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Prostate cancer (PCa) is one of the most common cancers worldwide and oxidative stress is involved in its occurrence, development and progression. In fact, in transgenic adenocarcinoma of mouse prostate (TRAMP) mice, prostate cancer onset is associated with the methylation of the first five CpG in the nuclear factor erythroid 2-related factor 2 (NRF2) promoter, a key regulator of oxidative stress response, leading to its downregulation and accumulation of reactive oxygen species (ROS). It has been demonstrated that both natural and synthetic compounds can reactivate NRF2 expression inhibiting the methylation status of its promoter by downregulation of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). Interestingly, NRF2 re-expression significantly reduced prostate cancer onset in TRAMP mice highlighting an important role of NRF2 in prostate tumorigenesis.We analysed the current literature regarding the role of natural and synthetic compounds in modulating NRF2 pathway in TRAMP mice, an in vivo model of prostate cancer, to give an overview on prostate carcinogenesis and its possible prevention.We can conclude that specific natural and synthetic compounds can downregulate DNMTs and/or HDACs inhibiting the methylation status of NRF2 promoter, then reactivating the expression of NRF2 protecting normal prostatic cells from ROS damage and tumorigenesis.

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PDF file, 22KB, Description of pathological specimens (Table S1) and immunohistochemical detection of c-FLIP in prostate tissues (Table S2).

PDF file, 41KB, Effects of SAHA and bicalutamide in inducing apoptosis detected by Annexin-V labelling.

PDF file, 252KB, The HDAC inhibitor Droxinostat down-regulates c-FLIP expression in androgen-dependent CaP cells and potentiates bicalutamide-induced apoptosis.

PDF file, 72KB, Characterization of differential AR and NF-κB activity in prostate cancer cell lines and the response to SAHA and bicalutamide.

PDF file, 202KB, Silencing of c-FLIP induces spontaneous apoptosis in CaP cells.

PDF file, 175KB, Castrate-resistant cells are insensitive to bicalutamide and SAHA.

Purpose: To characterize the importance of cellular Fas-associated death domain (FADD)–like interleukin 1β-converting enzyme (FLICE) inhibitory protein (c-FLIP), a key regulator of caspase-8 (FLICE)–promoted apoptosis, in modulating the response of prostate cancer cells to androgen receptor (AR)–targeted therapy.Experimental Design: c-FLIP expression was characterized by immunohistochemical analysis of prostatectomy tissue. The functional importance of c-FLIP to survival and modulating response to bicalutamide was studied by molecular and pharmacologic interventions.Results: c-FLIP expression was increased in high-grade prostatic intraepithelial neoplasia and prostate cancer tissue relative to normal prostate epithelium (P < 0.001). Maximal c-FLIP expression was detected in castrate-resistant prostate cancer (CRPC; P < 0.001). In vitro, silencing of c-FLIP induced spontaneous apoptosis and increased 22Rv1 and LNCaP cell sensitivity to bicalutamide, determined by flow cytometry, PARP cleavage, and caspase activity assays. The histone deacetylase inhibitors (HDACi), droxinostat and SAHA, also downregulated c-FLIP expression, induced caspase-8- and caspase-3/7–mediated apoptosis, and increased apoptosis in bicalutamide-treated cells. Conversely, the elevated expression of c-FLIP detected in the CRPC cell line VCaP underpinned their insensitivity to bicalutamide and SAHA in vitro. However, knockdown of c-FLIP induced spontaneous apoptosis in VCaP cells, indicating its relevance to cell survival and therapeutic resistance.Conclusion: c-FLIP reduces the efficacy of AR-targeted therapy and maintains the viability of prostate cancer cells. A combination of HDACi with androgen deprivation therapy may be effective in early-stage disease, using c-FLIP expression as a predictive biomarker of sensitivity. Direct targeting of c-FLIP, however, may be relevant to enhance the response of existing and novel therapeutics in CRPC. Clin Cancer Res; 18(14); 3822–33. ©2012 AACR.

PDF file, 214KB, SAHA targets the AR pathway in androgen-dependent CaP cells.

PDF file, 80KB, Bar graphs illustrating the effect of SAHA, bicalutamide or their combined administration upon (A), the AR-target gene PSA or (B) the NF-κB target gene Bcl-2 in VCaP cells.

Background: Prostate cancer (PCa) remains the most common diagnosed tumor and is the second-leading cause of cancer-related death in men. If the cancer is organ-confined it can be treated by various ablative therapies such as RP (radical prostatectomy), RT (radiation therapy), brachytherapy, cryosurgery or HIFU (High-Intensity Focused Ultrasound). However, advanced or metastatic PCa treatment requires systemic therapy involving androgen deprivation, but such patients typically progress to refractory disease designated as castration-resistant prostate cancer (CRPC). Interleukin-6 (IL-6) has been established as a driver of prostate carcinogenesis and tumor progression while less is known about the role of ciliary neurotrophic factor (CNTF), a member of the IL-6 cytokine family in prostate cancer. Moreover, MAPK/ERK, AKT/PI3K and Jak/STAT pathways that regulate proliferative, invasive and glucose-uptake processes in cancer progression are triggered by CNTF. Methods: We investigate CNTF and its receptor CNTFRα expressions in human androgen-responsive and castration-resistant prostate cancer (CRPC) by immunohistochemistry. Moreover, we investigated the role of CNTF in proliferative, invasive processes as well as glucose uptake using two cell models mimicking the PCa (LNCaP cell line) and CRPC (22Rv1 cell line). Conclusions: Our results showed that CNTF and CNTFRa were expressed in PCa and CRPC tissues and that CNTF has a pivotal role in prostate cancer environment remodeling and as a negative modulator of invasion processes of CRPC cell models.

Many reports have described a high incidence of acute kidney injury (AKI) among patients with COVID-19. Acute tubular necrosis has been reported to be the most common damage in these patients, probably due to hemodynamic instability. However, other complex processes may be involved, related to the cytokine storm and the activation of innate and adaptive immunity. Here, we describe a patient who developed an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with rapidly progressive glomerulonephritis and lung involvement and an antiphospholipid syndrome soon after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. After viral pneumonia was excluded by bronchoalveolar lavage, the patient has been treated with rituximab for amelioration of kidney function and resolution of thrombosis without any adverse event. We conclude that COVID-19 may trigger autoimmune diseases including ANCA-associated vasculitis. Thus, this diagnosis should be taken in consideration in COVID-19 patients, especially when they develop AKI with active urinary sediment. In addition, considering the relationship between these 2 diseases, SARS-CoV-2 infection should be excluded in all patients with a new diagnosis ANCA-associated vasculitis before starting immunosuppressive therapy.

Background The index lesion (IL) is the largest cancer focus, usually harbors the highest grade, and might drive the history of prostate cancer (PCA). Multiparametric magnetic resonance imaging (mp-MRI) has a high negative predictive value in ruling out clinically significant (cs)PCA. We aimed evaluating the efficiency of mp-MRI and targeted biopsy in detecting csPCA and the concordance between the MRI index lesion (MRI-IL) and the presence of csPCA inside it. Materials and Methods We retrospectively evaluated 158 men who underwent prostate biopsy after a positive pre-biopsy mp-MRI scan. All mp-MRI lesions were biopsied using a transrectal ultrasound elastic-fusion approach (2-4 targeted plus 10-12 random systematic biopsies). csPCA was defined as grading group ≥ 2 or > 3 cores with cancer or ≥ 50% of core involved by tumor. Results mp-MRI detected 158 ILs and 46 non-ILs. One hundred were Prostate Imaging-Reporting and Data System version 2 (PI-RADS v2) score 3, 84 score 4, and 20 score 5. csPCA was found in 63.9% of the MRI-ILs. Eighty percent of detected cancer using mp-MRI and targeted biopsy was clinically significant. Eighty-seven percent of the transitional zone lesions were clinically non-significant or negative for cancer. The probability of detecting csPCA increases with increasing size of MRI-IL, and every extra millimeter raises the odds of detecting csPCA of 12.2%. All PI-RADS v2 score lesions showed a strong association with csPCA. The risk of matching between MRI-IL and csPCA inside it increases by 36.2% as the total percentage of cancer in all cores increases. Conclusions mp-MRI showed high sensitivity in detecting csPCA in the peripheral zone, with concordance between MRI-IL and csPCA.

To develop a nomogram incorporating clinical and multiparametric magnetic resonance imaging (mpMRI) parameters for the detection of clinically significant prostate cancer (csCaP) at radical prostatectomy (RP).We retrospectively analyzed all consecutive patients who underwent robotic RP between 2016 and 2020. All patients underwent a 1.5-T mp-MRI according to the PI-RADS-v2 scoring system. RP specimens were examined with the whole-mount technique. csCaP definition: any tumor with a volume larger than 0.5 cmThe analysis involved 393 patients. The median age was 65(9) years. The median prostate specific antigen was 5.81(3.76) ng/ml. 363 had csCaP. PI-RADS v2 score of 4-5, prostate specific antigen density of 0.15 or more, and mpMRI index lesion (IL) size were significantly associated with csCaP in the multivariable regression analyses. Based on these variables, a diagnostic model was developed. The full model yielded an area under the curve of 0.77 (95%CI:0.75-0.80) which was significantly better than those excluding mpMRI findings (P = 0.02) Decision curve analysis showed a slight but significant net benefit associated with the use of the mp-MRI based nomograms compared with those excluding either PI-RADS score (Delta net benefit 0.0278) or mpMRI maximum IL size (Delta net benefit 0.0111).The nomogram constructed in this study can assist urologists in assessing an individual's risk of csCaP at RP.

Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma that originate from peripheral nerves or from cells associated with the nerve sheath. We report the case of a 30‑year‑old male patient with a history of neurofibromatosis type I (NF-1) and a MPNST located in the lumbar region. The mass was resecated but surgical margins weren't clear. Recurrence of disease was observed after few months. A close monitoring of subjects with NF-1 is crucial to diagnose MPNST at an earlier stage and allow a complete surgical resection.

Starting in the mid-1970s, we formed a group of pathologists with a major interest in uropathology. Originally, it included 2 (R.M. and M.S.). In the years the followed, the group was enlarged to include 4 more people, 2 in the mid- and late-1980s (A.L.B. and L.C.) and another in the mid-1990s (R.Ma.); a sixth (A.C.) joined the group ∼5 years ago. Two have reached the retirement age (R.M. and M.S.), while others are in the process of joining the group to replace them. A fruitful collaboration spanned for ∼45 years. This contribution is based on a series of personal recollections of the successive changes in the interpretation of prostate cancer and its precursors, starting in the mid-1970s. Here we have retraced our involvement steps, sharing issues related to them with a junior uropathologist (A.C.).

We are pleased to present this Special Issue of Cancers, entitled “Pathology of Urologic Cancers” [...]

Context Whole-mount histopathology, that is, large format histology or whole-mount sectioning, refers to the histopathological examination of tissue sections from specimens processed with large tissue cassette. In some institutions, it is applied routinely to specimens with genitourinary cancers. Objective To give an overview of the application of the large format histology to the morphological examination of the radical prostatectomy (RP) specimens. Evidence acquisition A comprehensive PubMed search was performed up to May 2020, using the keywords “prostate carcinoma,” “radical prostatectomy specimens,” “whole-mount histopathology,” “whole mount sectioning,” “large format histology,” “macrosectioning,” “diagnostic criteria,” and “prognosis.” The search, supplemented with a hand search, was restricted to articles published in the English language. No limitations were placed on the publication year. References in relevant articles were also reviewed. Evidence synthesis Even though the whole-mount sections of RPs appear not to be superior to regular sections in detecting adverse pathological features, their use has the advantage of displaying the architecture of the prostate gland and identifying and locating tumor nodule(s) more clearly, with particular reference to the index tumor. Further, it is easier to compare the pathological features with clinical findings derived, for instance, from digital rectal examination, transrectal ultrasound, multiparametric magnetic resonance imaging, surgical operation, and prostate biopsies. Conclusions Urologists, radiologists, and oncologists are updated about the step forward made by pathologists when diagnostic and prognostic information is derived from an approach that closely resembles that used by the clinicians when dealing with imaging findings. Patient summary Adoption of the whole-mount histopathology adds clinical value in correlation with clinical/imaging findings of radical prostatectomy specimens.

Simple Summary In 2021, the identification of effective biomarkers became a major focus of prostate cancer (PCa) in order to improve outcomes and select potentially responsive patients. The aim of this contribution is to review the main 2021 novelties in prognostic and therapeutic markers in PCa, with special reference to PCa grading, aggressive variant PCa and molecular markers predicting significant disease or response to therapy. Abstract The 2021 novelties in prognostic and therapeutic tissue markers in patients with prostate cancer (PCa) can be subdivided into two major groups. The first group is related to prognostic markers based on morphological and immunohistochemical evaluations. The novelties in this group can then be subdivided into two subgroups, one involving morphologic evaluation only, i.e., PCa grading, and the other involving both morphologic and immunohistochemical evaluations, i.e., aggressive variant PCa (AVPCa). Grading concerns androgen-dependent PCa, while AVPCa represents a late phase in its natural history, when it becomes androgen-independent. The novelties of the other major group are related to molecular markers predicting significant disease or response to therapy. This group mainly includes novelties in the molecular evaluation of PCa in tissue material and liquid biopsies.

The Gleason grading system, proposed by Dr. Donald F. Gleason in 1966, is one of the most important prognostic factors in men with prostate cancer (PCa). At consensus conferences held in 2005 and 2014, organized by the International Society of Urological Pathology (ISUP), the system was modified to reflect the current diagnostic and therapeutic approaches. In particular, in the 2014 Conference, it was recognized that there were weaknesses with the original and the 2005 ISUP modified Gleason systems. Based on the results of a research conducted by Prof. JI Epstein and his group, a new grading system was proposed by the ISUP in order to address some of such deficiencies: i.e., the five distinct Grade Groups (GGs). Since 2014, results of studies have been published by different groups and societies, including the Genitourinary Pathology Society (GUPS), giving additional support to the prognostic role of the architectural Gleason patterns and, in particular, of the GGs. A revised GG system, taking into account the percentage of Gleason pattern (GP) 4, cribriform and intraductal carcinoma, tertiary GP 5, and reactive stroma grade, has shown to have some advantages, however not ready for adoption in the current practice. The aim of this contribution was to review the major updates and recommendations regarding the GPs and GSs, as well as the GGs, trying to give an answer to the following questions: “How has the grade group system been used in the routine?” and “will the Gleason scoring system be replace by the grade groups?” We also discussed the potential implementation in the future of molecular pathology and artificial intelligence in grading to further define risk groups in patients with PCa.

Aims: To capture the complex relationships between risk factors and cancer incidences in the US and predict future cancer burden. Materials & methods: Two artificial neural network (ANN) algorithms were adopted: a multilayer feed-forward network (MLFFNN) and a nonlinear autoregressive network with eXogenous inputs (NARX). Data on the incidence of the four most common tumors (breast, colorectal, lung and prostate) from 1992 to 2016 (available from National Cancer Institute online datasets) were used for training and validation, and data until 2050 were predicted. Results: The rapid decreasing trend of prostate cancer incidence started in 2010 will continue until 2018–2019; it will then slow down and reach a plateau after 2050, with several differences among ethnicities. The incidence of breast cancer will reach a plateau in 2030, whereas colorectal cancer incidence will reach a minimum value of 35 per 100,000 in 2030. As for lung cancer, the incidence will decrease from 50 per 100,000 (2017) to 31 per 100,000 in 2030 and 26 per 100,000 in 2050. Conclusion: This up-to-date prediction of cancer burden in the US could be a crucial resource for planning and evaluation of cancer-control programs.

AT-rich interactive domain 1A (ARID1A, as known as BAF250a) is a subunit of human switch/sucrose nonfermentable chromatin remodeling complex with tumour suppressor function. Mutations of Arid1a have been reported in many human cancers and low expression of this protein has been correlated to a poor prognosis outcome in patients affected by some types of cancer. Although there are many studies regarding ARID1A functions in cancer, little is known about its role in regulating cell differentiation and normal tissues homeostasis. Here, we investigate ARID1A expression in normal placental tissues of first and third trimester of gestation and in pathological placental tissues of pregnancy complicated by preeclampsia (PE) and intrauterine growth restriction (IUGR) to evaluate a possible role of this protein in trophoblast differentiation. We found that ARID1A was specifically expressed in villous and extravillous cytotrophoblastic cells in normal placentas whereas syncytiotrophoblast was negative. Interestingly, ARID1A was expressed in both cytotrophoblastic cells and syncytiotrophoblast in placentas affected by PE and PE-IUGR. Moreover, ARID1A was also present in syncitial knots of pathological placentas. The present results indicate that ARID1A is a good marker of poor trophoblast differentiation in these pathologies, because the significant high positive staining in syncytiotrophoblast nuclei may suggest a poor differentiation of this trophoblast layer due to the cytotrophoblast cells fusion with the syncytiotrophoblast overlaying before arresting their cell cycle.

Most patients with bladder carcinoma are diagnosed with non-muscle-invasive disease, stage Ta, and pT1. Stage remains as the single most important prognostic indicator in urothelial carcinoma. Among the pT1 bladder cancer patients, recurrence and progression of disease occur in 50% and 10%, respectively. The identification of high-risk patients within the pT1 subgroup remains an important clinical goal and an active field of research. Substaging of pT1 disease has been claimed as important histologic discriminator by the 2016 World Health Organization (WHO) classification of the genitourinary tract tumors and by the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual supporting its implementation in clinical practice. Interobserver variation in pT1 diagnosis and the associated pitfalls in pT1 assessment are the critical pathological issues. The aim of this review paper is to provide the practicing pathologist with the state of the art of morphological and immunohistochemical features useful for the diagnosis of early invasive bladder carcinomas, including practical clues on how to avoid relevant interpretative pitfalls, and to summarize the current status of pT1 substaging.

Background A microscopic analysis of tissue is the gold standard for cancer detection. Hematoxylin-eosin (HE) for the reporting of prostate biopsy (PB) is conventionally based on fixation, processing, acquisition of glass slides, and analysis with an analog microscope by a local pathologist. Digitalization and real-time remote access to images could enhance the reporting process, and form the basis of artificial intelligence and machine learning. Fluorescence confocal microscopy (FCM), a novel optical technology, enables immediate digital image acquisition in an almost HE-like resolution without requiring conventional processing. Objective The aim of this study is to assess the diagnostic ability of FCM for prostate cancer (PCa) identification and grading from PB. Design, setting, and participants This is a prospective, comparative study evaluating FCM and HE for prostate tissue interpretation. PBs were performed (March to June 2019) at a single coordinating unit on consecutive patients with clinical and laboratory indications for assessment. FCM digital images (n = 427) were acquired immediately from PBs (from 54 patients) and stored; corresponding glass slides (n = 427) undergoing the conventional HE processing were digitalized and stored as well. A panel of four international pathologists with diverse background participated in the study and was asked to evaluate all images. The pathologists had no FCM expertise and were blinded to clinical data, HE interpretation, and each other’s evaluation. All images, FCM and corresponding HE, were assessed for the presence or absence of cancer tissue and cancer grading, when appropriate. Reporting was gathered via a dedicated web platform. Outcome measurements and statistical analysis The primary endpoint is to evaluate the ability of FCM to identify cancer tissue in PB cores (per-slice analysis). FCM outcomes are interpreted by agreement level with HE (K value). Additionally, either FCM or HE outcomes are assessed with interobserver agreement for cancer detection (presence vs absence of cancer) and for the discrimination between International Society of Urologic Pathologists (ISUP) grade = 1 and ISUP grade > 1 (secondary endpoint). Results and limitations Overall, 854 images were evaluated from each pathologist. PCa detection of FCM was almost perfectly aligned with HE final reports (95.1% of correct diagnosis with FCM, κ = 0.84). Inter-rater agreement between pathologists was almost perfect for both HE and FCM for PCa detection (0.98 for HE, κ = 0.95; 0.95 for FCM, κ = 0.86); for cancer grade attribution, only a moderate agreement was reached for both HE and FCM (HE, κ = 0.47; FCM, κ = 0.49). Conclusions FCM provides a microscopic, immediate, and seemingly reliable diagnosis for PCa. The real-time acquisition of digital images—without requiring conventional processing—offers opportunities for immediate sharing and reporting. FCM is a promising tool for improvements in cancer diagnostic pathways. Patient summary Fluorescence confocal microscopy may provide an immediate, microscopic, and apparently reliable diagnosis of prostate cancer on prostate biopsy, overcoming the standard turnaround time of conventional processing and interpretation.

Around 80–90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient’s response to androgen ablation therapy is variable, and 20–30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs.

The prostate gland, a male reproductive organ, is located posterior to the inferior symphysis pubis, superior to the urogenital diaphragm, and anterior to the rectum. McNeal has identified three zones. The transition zone surrounds the urethra between the colliculus and bladder neck; it is the usual location of benign prostatic hyperplasia. The peripheral and central zones are the most common locations of the putative preneoplastic and intra-acinar/intraductal neoplasms, such as prostatic intraepithelial neoplasia and intraductal carcinoma of the prostate. Atypical adenomatous hyperplasia (adenosis; AAH) has been considered a premalignant lesion of the transition zone; a direct transition from AAH to cancer has not been documented. Atypical small acinar proliferation (ASAP; also called atypical focus suspicious but not diagnostic of malignancy) is a diagnostic category and represents a microscopic growth of small acini with insufficient cytological abnormalities to warrant the diagnosis of malignancy. Prostate cancer (PCa) is the most frequently diagnosed noncutaneous malignant neoplasm in men. This chapter discusses the classification, grading, staging, and current definition of clinically significant PCa. Tissue biomarkers predicting upgrading and/or significant disease and tissue-based genomic tests for diagnosis and prognosis are mentioned briefly.

Prostate cancer (PCa) is one of the most common cancers worldwide but it presents many subtypes and patient heterogeneity. It is necessary to discriminate localised not aggressive PCa and metastatic cancer in order to better define the personalised treatment. The identification of an appropriate biomarker to combine with Gleason grading system, that is one of the most important prognostic factors in prostate cancer outcome, remains a major clinical issue. We have tested AT-rich interactive domain 1A (ARID1A) in prostate tissue is order to verify its possible role as morphological marker for prostate cancer progression. ARID1A is a tumour suppressor protein playing a pivotal role in chromatin remodelling during transcriptional regulation. It was decreased in many cancers correlating with tumour aggressiveness. Our data shown that ARID1A had a nuclear staining and that it is significantly decreased in prostate cancers suggesting that it can be involved in this neoplasm but it is not able to discriminate prostate cancer progression.

Context and Objectives The Vancouver consensus conference of the International Society of Urological Pathology provided the foundation for the 2016 World Health Organization (WHO) classification of the renal tumors. The aim of this contribution is to review some of the major changes and additions to tumor variants and variations in the current classification of the renal cell neoplasms in adults. Evidence acquisition and Evidence synthesis Several publications report no recurrence or metastasis in patients with multilocular cystic renal cell carcinoma (RCC). Multilocular cystic renal neoplasm of low malignant potential is now the term recommended by the WHO for this lesion. A similar recommendation has been made in the current literature for hybrid oncocytic/chromophobe tumors (ie, oncocytic neoplasia of uncertain malignant potential) and for clear cell papillary renal cell carcinoma (ie, neoplasm of low malignant potential). Some of the latter tumors were referred to as renal angioadenomatous tumors. Papillary RCC has traditionally been subdivided into type 1 and type 2 papillary RCCs. Recent molecular studies suggest that type 2 papillary RCCs may not constitute a single well-defined entity. There are newly recognized epithelial renal tumor entities in the 2016 WHO classification such as succinate dehydrogenase-deficient RCC. Conclusions and Patient summary There are some additional variations in the tumor types that are not included in the WHO classification, however, worth knowing, such as clear cell RCC with hemangioblastoma-like features and unclassified RCC with medullary phenotype.

Human trophoblast cell surface antigen 2 (Trop-2) is a 40-kDa transmembrane glycoprotein that was first identified as a marker of human trophoblast cells. Trop-2 acts on cell proliferation, adhesion, and migration by activating a number of intracellular signalling pathways. Elevated Trop-2 expression has been demonstrated in several types of cancer and correlated with aggressiveness and poor prognosis. Since no data are available on Trop-2 in bladder cancer (BC), the purpose of the study was to determine its levels in tissue specimens from normal individuals and patients with BC at different stages. Moreover, since according to recent evidence Trop-2 is a miR-125b target, miR-125b expression was also assessed in tissue specimens. Finally, the effect of the Trop-2/miR-125b axis on the proliferation and migration of BC cells was evaluated in vitro. The Trop-2/miR-125b axis was seen to be differentially expressed in normal urothelium, non-invasive BC and invasive BC tissue. Significant miR-125b down-regulation was associated with a significant increase in Trop-2 protein levels in BC tissue and correlated with disease severity. In vitro analysis confirmed the role of miR-125b in down-modulation of Trop-2 protein levels and showed that Trop-2/miR-125b axis affects cellular proliferation in bladder tissue. In conclusion, our findings highlight a role for the Trop-2/miR-125b axis in BC progression and suggest Trop-2 and miR-125b as diagnostic/prognostic marker candidates as well as druggable targets for innovative therapeutic approaches.

The association between inflammatory bowel disease (IBD) and colorectal cancer (CRC) is being increasingly investigated. HtrA1 overexpression inhibits cell growth and proliferation by influencing apoptosis, invasiveness and migration of tumour cells. In the present study, HtrA1 expression was analysed in 228 colon tissue samples from patients with CRC, adenoma with high-grade dysplasia (AHD), adenoma with low-grade dysplasia (ALD), ulcerative colitis of >10 year duration (UCL), ulcerative colitis of