The potential of using circulating tumour cells and their gene expression to predict docetaxel response in metastatic prostate cancer.

Background: Docetaxel improves overall survival (OS) in castration-resistant prostate cancer (PCa) (CRPC) and metastatic hormone-sensitive PCa (mHSPC). However, not all patients respond due to inherent and/or acquired resistance. There remains an unmet clinical need for a robust predictive test to stratify patients for treatment. Liquid biopsy of circulating tumour cell (CTCs) is minimally invasive, can provide real-time information of the heterogeneous tumour and therefore may be a potentially ideal docetaxel response prediction biomarker. Objective: In this study we investigate the potential of using CTCs and their gene expression to predict post-docetaxel tumour response, OS and progression free survival (PFS). Methods: Peripheral blood was sampled from 18 mCRPC and 43 mHSPC patients, pre-docetaxel treatment, for CTC investigation. CTCs were isolated using the epitope independent Parsortix® system and gene expression was determined by multiplex RT-qPCR. We evaluated CTC measurements for post-docetaxel outcome prediction using receiver operating characteristics and Kaplan Meier analysis. Results: Detection of CTCs pre-docetaxel was associated with poor patient outcome post-docetaxel treatment. Combining total-CTC number with PSA and ALP predicted lack of partial response (PR) with an AUC of 0.90, p= 0.037 in mCRPC. A significantly shorter median OS was seen in mCRPC patients with positive CTC-score (12.80 vs. 37.33 months, HR= 5.08, p= 0.0005), ≥3 total-CTCs/7.5mL (12.80 vs. 37.33 months, HR= 3.84, p= 0.0053), ≥1 epithelial-CTCs/7.5mL (14.30 vs. 37.33 months, HR= 3.89, p= 0.0041) or epithelial to mesenchymal transitioning (EMTing)-CTCs/7.5mL (11.32 vs. 32.37 months, HR= 6.73, p= 0.0001). Significantly shorter PFS was observed in patients with ≥2 epithelial-CTCs/7.5mL (7.52 vs. 18.83 months, HR= 3.93, p= 0.0058). mHSPC patients with ≥5 CTCs/7.5mL had significantly shorter median OS (24.57 vs undefined months, HR= 4.14, p= 0.0097). In mHSPC patients, expression of KLK2, KLK4, ADAMTS1, ZEB1 and SNAI1 was significantly associated with shorter OS and/or PFS. Importantly, combining CTC measurements with clinical biomarkers increased sensitivity and specificity for prediction of patient outcome. Conclusion: While it is clear that CTC numbers and gene expression were prognostic for PCa post-docetaxel treatment, and CTC subtype analysis may have additional value, their potential predictive value for docetaxel chemotherapy response needs to be further investigated in large patient cohorts.

The Identification of Plasma Exosomal miR-423-3p as a Potential Predictive Biomarker for Prostate Cancer Castration-Resistance Development by Plasma Exosomal miRNA Sequencing.

Castration-resistant prostate cancer (CRPC) is the major cause of death from prostate cancer. Biomarkers to improve early detection and prediction of CRPC especially using non-invasive liquid biopsies could improve outcomes. Therefore, we investigated the plasma exosomal miRNAs associated with CRPC and their potential for development into non-invasive early detection biomarkers for resistance to treatment. RNA-sequencing, which generated approximately five million reads per patient, was performed to identify differentially expressed plasma exosomal miRNAs in 24 treatment-naive prostate cancer and 24 CRPC patients. RT-qPCR was used to confirm the differential expressions of six exosomal miRNAs, miR-423-3p, miR-320a, miR-99a-5p, miR-320d, miR-320b, and miR-150-5p (p = 7.3 × 10-8, 0.0020, 0.018, 0.0028, 0.0013, and 0.0058, respectively) firstly in a validation cohort of 108 treatment-naive prostate cancer and 42 CRPC patients. The most significant differentially expressed miRNA, miR-423-3p, was shown to be associated with CRPC with area under the ROC curve (AUC) = 0.784. Combining miR-423-3p with prostate-specific antigen (PSA) enhanced the prediction of CRPC (AUC = 0.908). A separate research center validation with 30 treatment-naive and 30 CRPC patients also confirmed the differential expression of miR-423-3p (p = 0.016). Finally, plasma exosomal miR-423-3p expression in CRPC patients was compared to 36 non-CRPC patients under androgen depletion therapy, which showed significantly higher expression in CRPC than treated non-CRPC patients (p < 0.0001) with AUC = 0.879 to predict CRPC with no difference between treatment-naive and treated non-CRPC patients. Therefore, our findings demonstrate that a number of plasma exosomal miRNAs are associated with CRPC and miR-423-3p may serve as a biomarker for early detection/prediction of castration-resistance.

Noninvasive Detection of Clinically Significant Prostate Cancer Using Circulating Tumor Cells.

PURPOSE: Prostate specific antigen testing results in unnecessary biopsy and over diagnosis with consequent overtreatment. Tissue biopsy is an invasive procedure associated with significant morbidity. More accurate noninvasive or minimally invasive diagnostic approaches should be developed to avoid unnecessary prostate biopsy and over diagnosis. We investigated the potential of using circulating tumor cell analysis in cancer diagnosis, particularly to predict clinically significant prostate cancer in prebiopsy cases. MATERIALS AND METHODS: We enrolled 155 treatment naïve patients with prostate cancer and 98 before biopsy for circulating tumor cell enumeration. RNA was extracted from circulating tumor cells of 184 patients for gene expression analysis. The Kruskal-Wallis and Spearman rank tests, multivariate logistic regression and the random forest method were applied to assess the association of circulating tumor cells with aggressive prostate cancer. RESULTS: Of patients with localized prostate cancer 54% were scored as having positive circulating tumor cells, which was associated with a higher Gleason score (p=0.0003), risk group (p <0.0001) and clinically significant prostate cancer (p <0.0001). In the prebiopsy group a positive circulating tumor cell score combined with prostate specific antigen predicted clinically significant prostate cancer (AUC 0.869). A 12-gene panel prognostic for clinically significant prostate cancer was also identified. When combining the prostate specific antigen level, the circulating tumor cell score and the 12-gene panel, the AUC of clinically significant prostate cancer prediction was 0.927. Adding those data to cases with available multiparametric magnetic resonance imaging data significantly increased prediction accuracy (AUC 0.936 vs 0.629). CONCLUSIONS: Circulating tumor cell analysis has the potential to significantly improve patient stratification by prostate specific antigen and/or multiparametric magnetic resonance imaging for biopsy and treatment.

The potential of brentuximab vedotin, alone or in combination with current clinical therapies, in the treatment of testicular germ cell tumors.

Testicular germ cell tumors (TGCTs) are the commonest tumors in young men. With the advancement of chemotherapies, most TGCTs are successfully cured, even when diagnosed at an advanced and metastatic stage. However, a proportion of often young patients, median age 35-40, with advanced disease are not cured and will inevitably die. Therefore, there is an unmet need in this small population of young patients who are candidates for experimental approaches. We investigated a new therapeutic option for this group of patients, aiming to significantly improve their outcome. In recent years, many targeted therapies have been developed which demonstrated high efficacy and low toxicity. Brentuximab vedotin, a monomethyl auristatin E conjugated CD30 antibody, targets CD30 to kill cancer cells. As a large proportion of TGCTs express CD30, in particular embryonal carcinomas, we investigated in vitro the efficacy of brentuximab vedotin in treating TGCTs as a single therapy and in combination with commonly used chemotherapy drugs. We determined CD30 expression levels in 12 TGCT cell lines, including three cisplatin resistant sublines. In general, the efficiency of cancer cell inhibition by brentuximab vedotin correlates with CD30 expression, but there were some exceptions. We also determined the efficacy of brentuximab vedotin in combination with commonly used chemotherapy drugs and found synergistic/additive effects with etoposide, paclitaxel and SN-38. However, cisplatin, the most commonly used chemotherapy drug in TGCT treatment, exhibited antagonism and we showed that cisplatin selectively kills CD30 positive cells. We also found that certain agents, which have been reported to induce CD30 expression in other human malignant diseases, including DNA demethylation drugs, methotrexate and CD30 ligands, were unable to enhance CD30 expression or brentuximab vedotin efficacy in TGCT cells. This study will help to design clinical trials using brentuximab vedotin for the treatment of TGCTs, either as a single agent or in combination with current clinical therapies.

Identification of low oxygen-tolerating bacteria in prostate secretions of cancer patients and discussion of possible aetiological significance.

The microaerophylic organism Propionibacterium acnes has shown consistent association with prostate cancer (PC). Studies linking circumcision with reduced PC further support anaerobes involvement as circumcision reduces anaerobe colonisation on the glans penis. A 1988 study linked anaerobes with PC but considered them as opportunists in necrotic tumour. A hypothesis that a "Helicobacter-like" process causes PC justified this pilot study. Active surveillance patients were enrolled. Post-prostate massage urine samples were screened using the Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) technique for bacterial identification after culture in anaerobic and aerobic conditions. 8 out of 18 patients (41%) had either obligate anaerobic (n = 5) or microaerophilic (n = 4, one of whom also had anaerobes) organisms identified. None of 10 control samples contained obligate anaerobes. Although mean PSA was 63% higher in those with low oxygen tolerating bacteria, two high outliers resulted in this difference being non-significant. Given the substantially higher proportion of PC patients with organisms growing in a low concentration of oxygen when combined with previous studies compared to controls, the degree of significance was as high as smoking 5-9 cigarettes a day and needs further investigation. Translational research in trials combining Vitamin D and aspirin have begun as part of such investigation.

A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population.

Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.

Locally advanced and metastatic prostate cancer treated with intermittent androgen monotherapy or maximal androgen blockade: results from a randomised phase 3 study by the South European Uroncological Group.

BACKGROUND: Few randomised studies have compared antiandrogen intermittent hormonal therapy (IHT) with continuous maximal androgen blockade (MAB) therapy for advanced prostate cancer (PCa). OBJECTIVE: To determine whether overall survival (OS) on IHT (cyproterone acetate; CPA) is noninferior to OS on continuous MAB. DESIGN, SETTING, AND PARTICIPANTS: This phase 3 randomised trial compared IHT and continuous MAB in patients with locally advanced or metastatic PCa. INTERVENTION: During induction, patients received CPA 200 mg/d for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH; triptoreline 11.25 mg) analogue plus CPA 200 mg/d. Patients whose prostate-specific antigen (PSA) was <4 ng/ml after 3 mo of induction treatment were randomised to the IHT arm (stopped treatment and restarted on CPA 300 mg/d monotherapy if PSA rose to ≥20 ng/ml or they were symptomatic) or the continuous arm (CPA 200 mg/d plus monthly LHRH analogue). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome measurement was OS. Secondary outcomes included cause-specific survival, time to subjective or objective progression, and quality of life. Time off therapy in the intermittent arm was recorded. RESULTS AND LIMITATIONS: We recruited 1045 patients, of which 918 responded to induction therapy and were randomised (462 to IHT and 456 to continuous MAB). OS was similar between groups (p=0.25), and noninferiority of IHT was demonstrated (hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.76-1.07). There was a trend for an interaction between PSA and treatment (p=0.05), favouring IHT over continuous therapy in patients with PSA ≤1 ng/ml (HR: 0.79; 95% CI, 0.61-1.02). Men treated with IHT reported better sexual function. Among the 462 patients on IHT, 50% and 28% of patients were off therapy for ≥2.5 yr or >5 yr, respectively, after randomisation. The main limitation is that the length of time for the trial to mature means that other therapies are now available. A second limitation is that T3 patients may now profit from watchful waiting instead of androgen-deprivation therapy. CONCLUSIONS: Noninferiority of IHT in terms of survival and its association with better sexual activity than continuous therapy suggest that IHT should be considered for use in routine clinical practice.

Socio-economic inequalities in testicular cancer survival within two clinical studies.

BACKGROUND: Testicular cancer is the most common cancer in men under 35 years of age, and has the highest survival for adult male malignancies. Despite the fact that survival is very high, there is evidence that survival differs between socio-economic groups. METHODS: We analysed survival patterns for 1606 testicular cancer patients diagnosed during 1984-2001 and recruited to one of two clinical studies. The first was a surveillance study to determine relapse-free survival after orchidectomy in 865 patients with stage I nonseminomatous germ-cell testicular cancer diagnosed during 1984-1991 (TE04). The second study was a trial in which 1174 men with stage I seminomatous germ-cell tumours were randomised to receive radiotherapy or one injection of carboplatin between 1996 and 2001 (TE19). The number of men available for analysis from these two studies was 578 and 1028, respectively. We followed these patients up for their vital status, and assigned them an ecological measure of deprivation. Crude and relative survival were estimated at 5 and 10 years by socio-economic deprivation. RESULTS: No significant socio-economic gradient was seen: 1.3% (95% CI -0.3% to 3.1%) at 5 years and 2.1% (95% CI -0.5% to 4.7%) at 10 years. CONCLUSION: We conclude that, given equal treatment at a given stage of disease, survival from testicular cancer does not depend on socio-economic status. This suggests that the socio-economic gradient in testicular cancer survival in the general population is more likely to be attributable to health care system factors than to personal or socio-economic factors in the men themselves.

An improved prognostic model for stage T1a and T1b prostate cancer by assessments of cancer extent.

Treatment decisions on prostate cancer diagnosed by trans-urethral resection (TURP) of the prostate are difficult. The current TNM staging system for pT1 prostate cancer has not been re-evaluated for 25 years. Our objective was to optimise the predictive power of tumor extent measurements in TURP of the prostate specimens. A total of 914 patients diagnosed by TURP of the prostate between 1990 and 1996, managed conservatively were identified. The clinical end point was death from prostate cancer. Diagnostic serum prostate-specific antigen (PSA) and contemporary Gleason grading was available. Cancer extent was measured by the percentage of chips infiltrated by cancer. Death rates were compared by univariate and multivariate proportional hazards models, including baseline PSA and Gleason score. The percentage of positive chips was highly predictive of prostate cancer death when assessed as a continuous variable or as a grouped variable on the basis of and including the quintiles, quartiles, tertiles and median groups. In the univariate model, the most informative variable was a four group-split (≤10%, >10-25%, >25-75% and >75%); (HR=2.08, 95% CI=1.8-2.4, P<0.0001). The same was true in a multivariate model (ΔX(2) (1 d.f.)=15.0, P=0.0001). The current cutoff used by TNM (<=5%) was sub-optimal (ΔX(2) (1 d.f.)=4.8, P=0.023). The current TNM staging results in substantial loss of information. Staging by a four-group subdivision would substantially improve prognostication in patients with early stage disease and also may help to refine management decisions in patients who would do well with conservative treatments.

Measurements of cancer extent in a conservatively treated prostate cancer biopsy cohort.

The optimal method for measuring cancer extent in prostate biopsy specimens is unknown. Seven hundred forty-four patients diagnosed between 1990 and 1996 with prostate cancer and managed conservatively were identified. The clinical end point was death from prostate cancer. The extent of cancer was measured in terms of number of cancer cores (NCC), percentage of cores with cancer (PCC), total length of cancer (LCC) and percentage length of cancer in the cores (PLC). These were correlated with prostate cancer mortality, in univariate and multivariate analysis including Gleason score and prostate-specific antigen (PSA). All extent of cancer variables were significant predictors of prostate cancer death on univariate analysis: NCC, hazard ration (HR) = 1.15, 95% confidence interval (CI) = 1.04-1.28, P = 0.011; PPC, HR = 1.01, 95% CI = 1.01-1.02, P < 0.0001; LCC, HR = 1.02, 95% CI = 1.01-1.03, P = 0.002; PLC, HR = 1.01, 95% CI = 1.01-1.02, P = 0.0001. In multivariate analysis including Gleason score and baseline PSA, PCC and PLC were both independently significant P = 0.004 and P = 0.012, respectively, and added further information to that provided by PSA and Gleason score, whereas NNC and LCC were no longer significant (P = 0.5 and P = 0.3 respectively). In a final model, including both extent of cancer variables, PCC was the stronger, adding more value than PLC (χ² (1df) = 7.8, P = 0.005, χ² (1df) = 0.5, P = 0.48 respectively). Measurements of disease burden in needle biopsy specimens are significant predictors of prostate-cancer-related death. The percentage of positive cores appeared the strongest predictor and was stronger than percentage length of cancer in the cores.

Immunohistochemistry for p16, but not Rb or p21, is an independent predictor of prognosis in conservatively treated, clinically localised prostate cancer.

AIMS: Treatment decisions are difficult in clinically localised prostate cancer and further biomarkers of aggressive behaviour are required. We investigated the hypothesis that the tissue expression of three cell cycle markers, Rb, p21 and p16, would provide helpful prognostic information in a well characterised series of prostate cancers which were clinically localised and treated conservatively. METHODS: The immunohistochemical staining expression of these markers was assessed in tissue microarrays and correlated with 10 year prostate cancer survival and overall survival and then compared with pathological data including contemporary Gleason score, age, measures of tumour extent and initial serum prostate specific antigen (PSA) level. RESULTS: Rb overexpression did not show any significant association with Gleason score or prostate cancer survival. p21 protein expression showed a significant association with prostate cancer survival (p = 0.02) and overall survival (p = 0.01) in a univariate model but not in a multivariate model with pathological and serum PSA data. There was a significant association between p16 cytoplasmic expression and prostate cancer survival (HR = 2.52, 95%CI = 1.79-3.55, p < 0.001) and overall survival (HR = 1.54, 95% CI = 1.20-1.98, p = 0.001) in a univariate model. p16 expression remained an independent prognostic factor for prostate cancer survival (HR = 1.50, 95%CI = 1.05-2.14, p = 0.03). CONCLUSION: We conclude that p16 cytoplasmic expression can be used as a predictor of outcome in conservatively treated prostate cancer. Rb and p21 show no independent association with outcome and therefore further research is not warranted.

A comprehensive method for optical-emission computed tomography.

Optical-computed tomography (CT) and optical-emission computed tomography (ECT) are recent techniques with potential for high-resolution multi-faceted 3D imaging of the structure and function in unsectioned tissue samples up to 1-4 cc. Quantitative imaging of 3D fluorophore distribution (e.g. GFP) using optical-ECT is challenging due to attenuation present within the sample. Uncorrected reconstructed images appear hotter near the edges than at the center. A similar effect is seen in SPECT/PET imaging, although an important difference is attenuation occurs for both emission and excitation photons. This work presents a way to implement not only the emission attenuation correction utilized in SPECT, but also excitation attenuation correction and source strength modeling which are unique to optical-ECT. The performance of the correction methods was investigated by the use of a cylindrical gelatin phantom whose central region was filled with a known distribution of attenuation and fluorophores. Uncorrected and corrected reconstructions were compared to a sectioned slice of the phantom imaged using a fluorescent dissecting microscope. Significant attenuation artifacts were observed in uncorrected images and appeared up to 80% less intense in the central regions due to attenuation and an assumed uniform light source. The corrected reconstruction showed agreement throughout the verification image with only slight variations ( approximately 5%). Final experiments demonstrate the correction in tissue as applied to a tumor with constitutive RFP.

A validated prognostic index predicting response to dexamethasone and diethylstilbestrol in castrate-resistant prostate cancer.

BACKGROUND: The objective of this study was to identify subgroups of patients with castrate-resistant prostate cancer (CRPC) who had a prolonged response to combined dexamethasone and diethylstilbestrol (DS) therapy by constructing a prognostic index. METHODS: Multivariate and cutoff point analyses with bootstrapping were performed 1 month after commencing DS therapy, and data were validated using an independent external dataset. RESULTS: The median overall survival for 145 patients was 18.3 months (95% confidence interval [CI], 15.4-23.3 months). Only 2 factors were significant on multivariate analysis: a prostate-specific antigen (PSA) level below the median at the start of DS therapy and a decline>50% in the PSA level after 1 month on DS therapy. Subsequent cutoff point analyses revealed that a PSA level<88 ng/mL at the start of DS therapy and a reduction>53.1% in PSA after the first month of treatment were the most significant factors. These 2 factors were used to construct a prognostic index, which was validated successfully by the external dataset (median overall survival, 18.3 months [95% CI, 16.4-28.0 months]; concordance, 72% [95% CI, 68%-76%]). The prognostic index identified 3 prognostic groups: The 2-year overall survival rate for these 3 groups was 68% (95% CI, 57%-98%) for the good prognostic group, 40% (95% CI, 31%-52%) for the intermediate prognostic group, and 12% (95% CI, 5%-25%) for the poor prognostic group. CONCLUSIONS: The easy-to-use prognostic index that the authors developed was able to identify a subgroup of patients with CRPC who had prolonged survival only 1 month after starting DS therapy.

Regulation of macrophage motility by Irgm1.

IRG are a family of IFN-regulated proteins that are critical for resistance to infection. Mouse IRG proteins are divided into GMS and GKS subfamilies, based on a sequence within the G1 GTP-binding motif. The GMS proteins have a particularly profound impact on immunity, as typified by Irgm1, of which absence leads to a complete loss of resistance to a variety of intracellular bacteria and protozoa. The underlying molecular and cellular mechanisms are not clear. Here, we use time-lapse microscopy and cell-tracking analysis to demonstrate that Irgm1 is required for motility of IFN-gamma-activated macrophages. The absence of Irgm1 led to decreased actin remodeling at the leading edge of migrating macrophages, as well as decreased Rac activation. Although Irgm1 did not localize to the leading edge of migrating macrophages, it was found to regulate the localization of a GKS IRG protein, Irgb6, which in turn, concentrated on the plasma membrane in the advancing lamellipodia, in close apposition to molecular components that regulate membrane remodeling, including Rac, paxillin, and actin. Thus, Irgm1 likely controls macrophage motility by regulating the positioning of specific GKS IRG proteins to the plasma membrane, which in turn, modulate cytoskeletal remodeling and membrane dynamics.

The relative activity of cisplatin, oxaliplatin and satraplatin in testicular germ cell tumour sensitive and resistant cell lines.

BACKGROUND: Germ cell tumours (GCT) can become resistant to cisplatin, which is associated with a relatively poor prognosis. Oxaliplatin and satraplatin have been developed to overcome cisplatin resistance in other cancers, but their effect in cisplatin resistant (cisR) GCTs is unclear. In this work we address this issue by comparing their efficacy in three paired sensitive and cisR GCT cell lines. METHODS: Three established cisplatin sensitive (cisS) and resistant cell line pairs were used (GCT27, GCT27r: SUSA, SUSAr: 833k, 833kr). Viability was assessed using a luciferase based ATP assay and EC(50) and EC(80) concentrations were calculated. Western blot analysis and flow cytometry was used for further assessment. RESULTS: Sensitivity to the three platinum compounds was broadly similar in the three cisS lines GCT cell lines (EC(50) = 0.27-0.51 microM for cisplatin, 0.52-0.79 microM for oxaliplatin, 0.31-1.26 microM for satraplatin). EC(50) values for cisplatin in the three cisR sub lines were 1.8- to 3.8-fold higher than in the sensitive parental lines. Cross resistance to satraplatin and oxaliplatin occurred in all three cisR cell lines (resistance factor 1.9-4.4), with the exception of oxaliplatin in the 833Kr (resistance factor 0.9). Differences in the effect of specific drugs on cell cycle distribution, p53, p21 and MDM2 were observed. CONCLUSIONS: These data suggest that satraplatin and oxaliplatin could theoretically be used in chemo-naive GCTs and support the further clinical evaluation of these agents in this setting. The mechanism of cross resistance to these drugs appears multifactorial.

Prostate cancer prevention by short-term anti-androgens: the rationale behind design of pilot studies.

This paper sets out to review evidence that low-grade prostate inflammation is a precursor of prostate cancer development and the mechanisms by which it may account for the more than 50 years natural history from first infection to cancer. Though as yet there is no clear-cut specific associated infection, there is clear evidence that some sexually acquired infections damage the prostate and increase serum PSA with slow recovery back to normal. The demonstration that low-level solar exposure is protective provides a possible mechanism due to vitamin D's known benefit through action to boost macrophage-mediated immune surveillance. This observation and data demonstrating that non-steroidal anti-inflammatory drugs (NSAIDs) protect against prostate cancer provide the justification for trials of these two agents combined with short course intermittent anti-androgen therapy in populations at high risk of prostate cancer.

Four-dimensional analysis of vascularization during primary development of an organ, the gonad.

Time-lapse microscopy has advanced our understanding of yolk sac and early embryonic vascularization. However, it has been difficult to assess endothelial interactions during epithelial morphogenesis of internal organs. To address this issue we have developed the first time-lapse system to study vascularization of a mammalian organ in four dimensions. We show that vascularization of XX and XY gonads is a highly dynamic, sexually dimorphic process. The XX gonad recruits vasculature by a typical angiogenic process. In contrast, the XY gonad recruits and patterns vasculature by a novel remodeling mechanism beginning with breakdown of an existing mesonephric vessel. Subsequently, in XY organs individual endothelial cells migrate and reaggregate in the coelomic domain to form the major testicular artery. Migrating endothelial cells respect domain boundaries well before they are morphologically evident, subdividing the gonad into 10 avascular regions where testis cords form. This model of vascular development in an internal organ has a direct impact on the current dogma of vascular integration during organ development and presents important parallels with mechanisms of tumor vascularization.