Updated prostate imaging reporting and data system (PIRADS v2) recommendations for the detection of clinically significant prostate cancer using multiparametric MRI: critical evaluation using whole-mount pathology as standard of reference.

OBJECTIVES: To evaluate the recommendations for multiparametric prostate MRI (mp-MRI) interpretation introduced in the recently updated Prostate Imaging Reporting and Data System version 2 (PI-RADSv2), and investigate the impact of pathologic tumour volume on prostate cancer (PCa) detectability on mpMRI. METHODS: This was an institutional review board (IRB)-approved, retrospective study of 150 PCa patients who underwent mp-MRI before prostatectomy; 169 tumours ≥0.5-mL (any Gleason Score [GS]) and 37 tumours <0.5-mL (GS ≥4+3) identified on whole-mount pathology maps were located on mp-MRI consisting of T2-weighted imaging (T2WI), diffusion-weighted (DW)-MRI, and dynamic contrast-enhanced (DCE)-MRI. Corresponding PI-RADSv2 scores were assigned on each sequence and combined as recommended by PI-RADSv2. We calculated the proportion of PCa foci on whole-mount pathology correctly identified with PI-RADSv2 (dichotomized scores 1-3 vs. 4-5), stratified by pathologic tumour volume. RESULTS: PI-RADSv2 allowed correct identification of 118/125 (94 %; 95 %CI: 90-99 %) peripheral zone (PZ) and 42/44 (95 %; 95 %CI: 89-100 %) transition zone (TZ) tumours ≥0.5 mL, but only 7/27 (26 %; 95 %CI: 10-42 %) PZ and 2/10 (20 %; 95 %CI: 0-52 %) TZ tumours with a GS ≥4+3, but <0.5 mL. DCE-MRI aided detection of 4/125 PZ tumours ≥0.5 mL and 0/27 PZ tumours <0.5 mL. CONCLUSIONS: PI-RADSv2 correctly identified 94-95 % of PCa foci ≥0.5 mL, but was limited for the assessment of GS ≥4+3 tumours ≤0.5 mL. DCE-MRI offered limited added value to T2WI+DW-MRI. KEY POINTS: • PI-RADSv2 correctly identified 95 % of PCa foci ≥0.5 mL • PI-RADSv2 was limited for the assessment of GS ≥4+3 tumours ≤0.5 mL • DCE-MRI offered limited added value to T2WI+DW-MRI.

Clinical nodal staging scores for prostate cancer: a proposal for preoperative risk assessment.

BACKGROUND: Pelvic lymph node dissection in patients undergoing radical prostatectomy for clinically localised prostate cancer is not without morbidity and its therapeutical benefit is still a matter of debate. The objective of this study was to develop a model that allows preoperative determination of the minimum number of lymph nodes needed to be removed at radical prostatectomy to ensure true nodal status. METHODS: We analysed data from 4770 patients treated with radical prostatectomy and pelvic lymph node dissection between 2000 and 2011 from eight academic centres. For external validation of our model, we used data from a cohort of 3595 patients who underwent an anatomically defined extended pelvic lymph node dissection. We estimated the sensitivity of pathological nodal staging using a beta-binomial model and developed a novel clinical (preoperative) nodal staging score (cNSS), which represents the probability that a patient has lymph node metastasis as a function of the number of examined nodes. RESULTS: In the development and validation cohorts, the probability of missing a positive lymph node decreases with increase in the number of nodes examined. A 90% cNSS can be achieved in the development and validation cohorts by examining 1-6 nodes in cT1 and 6-8 nodes in cT2 tumours. With 11 nodes examined, patients in the development and validation cohorts achieved a cNSS of 90% and 80% with cT3 tumours, respectively. CONCLUSIONS: Pelvic lymph node dissection is the only reliable technique to ensure accurate nodal staging in patients treated with radical prostatectomy for clinically localised prostate cancer. The minimum number of examined lymph nodes needed for accurate nodal staging may be predictable, being strongly dependent on prostate cancer characteristics at diagnosis.

Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice.

Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a Cre-LoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/- cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTOR-positive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT-mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis.

Genetic analysis of carbon isotope discrimination and agronomic characters in a bread wheat cross.

Carbon isotope discrimination (Δ) has been suggested as a selection criterion to improve transpiration efficiency (W) in bread wheat (Triticum aestivum L.). Cultivars 'Chinese Spring' with low A (high W) and 'Yecora Rojo' with high Δ (low W) were crossed to develop F1, F2, BC1, and BC2 populations for genetic analysis of Δ and other agronomic characters under well-watered (wet) and water-stressed (dry) field conditions. Significant variation was observed among the generations for Δ only under the wet environment. Generation x irrigation interactions were not significant for Δ. Generation means analysis indicated that additive gene action is of primary importance in the expression of Δ under nonstress conditions. Dominance gene action was also detected for Δ, and the direction of dominance was toward higher values of Δ. The broad-sense and the narrow-sense heritabilities for Δ were 61 % and 57% under the wet conditions, but were 48% and 12% under the draughted conditions, respectively. The narrow-sense heritabilities for grain yield, above-ground dry matter, and harvest index were 36%, 39%, and 60% under the wet conditions and 21%, 44%, and 20% under dry conditions, respectively. The significant additive genetic variation and moderate estimate of the narrow-sense heritability observed for Δ indicated that selection under wet environments should be effective in changing Δ in spring bread wheat.

Simulation of cyclic single cross selection.

Computer simulation was used to compare Hallauer's cyclic single cross selection (CSCS) with reciprocal recurrent selection (RRS). Three epistatic and three non-epistatic models with 60 loci determining a single character provided the genetic base. The rate of advance over seven cycles was always greater for CSCS than for RRS on either a cycle or generation basis. No genetic conditions were found where CSCS failed to respond. The advantages of CSCS increases as the proportion of non-additive genetic variance increases. Genetic advance of the hybrid population was shown to result from the joint effects of an average change in gene frequency and complementary effects (nicking) of selection. Nicking effects accounted for most of the advance for some starting conditions. RRS generally had higher selection limits with no epistasis or low gene frequency of the dominant allele. CSCS generally had higher limits with epistasis or high frequency of the dominant allele. We suggested that CSCS begin with divergent genetic populations and strong selection intensity for three cycles. Final selection of superior single crosses was indicated when the lines were completely inbred.

Adaptation of safflower genotypes Carthamus tinctorius L.

Adaptation reactions of 33 genotypes of safflower Carthamus tinctorius L. were studied under 7 different climatic conditions. The genotpyes were divided into two sets. Set I consisted of 15 genotpyes selected from the local populations. Set II had 15 introduced and local varieties. Three control genotpyes, Ute, Ferio, and Local Arak, were common to both sets.Genotpye-environment interaction was not significant for Set I but it was highly significant for Set II. Three environmental indices were obtained and used in the adaptation analyses of the genotpyes in Set II. One of the environmental indices, designated EI, was dependent on the genotypes of Set II. The other two indices, designated EI-1 and EI-2, were independent of the genotpyes of Set II. The methods of Eberhart and Russell (1966) were used in analyses of adaptation by Index EI and the methods of Freeman and Perkins (1971) for Indices EI-1 and EI-2.The mean square associated with genotype-environment interaction was partitioned into two components, heterogeneity of regression and its residual, under EI-1 and EI-2. Both components were highly significant for both cases. However, the mean square of heterogeneity of regression was equal to its residual under EI-1 and even smaller than its residual under EI-2. These observations indicate that a major part of genotpye-environment interaction can not be accounted for by differences in the regressions of the individual genotypes. As well as this overall test, individual regression analyses for single genotypes were also considered. None of the genotypes had significant regression mean square under EI-1. Only two introduced genotypes had significant regression mean squares when EI-2 was used. The overall test of equality of the slopes of the regression for the genotypes of Set II was rejected at the 1% level under EI. This test indicated that genotypes of Set II were significantly different in their association with the EI. The significant differences among the genotypes of Set II were also shown by an F test of the pooled deviation mean square divided by the pooled error mean square. Individual regression analyses for single genotpyes of Set II were considered under EI. Mixed adaptation reactions were observed for different genotypes. Among 18 genotypes of Set II, regression mean squares were significant for only 10 genotpyes. Therefore, it appeared that the dependent environmental indices are more useful than the independent environmental indices when statistical theory of regression is used in the analysis of adaptation. Observations in the present study were not in agreement with the hypothesis that the relation between the performance of different genotypes in the various environments and some measure of these environments is linear or nearly so.Among the 12 introduced genotypes, only one, Ute, was identified as stable and high-yielding. Among the 15 selected from the locally adapted populations, eleven did not differ significantly from Ute in mean yield but four exceeded Ute significantly in mean productivity. The present study thus indicates that the Iranian safflower breeding project has been successful in identifying genotpyes which give high and stable yields under diverse environmental conditions. It does not indicate that introduced and exotic germplasms are unimportant in the breeding projects; it is quite possible that still more desirable genotypes can be developed by incorporating introduced genetic variability into the local germplasm.