LGALS3 cfDNA methylation in seminal fluid as a novel prostate cancer biomarker outperforming PSA.

BACKGROUND: The unmet challenge in prostate cancer (PCa) management is to discriminate it from benign prostate hyperplasia (BPH) due to the lack of specific diagnostic biomarkers. Contemporary research on potential PCa biomarkers is directed toward methylated cell-free DNA (cfDNA) from liquid biopsies since epigenetic mechanisms are strongly involved in PCa development. METHODS: In the present research, cfDNA methylation of the LGALS3 gene in blood and seminal plasma of PCa and BPH patients was assessed using pyrosequencing, as well as LGALS3 DNA methylation in tissue biopsies. Liquid biopsy samples were taken from patients with clinical suspicion of PCa, who were subsequently divided into two groups, that is, 42 with PCa and 55 with BPH, according to the histopathological analysis. RESULTS: Statistically significant higher cfDNA methylation of LGALS3 in seminal plasma of BPH than in PCa patients was detected by pyrosequencing. ROC curve analysis showed that it could distinguish PCa and BPH patients with 56.4% sensitivity and 70.4% specificity, while PSA did not differ between the two patient groups. In contrast, there was no statistically significant difference in LGALS3 cfDNA methylation in blood plasma between the two patient groups. In prostate tumor tissue, there was a statistically significant DNA hypermethylation of LGALS3 compared to surrounding nontumor tissue and BPH tissue. CONCLUSIONS: The DNA hypermethylation of the LGALS3 gene represents an event specific to PCa development. In conclusion, LGALS3 cfDNA methylation in seminal fluid discriminates early PCa and BPH presenting itself as a powerful novel PCa biomarker highly outperforming PSA.

Involvement of M1-Activated Macrophages and Perforin/Granulysin Expressing Lymphocytes in IgA Vasculitis Nephritis.

We investigated the polarisation of CD68+ macrophages and perforin and granulysin distributions in kidney lymphocyte subsets of children with IgA vasculitis nephritis (IgAVN). Pro-inflammatory macrophage (M)1 (CD68/iNOS) or regulatory M2 (CD68/arginase-1) polarisation; spatial arrangement of macrophages and lymphocytes; and perforin and granulysin distribution in CD3+ and CD56+ cells were visulaised using double-labelled immunofluorescence. In contrast to the tubules, iNOS+ cells were more abundant than the arginase-1+ cells in the glomeruli. CD68+ macrophage numbers fluctuated in the glomeruli and were mostly labelled with iNOS. CD68+/arginase-1+ cells are abundant in the tubules. CD56+ cells, enclosed by CD68+ cells, were more abundant in the glomeruli than in the tubuli, and co-expressed NKp44. The glomerular and interstitial/intratubular CD56+ cells express perforin and granulysin, respectively. The CD3+ cells did not express perforin, while a minority expressed granulysin. Innate immunity, represented by M1 macrophages and CD56+ cells rich in perforin and granulysin, plays a pivotal role in the acute phase of IgAVN.

Two sides of the same coin: a complex presentation of autosomal dominant tubulointerstitial kidney diseases: a literature review and case reports.

Introduction: Genetic kidney diseases are underdiagnosed; namely, from 7% to 40% of patients suffering from chronic kidney disease (CKD) can carry a pathogenic variant, depending on population characteristics. Hereditary tubulointerstitial kidney diseases, including autosomal dominant tubulointerstitial kidney diseases (ADTKD), are even more challenging to diagnose. ADTKD is a rare form of genetic kidney disease resulting from pathogenic variants in the MUC1, UMOD, HNF1B, REN, SEC61A1, and DNAJB11 genes. There is no typical clinical or histopathological sign of ADTKD, it is characterized by progressive CKD, an autosomal dominant inheritance pattern, and tubular atrophy with interstitial fibrosis on kidney biopsy. There is no significant proteinuria, and the urinary sediment is bland. The patients usually do not have severe arterial hypertension. There can be a history of early gout, especially when compared to the UMOD gene variants. Children can have enuresis due to a loss of renal concentration. On ultrasound, the kidneys can appear normal or small in size. Renal cysts are not pathognomonic for any of the named diseases. End-stage renal disease (ESRD) develops at the average age of 45, but this can be very variable. Family history that suggests autosomal dominant inheritance and CKD fulfilling the aforementioned characteristics of tubulointerstitial kidney disease should raise suspicion of ADTKD. In the setting of a negative family history for CKD, clinical suspicion should be raised based on clinical characteristics, including early onset of hyperuricemia or gout and compatible histology on the kidney biopsy. Contrary to the aforementioned characteristics of ADTKD, in the case of HNF1B-related disease, there is a more complex clinical presentation with extrarenal manifestations of the disease (diabetes mellitus, hypomagnesemia, neurologic and psychiatric disturbances, etc.). The diagnosis of ADTKD is based on a positive family history and a detection of the pathogenic variant in one of the genes in an affected individual. Aim: The aim of our study is to present two case reports of ADTKD with different characteristics (slowly progressive CKD vs. complex clinical presentation with an extrarenal manifestation of the disease) with a literature review. Methods: A 34-year-old patient with CKD and a positive family history of CKD in whom kidney biopsy showed nonspecific chronic changes, with only genetic analysis confirming the diagnosis of MUC1-related ADTKD. Our second case is of a 17-year-old patient with an unremarkable family history who was initially referred to genetic counseling due to cognitive and motor impairment with long-lasting epilepsy. Extensive workup revealed increased serum creatinine levels with no proteinuria and bland urinary sediment, along with hypomagnesemia. His genetic analysis revealed 17q12 deletion syndrome, causing the loss of one copy of the HNF1B gene, the AATF, and the LHX1 gene. Conclusion: Autosomal dominant tubulointerstitial kidney diseases are challenging to diagnose due to a lack of typical clinical or histopathological signs as well as an uncharacteristic and versatile clinical presentation. Increased clinical awareness is crucial for the detection of these diseases.

Low-grade oncocytic tumour of the kidney is characterised by genetic alterations of TSC1, TSC2, MTOR or PIK3CA and consistent GATA3 positivity.

Low-grade oncocytic tumour (LOT) of the kidney has recently emerged as a potential novel tumour type. Despite similarity to oncocytoma or eosinophilic chromophobe renal cell carcinoma, it shows diffuse keratin 7 immunohistochemistry (IHC) and negative KIT (CD117), which differs from both. We aimed to identify the molecular characteristics of these tumours. Seventeen tumours (one male, 16 female, nine previously published) fitting the original description of this entity (solid eosinophilic cell morphology, often with areas of tumour cells loosely stretched in oedematous stroma, and the above IHC features) were analysed with a next-generation sequencing panel of 324 cancer-associated genes from formalin-fixed, paraffin-embedded tissue. All tumours harboured at least one alteration in either TSC1 (n = 7, 41%), TSC2 (n = 2, 12%), MTOR (n = 5, 29%) or PIK3CA (n = 4, 24%). Four tumours harboured a second alteration, including two NF2, one each in conjunction with MTOR and TSC2 alterations, one PTEN with TSC1 alteration and one tumour with both MTOR and TSC1 alterations. No other renal cancer-related or recurring gene alterations were identified. In addition to the previously described IHC findings, 16 of 16 were positive for GATA3. Eleven patients with follow-up had no metastases or recurrent tumours. Recurrent tuberous sclerosis/MTOR pathway gene alterations in LOT support its consideration as a distinct morphological, immunohistochemical and genetic entity. PIK3CA is another pathway member that may be altered in these tumours. Further study will be necessary to determine whether tumour behaviour or syndromic associations differ from those of oncocytoma and chromophobe carcinoma, warranting different clinical consideration.

Semiquantitative classification (SQC) and Oxford classifications predict poor renal outcome better than The International Study of Kidney Disease in Children (ISKDC) and Haas in patients with IgAV nephritis: a multicenter study.

INTRODUCTION: Several histologic classifications are used in the evaluation of IgA vasculitis nephritis (IgAVN), however, to date, no studies have determined which one has the strongest association with the severity of IgAVN and, as a consequence, its outcomes. MATERIALS AND METHODS: Patients included in the study were diagnosed with IgAV and IgAVN in seven tertiary university medical centers in Croatia, Italy and Israel. The International Study of Kidney Disease in Children (ISKDC), Haas, Oxford, and Semiquantitative classification (SQC) classifications were used in the analysis and description of renal biopsy. Time from biopsy to outcome evaluation was a statistically significant factor in outcome prediction that was used to define the base model, and was a covariate in all the tested models. RESULTS: Sixty-seven patients were included in this study. The SQC classification proved to be the best one in outcome prediction, followed by the Oxford classification. The ISKDC and Haas classifications could not predict renal outcome. The Oxford parameters for mesangial hypercellularity and tubular atrophy, as well as the SQC parameters for cellular crescents showed an independent statistically significant contribution to outcome prediction. High level of twenty-four hour protein excretion was associated with a higher grade in the Oxford, SQC and ISKDC classifications. Endocapillary proliferation was positively associated with the Pediatric Vasculitis Activity Score (PVAS) at diagnosis, while tubular atrophy was negatively associated. CONCLUSION: The SQC, followed by the Oxford classification were found to provide the best classifications of renal biopsy analysis in patients to predict the outcome in patients with IgAVN. Cellular crescents, mesangial hypercellularity and tubular atrophy showed significant contributions, indicating that active and chronic variables should be included in the estimation.

Methylation pattern of caveolin-1 in prostate cancer as potential cfDNA biomarker.

High prevalence and mortality of prostate cancer (PCa) are well known global health issues. Novel biomarkers for better identifying patients with PCa are the subject of extensive research. Prostate specific antigen (PSA) shows low specificity in screening and diagnostics, leading to unnecessary biopsies and health costs. Eighty patients with PCa and benign prostate hyperplasia (BPH) were included in the study. We analyzed CAV1 gene expression and methylation in tissue. CAV1 cfDNA methylation from blood and seminal plasma was accessed as a potential PCa biomarker. Although methylation in blood plasma did not differ between PCa and BPH patients, methylation in seminal plasma showed better PCa biomarker performances than tPSA (AUC 0.63 vs. AUC 0.52). Discrimination of BPH and Gleason grade group 1 PCa patients from patients with higher Gleason grade groups revealed very good performance as well (AUC 0.72). CAV1 methylation is useful biomarker with potential for further seminal plasma cfDNA research, but its diagnostic accuracy should be improved, as well as general knowledge about cfDNA in seminal plasma.

TRENDS IN PROSTATE CANCER DIAGNOSIS DURING THE COVID-19 PANDEMIC: SINGLE-INSTITUTION EXPERIENCE.

The aim of this study was to compare the number of biopsy and surgical procedures on prostate, as well as the number of newly diagnosed, histologically confirmed cases of prostate cancer during the COVID-19 pandemic at Zagreb University Hospital Center (UHC). We retrospectively collected and processed a total of 1344 histopathologic findings of the prostate at the Zagreb UHC. Our results show that during the COVID-19 pandemic, there was a statistically significant decrease in the absolute number of biopsy and surgical procedures on prostate at Zagreb UHC, and so was the number of newly diagnosed, histologically confirmed cases of prostate cancer. During the observed time of the pandemic (March 19, 2020 to December 31, 2020), there was a 37.5% decrease in the absolute number of newly diagnosed prostate cancer cases compared to the same period of the previous year (March 19, 2019 to December 31, 2019). To our knowledge, this is the first study of this kind that is based on the number of prostate cancer diagnoses in Croatia. By observing the early period of the pandemic, our results provide important guidelines for monitoring and understanding the long-term consequences of the pandemic on the prostate cancer morbidity and mortality.

Histologic diversity in chromophobe renal cell carcinoma does not impact survival outcome: A comparative international multi-institutional study.

Predicting the clinical behavior and trajectory of chromophobe renal cell carcinoma (ChRCC) by histologic features has so far proven to be challenging. It is known that ChRCC represents a heterogeneous group of neoplasms demonstrating variable, yet distinctive morphologic and genetic profiles. In this international multi-institutional study, we aimed to assess the impact of histologic diversity in ChRCC (classic/eosinophilic versus rare subtypes) on survival outcome. This is an international multi-institutional matched case-control study including 14 institutions, examining the impact of histologic subtypes of ChRCC on survival outcome. The study group (cases) included 89 rare subtypes of ChRCC. The control group consisted of 70 cases of ChRCC including classic and eosinophilic features, age- and tumor size-matched. Most of the rare subtypes were adenomatoid cystic/pigmented ChRCC (66/89, 74.2%), followed by multicystic ChRCC (10/89, 11.2%), and papillary ChRCC (9/89, 10.1%). In the control group, there were 62 (88.6%) classic and 8 (11.4%) eosinophilic ChRCC. There were no statistically significant differences between the study and control groups for age at diagnosis, gender distribution, tumor size, presence of tumor necrosis, presence of sarcomatoid differentiation, and adverse outcomes. No statistically significant differences were found in clinical outcome between the rare subtypes and classic/eosinophilic groups by tumor size, necrosis, and sarcomatoid differentiation. Further, no statistically significant differences were found in clinical outcome between the two groups, stratified by tumor size, necrosis, and sarcomatoid differentiation. Our findings corroborated previous studies that both sarcomatoid differentiation and tumor necrosis were significantly associated with poor clinical outcome in classic/eosinophilic ChRCC, and this was proven to be true for ChRCC with rare histologic subtypes as well. This study suggests that rare morphologic patterns in ChRCC without other aggressive features play no role in determining the clinical behavior of the tumor.

Small cell variant of chromophobe renal cell carcinoma: Clinicopathologic and molecular-genetic analysis of 10 cases.

The morphologic diversity of chromophobe renal cell carcinoma (ChRCC) is well-known. Aside from typical morphology, pigmented adenomatoid, multicystic and papillary patterns have been described. Ten cases of CHRCC composed of small cell population in various percentages were analysed, using morphologic parameters, immunohistochemistry and next-generation sequencing (NGS) testing. Patients were five males and five females, with age ranging from 40 to 78years. The size of tumors ranged from 2.2 cm to 11 cm (mean 5.17 cm). Small cell component comprised 10 to 80% of the tumor volume, while the remaining was formed by cells with classic ChRCC morphology. The immunohistochemical profile of the small cell component was consistent with typical ChRCC immunophenotype, with CD117 and CK7 positivity. Neuroendocrine markers were negative. Mutations of 13 genes were found: DCIER1, FGFR3, JAK3, SUFO, FAM46C, FANCG, MET, PLCG2, APC, POLE, EPICAM, MUTYH and AR. However, only the PLCG2 mutation is considered pathogenic.The small cell variant of ChRCC further highlights and expand upon existing morphologic heterogeneity spectrum. Recognition of small cell variant of CHRCC is not problematic in tumors, where the "classic" CHRCC component is present. However, in limited material (i.e., core biopsy), this may present a diagnostic challenge. Based on the limited follow-up data available, it appears that the small cell tumor component had no impact on prognosis, since there was no aggressive behavior documented.   Awareness of this unusual pattern and applying additional sections to find classic morphology of ChRCC, as well as excluding neuroendocrine nature by immunohistochemistry, may help resolve difficult cases.

First Characterization of ADAMTS-4 in Kidney Tissue and Plasma of Patients with Chronic Kidney Disease-A Potential Novel Diagnostic Indicator.

Background: We have previously shown that metzincin protease ADAMTS-4 accompanies renal fibrogenesis, as it appears in the blood of hemodialysis patients. Methods: Native kidney (NKB) and kidney transplant (TXCI) biopsy samples as well as plasma from patients with various stages of CKD were compared to controls. In paired analysis, 15 TXCI samples were compared with their zero-time biopsies (TX0). Tissues were evaluated and scored (interstitial fibrosis and tubular atrophy (IFTA) for NKB and Banff ci for TXCI). Immunohistochemical (IHC) staining for ADAMTS-4 and BMP-1 was performed. Plasma ADAMTS-4 was detected using ELISA. Results: ADAMTS-4 IHC expression was significantly higher in interstitial compartment (INT) of NKB and TXCI group in peritubular capillaries (PTC) and interstitial stroma (INT). Patients with higher stages of interstitial fibrosis (ci > 1 and IFTA > 1) expressed ADAMTS-4 in INT more frequently in both groups (p = 0.005; p = 0.013; respectively). In paired comparison, TXCI samples expressed ADAMTS-4 in INT and PTC more often than TX0. ADAMTS-4 plasma concentration varied significantly across CKD stages, being highest in CKD 2 and 3 compared to other groups (p = 0.0064). Hemodialysis patients had higher concentrations of ADAMTS-4 compared to peritoneal dialysis (p < 0.00001). Conclusion: ADAMTS-4 might have a significant role in CKD as a potential novel diagnostic indicator.

Immunohistochemical Expression of Wnt-4 Protein in Clear Cell Renal Carcinoma.

Wingless binding integration site proteins (Wnt) have an important role in normal kidney development and in various kidney diseases. They are required for complete epithelial differentiation and normal nephron formation. Changes in these proteins could also have important role in carcinogenesis. This study included 185 patients with clear cell renal carcinoma (ccRCC) in whom immunohistochemical expression of Wnt-4 protein in healthy and tumorous tissue after surgery was investigated. There was higher expression of Wnt-4 in healthy than in tumor tissue. No difference between Fuhrman's grade and Wnt-4 expression was found. A poor negative correlation between tumor size and Wnt-4 expression was found. Patients with suspected metastatic diseases had higher Wnt-4 expression. There was no difference in survival rates between Wnt-4 negative and positive groups. In our study we have shown that high Wnt-4 expression in healthy tissue decreases in low-grade tumors but then increases in high-grade tumors, suggesting that tumor progression requires Wnt-4 activation or reactivation.

Histopathologic findings on indication renal allograft biopsies after recovery from acute COVID-19.

Current knowledge on histopathological changes occurring after COVID-19 in transplanted kidneys is limited. Herein, we present renal allograft pathology findings in patients recovered from COVID-19. Six patients underwent indication biopsy, and one required allograft nephrectomy after acute COVID-19. Demographic data, clinical characteristics, and laboratory findings were recorded. The histopathological analysis included light microscopy, immunostaining, and electron microscopy. Five patients were hospitalized for acute COVID-19, and all were diagnosed with imaging-confirmed pneumonia, one requiring mechanical ventilation, and two requiring dialysis. Two patients had mild form. Histopathologic examination of renal allograft specimens revealed collapsing, perihilar, tip-lesion and secondary FSGS in one patient each. One patient had borderline acute cellular rejection, and two had chronic antibody-mediated rejection. Histopathologic changes of glomerular tufts were accompanied by acute tubular injury in four patients. None of our patients had signs of viral inclusions in kidney cells. One patient died and one remained dialysis-dependent after the good initial response to treatment. Patients with collapsing and perihilar FSGS had further progression of their chronic allograft nephropathy still without need for dialysis. In conclusion, diverse kidney pathology may be found in SARS-CoV-2-infected renal transplant patients. It seems that viral infection may affect the immune system with triggering of glomerular diseases, while the acute tubular injury is of multifactorial etiology. Direct viral effect is less likely.

Gastrointestinal involvement and its association with the risk for nephritis in IgA vasculitis.

BACKGROUND: We analysed clinical and biochemical parameters in predicting severe gastrointestinal (GI) manifestations in childhood IgA vasculitis (IgAV) and the risk of developing renal complications. METHODS: A national multicentric retrospective study included children with IgAV reviewed in five Croatian University Centres for paediatric rheumatology in the period 2009-2019. RESULTS: Out of 611 children, 281 (45.99%) had at least one GI manifestation, while 42 of 281 (14.95%) had the most severe GI manifestations. Using logistic regression several clinical risk factors for the severe GI manifestations were identified: generalized rash [odds ratio (OR) 2.09 (95% confidence interval (CI) 1.09-4.01)], rash extended on upper extremities (OR 2.77 (95% CI 1.43-5.34)] or face [OR 3.69 (95% CI 1.42-9.43)] and nephritis (IgAVN) [OR 4.35 (95% CI 2.23-8.50)], as well as lower values of prothrombin time (OR 0.05 (95% CI 0.01-0.62)], fibrinogen [OR 0.45 (95% CI 0.29-0.70)] and IgM [OR 0.10 (95% I 0.03-0.35)]] among the laboratory parameters. Patients with severe GI involvement more frequently had relapse of the disease [OR 2.14 (CI 1.04-4.39)] and recurrent rash [OR 2.61 (CI 1.27-5.38)]. Multivariate logistic regression found that the combination of age, GI symptoms at the beginning of IgAV and severity of GI symptoms were statistically significant predictors of IgAVN. Patients in whom IgAV has started with GI symptoms [OR 6.60 (95% CI 1.67-26.06)], older children [OR 1.22 (95% CI 1.02-1.46)] with severe GI form of IgAV (OR 5.90 (95% CI 1.12-31.15)] were particularly high-risk for developing IgAVN. CONCLUSION: We detected a group of older children with the onset of GI symptoms before other IgAV symptoms and severe GI form of the IgAV, with significantly higher risk for acute and chronic complications of IgAV.

The Onset of Systemic Oxidative Stress Associated with the Accumulation of Lipid Peroxidation Product Acrolein in the Skin of Patients with Small-Vessel Vasculitis.

Small-vessel vasculitis (SVV) is the inflammation of the vessel wall that can result in hemorrhage and/or ischemia. Among the histological findings in SVV are increased infiltrating neutrophils, which, due to their oxidative burst and myeloperoxidase activity, release excessive reactive oxygen species, triggering a chain reaction of lipid peroxidation and yielding reactive aldehydes such as acrolein. The implication of oxidative stress in the pathogenesis of SVV was studied, focusing on acrolein immunohistochemistry in the affected skin vessels and systemic stress response. Samples from SVV patients and healthy subjects were collected and analyzed for total serum peroxides, total antioxidant capacity, inflammatory and immunological parameters, as well as for the presence of acrolein-protein adducts in the skin tissue specimens. The obtained data showed that systemic redox homeostasis and iron metabolism are altered in SVV patients. Possible biomarkers in the evaluation of oxidative status, disease activity and prevalence were indicated. Furthermore, a strong correlation between the accumulation of acrolein-protein adducts in the skin and the progression of the disease was revealed. Thus, the results of this study demonstrate that SVV is not only associated with systemic oxidative stress but also with tissue-specific oxidative stress that promotes acrolein formation and protein modification correlating with the severity of cutaneous vasculitis.

Molecular Genetic Features of Primary Nonurachal Enteric-type Adenocarcinoma, Urachal Adenocarcinoma, Mucinous Adenocarcinoma, and Intestinal Metaplasia/Adenoma: Review of the Literature and Next-generation Sequencing Study.

The diagnosis of primary adenocarcinoma of the urinary bladder may be challenging in routine practice. These tumors may morphologically and immunohistochemically overlap with urachal adenocarcinoma and colorectal adenocarcinoma. Further, their genetic background is poorly understood. We systematically searched the PubMed database for results of complex genetic evaluation of primary bladder adenocarcinoma subtypes. Subsequently, we designed our own series of bladder lesions. We evaluated 36 cases: 16 primary enteric-type adenocarcinomas, 7 urachal enteric adenocarcinomas, 3 primary mucinous/colloid adenocarcinomas, and 10 intestinal-type metaplasia/villous adenoma. Detailed clinical data were collected, and all cases were examined using targeted next-generation sequencing. On the basis of the literature, the first mutated gene in these tumors was reported to be KRAS in 11.3% of cases, followed by TERT promoter mutations in 28.5%. In addition to KRAS and TERT, other genes were also found to be frequently mutated in primary bladder adenocarcinoma, including TP53, PIK3CA, CTNNB1, APC, FBXW7, IDH2, and RB1. In our series, the most frequent gene mutations in primary enteric-type adenocarcinomas were as follows: TP53 (56%); BRCA2, KMT2B (both 33%); NOTCH2, KDR, ARID1B, POLE, PTEN, KRAS (all 28%); in urachal enteric adenocarcinoma they were as follows: TP53 (86%); PTEN, NOTCH (both 43%); in primary mucinous/colloid adenocarcinomas they were as follows: KRAS, GRIN2A, AURKB (all 67%); and, in intestinal-type metaplasia/villous adenoma, they were as follows: APC, PRKDC (both 60%); ROS1, ATM, KMT2D (all 50%). No specific mutational pattern was identified using cluster analysis for any of the groups. Herein, we describe the pathologic features and immunohistochemical staining patterns traditionally used in the differential diagnoses of glandular lesions of the bladder in routine surgical pathology. We outline the mutational landscape of these lesions as an aggregate of published data with additional data from our cohort. Although diagnostically not discriminatory, we document that the most common genetic alterations shared between these glandular neoplasms include TP53, APC (in the Wnt pathway), and KRAS (in the MAPK pathway) mutations.

Targeted prostate biopsy using a cognitive fusion of multiparametric magnetic resonance imaging and transrectal ultrasound in patients with previously negative systematic biopsies and non-suspicious digital rectal exam.

AIM: To compare cognitive fusion targeted and systematic prostate biopsy in patients with repeated negative systematic biopsy but persistent clinical suspicion for prostate cancer. METHODS: The study enrolled 63 patients with at least one previously negative systematic biopsy who underwent targeted prostate biopsy using multiparametric magnetic resonance imaging (mpMRI) and transrectal ultrasound (TRUS) in addition to standardized systematic biopsy from July 2016 to May 2018. Multiparametric MRI was performed with 3 Tesla device by uro-radiologists experienced in prostate cancer. Lesions with Prostate Imaging Reporting and Data System 3, 4, and 5 were considered suspicious. Targeted biopsies were performed with cognitive fusion of TRUS and mpMRI. RESULTS: Prostate cancer detection, using either targeted or systematic biopsy, was 60.32%. Targeted biopsies were positive in 52.38% and systematic biopsies in 47.62% of patients. The median highest percentage of cancer involvement per biopsy core was significantly higher in targeted cylinders. The biopsies obtained by using the two techniques did not significantly differ in Gleason score. CONCLUSION: Cognitive targeted prostate biopsy based on mpMRI presents a valuable addition to systematic biopsy in patients with repeated negative systematic biopsies but persistent clinical suspicion of prostate cancer.

Leukocytoclastic vasculitis associated with sorafenib treatment for hepatocellular carcinoma.

Small-vessel vasculitis is an uncommon diagnosis associated with many causes, including certain medication. Characteristic findings are immune complex deposition, vessel wall damage, and erythrocyte extravasation. We present a case of a 77-year-old man with advanced hepatocellular carcinoma who was treated with sorafenib. Twenty days post introduction to sorafenib, the patient experienced high fever and painful purpura on the lower limbs. The results of the skin biopsy confirmed the diagnosis. More extensive diagnostics was undertaken, which excluded other possible causes of vasculitis and infectious disease. Following a full recovery, after the steroid treatment was completed, sorafenib has been continued until the progression of the carcinoma. This is the second described case of hepatocellular carcinoma associated with sorafenib treatment and leukocytoclastic vasculitis. Sorafenib is a potential cause of vasculitis, and clinicians should bear in mind to differentiate it from hand-foot skin reaction, which is a common side effect of multikinase inhibitors. The result of our assessment is important considering that vasculitis requires more specific diagnostic procedures, treatment, and often drug discontinuation.

Combined association of recipient killer cell immunoglobulin-like haplotype AA and donor HLA-C*07 gene with BK virus associated nephropathy in kidney transplant patients.

Kidney transplant recipient killer cell immunoglobulin-like receptors (KIR) genotype and HLA-C status of their donors have been separately associated with BK virus-associated nephropathy (BKVAN) and BK virus infection. Our aim was to determine whether different combinations of recipients KIR genes and donor HLA-C ligands influence the risk of BKVAN. Retrospective case-control study included 23 recipients with BKVAN and 46 recipients with persistently negative BK virus. Donor HLA-C*07 positivity was associated with lower odds for BKVAN, recipients bearing KIR haplotype AA or lacking any activating KIR genes were more frequent in BKVAN while recipient/donor combination HLA-C*07 negative/KIR AA positive was significantly associated with BKVAN. Our study complements and confirms results from several previously published studies, suggesting potential clinical usefulness.

Clear cell renal cell carcinoma with Paneth-like cells: Clinicopathologic, morphologic, immunohistochemical, ultrastructural, and molecular analysis of 13 cases.

Clear cell renal cell carcinoma (CRCC) is well known for its intratumoral heterogeneity. Paneth-like cells (PLC) have been reported in variable organs (i.e., hepatobiliary, genitourinary, and female genital tract). In genitourinary system, it is possible to find PLCs in epididymis, urinary bladder and prostate. The objective of this study was to assess PLC in CRCCs 13 CRCCs with prominent PLC (CRCCPLC) were selected out of 1378 CRCCs in our registry. The tumors were analyzed using morphologic, immunohistochemical, ultrastructural, and molecular genetic methods. CRCCPLCs were mostly of low histologic grade (12/13). Immunohistochemical profile was compatible with classic CRCC. PLC constituted 10 to-70% of the tumor volume (mean 17.7%, median 10%). PLCs did not express neuroendocrine markers (chromogranin, synaptophysin, CD56, INSM-1). Ultrastructurally, PLCs were filled by membrane bounded vesicles of various sizes and were compatible with secretory type of cells. VHL mutation was found in 9/9 cases, and LOH3p was found in 6/8 analyzable cases. Conclusions: PLC morphology can variably be present in "classic" CRCC, even in a substantial proportion. Ultrastructurally, PLCs have all attributes of secretory cells. Preliminary follow up data showed that these tumors may not be associated with aggressive clinical behavior.