Corrigendum: mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.

This corrects the article DOI: 10.1038/nature22964.

Macrophage polarization in lymph node granulomas from cattle and pigs naturally infected with Mycobacterium tuberculosis complex.

Tuberculosis in animals is caused by members of the Mycobacterium tuberculosis complex (MTC), with the tuberculous granuloma being the main characteristic lesion. The macrophage is the main cell type involved in the development of the granuloma and presents a wide plasticity ranging from polarization to classically activated or pro-inflammatory macrophages (M1) or to alternatively activated or anti-inflammatory macrophages (M2). Thus, this study aimed to analyze macrophage polarization in granulomas from cattle and pig lymph nodes naturally infected with MTC. Tuberculous granulomas were microscopically categorized into four stages and a panel of myeloid cells (CD172a/calprotectin), M1 macrophage polarization (iNOS/CD68/CD107a), and M2 macrophage polarization (Arg1/CD163) markers were analyzed by immunohistochemistry. CD172a and calprotectin followed the same kinetics, having greater expression in late-stage granulomas in pigs. iNOS and CD68 had higher expression in cattle compared with pigs, and the expression was higher in early-stage granulomas. CD107a immunolabeling was only observed in porcine granulomas, with a higher expression in stage I granulomas. Arg1+ cells were significantly higher in pigs than in cattle, particularly in late-stage granulomas. Quantitative analysis of CD163+ cells showed similar kinetics in both species with a consistent frequency of immunolabeled cells throughout the different stages of the granuloma. Our results indicate that M1 macrophage polarization prevails in cattle during early-stage granulomas (stages I and II), whereas M2 phenotype is observed in later stages. Contrary, and mainly due to the expression of Arg1, M2 macrophage polarization is predominant in pigs in all granuloma stages.

Prevalence of non-coeliac gluten sensitivity and assessment of the response to gluten-free diet in a cohort of patients with fibromyalgia.

OBJECTIVES: To establish the prevalence of non-coeliac gluten sensitivity (NCGS) in a cohort of fibromyalgia patients and to evaluate their clinical response to a six-week gluten-free diet (GFD), the improvement in their symptoms, the percentage of diet responders who did not fulfil the diagnostic criteria for NCGS and the baseline characteristics that were associated with diet response and diagnostic criteria fulfilment. METHODS: Uncontrolled prospective experimental study in a cohort of patients with fibromyalgia from a specialized hospital unit. The percentage of patients that fulfilled the Salerno Experts' Criteria, that responded to GFD, that improved their symptomatology and baseline characteristics associated with GFD response and diagnostic criteria fulfilment was analysed. RESULTS: In total, 142 patients were selected and a NCGS prevalence of 5.6% was observed. A total of 21.8% responded to GFD due to their improvement in intestinal symptoms. In total, 74.2% of the responders did not fulfil the Salerno Experts' Criteria. The presence of diarrhoea and intraepithelial lymphocytosis and lower levels of anxiety were predictive factors of GFD response. No predictive factors of NCGS criteria fulfilment were found due to the low number of discriminators between gluten and placebo. CONCLUSIONS: A NCGS prevalence similar to that estimated in the general population was found. A GFD cannot be systematically recommended to all patients with fibromyalgia, although it could be evaluated in those with diarrhoea or intraepithelial lymphocytosis to evaluate if there are improvements in their intestinal symptoms.

Metastatic solid tumours to the penis: a clinicopathologic evaluation of 109 cases from an international collaboration.

AIMS: To elucidate the spectrum of metastatic tumours to the penis and their clinicopathologic features. METHODS: The databases and files of 22 pathology departments from eight countries on three continents were queried to identify metastatic solid tumours of the penis and to characterize their clinical and pathologic features. RESULTS: We compiled a series of 109 cases of metastatic solid tumours that secondarily involved the penis. The mean patient age at diagnosis was 71 years (range, 7-94 years). Clinical presentation commonly included a penile nodule/mass (48/95; 51%) and localised pain (14/95; 15%). A prior history of malignancy was known in 92/104 (89%) patients. Diagnosis was made mainly on biopsy (82/109; 75%), or penectomy (21/109; 19%) specimens. The most common penile locations were the glans (45/98; 46%) and corpus cavernosum (39/98; 39%). The most frequent histologic type was adenocarcinoma (56%). Most primary carcinomas originated in the genitourinary (76/108; 70%) and gastrointestinal (20/108; 18%) tracts, including prostate (38/108; 35%), urinary bladder (27/108; 25%), and colon/rectum (18/108; 17%). Concurrent or prior extrapenile metastases were identified in 50/78 (64%) patients. Clinical follow-up (mean 22 months, range 0-171 months) was available for 87/109 (80%) patients, of whom 46 (53%) died of disease. CONCLUSION: This is the largest study to date of metastatic solid tumours secondarily involving the penis. The most frequent primaries originated from the genitourinary and gastrointestinal tracts. Metastatic penile tumours usually presented with penile nodules/masses and pain, and they often occurred in the setting of advanced metastatic disease, portending poor clinical outcomes.

Accurate diagnosis of prostate cancer by combining Proclarix with magnetic resonance imaging.

OBJECTIVES: To assess of the clinical performance of Proclarix® (a novel Conformité Européenne [CE]-marked biomarker test aiding in the identification of clinically significant prostate cancer [csPCa]) alone or in combination with multiparametric magnetic resonance imaging (mpMRI) to predict csPCa (International Society of Urological Pathology Grade Group ≥2). PATIENTS AND METHODS: The study included blood samples from 721 men undergoing mpMRI followed by biopsy at University College London, London, and Vall d'Hebron University Hospital, Barcelona. Samples were tested blindly. The Proclarix-MRI model combining prostate volume, Proclarix and mpMRI results was trained using the UCL cohort (n = 159) and validated in the Vall d'Hebron cohort (n = 562). Its diagnostic performance was established in correlation to biopsy outcome and compared to available clinical parameters and risk calculators. RESULTS: Clinical performance of the Proclarix-MRI model in the validation cohort did not significantly differ from the training cohort and resulted in a sensitivity for csPCa of 90%, 90% negative predictive value and 66% positive predictive value. The Proclarix-MRI score's specificity (68%) was significantly (P < 0.001) better than the MRI-European Randomized study of Screening for Prostate Cancer risk score (51%), Proclarix (27%) or mpMRI (28%) alone. In addition, Proclarix by itself was found to be useful in the MRI Prostate Imaging-Reporting and Data System (PI-RADS) score 3 subgroup by outperforming prostate-specific antigen density in terms of specificity (25% vs 13%, P = 0.004) at 100% sensitivity. CONCLUSION: When combined with mpMRI and prostate volume, Proclarix reliably predicted csPCa and ruled out men with no or indolent cancer. A large reduction of two thirds of unneeded biopsies was achieved. Proclarix can further be used with high confidence to reliably detect csPCa in men with an indeterminate PI-RADS score 3 mpMRI. Despite these encouraging results, further validation is needed.

mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer.

Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

Application of One-Step Nucleic Acid Amplification (OSNA) in different cancer entities and usefulness in prostate cancer: a systematic review.

BACKGROUND: Lymph node (LN) status is a key prognostic factor in the decision-making process of different cancer entities, including prostate cancer (PCa). Sectioning and haematoxylin and eosin (H&E) staining technique remain the gold standard for the evaluation of LN metastases despite some limitations, especially low sensitivity in detecting an accurate tumour burden within the LN, as well as a subjective and time-consuming result. One-step nucleic acid amplification (OSNA) quantifies mRNA copies of cytokeratin 19 (CK19) in a fast, objective, automated, and reproducible way, raising a general interest to explore its utility for lymphatic metastasis identification in different malignancies. METHODS: To present the latest evidence related to the detection of LN metastases in several tumours by using OSNA compared with the conventional H&E method, a systematic review of articles published since March 2021 was conducted using PubMed, Cochrane Library, and Web of Science databases. References from primary papers and review articles were checked to obtain further potential studies. Our procedure for evaluating records identified during the literature search followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. With the aim to design and justify future clinical routine use of OSNA in PCa, novel PCa evidence has been included in this review for the first time. RESULTS: Twenty five studies were included. LN from six different groups of tumours: breast, gastrointestinal, gynecological, lung, head and neck and prostate cancers has been assessed. OSNA was compared with post-operative formalin-fixed paraffin-embedded tissue sections with H&E staining as the reference standard. Contingency tables were created, and concordance rate, sensitivity, specificity and predictive values were reported. Seventeen studies analysed the discordant cases using different techniques. CONCLUSION: OSNA method has a high diagnostic accuracy for the detection of LN metastases in several CK19 expressing tumours. Available evidence might encourage future investigations about its usage in PCa patients to improve LN staging and prognosis.

The current recommendation for the management of isolated high-grade prostatic intraepithelial neoplasia.

OBJECTIVE: To analyse the current predictive value of isolated high-grade prostatic intraepithelial neoplasia (HGPIN) for clinically significant prostate cancer (csPCa) detection in repeat biopsies. PATIENTS AND METHODS: A cohort of 293 men with isolated HGPIN detected in previous biopsies performed without multiparametric magnetic resonance imaging (mpMRI), and who underwent repeat biopsy within 1 to 3 years, was analysed. Pre-repeat biopsy mpMRI and guided biopsies to suspicious lesions (Prostate Imaging - Reporting and Data System [PI-RADS] ≥3) and/or and systematic biopsies were performed. Persistent prostate cancer (PCa) suspicion, defined as sustained serum prostate-specific antigen level >4 ng/mL and/or abnormal digital rectal examination, was present in 248 men (84.6%), and was absent in 45 men (15.4%). A control group of 190 men who had no previous HGPIN, atypical small acinar proliferation or HGPIN with atypia who were scheduled to undergo repeat biopsy due to persistent PCa suspicion were also analysed. csPCa was defined as tumours of Grade Group ≥2. RESULTS: In the subset of 45 men with isolated HGPIN, in whom PCa suspicion disappeared, only one csPCa (2.2%) and one insignificant PCa (iPCa) were detected. csPCa was detected in 34.7% of men with persistent PCa suspicion and previous HGPIN, and in 28.4% of those without previous HGPIN (P =0.180). iPCa was detected in 12.1% and 6.3%, respectively (P =0.039). Logistic regression analysis showed that the risk of csPCa detection was not predicted by previous HGPIN: odds ratio (OR) 1.369 (95% confidence interval [CI] 0.894-2.095; P =0.149); however, previous HGPIN increased the risk of iPCa detection: OR 2.043 (95% CI 1.016-4.109; P =0.006). CONCLUSION: The risk of csPCa in men with isolated HGPIN, in whom PCa suspicion disappears, is extremely low. Moreover, in those men in whom PCa suspicion persists, the risk of csPCa is not influenced by the previous finding of HGPIN. However, previous HGPIN increases the risk of iPCa detection. Therefore, repeat prostate biopsy should not be recommended solely because of a previous HGPIN.

Activation of regulated cell death in the lung of piglets infected with virulent PRRSV-1 Lena strain occurs earlier and mediated by cleaved Caspase-8.

PRRSV-1 virulent strains cause high fever, marked respiratory disease and severe lesions in lung and lymphoid organs. Regulated cell death (RCD), such as apoptosis, necroptosis and pyroptosis, is triggered by the host to interrupt viral replication eliminating infected cells, however, although it seems to play a central role in the immunopathogenesis of PRRSV, there are significant gaps regarding their sequence and activation upon PRRSV-infection. The present study evaluated RCD events by means of caspases expression in the lung of PRRSV-1-infected pigs and their impact on pulmonary macrophage subpopulations and lung lesion. Conventional piglets were intranasally inoculated with the virulent subtype 3 Lena strain or the low virulent subtype 1 3249 strain and euthanised at 1, 3, 6, 8 and 13 dpi. Lena-infected piglets showed severe and early lung damage with a high frequency of PRRSV-N-protein+ cells, depletion of CD163+ cells and high viral load in the lung. The number of TUNEL+ cells was significantly higher than cCasp3+ cells in Lena-infected piglets during the first week post-infection. cCasp8 and to a lesser extent cCasp9 were activated by both PRRSV-1 strains after one week post-infection together with a replenishment of both CD163+ and Arg-1+ pulmonary macrophages. These results highlight the induction of other forms of RCD beyond apoptosis, such as, necroptosis and pyroptosis during the first week post-infection followed by the activation of, mainly, extrinsic apoptosis during the second week post-infection. The recovery of CD163+ macrophages at the end of the study represents an attempt to restore pulmonary macrophage subpopulations lost during the early stages of the infection but also a macrophage polarisation into M2 macrophages.

Melanosis Coli in Pigs Coincides With High Sulfate Content in Drinking Water.

Melanosis coli is a well-described condition in humans, characterized by the accumulation of lipofuscin-laden macrophages in the lamina propria of the colon, giving it a dark tone. An increased apoptosis rate of colonic epithelial cells appears to be the underlying pathogenesis. In pigs, oxidative damage has been proposed as one of the causes for melanosis coli. In this article, we report a series of cases of melanosis coli in pigs affecting several finishing units in the south of Spain. Large intestines had dark green to brown pigmentation of the mucosa. Histological, histochemical, and ultrastructural studies confirmed a high number of lipofuscin-laden macrophages in the lamina propria of the rectum and colon, which additionally stained positive for the apoptosis marker cleaved caspase-3. Of note, all affected finishing units utilized water supply with a high content of sulfates, which may be one of the causes for melanosis coli development in pigs.

Peripheral Corticotropin-Releasing Factor Triggers Jejunal Mast Cell Activation and Abdominal Pain in Patients With Diarrhea-Predominant Irritable Bowel Syndrome.

INTRODUCTION: To determine the effect of peripheral CRF on intestinal barrier function in diarrhea-predominant IBS (IBS-D). Irritable bowel syndrome (IBS) pathophysiology has been linked to life stress, epithelial barrier dysfunction, and mast cell activation. Corticotropin-releasing factor (CRF) is a major mediator of stress responses in the gastrointestinal tract, yet its role on IBS mucosal function remains largely unknown. METHODS: Intestinal response to sequential i.v. 5-mL saline solution (placebo) and CRF (100 µg) was evaluated in 21 IBS-D and 17 healthy subjects (HSs). A 20-cm jejunal segment was perfused with an isosmotic solution and effluents collected at baseline, 30 minutes after placebo, and 60 minutes after CRF. We measured water flux, albumin output, tryptase release, stress hormones, cardiovascular and psychological responses, and abdominal pain. A jejunal biopsy was obtained for CRF receptor expression assessment. RESULTS: Water flux did not change after placebo in IBS-D and HS but significantly increased after CRF in IBS-D (P = 0.007). Basal luminal output of albumin was higher in IBS-D and increased further after CRF in IBS-D (P = 0.042). Basal jejunal tryptase release was higher in IBS-D, and CRF significantly increased it in both groups (P = 0.004), the response being higher in IBS-D than in HS (P = 0.0023). Abdominal pain worsened only in IBS-D after CRF and correlated with jejunal tryptase release, water flux, and albumin output. IBS-D displayed jejunal up-regulation of CRF2 and down-regulation of CRF1 compared with HS. DISCUSSION: Stress via CRF-driven mast cell activation seems to be relevant in the pathophysiology of IBS-D.

How to implement magnetic resonance imaging before prostate biopsy in clinical practice: nomograms for saving biopsies.

PURPOSE: To combine multiparametric MRI (mpMRI) findings and clinical parameters to provide nomograms for diagnosing different scenarios of aggressiveness of prostate cancer (PCa). METHODS: A cohort of 346 patients with suspicion of PCa because of abnormal finding in digital rectal examination (DRE) and/or high prostate specific antigen (PSA) level received mpMRI prior to prostate biopsy (PBx). A conventional 12-core transrectal PBx with two extra cores from suspicious areas in mpMRI was performed by cognitive fusion. Multivariate logistic regression analysis was performed combining age, PSA density (PSAD), DRE, number of previous PBx, and mpMRI findings to predict three different scenarios: PCa, significant PCa (ISUP-group ≥ 2), or aggressive PCa (ISUP-group ≥ 3). We validate models by ROC curves, calibration plots, probability density functions (PDF), and clinical utility curves (CUC). Cut-off probabilities were estimated for helping decision-making in clinical practice. RESULTS: Our cohort showed 39.6% incidence of PCa, 32.6% of significant PCa, and 23.4% of aggressive PCa. The AUC of predictive models were 0.856, 0.883, and 0.911, respectively. The PDF and CUC showed 11% missed diagnoses of significant PCa (35 cases of 326 significant PCa expected in 1000 proposed Bx) when choosing < 18% as the cutoff of probability for not performing PBx; the percentage of saved PBx was 47% (474 avoided PBx in 1000 proposed). CONCLUSION: We developed clinical and mpMRI-based nomograms with a high discrimination ability for three different scenarios of PCa aggressiveness (https://urostatisticalsolutions.shinyapps.io/MRIfusionPCPrediction/). Specific clinical cutoff points allow us to save a high number of PBx with a minimum of missed diagnoses.

Integrating clinical, molecular, proteomic and histopathological data within the tissue context: tissunomics.

Malignant tumours show a marked degree of morphological, molecular and proteomic heterogeneity. This variability is closely related to microenvironmental factors and the location of the tumour. The activation of genetic alterations is very tissue-dependent and only few tumours have distinct genetic alterations. Importantly, the activation state of proteins and signaling factors is heterogeneous in the primary tumour and in metastases and recurrences. The molecular diagnosis based only on genetic alterations can lead to treatments with unpredictable responses, depending on the tumour location, such as the tumour response in melanomas versus colon carcinomas with BRAF mutations. Therefore, we understand that the correct evaluation of tumours requires a system that integrates both morphological, molecular and protein information in a clinical and pathological context, where intratumoral heterogeneity can be assessed. Thus, we propose the term 'tissunomics', where the diagnosis will be contextualised in each tumour based on the complementation of the pathological, molecular, protein expression, environmental cells and clinical data.

Sclerosing Cholangitis Related to IgG4: Not Always a Curable Entity.

IgG4-related disease is a recently-described fibro-inflammatory condition with characteristic histopathological findings in the organs involved. The most commonly affected organs are pancreas, lymph nodes, and retroperitoneum. Liver disease usually involves bile structures and therefore IgG4-related disease is considered a cause of secondary sclerosing cholangitis. One out of three patients with IgG4 sclerosing cholangitis also presents autoimmune pancreatitis, although it can be associated with manifestations in other organs. One of the main features of IgG4-related disease is its good prognosis due to the great response to glucocorticoid therapy. However, relapse of the disease is not uncommon, especially when steroid therapy is decreased or stopped. Rituximab seems to be an effective treatment to achieve remission of the disease. We report the case of a 74 year-old man diagnosed with IgG4-related disease based on increase of serum IgG4 levels, imaging and histopathological findings, with systemic involvement including sclerosing cholangitis. Despite the absence of liver fibrosis at onset, the early use of glucocorticoids and rituximab therapy, the patient presented clinical and analytical deterioration, leading to secondary biliary cirrhosis. In conclusion, this clinical case highlights the importance of prompt diagnosis and therapeutics for sclerosing cholangitis secondary to IgG4-related disease in order to avoid progression of the disease and development of liver cirrhosis, as well as the refractory, aggressive nature of the disease in some cases as this one.

miR-16 and miR-125b are involved in barrier function dysregulation through the modulation of claudin-2 and cingulin expression in the jejunum in IBS with diarrhoea.

OBJECTIVE: Micro-RNAs (miRNAs) play a crucial role in controlling intestinal epithelial barrier function partly by modulating the expression of tight junction (TJ) proteins. We have previously shown differential messenger RNA (mRNA) expression correlated with ultrastructural abnormalities of the epithelial barrier in patients with diarrhoea-predominant IBS (IBS-D). However, the participation of miRNAs in these differential mRNA-associated findings remains to be established. Our aims were (1) to identify miRNAs differentially expressed in the small bowel mucosa of patients with IBS-D and (2) to explore putative target genes specifically involved in epithelial barrier function that are controlled by specific dysregulated IBS-D miRNAs. DESIGN: Healthy controls and patients meeting Rome III IBS-D criteria were studied. Intestinal tissue samples were analysed to identify potential candidates by: (a) miRNA-mRNA profiling; (b) miRNA-mRNA pairing analysis to assess the co-expression profile of miRNA-mRNA pairs; (c) pathway analysis and upstream regulator identification; (d) miRNA and target mRNA validation. Candidate miRNA-mRNA pairs were functionally assessed in intestinal epithelial cells. RESULTS: IBS-D samples showed distinct miRNA and mRNA profiles compared with healthy controls. TJ signalling was associated with the IBS-D transcriptional profile. Further validation of selected genes showed consistent upregulation in 75% of genes involved in epithelial barrier function. Bioinformatic analysis of putative miRNA binding sites identified hsa-miR-125b-5p and hsa-miR-16 as regulating expression of the TJ genes CGN (cingulin) and CLDN2 (claudin-2), respectively. Consistently, protein expression of CGN and CLDN2 was upregulated in IBS-D, while the respective targeting miRNAs were downregulated. In addition, bowel dysfunction, perceived stress and depression and number of mast cells correlated with the expression of hsa-miR-125b-5p and hsa-miR-16 and their respective target proteins. CONCLUSIONS: Modulation of the intestinal epithelial barrier function in IBS-D involves both transcriptional and post-transcriptional mechanisms. These molecular mechanisms include miRNAs as master regulators in controlling the expression of TJ proteins and are associated with major clinical symptoms.

Differential Expression of PD-L1 in High Grade T1 vs Muscle Invasive Bladder Carcinoma and its Prognostic Implications.

PURPOSE: PD-L1 is expressed on tumor cells and tumor immune cell infiltrates. In metastatic bladder cancer increased tumor immune cell infiltrate PD-L1 positivity correlated with better overall survival. However, to our knowledge in high grade T1 bladder tumors positivity on tumor cells and tumor immune cell infiltrates, and correlation with outcomes or pathological features remain unknown. MATERIALS AND METHODS: Formalin fixed, paraffin embedded tumor samples from 140 patients with clinically annotated, high grade T1 bladder tumors were retrieved. All patients were initially diagnosed with high grade T1 bladder tumors by transurethral resection, subsequently received bacillus Calmette-Guérin and had a median followup of 7.4 years. PD-L1 positivity on initial transurethral resection was evaluated by immunohistochemistry using a mouse monoclonal antiPD-L1 antibody (405.9A11). Tumor cell PD-L1 positivity was defined as staining of 5% of the tumor cell membrane. Tumor immune cell infiltrate PD-L1 positivity was scored based on the extent of infiltrate and the percent of positive cells. The Fisher exact test was used to assess associations of PD-L1 positivity with disease outcomes, carcinoma in situ presence and the difference between high grade T1 bladder tumors and muscle invasive bladder cancer. RESULTS: Among 140 patients with high grade T1 bladder tumors tumor cells and tumor immune cell infiltrate PD-L1 positivity was seen in 6 (4%) and 48 (34.3%), respectively. In a subset of 106 patients with adequate followup PD-L1 positivity did not correlate with disease outcomes on tumor cells (p = 0.3) or on tumor immune cell infiltrates (p = 0.47). PD-L1 positivity also did not correlate with the presence of carcinoma in situ. Tumor cell PD-L1 positivity was significantly less in high grade T1 bladder tumors than in muscle invasive bladder cancer (p <0.001). CONCLUSIONS: PD-L1 is widely expressed on tumor immune cell infiltrates but not on tumor cells in high grade T1 bladder tumors. We did not find a correlation between PD-L1 positivity and outcomes or carcinoma in situ presence. Tumor cell PD-L1 positivity is significantly lower in high grade T1 bladder tumors than in muscle invasive bladder cancer.

Clinical Significance of Proliferative Inflammatory Atrophy in Negative Prostatic Biopsies.

PURPOSE: To analyze the association between prostatic proliferative inflammatory atrophy finding in negative prostate biopsies and future detection of prostate cancer (PCa) and its aggressiveness in men subjected to repeat biopsies, due to persistent suspicion of PCa. MATERIALS AND METHODS: Prospective and observational study of 474 men scheduled to repeated PBs. Assessment of PIA and its extension in the previous biopsy. PCa detection rate and tumor aggressiveness. Age, serum total PSA, free PSA, percent free PSA (%fPSA), digital rectal exam (DRE), prostate volume (PV), PSA density (PSAD), PSA kinetics (PSAV and PSADT) findings of PIA and HGPIN, and number of affected cores in previous PBs were included in the univariate and multivariate analysis. Aggressive tumors were considered when any Gleason pattern 4 was found. RESULTS: PCa was detected in 133 men (28.1%). Age, serum total PSA, %fPSA, PV, PSAD, PSAV, PSADT, and PIA finding were significantly associated to PCa detection. However, only age, OR: 1.06 (95%CI: 1.03-1.10), P < 0.01; DRE, OR: 1.76 (95%CI: 1.05-2.92), P = 0.03; %fPSA, OR: 0.96 (95%CI: 0.93-0.99), P = 0.03; PV, OR: 0.98 (95%CI: 0.97-0.99) and PIA finding, OR: 0.49 (95%CI: 0.29-0.83), P < 0.01, were independent predictors of PCa detection. PCa was found in 18% of 159 men with previous PIA finding while in 33% of 315 men without previous PIA (P < 0.01). None of the studied parameters including PIA in the previous biopsy were related with subsequent PCa aggressiveness. CONCLUSIONS: PIA finding in negative biopsies correlates with a decreased frequency of detecting PCa in men with persistent suspicion of PCa. The aggressiveness of future detected tumors was not associated with previous PIA finding. Prostate 76:1501-1506, 2016. © 2016 Wiley Periodicals, Inc.

Identification of somatic gene mutations in penile squamous cell carcinoma.

There is a lack of studies on somatic gene mutations and cell signaling driving penile carcinogenesis. Our objective was to analyze somatic mutations in genes downstream of EGFR in penile squamous cell carcinomas, especially the mTOR and RAS/MAPK pathways. We retrospectively analyzed somatic mutations in 10 in situ and 65 invasive penile squamous cell carcinomas by using Sequenom's Mass Spectrometry iPlex Technology and Oncocarta v1.0 Panel. The DNA was extracted from FFPE blocks and we identified somatic missense mutations in three in situ tumors and in 19 invasive tumors, mostly in PIK3CA, KRAS, HRAS, NRAS, and PDGFA genes. Somatic mutations in the PIK3CA gene or RAS family genes were neither associated with tumor grade, stage or outcome, and were equally often identified in hrHPV positive and in hrHPV negative tumors that showed no p53 expression. Mutations in PIK3CA, KRAS, and HRAS are frequent in penile squamous cell carcinoma and likely play a role in the development of p53-negative tumors. Although the presence of these mutations does not seem to correlate with tumoral behavior or outcome, they could be biomarkers of treatment failure with anti-EGFR mAb in patients with penile squamous cell carcinoma.

Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations.

BACKGROUND AND AIMS: Altered intestinal barrier is associated with immune activation and clinical symptoms in diarrhoea-predominant IBS (IBS-D). Increased mucosal antigen load may induce specific responses; however, local antibody production and its contribution to IBS aetiopathogenesis remain undefined. This study evaluated the role of humoral activity in IBS-D. METHODS: A single mucosal jejunal biopsy, luminal content and blood were obtained from healthy volunteers (H; n=30) and IBS-D (n=49; Rome III criteria) participants. Intraepithelial lymphocytes, mast cells, B lymphocytes and plasma cells were studied by imaging techniques. Differential gene expression and pathway analysis were assessed by microarray and PCR techniques. Blood and luminal immunoglobulins (Igs) were quantified. Gastrointestinal symptoms, respiratory atopy and stress and depression were also recorded. RESULTS: Patients with IBS-D showed a higher number and activation of mucosal B lymphocytes and plasma cells (p<0.05). Mast cell density was increased in patients with IBS-D (non-atopic) and in close proximity to plasma cells (p<0.05). Microarray profiling identified differential humoral activity in IBS-D, involving proliferation and activation of B lymphocytes and Igs production (p<0.001). Mucosal humoral activity was higher in IBS-D, with upregulation of germline transcripts and Ig genes (1.3-fold-1.7-fold increase; p<0.05), and increased IgG(+) cells and luminal IgG compared with H (p<0.05), with no differences in blood. Biological markers of humoral activity correlated positively with bowel movements, stool form and depression. CONCLUSIONS: Enhanced small bowel humoral immunity is a distinctive feature of IBS-D. Mucosal Ig production contributes to local inflammation and clinical manifestations in IBS-D.

Clinical significance of proliferative inflammatory atrophy finding in prostatic biopsies.

BACKGROUND: Proliferative inflammatory atrophy (PIA) has been involved in prostatic carcinogenesis. However, little is known about the clinical significance of a PIA finding in prostatic biopsies (PBs). The aim of this study is to determine the incidence of prostate inflammatory atrophy (PIA) in prostate biopsies (PBs), its association to high-grade prostatic intraepithelial neoplasia (HGPIN), prostate cancer (PCa), and tumor aggressiveness. METHODS: Prospective and observational study of PIA lesion in 528 extended PBs and 200 radical prostatectomy specimens (RPS). OUTCOME MEASUREMENTS: PIA, HGPIN, PCa incidence, Gleason score, clinical and pathologic tumor stage and insignificant tumor rate. Univariate and multivariate analysis. RESULTS: Overall incidence of PIA and HGPIN was 30.3% and 54%. In RPS, the incidence was 30.5% and 72%, respectively. No significant association was found between PIA and HGPIN. Overall PCa detection rate in PBs was 38.1%. PCa was found in 27.5% PBs with PIA and 42.7% of those without PIA, P < 0.001. In contrast, PCa was detected in 50.9% of PBs with HGPIN and 23% of those without HGPIN, P = 0.001. Multivariate analysis revealed that PIA decreased the risk of PCa, OR:0.59 (95%CI:0.37-0.95), P = 0.029, while HGPIN increased OR:3.16 (95%CI:2.04-4.90), P = 0.001. PIA was not related to Gleason grade and clinical stage, however it was associated to an insignificant tumors increase, OR:3.08 (95%CI:1.09-8.7), P = 0.033. The information in RPS suggests that PIA is associated with less aggressive tumors and a higher probability of insignificant tumors. CONCLUSIONS: PIA is present in one third of PBs, HGPIN in one half of them, and no association exists between both lesions. Contrary to HGPIN, PIA finding is associated to lower risk of PCa detection. Tumors accompanying PIA seem to be less aggressive and have a greater probability of being insignificant.