Mitochondrial caseinolytic protease p: A possible novel prognostic marker and therapeutic target in cancer

Caseinolytic protease P (ClpP) is a mitochondrial serine protease. In mammalian cells, the heterodimerization of ClpP and its AAA+ ClpX chaperone results in a complex called ClpXP, which has a relevant role in protein homeostasis and in maintaining mitochondrial functionality through the degradation of mitochondrial misfolded or damaged proteins. Recent studies demonstrate that ClpP is upregulated in primary and metastatic human tumors, supports tumor cell proliferation, and its overexpression desensitizes cells to cisplatin. Interestingly, small modulators of ClpP activity, both activators and inhibitors, are able to impair oxidative phosphorylation in cancer cells and to induce apoptosis. This review provides an overview of the role of ClpP in regulating mitochondrial functionality, in supporting tumor cell proliferation and cisplatin resistance; finally, we discuss whether this protease could represent a new prognostic marker and therapeutic target for the treatment of cancer

Metaplasia ossea diagnosticata su leiomioma uterino

Riportiamo un caso di metaplasia ossea in un leiomioma uterino scoperto casualmente in una donna di 53 anni operata di isterectomia totale per una neoformazione annessial

Clinical relevance of thymidylate syntetase expression in the signet ring cell histotype component of colorectal carcinoma

Thymidylate Synthase (TS) is the key enzyme for DNA synthesis pathways and is inhibited by 5-fluorouracil (5FU). The aim of this work was to study TS expression and the proliferation rate in the different histological types of colorectal carcinoma (CRC). 50 patients with CRC were included in this study and evaluated immunohistochemically using the monoclonal antibodies, TS106 and Ki67. 20 tumours were of the intestinal type, 15 cases were signet ring cell carcinoma (SRCCs) and 15 cases were "mixed-type", with at least two different histological components. Intestinal and mucinous histotypes were positive for TS and Ki67, while "signet ring cell" samples were negative or showed only weak and focal positivity for both the TS and Ki67 antibodies. Our results show that signet ring cells (that are also often present in intestinal and mucinous carcinomas), are in the post-mitotic phase of the cell cycle and show a low proliferation index and TS expression. As TS is the key enzyme for DNA synthesis pathways and is inhibited by 5-fluorouracil (5FU), we can hypothesise that TS expression levels in the different histotypes of CRC could affect the potential responsiveness of these tumours to fluoropyrimidine chemotherapy, with a low efficacy being expected in signet ring cell areas

A Troubling Diagnosis of Verrucous Squamous Cell Carcinoma (“the Bad Kind” of Keratosis) and the Need of Clinical and Pathological Correlations: A Review of the Literature with a Case Report

Verrucous carcinoma (also known as Ackerman tumor) is an uncommon exophytic low-grade well-differentiated variant of squamous cell carcinoma. This neoplasm typically involves the oral cavity, larynx, genitalia, skin, and esophagus. It is well known for its locally aggressiveness and for its clinically slow-growing behaviour with minimal metastatic potential. Verrucous carcinoma of oral cavity is so closely aligned with the use of snuff and chewing tobacco that it has been called the “snuff dipper's cancer”. Recent studies have proved the role of HPV. The typical clinical presentation of oral verrucous carcinoma has long been known, as its remarkably innocuous appearance and biological behaviour. In this work, we report a review of the scientific literature and describe a troublesome case of oral verrucous cancer

The effect of CYP3A5 and ABCB1 single nucleotide polymorphisms on tacrolimus dose requirements in Caucasian liver transplant patients

Background: Tacrolimus is a substrate of cytochrome P-450 (CYP) 3A enzyme and of the drug transporter ABCBl. We have investigated the effects of possible relevant CYP3A5 and ABCBl single nucleotide polymorphisms (SNPs) present in both donors and recipients on tacrolimus blood levels achieved in a population of 32 Caucasian liver transplant patients. Material/Methods: At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C0) were determined. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for gen-otyping CYP3A5*3 [6986A>G] as well as ABCBl at exons 21 [2677G>T] and 26 [3435C>T]. Results:87.5% of the population showed a CYP3A5*3/*3 genotype. For the ABCBl SNPs, in the case of 3435C>T the total frequency observed for the allelic variant was 50%. For the 2677G>T, the total frequency of the allelic variant was 12.5%, lower than in other Caucasian populations and without any significant linkage with 3435C>T. At 3 and 6 months after transplantation, tacrolimus dose requirements were significantly higher in patients receiving a liver with one copy of the *1 al-lele compared to those homozygous for the *3 allele (0.111±0.057 vs. 0.057±0.030 [P<0.05] at 3 month and 0.086±0.051 vs. 0.044±0.025 [P<0.05] at 6 month). For the recipients' genotypes, the presence of at least one *1 copy tended, though not statistically significantly, to increase tacrolimus doses. With regard to the ABCBl SNPs, they did not show any influence on tacrolimus dosing requirements. Conclusions: Pharmacogenetic analysis of CYP3A5 in the donor could contribute to determine the appropriate initial dosage of tacrolimus in liver transplant patient

Prostate cancer biomarkers: a practical review based on different clinical scenarios

Traditionally, diagnosis and staging of prostate cancer (PCa) have been based on prostate-specific antigen (PSA) level, digital rectal examination (DRE), and transrectal ultrasound (TRUS) guided prostate biopsy. Biomarkers have been introduced into clinical practice to reduce the overdiagnosis and overtreatment of low-grade PCa and increase the success of personalized therapies for high-grade and high-stage PCa. The purpose of this review was to describe available PCa biomarkers and examine their use in clinical practice. A nonsystematic literature review was performed using PubMed and Scopus to retrieve papers related to PCa biomarkers. In addition, we manually searched websites of major urological associations for PCa guidelines to evaluate available evidence and recommendations on the role of biomarkers and their potential contribution to PCa decision-making. In addition to PSA and its derivates, thirteen blood, urine, and tissue biomarkers are mentioned in various PCa guidelines. Retrospective studies have shown their utility in three main clinical scenarios: (1) deciding whether to perform a biopsy, (2) distinguishing patients who require active treatment from those who can benefit from active surveillance, and (3) defining a subset of high-risk PCa patients who can benefit from additional therapies after RP. Several validated PCa biomarkers have become commercially available in recent years. Guidelines now recommend offering these tests in situations in which the assay result, when considered in combination with routine clinical factors, is likely to affect management. However, the lack of direct comparisons and the unproven benefits, in terms of long-term survival and cost-effectiveness, prevent these biomarkers from being integrated into routine clinical use

Bioptic prostatic inflammation correlates with false positive rates of multiparametric magnetic resonance imaging in detecting clinically significant prostate cancer

ntroduction: The aim of this article was to determine the impact of bioptic prostatic inflammation (PI) on the false positive rate of multiparametric magnetic resonance imaging (mp-MRI) in detecting clinically significant prostate ancer (csPCa). Material and methods: Our prostate biopsy database was queried to identify patients who underwent mp-MRI before PB at our institution. A dedicated uropathologist prospectively assessed bioptic PI using the Irani scores. We evaluated the association between mp-MRI findings, bioptic Gleason grade (GG) and aggressiveness of PI, and PCa detection. Results: In total, 366 men were included. In patients with Prostate Imaging Reporting and Data System (PIRADS) 4-5 lesions, the csPCa (GG ≥2) rate was significantly higher in those with low-grade than in those with high-grade PI (36% vs 29.7%; p = 0.002), and in those with low-aggressive than in those with high-aggressive PI (37.7% vs 30.1%; p = 0.0003). The false positive rates of PIRADS 4-5 lesions for any PCa were 34.2% and 57.8% for low- and high-grade PI, respectively (p = 0.002); similarly, they were 29.5% and 59.4% for mildly and highly-aggressive PI (p = 0.0003). Potential study limitations include its retrospective analysis and single-center study and lack of assessment of the type of PI. Conclusions: Bioptic PI directly correlates with false positive rates of mp-MRI in detecting csPCa. Clinicians should be aware that PI remains the most common pitfall of mp-MRI

Types of pathological progression within Spanish Register on Active Surveillance and their relevance in radical prostatectomy specimens

Resumen presentado en: 11th European Multidisciplinary Congress on Urological Cancers (EMUC19) In active surveillance (AS) management, there are controversies for the different pathological progression (PP) criteria from prostate cancer (PCa) GGI (Gleason 3+3). Our objective is to know if PP just in tumoral volumen is irrelevant vs PP in grade..