Association between Average Vitamin D Levels and COVID-19 Mortality in 19 European Countries-A Population-Based Study.

Early epidemic reports have linked low average 25(OH) vitamin D levels with increased COVID-19 mortality. However, there has been limited updated research on 25(OH) vitamin D and its impact on COVID-19 mortality. This study aimed to update the initial report studying the link between vitamin D deficiency and COVID-19 mortality by using multi-country data in 19 European countries up to the middle of June 2023. COVID-19 data for 19 European countries included in this study were downloaded from Our World in Data from 1 March 2020, to 14 June 2023, and were included in the statistical analysis. The 25(OH) vitamin D average data were collected by conducting a literature review. A generalized estimation equation model was used to model the data. Compared to European countries with 25(OH) vitamin D levels of ≤50 nmol/L, European countries with 25(OH) vitamin D average levels greater than 50 nmol/L had lower COVID-19 mortality rates (RR = 0.794, 95% CI: 0.662-0.953). A statistically significant negative Spearman rank correlation was observed between 25(OH) vitamin D average levels and COVID-19 mortality. We also found significantly lower COVID-19 mortality rates in countries with high average 25(OH) vitamin D levels. Randomized trials on vitamin D supplementation are needed. In the meantime, the issue of vitamin D use should be debated in relation to the ongoing discussions of national post-COVID-19 resilience against future pandemics.

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.

Evaluation of two collocated federal equivalent method PM2.5 instruments over a wide range of concentrations in Sarajevo, Bosnia and Herzegovina.

Two widely used PM2.5 monitors in the United States (U.S.) designated as federal equivalent methods (FEMs) by the U.S. Environmental Protection Agency were collocated for 15 months in Sarajevo, Bosnia and Herzegovina (BiH) to evaluate their comparability. With differing measurement principles, the FEMs (Met One BAM-1020 and Teledyne API T640) exhibited unique responses to the significant range in PM2.5 over the study period. During the winter months when concentrations greatly increased (e.g., daily PM2.5 > 100 µg m-3), the BAM-1020 had intermittent malfunctioning nozzle contact to the collection tape, resulting in periods of data invalidation. Increased operator observation and doubling the cleaning frequency were required to maintain proper operation. The hourly data from the BAM-1020, which detects PM2.5 via beta-attenuation of particles loaded to the collection tape, indicated higher noise at concentrations below 40 µg m-3 relative to the T640, which detects PM2.5 via an optical method. Above this concentration threshold, the two instruments appear to have comparable hourly fluctuations in the data. Relative to the BAM-1020, the T640 reported higher concentrations when PM2.5 is above 80 µg m-3. A linear regression equation was developed and applied to adjust T640 PM2.5 high concentration values, resulting in 24-hr average T640adj PM2.5 values closely matching that from the BAM-1020 for the full concentration range. Based on the T640adj values, the annual average for Sarajevo was calculated at the site to be 42 µg m-3, with significant seasonality resulting in over 7-fold higher concentrations in the months of December-January compared to June-July.

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.

Immunity-related GTPase M (IRGM) proteins influence the localization of guanylate-binding protein 2 (GBP2) by modulating macroautophagy.

The immunity-related GTPases (IRGs) are a family of proteins induced by interferon-γ that play a crucial role in innate resistance to intracellular pathogens. The M subfamily of IRG proteins (IRGM) plays a profound role in this context, in part because of the ability of its members to regulate the localization and expression of other IRG proteins. We present here evidence that IRGM proteins affect the localization of the guanylate-binding proteins (GBPs), a second family of interferon-induced GTP-binding proteins that also function in innate immunity. Absence of Irgm1 or Irgm3 led to accumulation of Gbp2 in intracellular compartments that were positive for both the macroautophagy (hereafter referred to as autophagy) marker LC3 and the autophagic adapter molecule p62/Sqstm1. Gbp2 was similarly relocalized in cells in which autophagy was impaired because of the absence of Atg5. Both in Atg5- and IRGM-deficient cells, the IRG protein Irga6 relocalized to the same compartments as Gbp2, raising the possibility of a common regulatory mechanism. However, other data indicated that Irga6, but not Gbp2, was ubiquitinated in IRGM-deficient cells. Similarly, coimmunoprecipitation studies indicated that although Irgm3 did interact directly with Irgb6, it did not interact with Gbp2. Collectively, these data suggest that IRGM proteins indirectly modulate the localization of GBPs through a distinct mechanism from that through which they regulate IRG protein localization. Further, these results suggest that a core function of IRGM proteins is to regulate autophagic flux, which influences the localization of GBPs and possibly other factors that instruct cell-autonomous immune resistance.

TRPV4-mediated calcium influx into human bronchial epithelia upon exposure to diesel exhaust particles.

BACKGROUND: Human respiratory epithelia function in airway mucociliary clearance and barrier function and have recently been implicated in sensory functions. OBJECTIVE: We investigated a link between chronic obstructive pulmonary disease (COPD) pathogenesis and molecular mechanisms underlying Ca2+ influx into human airway epithelia elicited by diesel exhaust particles (DEP). METHODS AND RESULTS: Using primary cultures of human respiratory epithelial (HRE) cells, we determined that these cells possess proteolytic signaling machinery, whereby proteinase-activated receptor-2 (PAR-2) activates Ca2+-permeable TRPV4, which leads to activation of human respiratory disease-enhancing matrix metalloproteinase-1 (MMP-1), a signaling cascade initiated by diesel exhaust particles (DEP), a globally relevant air pollutant. Moreover, we observed ciliary expression of PAR-2, TRPV4, and phospholipase-Cß3 in human airway epithelia and their DEP-enhanced protein-protein complex formation. We also found that the chronic obstructive pulmonary disease (COPD)-predisposing TRPV4P19S variant enhances Ca2+ influx and MMP 1 activation, providing mechanistic linkage between man-made air pollution and human airway disease. CONCLUSION: DEP evoked protracted Ca2+ influx via TRPV4, enhanced by the COPD-predisposing human genetic polymorphism TRPV4P19S. This mechanism reprograms maladaptive inflammatory and extracellular-matrix-remodeling responses in human airways. The novel concept of air pollution-responsive ciliary signal transduction from PAR-2 to TRPV4 in human respiratory epithelia will accelerate rationally targeted therapies, possibly via the inhalatory route.

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.