing evidence suggest neoadjuvant taxane-based chemotherapy in the context of a multimodal approach may be beneficial. CONCLUSIONS: Men with very-high-risk tumors may benefit from local definitive treatment in the setting of a multimodal regimen, offering local control and possibly cure in well selected patients. Further studies are necessary to better characterize the 'very'-high-risk category and determine the optimal therapy for the individual patient.

Complex cellular responses to tooth wear in rodent molar.

The arrangement and roles of the odontoblast and its process in sensing and responding to injuries such as tooth wear are incompletely understood. Evidence is presented that dentine exposure by tooth wear triggers structural and functional changes that aim to maintain tooth integrity. Mandibular first molars from freshly culled 8 week Wistar rats were prepared for light microscopy ground-sections (n=6), or fixed in 4% paraformaldehyde, decalcified in 17% EDTA, sectioned and stained with antibodies to cyto-skeletal proteins (vimentin (vim), α-tubulin (tub) and α-actin), cellular homeostatic elements (sodium potassium ATPase (NaK-ATPase) and sodium hydrogen exchanger (NHE-1)), and sensory nerve fibres (CGRP) (n=10) for fluorescence microscopy of worn and unworn regions of the mesial cusp. Immunoreactivity (IR) to vim, actin, NaK-ATPase and CGRP was confined to the pulpal third of odontoblast processes (OPs). IR to tub and nhe-1 was expressed by OPs in full dentine thickness. In areas associated with dentine exposure, the tubules contained no OPs. In regions with intact dentine, odontoblasts were arranged in a single cell layer and easily distinguished from the sub-odontoblast cells. In regions with open tubules, the odontoblasts were in stratified or pseudo-stratified in arrangement. Differences in structural antibody expression suggest a previously unreported heterogeneity of the odontoblast population and variations in different regions of the OP. This combined with differences in OPs extension and pulp cellular arrangement in worn and unworn regions suggests active and dynamic cellular responses to the opening of dentinal tubules by tooth wear.

Number of metastatic lymph nodes as determinant of outcome after salvage radical prostatectomy for radiation-recurrent prostate cancer. / Número de ganglios linfáticos metastásicos como determinante de los resultados de la prostatectomía radical de rescate en el cáncer de próstata de recidivante tras radioterapia.

BACKGROUND: Presence of lymph node metástasis (LNM) at salvage radical prostatectomy (sRP) is associated with poor outcome. Predictors of outcome in this context remain undetermined. ThE objective was to assess the role of number of positive lymph node on outcome of patients with LNM after sRP and for radio-recurrent prostate cancer. MATERIAL AND METHODS: We analyzed data from a consecutive cohort of 215 men treated with sRP at a single institution. We used univariate Cox proportional hazard regression models for biochemical recurrence (BCR) and metastatic outcomes, with prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesicle invasion, time between radiation therapy and sRP, and number of positive nodes as predictors. RESULTS: Of the 47 patients with LNM, 37 developed BCR, 11 developed distant metastasis and 4 died with a median follow-up of 2.3 years for survivors. The risk of metastases increased with higher pre-operative PSA levels (HR 1.19 per 1ng/ml; 95% CI: 1.06-1.34; P=.003). The remaining predictors did not reach conventional levels of significance. However, removal of 3 or more positive lymph nodes demonstrated a positive association, as expected, with metastatic disease (HR 3.44; 95% CI: 0.91-13.05; P=.069) compared to one or 2 positive nodes. Similarly, the presence of extraprostatic extension, seminal vesicle invasion and Gleason grade greater than 7 also demonstrated a positive association with higher risk of metástasis, with hazard ratios of 3.97 (95% CI: 0.50, 31.4; P=.2), 3.72 (95% CI: 0.80-17.26; P=.1), and 1.45 (95% CI: 0.44-4.76; P=.5), respectively. CONCLUSIONS: In patients with LNM after sRP for radio-recurrent prostate cancer, the risk of distant metástasis is likely to be influenced by the number of positive nodes (3 or more), high preoperative PSA, Gleason grade and advanced pathologic stage. These results are consistent with the findings of number of nodes (1 to 2 vs. 3 or more nodes positive) as a prognostic indicator after primary radical prostatectomy and strengthen the plea for a revision of the nodal staging for prostate cancer.

Loss of p53 function leads to metastasis in ras+myc-initiated mouse prostate cancer.

To study the interactions between dominantly acting oncogenes and tumor suppressor genes we used p53 'knockout' mouse urogenital sinus tissue for retroviral transduction of ras and myc in the mouse prostate reconstitution (MPR) model system. Epithelial hyperplasia was observed in all wild-type p53 MPRs with one small focal cancer and no evidence of metastasis. Prostatic cancer was found in 100% of the heterozygous and homozygous p53 mutant MPRs with metastatic deposits in 95% of the mice. The pattern of metastasis was remarkably similar to that in human prostate cancer with gross metastatic deposits in the lung, lymph nodes, bone and liver of many animals. Progression of carcinomas in the ras+myc-initiated heterozygous p53 mutant MPRs was invariably associated with either complete loss, partial deletion or loss of expression of the wild-type p53 allele. Southern blotting analysis of proviral-cellular DNA junction fragments in primary carcinomas and cell lines derived from metastatic deposits revealed that metastases do not necessarily seed out from the most abundant clone in the primary carcinoma.