p16 and its putative interplay with metabolic factors in prostate cancer: An analysis based on public TCGA data

p16 is one of the most common tumour suppressor genes, mainly due to its genetic inactivation. However, the clinical significance of p16 in prostate cancer is not yet fully understood, and although p16 acts as a tumour suppressor gene, stress or oncogenic factors or alternative molecular events may overcome the role of p16 as a negative cell cycle regulator. p16 seems to be involved in the metabolic switch to glycolysis during tumorigenesis, possibly interacting with NADPH oxidase 4 (NOX4) and pyruvate kinase type M2 (PKM2), involved in energy metabolism, with differences depending on cell type. The aim of this study was to assess the putative crosstalk between p16, NOX4 and PKM2, with an involvement of miRNA-mediated regulation, in prostate cancer. Transcriptome data from a cohort of 243 patients were extracted from The Cancer Genome Atlas (TCGA) database. An elevated p16 expression level was significantly associated a high Gleason score, decreasing with the score (P<0.0001). NOX4 and PKM2 expression exhibited a similar trend as p16, with higher values in the samples with Gleason scores of 9-10 samples (P<0.0001 and P=0.02, respectively). Moreover, bioinformatics analysis by TargetScan revealed that miR-625-5p could bind to the 3'UTR of p16. A consequential pairing of the NOX4 and PKM2 target region with miR-23a-3p and miR-122-5p, respectively was also found. Of note, the miR-625-5p levels inversely correlated with p16 expression, miR-23a-3p and miR-122 with NOX4 and PKM2, respectively (data not shown). Taken together, these data suggest an interplay between p16 and metabolic factors, such as NOX4 and PKM2, and a miRNA regulation, with a potential clinical impact for the development of novel therapeutic strategies in prostate tumours

Intraductal prostate cancer: An aggressive subset of prostate cancers? Immunophenotypic evaluation

Introduction: The presence of intraductal prostate cancer in a sample is often associated with large tumor volume, an advanced stage of the disease, a high Gleason score and an increased risk of recurrence, and resistance to androgen suppression and chemotherapy, which are also correlated with reduced progression-free survival and with postoperative, biochemical relapse. Methods: The aim of our study was to investigate whether carbonic anhydrase IX (CA IX) is upregulated in prostate cancer and to investigate ERG and EZH2 as potential markers for cancer aggression in aggressive acinar disease with intraductal component prostate cancer. The series consisted of 79 cases of prostate cancer. Immunohistochemical staining was performed for EZH2 ERG and CA IX. Results: The results of this study underline the fact that EZH2 protein expression is a powerful predictor of PSA relapse in prostate cancer and that this effect is stronger in ERG-positive cancers than in ERG-negative cancers. Evident EZH2 nuclear expression was found in prostatic tumor, proposing increased EZH2 expression important for the spread of prostate cancer. Conclusions: The relationship to tumor phenotype and prognosis was more considerable in ERG-positive tumors than in ERG-negative tumors. EZH2 has gained great interest as a target for epigenetic cancer therapy. Although prostate cancer is a hypoxic tumor, it does not express CA IX and cannot be used as an endogenous marker for hypoxia. © 2022 Wolters Kluwer Medknow Publications. All rights reserved

Primary small cell carcinoma of the ureter: Case report and review of the literature

Abstract Rationale: Primitive small cell carcinoma of the ureter is extremely rare, in this case report is meticulously described its aggressive clinical course and the pathological clues that help with the diagnosis. Also, a detailed table with the clinico-pathological features of analogous case reports in literature is provided. Patient concerns: A 79-year-old female presented with gross hematuria and flank pain. Diagnoses: Small cell carcinoma of the ureter. The surgical specimen showed a mixed histology of small cell carcinoma and transitional cell carcinoma; the common neuroendocrine markers (chromogranin A, synaptophysin, CD56) were positive, and vimentin and thyroid transcription factor 1 were negative. The patient had an advanced stage at presentation with regional nodes involvement (pT3N1). Interventions: Segmental ureterectomy was performed but it was only possible to administer 1 cycle of platinum-based adjuvant chemotherapy due to the rapid decline of her clinical parameters. Outcomes: The disease rapidly spread locally and metastasized

Membranous Nephropathy Associated with Eosinophilic Gastroenteritis: First Report

Membranous nephropathy represents the most common cause of nephrotic syndrome in adult patients. In 85% of cases the disease is classified as idiopathic membranous nephropathy, and in the remainder 15 % as secondary membranous nephropathy (systemic lupus erythematosus, infections, drugs, tumors, inorganics salts). Treatment of secondary membranous nephropathy is guided by therapy of the original disease, or by elimination of the responsible cause. Eosinophilic gastroenteritis is a rare uncommon disease of unknown origin affecting the gastrointestinal apparatus and is characterized by diffuse eosinophilic infiltration of the gastro-enteric wall. Any segment of gastrointestinal tract can be interested, but the stomach results to be the most commonly affected organ, followed by the small intestine and the colon. The diagnosis is based on the presence of gastrointestinal symptoms, documented eosinophilic gut infiltration and the exclusion of intestinal parasites or extraintestinal disease. To date there are no randomized prospective therapeutic trials. The mainstay of treatment is represented by use of corticosteroids (with 90% of remission rate in some reports). We describe for the first time the case of a 43-year-old man affected by eosinophilic gastroenteritis who developed a nephrotic syndrome due to membranous nephropathy after he voluntarily stopped the steroidal oral therapy. Reintroduction of corticosteroid treatment led to the complete remission of the nephrotic syndrome within 6 months treatment

Lymphoepithelioma-like hepatocellular carcinoma: Case report and review of the literature

Lymphoepithelioma-like hepatocellular carcinoma (LELHCC) is a rare form of undifferentiated carcinoma of the liver characterized by the presence of an abundant lymphoid infiltrate. Here, a case of LEL-HCC is described. An 81-year-old woman with a chronic hepatitis C infection was referred to the general surgery department of our hospital in August 2013 with a diagnosis of HCC. A past ultrasound examination had revealed a 60 mm-diameter nodular lesion in the third segment of the liver. After a needle biopsy, the lesion was diagnosed as HCC. The patient underwent surgery with a liver segmentectomy. Two additional nodes on the gastric wall were detected during the surgical operation. The histology of the removed specimen showed a poorly differentiated HCC with significant lymphoid stroma. Immunohistochemical studies revealed that the epithelial component was reactive for CK CAM5.2, CK8, CK18, CEA (polyclonal) and was focally positive for hepar-1 and that the lymphoid infiltrate was positive for CD3, CD4 and CD8. The tumor cells were negative for Epstein-Barr virus. The gastric nodes were ultimately determined to be two small gastrointestinal stromal tumors (GISTs). The synchronous occurrence of HCC and GIST is another very uncommon finding rarely described in the literature. Here, we report the clinicopathological features of our case, along with a review of the few cases present in the literature

Proposal for a New Diagnostic Histopathological Approach in the Evaluation of Ki-67 in GEP-NETs

Abstract Introduction: Studies have shown that the Ki-67 index is a valuable biomarker for the diagnosis, and classification of gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). We re-evaluated the expression of Ki-67 based on the intensity of the stain, basing our hypothesis on the fact that the Ki-67 protein is continuously degraded. Background: The aim was to evaluate whether a new scoring method would be more effective in classifying NETs by reducing staining heterogeneity. Methods: Patients with GEP-NET (n = 87) were analyzed. The classification difference between the two methods was determined. Results: The classification changed significantly when the Ki-67 semiquantal index was used. The percentage of G1 patients increased from 18.4% to 60.9%, while the G2 patients decreased from 66.7% to 29.9% and the G3 patients also decreased from 14.9% to 9.2%. Moreover, it was found that the traditional Ki-67 was not significantly related to the overall survival (OS), whereas the semiquantal Ki-67 was significantly related to the OS. Conclusions: The new quantification was a better predictor of OS and of tumor classification. Therefore, it could be used both as a marker of proliferation and as a tool to map tumor dynamics that can influence the diagnosis and guide the choice of therapy

Management of peritoneal carcinomatosis with cytoreductive surgery combined with intraperitoneal chemohyperthermia at a novel italian center

Background: Peritoneal carcinomatosis (PC) is a common manifestation of many gastrointestinal (GI) malignancies and is an advanced stage that is often associated with disseminated disease. Considerable progress has been made to achieve safe elimination of macroscopic disease using cytoreductive surgery (CRS) and more recently in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of microscopic disease or disease with minimal volume. The aim of this study was to assess the effects of such procedures on the quality of life (QoL), the long-term benefit and the functional status of the treated patients. Patients and Methods: Data from patients who underwent CRS-HIPEC for peritoneal metastasis (PM) at our center from November 2016 to November 2018 were analyzed retrospectively. The drugs administered were mitomycin and cisplatin. Quality of life (QoL) was assessed using the Euroquol-5D-5L and National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index v2 questionnaires before CRS-HIPEC, and 1, 3 and 6 months after were administered. Results: In our series, the survival efficacy of CRS plus HIPEC was confirmed in the treatment of primary and secondary peritoneal pathologies, particularly in ovarian cancer, although larger studies are needed to investigate its role in the pathology of gastric, colonic and rectal cancer. The QoL data were promising, with essentially stable values between the preoperative and the 1-month follow-up, but with incremental benefits from the second to the third month

A polymorphism in the promoter is associated with EZH2 expression but not with outcome in advanced pancreatic cancer patients

Aim: EZH2 expression is a prognostic marker in radically resected pancreatic ductal adenocarcinoma (PDAC) patients. Here we investigated its role in locally advanced/metastatic patients, as well as candidate polymorphisms. Materials & methods: EZH2 expression and polymorphisms were evaluated by quantitative reverse transcription PCR in 32 laser microdissected tumors, while polymorphisms were also studied in blood samples from two additional cohorts treated with gemcitabine monotherapy (n = 93) or polychemotherapeutic regimens (n = 247). Results: EZH2 expression correlated with survival and with the rs6958683 polymorphism in the first cohort of patients, but this polymorphism was not associated with survival in our larger cohorts. Conclusion: EZH2 is a prognostic factor for locally advanced/metastatic PDACs, while candidate polymorphisms cannot predict clinical outcome. Other factors involved in EZH2 regulation, such as miR-101, should be investigated in accessible samples in order to improve the clinical management of advanced PDAC

Molecular and pathological characterization of the EZH2 rs3757441 single nucleotide polymorphism in colorectal cancer

Background The enhancer of zeste-homolog 2 (EZH2) is involved in cancer development through gene silencing by trimethylation of lysine 27 of histone 3 (H3K27me3). The C/C genotype for the EZH2 rs3757441 single-nucleotide polymorphism (SNP) is linked with poor prognosis in metastatic colorectal cancer (CRC), but molecular and pathological characterization of this SNP is lacking. Methods 119 primary CRCs were analyzed. SNP was evaluated by real-time PCR from colonic healthy tissue, while EZH2 and H3K27me3 expression were studied by immunohistochemistry. We primarily looked for correlation between EZH2 rs3757441 genotypes and EZH2/H3K27me3 expression. Potential associations between EZH2/H3K27me3 expression and clinico-pathological features or KRAS exon 2 and BRAF exon 15 mutations were secondary endpoints. Statistical analysis was performed by chi-square test, T-test or ANOVA. Results The C/C genotype was significantly associated with higher EZH2 (100 vs. 44 %; P = 0.019) and H3K27me3 (100 vs. 38 %; P = 0.009) staining intensity compared with C/T and T/T. EZH2 3+ staining significantly correlated with stronger H3K27me3 expression (P = 0.039). KRAS and BRAF mutations were not associated with EZH2 or H3K27me3 expression. Conclusion EZH2 rs3757441 C/C genotype is associated with stronger EZH2 and H3K27me3 immunoreactivity in primary CRC: this SNP may serve as a promising biomarker for EZH2-targeting agents and may add independent information to KRAS and BRAF testing