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The molecular mechanisms leading to aryl hydrocarbon receptor interacting protein ( AIP ) mutation-induced aggressive, young-onset growth hormone-secreting pituitary tumors are not fully understood. In this study, we have identified that AIP -mutation-positive tumors are infiltrated by a large number of macrophages compared to sporadic tumors. Tissue from pituitary-specific Aip -knockout ( Aip Flox/Flox ;Hesx1 Cre/+ ) mice recapitulated this phenotype. Our human pituitary tumor transcriptome data revealed the “epithelial-to-mesenchymal transition (EMT) pathway” as one of the most significantly altered pathways in AIP pos tumors. Our in vitro data suggest that bone marrow-derived macrophage-conditioned media induces more prominent EMT-like phenotype and enhanced migratory and invasive properties in Aip -knockdown somatomammotroph cells compared to non-targeting controls. We identified that tumor-derived cytokine CCL5 is upregulated in AIP -mutation-positive human adenomas. Aip -knockdown GH3 cell-conditioned media increases macrophage migration, which is inhibited by the CCL5/CCR5 antagonist maraviroc. Our results suggest that a crosstalk between the tumor and its microenvironment plays a key role in the invasive nature of AIP -mutation-positive tumors and the CCL5/CCR5 pathway is a novel potential therapeutic target.

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials. Joint analysis of new and previously published sequencing data for primary and metastatic prostate cancers identifies new candidate driver mutations and provides insights into disease progression and potential drug targets.

The International Society of Urological Pathology (ISUP) hosts a reference image database supervised by experts with the purpose of establishing an international standard in prostate cancer grading. Here, we aimed to identify areas of grading difficulties and compare the results with those obtained from an artificial intelligence system trained in grading. In a series of 87 needle biopsies of cancers selected to include problematic cases, experts failed to reach a 2/3 consensus in 41.4% (36/87). Among consensus and non-consensus cases, the weighted kappa was 0.77 (range 0.68–0.84) and 0.50 (range 0.40–0.57), respectively. Among the non-consensus cases, four main causes of disagreement were identified: the distinction between Gleason score 3 + 3 with tangential cutting artifacts vs. Gleason score 3 + 4 with poorly formed or fused glands (13 cases), Gleason score 3 + 4 vs. 4 + 3 (7 cases), Gleason score 4 + 3 vs. 4 + 4 (8 cases) and the identification of a small component of Gleason pattern 5 (6 cases). The AI system obtained a weighted kappa value of 0.53 among the non-consensus cases, placing it as the observer with the sixth best reproducibility out of a total of 24. AI may serve as a decision support and decrease inter-observer variability by its ability to make consistent decisions. The grading of these cancer patterns that best predicts outcome and guides treatment warrants further clinical and genetic studies. Results of such investigations should be used to improve calibration of AI systems.

BackgroundA Urological Pathology External Quality Assurance (EQA) Scheme in the UK has reported observer variation in the diagnosis and grading of adenocarcinoma in prostatic biopsies using basic κ statistics, which rate all disagreements equally.AimThe aim of this study is to use customised weighting schemes to report κ statistics that reflect the closeness of interobserver agreement in the prostate EQA scheme.MethodsA total of 83, 114 and 116 pathologists took part, respectively, in three web-based circulations and were classified as either expert or other readers. For analyses of diagnosis, there were 10, 8 and 8 cases in the three circulations, respectively. For analyses of Gleason Sum Score, only invasive cases were included, leaving 5, 5 and 6 cases, respectively. Analyses were conducted using customised weighting schemes with ‘pairwise-weighted’ κ for multiple readers.ResultsAnalysis of diagnosis for all circulations and all readers gave a composite κ value of 0.86 and pairwise-weighted κ (κp–w) value of 0.91, both regarded as ‘almost perfect’ agreement. This was due to the high proportion of responses that showed partial agreement. Analysis of Gleason Sum Score gave κ=0.38 and κp–w=0.58 over all circulations and all readers, indicating that discrepancies occur at the boundary between adjacent grades and may not be as clinically significant as suggested by composite κ.ConclusionWeighted κ show higher levels of agreement than previously reported as they have the advantage of applying weighting, which reflects the relative importance of different types of discordance in diagnosis or grading. Agreement on grading remained low.

BackgroundKappa statistics are frequently used to analyse observer agreement for panels of experts and External Quality Assurance (EQA) schemes and generally treat all disagreements as total disagreement. However, the differences between ordered categories may not be of equal importance (eg, the difference between grades 1 vs 2 compared with 1 vs 3). Weighted kappa can be used to adjust for this when comparing a small number of readers, but this has not as yet been applied to the large number of readers typical of a national EQA scheme.AimTo develop and validate a method for applying weighted kappa to a large number of readers within the context of a real dataset: the UK National Urological Pathology EQA Scheme for prostatic biopsies.MethodsData on Gleason grade recorded by 19 expert readers were extracted from the fixed text responses of 20 cancer cases from four circulations of the EQA scheme. Composite kappa, currently used to compute an unweighted kappa for large numbers of readers, was compared with the mean kappa for all pairwise combinations of readers. Weighted kappa generalised for multiple readers was compared with the newly developed ‘pairwise-weighted’ kappa.ResultsFor unweighted analyses, the median increase from composite to pairwise kappa was 0.006 (range −0.005 to +0.052). The difference between the pairwise-weighted kappa and generalised weighted kappa for multiple readers never exceeded ±0.01.ConclusionPairwise-weighted kappa is a suitable and highly accurate approximation to weighted kappa for multiple readers.

Background A Urological Pathology External Quality Assurance (EQA) Scheme in the UK has reported observer variation in the diagnosis and grading of adenocarcinoma in prostatic biopsies using basic κ statistics, which rate all disagreements equally. Aim The aim of this study is to use customised weighting schemes to report κ statistics that reflect the closeness of interobserver agreement in the prostate EQA scheme. Methods A total of 83, 114 and 116 pathologists took part, respectively, in three web-based circulations and were classified as either expert or other readers. For analyses of diagnosis, there were 10, 8 and 8 cases in the three circulations, respectively. For analyses of Gleason Sum Score, only invasive cases were included, leaving 5, 5 and 6 cases, respectively. Analyses were conducted using customised weighting schemes with 'pairwise-weighted' κ for multiple readers. Results Analysis of diagnosis for all circulations and all readers gave a composite κ value of 0.86 and pairwise-weighted κ (κp-w ) value of 0.91, both regarded as 'almost perfect' agreement. This was due to the high proportion of responses that showed partial agreement. Analysis of Gleason Sum Score gave κ =0.38 and κp-w =0.58 over all circulations and all readers, indicating that discrepancies occur at the boundary between adjacent grades and may not be as clinically significant as suggested by composite κ. Conclusion Weighted κ show higher levels of agreement than previously reported as they have the advantage of applying weighting, which reflects the relative importance of different types of discordance in diagnosis or grading. Agreement on grading remained low.

Aim： To investigate the existence of TMPRSS2：ERG fusion gene in circulating tumor cells （CTC） from prostate cancer patients and its potential in monitoring tumor metastasis. Methods- We analyzed the frequency of TMPRSS2： ERG and TMPRSS2：ETV1 transcripts in 27 prostate cancer biopsies from prostatectomies, and TMPRSS2：ERG transcripts in CTC isolated from 15 patients with advanced androgen independent disease using reverse transcription polymerase chain reaction （RT-PCR）. Fluorescence in situ hybridization （FISH） was applied to analyze the genomic truncation of ERG, which is the result of TMPRSS2：ERG fusion in 10 of the 15 CTC samples. Results： TMPRSS2： ERG transcripts were found in 44% of our samples, but we did not detect expression of TMPRSS2：ETV1. Using FISH analysis we detected chromosomal rearrangements affecting the ERG gene in 6 of 10 CTC samples, including 1 case with associated TMPRSS2：ERG fusion at the primary site. However, TMPRSS2：ERG transcripts were not detected in any of the 15 CTC samples, including the 10 cases analyzed by FISH. Conclusion： Although further study is required to address the association between TMPRSS2：ERG fusion and prostate cancer metastasis, detection of genomic truncation of the ERG gene by FISH analysis could be useful for monitoring the appearance of CTC and the potential for prostate cancer metastasis.

Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1–100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential. Ionizing radiation may induce irreparable DNA damage leading to cancer. Here, the authors identify a specific signature of mutations arising in patients exposed to ionizing radiation and suggest that radiation-induced tumorigenesis is associated with higher rates of genome-wide deletions and balanced inversions.

Context.— Prostate cancer remains a significant public health problem. Recent publications of randomized trials and the US Preventive Services Task Force recommendations have drawn attention to overtreatment of localized, low-risk prostate cancer. Active surveillance, in which patients undergo regular visits with serum prostate-specific antigen tests and repeat prostate biopsies, rather than aggressive treatment with curative intent, may address overtreatment of low-risk prostate cancer. It is apparent that a greater awareness of the critical role of pathologists in determining eligibility for active surveillance is needed. Objectives.— To review the state of current knowledge about the role of active surveillance in the management of prostate cancer and to provide a multidisciplinary report focusing on pathologic parameters important to the successful identification of patients likely to succeed with active surveillance, to determine the role of molecular tests in increasing the safety of active surveillance, and to provide future directions. Design.— Systematic review of literature on active surveillance for low-risk prostate cancer, pathologic parameters important for appropriate stratification, and issues regarding interobserver reproducibility. Expert panels were created to delineate the fundamental questions confronting the clinical and pathologic aspects of management of men on active surveillance. Results.— Expert panelists identified pathologic parameters important for management and the related diagnostic and reporting issues. Consensus recommendations were generated where appropriate. Conclusions.— Active surveillance is an important management option for men with low-risk prostate cancer. Vital to this process is the critical role pathologic parameters have in identifying appropriate candidates for active surveillance. These findings need to be reproducible and consistently reported by surgical pathologists with accurate pathology reporting.

Background Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue ( n  = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. Results Single nucleotide variants ( P  = 7.0 × 10 –03 , Wilcoxon rank sum test) and small insertions and deletions (indels, P  = 8.7 × 10 –06 ) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer ( P  = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial ( P  = 5.94 × 10 –05 , paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants ( P  = 3.72 × 10 –09 , paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. Conclusions Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches.