Cytoplasmic expression of ß-catenin is an independent predictor of progression of conventional renal cell carcinoma: a simple immunostaining score.

AIMS: The aims of this study were to investigate the potential of ß-catenin as a biomarker for predicting cancer-specific survival, and to find a reproducible mode of evaluation of immunohistochemistry. METHODS AND RESULTS: ß-Catenin expression was analysed by immunohistochemistry in a cohort of 488 patients with conventional renal cell carcinoma (RCC) operated on between 2000 and 2010. The association between ß-catenin expression and cancer-specific survival was assessed with univariate and multivariate Cox regression models in relation to conventional clinical pathological prognostic factors, and by Kaplan-Meier survival analysis with the log rank test. The univariate Cox regression model revealed an association of cytoplasmic ß-catenin positivity and pathological variables with cancer-specific death. The multivariate Cox regression model analysis of tumours without metastatic disease at the first presentation identified the T-classification (P < 0.001) and cytoplasmic ß-catenin positivity as risk factors for postoperative tumour progression. Specifically, cytoplasmic ß-catenin expression was an independent factor indicating an unfavourable prognosis, with a four-fold higher risk of cancer-specific death (relative risk 4.017; 95% confidence interval 2.489-6.482; P < 0.001). The median survival time for patients with tumours showing cytoplasmic accumulation of ß-catenin was 48 months, whereas the overall survival time was 166 months. CONCLUSIONS: Cytoplasmic ß-catenin expression is an independent prognostic factor for conventional RCC, and may help to identify patients with a high risk of cancer-specific death and to direct optimized active surveillance or adjuvant therapy.

Bearberry in the treatment of acute uncomplicated cystitis (BRUMI): protocol of a multicentre, randomised double-blind clinical trial.

BACKGROUND: Bearberry (Arctostaphylos uva-ursi) leaf is available as a treatment of uncomplicated cystitis in several European countries. The antimicrobial activity of its extracts and some of its individual constituents has been observed in vitro; however, the efficacy of bearberry compared with standard antimicrobial therapy has not been assessed yet. OBJECTIVE: The objective of the study is to assess the safety and non-inferiority of bearberry as an alternative therapy in the treatment of acute uncomplicated cystitis in comparison with standard antibiotic therapy (fosfomycin). METHODS AND ANALYSIS: This is a randomised controlled double-blinded multicentre trial. Eligible patients will be premenopausal women with a sum score of ≥6 for the typical acute uncomplicated cystitis symptoms (frequency, urgency, painful urination, incomplete emptying, suprapubic pain and visible haematuria) reported on the Acute Cystitis Symptom Score (ACSS) typical domain and pyuria. Patients will be randomly assigned to receive 3 g single dose of fosfomycin powder and two placebo tablets three times a day for 7 days or B a single dose of placebo powder and two tablets containing a dry extract of Uvae ursi folium. At least 504 patients (allocated as 1:1) will need to be enrolled to access non-inferiority with a non-inferiority limit of 14% for the primary endpoint.Improvement of symptoms of uncomplicated cystitis (based on the ACSS score) at day 7 is defined as the primary endpoint, whereas several secondary endpoints such as the number and ratio of patients with bacteriuria at day 7, frequency and severity of side effects; recurrence of urinary tract infection, concurrent use of other over the counter (OTC) medications and food supplements will be determined to elucidate more detailed differences between the groups. The number of recurrences and medications taken for treatment will be monitored for a follow-up period of 90 days (80-100 days). ETHICS AND DISSEMINATION: This study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (IV/4225-1/2021/EKU). The results will be disseminated by publication of peer-reviewed manuscripts. TRIAL REGISTRATION NUMBER: NCT05055544.

Invariant Valpha7.2-Jalpha33 TCR is expressed in human kidney and brain tumors indicating infiltration by mucosal-associated invariant T (MAIT) cells.

The anti-tumor response of human invariant NKT (NKT) cells is well established. A novel T cell subset, mucosal-associated invariant T (MAIT) cells, possesses similar regulatory properties to NKT cells in autoimmune models and disease. Here, we examined the clonality of four T cell subsets expressing invariant alphaTCR, including Valpha7.2-Jalpha33 of MAIT cells, in 19 kidney and brain tumors. The MAIT clonotype was identified and co-expressed with NKT clonotype in half of the tumors. In contrast, two other invariant T cell clonotypes (Valpha4 and Valpha19) were not present in tumors. Such tumors also expressed Vbeta2 and Vbeta13, the restricted TCRbeta chain of MAIT cells and the antigen-presenting molecule MR1. A high percentage of infiltrating T cells was CD8+ and expressed HLA-DR suggesting activation. Although the MAIT alphaTCR was identified in both peripheral CD56+ and CD56- subsets, infiltrating lymphocytes were CD56 negative. The clonal presence of MAIT cells in tumors correlated with the expression of pro-inflammatory cytokines but no IL-4, IL-5 and IL-10, suggesting that a pro-inflammatory subset of human MAIT cells may exist. Our data imply that a CD56- subset of MAIT cells may participate in tumor immune responses similarly to NKT cells.

Expression of inflammatory lipopolysaccharide binding protein (LBP) predicts the progression of conventional renal cell carcinoma - a short report.

BACKGROUND: The mortality of conventional renal cell carcinoma (RCC) correlates directly with the presence or postoperative development of metastases. The aim of this study was to identify new markers associated with the postoperative progression of conventional RCC. METHODS: Tissue microarrays (TMA) of conventional RCC from a cohort of 414 patients were analysed by immunohistochemistry for expression of the lipopolysaccharide binding protein (LBP), which was identified as a candidate biomarker through Affymetrix U133 Plus 2.0 array analysis. Univariate and multivariate Cox regression models were addressed to cancer-specific survival in association with age, sex, clinicopathological parameters and LBP expression. The survival time of the patients was estimated by Kaplan-Meier analyses, and comparisons of survival curves were made using the Log rank test. RESULTS: Univariate analysis revealed an association of patient survival with all clinicopathological parameters tested and LBP expression. In multivariate analysis only T classification, grade and LBP staining showed a significant association with postoperative cancer-specific survival (p < 0.001). LBP expression was found to be associated with a poor patient survival in Kaplan-Meier analyses. The estimated median survival time for patients with tumours showing LBP expression was 74 months, whereas the overall survival time was 142 months. CONCLUSION: LBP expression in conventional RCC defines a group of patients at a high risk of postoperative progression and may help to direct optimized active surveillance and timely adjuvant therapy.

Lack of TMEM27 expression is associated with postoperative progression of clinically localized conventional renal cell carcinoma.

PURPOSE: In spite of early detection of conventional renal cell carcinoma (RCC) by widespread use of abdominal imaging, approximately 10-15 % of patients will die due to disease. The aim of this study was to identify new biomarkers predicting the postoperative progression of conventional RCC. METHODS: Tissue multiarrays (TMA) of conventional RCC from a cohort of 486 patients were analysed by immunohistochemistry for expression of the transmembrane protein TMEM27, which was identified as a candidate biomarker by Affymetrix U133 Plus 2.0 array. Univariate and multivariate Cox regression models were addressed to assess cancer-specific survival in association with clinicopathological variables and TMEM27 expression. Cancer-specific survival time was estimated with Kaplan-Meier analysis, and the comparison of survival curves was made with the log-rank test. RESULTS: The Kaplan-Meier survival analysis indicated a poor disease-specific survival rates for tumours without TMEM27 staining. Univariate analysis revealed an association of patient survival with T stadium, grade, stage and size of tumour and TMEM27 expression in all cases as well as in the cohort of patients with postoperative tumour progression. In multivariate analysis, only T stadium and TMEM27 staining showed a significant association with postoperative cancer-specific death (p < 0.001). CONCLUSIONS: Lack of expression of the TMEM27 in conventional RCC defines a group of patients at high risk for cancer-related death.

Examination of PACAP-Like Immunoreactivity in Urogenital Tumor Samples.

Numerous studies investigated the localization of pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors in different tumors and described the effects of analogs on tumor growth to show its potential role in oncogenesis. Recently, our research group has found significantly lower levels of PACAP27-like immunorreactivity (LI) and PACAP38-LI in different human samples of primary small cell lung cancer and colon cancer compared to normal healthy tissues. There are only few human studies showing the presence of PACAP and its receptors in urogenital tumors; therefore, the aim of the present study was to compare PACAP-LI in different healthy and pathological human samples from urogenital organs (kidney, urinary bladder, prostate, testis) with radioimmunoassay (RIA) method. Similar to our earlier observations, the PACAP27-LI was significantly lower compared to PACAP38-LI in all samples. We did not find significant alterations in PACAP-LI between healthy and tumoral samples from the urinary bladder and testis. On the other hand, we found significantly lower PACAP38-LI level in kidney tumors compared with healthy tissue samples, and we showed higher PACAP27-LI in prostatic cancer compared to samples from benign prostatic hyperplasia. These data indicate that PACAP levels of different tissue samples are altered under pathological conditions suggesting a potential role of PACAP in the development of different urogenital tumors.

Interleukin and interleukin receptor gene polymorphisms in inflammatory bowel diseases susceptibility.

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), represents a group of chronic inflammatory disorders caused by dysregulated immune responses in genetically predisposed individuals. Genetic markers are associated with disease phenotype and long-term evolution, but their value in everyday clinical practice is limited at the moment. IBD has a clear immunological background and interleukins play key role in the process. Almost 130 original papers were revised including meta-analysis. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but text often do not available for the doctors use these in the clinical practice nowadays. We conducted a systematic review of the current literature on interleukin and interleukin receptor gene polymorphisms associated with IBD, performing an electronic search of PubMed Database from publications of the last 10 years, and used the following medical subject heading terms and/or text words: IBD, CD, UC, interleukins and polymorphisms.

Genetic update on inflammatory factors in ulcerative colitis: Review of the current literature.

Ulcerative colitis (UC) is one of the main types of inflammatory bowel disease, which is caused by dysregulated immune responses in genetically predisposed individuals. Several genetic factors, including interleukin and interleukin receptor gene polymorphisms and other inflammation-related genes play central role in mediating and modulating the inflammation in the human body, thereby these can be the main cause of development of the disease. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but summarized literature is exiguous for challenge health specialist that can used in the clinical practice nowadays. This review summarizes the current literature on inflammation-related genetic polymorphisms which are associated with UC. We performed an electronic search of Pubmed Database among publications of the last 10 years, using the following medical subject heading terms: UC, ulcerative colitis, inflammation, genes, polymorphisms, and susceptibility.

Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications.

Rheumatoid arthritis (RA) is an autoimmune disease, resulting in a chronic, systemic inflammatory disorder. It may affect many tissues and organs, but it primarily affects the flexible joints. In clinical practice patient care generates many questions about diagnosis, prognosis, and treatment. It is challenging for health care specialists to keep up to date with the medical literature. This review summarizes the pathogenesis, the polymorphisms of interleukin and interleukin genes and the standard available and possible future immunologic targets for RA treatment. The identification of disease-associated interleukin and interleukin receptor genes can provide precious insight into the genetic variations prior to disease onset in order to identify the pathways important for RA pathogenesis. The knowledge of the complex genetic background may prove useful for developing novel therapies and making personalized medicine based on the individual's genetics.