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DNA methylation is an epigenetic process that commonly occurs in genes' promoters and results in the transcriptional silencing of genes. DNA methylation is a frequent event in bladder cancer, participating in tumor initiation and progression. Bladder cancer is a major health issue in patients suffering from neurogenic lower urinary tract dysfunction (NLUTD), although the pathogenetic mechanisms of the disease remain unclear. In this population, bladder cancer is characterized by aggressive histopathology, advanced stage during diagnosis, and high mortality rates. To assess the DNA methylation profiles of five genes' promoters previously known to be associated with bladder cancer in bladder tissue of NLUTD patients, we conducted a prospective study recruiting NLUTD patients from the neuro-urology unit of a public teaching hospital. Cystoscopy combined with biopsy for bladder cancer screening was performed in all patients following written informed consent being obtained. Quantitative methylation-specific PCR was used to determine the methylation status of RASSF1, RARβ, DAPK, hTERT, and APC genes' promoters in bladder tissue samples. Twenty-four patients suffering from mixed NLUTD etiology for a median duration of 10 (IQR: 12) years were recruited in this study. DNA hypermethylation was detected in at least one gene of the panel in all tissue samples. RAR-β was hypermethylated in 91.7% samples, RASSF and DAPK were hypermethylated in 83.3% samples, APC 37.5% samples, and TERT in none of the tissue samples. In 45.8% of the samples, three genes of the panel were hypermethylated, in 29.2% four genes were hypermethylated, and in 16.7% and in 8.3% of the samples, two and one gene were hypermethylated, respectively. The number of hypermethylated genes of the panel was significantly associated with recurrent UTIs (p = 0.0048). No other significant association was found between DNA hypermethylation or the number of hypermethylated genes and the clinical characteristics of the patients. Histopathological findings were normal in 8.3% of patients, while chronic inflammation was found in 83.3% of patients and squamous cell metaplasia in 16.7% of patients. In this study, we observed high rates of DNA hypermethylation of genes associated with bladder cancer in NLUTD patients, suggesting an epigenetic field effect and possible risk of bladder cancer development. Recurrent UTIs seem to be associated with increased DNA hypermethylation. Further research is needed to evaluate the impact of recurrent UTIs and chronic inflammation in DNA hypermethylation and bladder cancer etiopathogenesis in NLUTD patients. [ABSTRACT FROM AUTHOR]

The article describes the case of a four-month-old female with a one-month history of progressive inspiratory stridor, respiratory distress, and feeding problems and was diagnosed with patent ductus arteriosus, on the first day of life. Topics discussed include the two episodes of sepsis suffered by the patient during her hospitalization, the intubation of the patient, and finding on histopathologic examination.

The aim of this study is to investigate the prevalence of occult malignant mesenchymal tumors in patients operated on for uterine fibroids in relation to the surgical approach and type of operation. A retrospective review of all patients that underwent surgery for uterine fibroids (January 2011–December 2018) at the 1st Department of Obstetrics & Gynecology at "Papageorgiou" Hospital. The surgical approach and clinicopathological characteristics were analyzed. A total of 803 patients were operated on: 603 (75.1%) with laparotomy, 187 (23.3%) laparoscopically, and 13 (1.6%) vaginally. Furthermore, 423 (52.7%) patients underwent hysterectomy and 380 (47.3%) myomectomies. Laparoscopy and myomectomy were offered to younger patients with fewer smaller uterine fibroids and were associated with statistically significant shorter hospitalization. The pathological reports revealed: 690 (86%) benign leiomyomas, 32 (4%) cellular leiomyomas, 29 (3.6%) degenerated leiomyomas, 22 (2.7%) adenomyomas, 18 (2.2%) atypical-bizarre leiomyomas, 1 (0.1%) STUMP, 5 (0.65%) endometrial stromal sarcomas, and 6 (0.75%) cases of leiomyosarcomas (LMS). All LMS were preoperatively characterized as suspicious and underwent abdominal hysterectomy. Morcellation was offered in two cases of atypical leiomyomas, with no morcellation-associated complication. Laparoscopy as a valuable surgical approach for young patients with fewer in number and smaller in size fibroids is associated with shorter hospitalization. The risk of unintended morcellation of LMS seems to be very low and can be reduced with careful preoperative work-up but not eliminated. [ABSTRACT FROM AUTHOR]

Simple Summary: As patients with neurogenic bladders are at higher risk for advanced-stage bladder cancer, it is important to develop non-invasive screening methods for bladder cancer other than cystoscopy in this patient population. We conducted a study to explore changes in five bladder cancer-associated genes in the urine of such patients in comparison with healthy controls, and found that changes in certain tumor-suppressing genes associated with bladder cancer were significantly more frequent in the neurogenic group. Apart from a neurogenic bladder, male gender was another risk factor for such gene changes. Bladder biopsies taken from these patients revealed a high percentage of chronic inflammation. We need larger long-term studies to establish the value of this non-invasive method in the screening and diagnosis of bladder cancer, but also to explore possible associations between gene changes in the urine, chronic bladder inflammation and bladder cancer in the neurogenic population. Background: Bladder cancer (BCa) in patients suffering from neurogenic lower urinary tract dysfunction (NLUTD) is a significant concern due to its advanced stage at diagnosis and high mortality rate. Currently, there is a scarcity of specific guidelines for BCa screening in these patients. The development of urine biomarkers for BCa seems to be an attractive non-invasive method of screening or risk stratification in this patient population. DNA methylation is an epigenetic modification, resulting in the transcriptional silencing of tumor suppression genes, that is frequently detected in the urine of BCa patients. Objectives: We aimed to investigate DNA hypermethylation in five gene promoters, previously associated with BCa, in the urine of NLUTD patients, and in comparison with healthy controls. Design, setting and participants: This was a prospective case–control study that recruited neurourology outpatients from a public teaching hospital who had suffered from NLUTD for at least 5 years. They all underwent cystoscopy combined with biopsy for BCa screening following written informed consent. DNA was extracted and DNA methylation was assessed for the RASSF1, RARβ, DAPK, TERT and APC gene promoters via quantitative methylation-specific PCR in urine specimens from the patients and controls. Results: Forty-one patients of mixed NLUTD etiology and 35 controls were enrolled. DNA was detected in 36 patients' urine specimens and in those of 22 controls. In the urine specimens, DNA was hypermethylated in at least one of five gene promoters in 17/36 patients and in 3/22 controls (47.22% vs. 13.64%, respectively, p = 0.009). RASSF1 was hypermethylated in 10/17 (58.82%) specimens with detected methylation, APC in 7/17 (41.18%), DAPK in 4/17 (23.53%), RAR-β2 in 3/17 (17.56%) and TERT in none. According to a multivariate logistic regression analysis, NLUTD and male gender were significantly associated with hypermethylation (OR = 7.43, p = 0.007 and OR = 4.21; p = 0.04, respectively). In the tissue specimens, histology revealed TaLG BCa in two patients and urothelial squamous metaplasia in five patients. Chronic bladder inflammation was present in 35/41 bladder biopsies. Conclusions: DNA hypermethylation in a panel of five BCa-associated genes in the urine was significantly more frequent in NLUTD patients than in the controls. Our results warrant further evaluation in longitudinal studies assessing the clinical implications and possible associations between DNA hypermethylation, chronic inflammation and BCa in the NLUTD population. [ABSTRACT FROM AUTHOR]

The data on tumor molecular profiling of European patients with prostate cancer is limited. Our aim was to evaluate the prevalence and prognostic and predictive values of gene alterations in unselected patients with prostate cancer. The presence of gene alterations was assessed in patients with histologically confirmed prostate cancer using the ForeSENTIA® Prostate panel (Medicover Genetics), targeting 36 clinically relevant genes and microsatellite instability testing. The primary endpoint was the prevalence of gene alterations in homologous recombination repair (HRR) genes. Overall, 196 patients with prostate cancer were evaluated (median age 72.2 years, metastatic disease in 141 (71.9%) patients). Gene alterations were identified in 120 (61%) patients, while alteration in HRR genes were identified in 34 (17.3%) patients. The most commonly mutated HRR genes were ATM (17, 8.7%), BRCA2 (9, 4.6%) and BRCA1 (4, 2%). The presence of HRR gene alterations was not associated with advanced stage (p = 0.21), age at diagnosis (p = 0.28), Gleason score (p = 0.17) or overall survival (HR 0.72; 95% CI: 0.41–1.26; p = 0.251). We identified clinically relevant somatic gene alterations in European patients with prostate cancer. These molecular alterations have prognostic significance and therapeutic implications and/or may trigger genetic testing in selected patients. In the era of precision medicine, prospective research on the predictive role of these alterations for innovative treatments or their combinations is warranted. [ABSTRACT FROM AUTHOR]

Objective Chorioamnionitis and fetal inflammatory response syndrome (FIRS) are significant risk factors for early onset sepsis (EOS). Recently, the use “Intrauterine Inflammation or Infection or both” or triple I has been proposed, classifying cases into an isolated maternal fever, suspected triple I, or confirmed chorioamnionitis. Evidence suggests that the association between suspected chorioamnionitis and confirmed histological chorioamnionitis (HCA) is not consistent, as well as the impact of HCA on the development of EOS. We aimed to evaluate the association between suspected chorioamnionitis and HCA, the impact of HCA on EOS, and the effect of antepartum antibiotic prophylaxis on EOS. Methods We retrospectively reviewed the medical records of all infants admitted to our institution, between 2017 and 2018, with a diagnosis of chorioamnionitis. We recorded the clinical evidence of chorioamnionitis, the histologic report of the placenta, the maternal and neonatal data, the neonatal inflammatory markers including C-reactive protein (CRP), and the incidence of EOS. The impact of antepartum antibiotic prophylaxis on the infants’ CRP and EOS was calculated, and the logistic regression model was performed to estimate the association of confirmed HCA with EOS, while controlling for FIRS stage, gestation age, birth weight, maternal fever, foul-smelling amniotic fluid, and prolonged rupture of membranes. Results During the study period, a total of 266 infants were identified; 81 (30%) infants had a confirmed HCA (HCA-present cases), and 185 (70%) infants were diagnosed with suspected triple I (HCA-absent cases). Antepartum antibiotics had been commenced in a significantly higher proportion in HCA-present cases (46%) in comparison to 14% of HCA-absent cases (p < .001). HCA-present infants were of significantly lower gestation (31.6 ± 4weeks versus 33.3 ± 4weeks, p = .004), and birth weight (1826 ± 840 g versus 2092 ± 849 g, p = .019), they had a significantly higher rate of clinical symptoms (31% versus 6%, p < .001), and a higher CRP at birth and 24 h (1.4 ± 1.5 mg/dL versus 0.3 ± 0.2 mg/dL, p < .001, and 2.1 ± 2.3 mg/dL versus 0.4 ± 0.6 mg/dL, p < .001, respectively). All HCA-present cases had evidence of FIRS; 43% were stage I, 25% stage II, and 32% were FIRS stage III. A significantly higher proportion of HCA-present infants were diagnosed with EOS (46% as compared to 6%, p < .001). The antepartum antibiotic administration was related to a significantly lower CRP at birth and 24 h only in HCA-present cases, albeit not with any reduction ιn EOS incidence. HCA was significantly associated with EOS (RR 3.18, 95% CI 2.81–5.18, p < .001). After adjusting for perinatal factors, the presence of HCA (OR 7.89, 95% CI 1.19-23.34, p = .032) and an advanced FIRS stage (OR 10.35, 95% CI 4.23–25.32, p < .001) were significantly associated with EOS. Conclusions Amongst infants with suspected chorioamnionitis, the diagnosis is partially supported by histological confirmation, and that is more prominent in pregnancies of a lower gestation. The presence of HCA and an advanced FIRS stage predispose to an increased risk of EOS after adjusting for other perinatal and neonatal factors. The antepartum prophylaxis against intra-amniotic infection was related to a significantly lower CRP in HCA-present cases. [ABSTRACT FROM AUTHOR]

In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), mRNA and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Central review of HER2 status by IHC and fluorescence in situ hybridization revealed that of the 227 patients, only 139 (61.2%) were truly HER2-positive. Regarding the 191 patients treated with trastuzumab as first-line therapy, median time to progression (TTP) was 15.3 and 10.4 months for HER2-positive and HER2-negative participants, respectively, whereas median survival was 50.4 and 38.1 months, respectively. In HER2-positive patients, high HER3 mRNA expression was of favorable prognostic significance for TTP and survival (HR = 0.43, 95% CI 0.21–0.88, Wald’s p = 0.022 and HR = 0.43, 95% CI 0.21–0.88, p = 0.021, respectively), while EGFR copy gain and EGFR protein expression were associated with higher risk for disease progression in HER2-negative patients (HR = 3.53, 95% CI 1.19–10.50, p = 0.023 and HR = 3.37, 95% CI 1.12–10.17, p = 0.031, respectively). Positive HER3 protein expression was a favorable factor for TTP in HER2-negative patients (HR = 0.43, 95% CI 0.22–0.84, p = 0.014). In the multivariate analysis, only EGFR copy gain retained its prognostic significance for TTP in the HER2-negative population (HR = 3.96, 95% CI 1.29–12.16, p = 0.016), while high HER3 mRNA expression retained its favorable prognostic significance for TTP in the HER2-positive subgroup (HR = 0.47, 95% CI 0.23–0.99, p = 0.048). The present study suggests that EGFR copy gain represents a negative prognostic factor for TTP in HER2-negative patients with metastatic breast cancer treated with trastuzumab. In addition, high HER3 mRNA expression appears to be of favorable prognostic significance for TTP in HER2-positive patients. Given the small number of patients included in the current analysis and the retrospective nature of the study, our findings should be validated in larger cohorts. [ABSTRACT FROM AUTHOR]

This study essentially aims to contribute to the immunohistochemical investigation of the use of pituitary tumor transforming gene (PTTG) as a marker of cell proliferation or advanced tumor grade in meningiomas of various WHO grades. In all, 51 cases were recovered in total, 21 Grade‐I, 23 Grade‐II and 7 Grade‐III meningiomas. Mitotic index (MI), Ki‐67/MiB‐1 positivity percentage and PTTG expression were analyzed in correlation to each other as well as to the tumor WHO grades. All three biomarkers showed a high diagnostic significance and a strong association with WHO grades. In comparison, PTTG expression was on a par with the other two indices, and performed very well regarding identification of advanced grade tumors. PTTG may be considered an important diagnostic tool and serve in the future as a novel prognosticator of the biological behavior of all grade meningiomas as well as a useful high‐risk patient selection tool. [ABSTRACT FROM AUTHOR]

A testicular granulosa cell tumor of the adult type is very rare. Isolated case reports and small series have been published in the English literature. Here, we analyze an incidentally discovered testicular granulosa cell tumor in a 29-year-old man to discuss the radiological evaluation of this entity and review the literature. [ABSTRACT FROM AUTHOR]

Myxofibrosarcoma is a common malignant fibroblastic neoplasm with variably myxoid stroma and represents one of the most common soft tissue sarcoma types in elderly patients [2]. Specifically, the differential diagnosis of intracranial myxofibrosarcomas includes lesions with myxoid stroma, such as myxoid liposarcoma, extraskeletal myxoid chondrosarcoma, and low-grade fibromyxoid sarcoma, all of which have been reported as intracranial lesions [[1], [3]], and other more common entities presented intracranially, such as glioblastomas and gliosarcomas. Unlike myxoid liposarcomas, extraskeletal myxoid chondrosarcomas, low-grade fibromyxoid sarcomas and myxofibrosarcomas, the neoplastic cells of glioblastomas and partly (at least the astroglial component) of gliosarcomas are positive for GFAP. [Extracted from the article]

Background: The use of sentinel lymph node biopsy (SLNB) for high-risk cutaneous squamous cell carcinoma (CSCC) is not yet clearly documented, especially for the head and neck area, due to its rich and cross-branching lymphatic system. We present the first prospective randomized study on the use of SLNB in high-risk CSCCs of the head and neck., Methods: Seventy-six patients with high-risk CSCCs of the head and neck were randomly divided into two groups: A (n = 38) and B (n = 38). In group A, SLNB was performed additionally to the excision of squamous cell carcinoma, whereas in group B, only excision of the lesion was performed. The patients were followed up for 5 years postoperatively, and local recurrences, regional metastases (regional lymph nodes), and mortality were documented., Results: One patient of group A, who never attended any follow-up, was excluded. Both groups had similar characteristics regarding Breslow thickness, perineurial invasion, peripheral limits, differentiation, size, previous incomplete excision, age, sex, education, sun exposure, Fitzpatrick score, previous incomplete excision, previous skin cancer, and smoking. Two patients had a positive sentinel lymph node and were submitted to regional lymphadenectomy. We documented deaths (three in group A and two in group B; P = 0.674), local recurrence (seven in group A and six in group B; P = 0.768), and regional metastasis (zero in group A and two in group B; P = 0.159)., Conclusion: There is no clear benefit on the use of SLNB in high-risk CSCCs of the head and neck regarding metastasis, mortality, or local recurrence control., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Genotypic and phenotypic comparisons of tumors in multiple tissue samples from the same patient are important for understanding disease evolution and treatment possibilities. Panel NGS genotyping is currently widely used in this context, whereby NGS variant filtering and final evaluation constitute the basis for meaningful comparisons. Here, we present the genotype data used for genotype / phenotype comparisons between matched primary / metastatic colorectal tumors in the work by Chatzopoulos et al (doi: 10.1016/j.humpath.2020.10.009), as well as the process followed for obtaining these data. We describe key issues while processing routinely formalin-fixed paraffin-embedded (FFPE) tumors for genotyping, NGS application (Ion Torrent), a stringent variant filtering algorithm for genotype analyses in FFPE tissues and particularly in matched tumor samples, and provide the respective datasets. Apart from research, tumor NGS genotyping is currently applied for clinical diagnostic purposes in Oncology. The datasets and method description provided herein (a) are important for comprehending the peculiarities of FFPE tumor genotyping, which is still mostly based on principles of germline DNA genotyping; (b) can be used in pooled analyses, e.g., of primary / metastatic tumors for the investigation of tumor evolution., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Authors.)

Biliary tract cancer (BTC) represents a heterogeneous disease with dismal outcome. Herein, we examined genotype and angiogenesis features in BTC. We applied genotyping (Sanger, qPCR, 101-gene panel NGS), mRNA relative quantification methods, and β-catenin immunohistochemistry in 84 FFPE BTC (55 gallbladder [GBC], 14 intrahepatic [ICC], 15 extrahepatic [ECC] carcinomas). We identified 541 mutations in 68 (81%) tumors. Top mutated genes were CTNNB1 (36%); PTEN (33%); TP53 (31%); PIK3R1 (29%); PIK3CA (13%); BRCA2 and KRAS (12%); BRCA1 (11%). Six GBCs were hypermutated [hm] displaying a distinct mutational pattern. Mutations in TP53 and PI3K, Wnt and RAS components were prevalent among non-hypermutated tumors. All hmGBCs carried mutations in BRCA2 and other homologous recombination repair (HRR) genes, in PD1, but not in CTNNB1 and KRAS. None of the pathogenic BRCA2 p.D2723G and BRCA1 p.Q563* and c.5266dupC was present at frequencies expected for germline mutations. We observed copy gains (>6 copies) in EGFR (9% of informative tumors), PRKAR1A (7%), PIK3CA (6%), ERBB2 (5%) and MET (4%). TP53 mutations were prevalent in GBC (P<0.001) and PRKAR1A copy gains in ICC (P=0.007). PTEN was frequently co-mutated with CTNNB1 (P<0.001). Unrelated to CTNNB1 mutations, nuclear β-catenin was detected in 45% of tumors, among them in 5/6 hmGBC. We observed strong mRNA expression correlation of the two neuropilins (NRP1 and NRP2) with each other (Spearman's rho 0.59) and with the endothelin receptor (NRP2 rho 0.66; NRP2 rho 0.51), and between VEGFA and its receptors (FLT1 rho 0.49; KDR rho 0.45). All PIK3CA mutated tumors expressed endothelin 1 mRNA (P=0.010). Most tumors expressing nuclear β-catenin were negative for VEGFC (P=0.009) and FLT4 (P=0.002) mRNA expression. In conclusion, we confirmed the presence of known genomic aberrations in BTC and different genotypes between BTC subsets. Novel findings are the coexistence of PI3K and WNT pathway gene alterations in BTC, their association with angiogenesis, and the hypermutated GBCs with HRR gene mutations, all of which may be considered for new treatment options in this difficult to treat disease., Competing Interests: None.

Background: Gastric cancer is a relatively common malignancy. Recently, the presence of the human epidermal growth factor receptor 2 (HER2) was identified as a molecular target in a proportion of patients who benefited from the addition of appropriate anti-HER2 treatments. Our study explored the clinical and prognostic role of known HER family members, human epidermal growth factor receptor 1 (EGFR or HER1), HER2, HER3 and HER4., Patients and Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 249 gastric cancer patients were studied by immunohistochemistry for protein expression of EGFR, HER2, HER3 and HER4., Results: Of the 249 evaluable patients, 32 did not have complete data of treatment details and/or follow-up and were excluded from the survival analyses. Of the 217 patients with complete treatment and follow-up data, 178 were operated and treated for early disease (group 1), while 39 for advanced disease (group 2). The frequency of positive EGFR, HER2, HER3 and HER4 protein expression in all patients was 17.5%, 11.8%, 14.8% and 32.9%, respectively. There were no differences in protein expression of any of the markers between the two groups. There were, however, statistically significant associations between HER4 and all other HER family members, as well as between HER2 and HER3 expression. Of note, EGFR-positive membranous protein expression was significantly associated with the presence of lymphovascular invasion (p=0.027) and HER3 and HER4 negative cytoplasmic protein expression with well/moderately-differentiated tumors (p=0.030 and p=0.014, respectively). None of the HER family members were of prognostic value for OS in univariate analysis., Conclusion: The present study confirmed the known protein expression frequencies of HER family members in gastric cancer in a Greek population. Several associations were observed among the HER family members and between clinicopathological characteristics and HER family members. Further research is needed on their exact prognostic role, as well as their therapeutic targeting., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Cystic adventitial disease is a rare condition that usually affects the popliteal artery, and is a rare cause of non-atherosclerotic stenosis. It is most commonly found in young or middle-aged men with intermittent claudication. Herein we present a histologically proven case of cystic adventitial disease of the popliteal artery in a 53-year-old man. We describe the imaging findings on gray-scale, Doppler and triplex ultrasonography, computed tomography with 3D reconstruction and digital subtraction angiography.

Background: Placental hemangioma (chorioangioma) and congenital hemangioma are relatively common tumors, which on rare occasions may occur together. Very little is known about the pathogenetic mechanisms underlying these lesions., Case: Herein we describe a rare case of a stillborn infant with chorioangioma, placental mesenchymal dysplasia, and liver cavernous hemangioma. In addition, we present the findings of the karyotype analysis of these lesions, which was done with the bacterial artificial chromosome arrays using the comparative genomic hybridization method. The chromosomal abnormalities that we found were deletions at 2q13 and 7p21.1 and were common to both placental and liver lesions., Conclusions: None of the identified chromosomal aberrations have been previously associated with chorioangiomas or hemangiomas. Important genes that lie in these DNA regions may be implicated in the pathogenesis of congenital hemangiomas and mesenchymal dysplasia.