Expression of Syndecan-1 in Chronic Liver Diseases: Correlation With Hepatic Fibrosis.

BACKGROUND/AIM: The mechanisms underlying the contribution of the heparan sulfate proteoglycan syndecan-1 to liver tissue injury and to crucial biological processes, such as fibrogenesis, remain to be elucidated. Therefore, we investigated the immunohistochemical expression of syndecan-1 in chronic liver diseases (CLDs) and its probable role in hepatic fibrosis. MATERIALS AND METHODS: Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections of biopsy material obtained from 128 patients diagnosed with CLDs. The correlation between syndecan-1 expression and the stage of fibrosis was investigated. RESULTS: According to the severity of fibrosis, cases were categorized into three groups: early fibrosis; intermediate fibrosis; advanced fibrosis. Syndecan-1 expression was significantly enhanced in advanced fibrosis compared to early (p<0.012) and intermediate (p<0.003) fibrosis. CONCLUSION: In CLDs, syndecan-1 immunohisto-chemical overexpression was found to be positively correlated with the severity of fibrosis, suggesting its probable role in hepatic fibrogenesis.

Primary squamous cell carcinoma of the ovary. Review of the literature.

PURPOSE: Primary squamous cell carcinoma (SCC) of the ovary is rare. Most cases arise from a cystic teratoma or less frequently from Brenner tumor or endometriosis. We reviewed 36 cases of primary ovarian SCC reported in the literature including a case diagnosed and treated in our institution. METHODS: Data was collected by using the key-words "primary squamous cell carcinoma" and "ovary" on Google Scholar and PubMed in April 2018. All reviewed cases were analyzed according to diagnosis, surgical approach, adjuvant therapy and outcome. RESULTS: To date 23 articles presenting 36 cases of primary ovarian SCC are reported. Nine patients had stage I, 8 stage II, 11 stage III and 5 stage IV disease, whereas 3 patients had in situ carcinoma. All patients underwent surgery (mainly hysterectomy with bilateral salpingo-oophorectomy). Adjuvant therapy was reported in 24 patients, 15 of which received chemotherapy, 6 radiotherapy and 3 a combination of both. Chemotherapy regimens were similar to the ones used in ovarian carcinoma (more often platinum plus paclitaxel). Follow-up period was in general short and survival varied between 9 days and 14 years, depending on the stage at diagnosis. CONCLUSIONS: Primary ovarian SCC is a rare entity with poor prognosis, compared to serous carcinoma. Treatment is usually extrapolated from classical ovarian carcinoma algorithms, including surgical management combined with adjuvant chemotherapy with or without radiotherapy. Further investigations are needed to define optimal treatment, such as chemotherapy regimens and the role of radiotherapy and lymph node dissection.

Association of low Syndecan-1 expression with adverse histopathological parameters in gastric carcinomas.

PURPOSE: Since syndecan-1 is an adhesion molecule involved in tumor invasion and metastasis, we evaluated the relationship between syndecan-1 expression and histopathological features of gastric carcinomas. METHODS: Syndecan-1 expression was evaluated in 104 gastric carcinomas using immunohistochemistry. RESULTS: High, moderate and low syndecan-1 expression in carcinoma cells was observed in 17/104, 25/104 and 62/104 cases, respectively. High, moderate and low syndecan-1 expression in stromal cells was observed in 5/104, 22/104 and 77/104 cases, respectively. Low epithelial syndecan-1 expression was significantly associated with increased depth of invasion (p=0.034) and lymph vessel invasion (p=0.035). Low stromal syndecan-1 expression was significantly associated with histologic type (intestinal vs diffuse/mixed; p=0.04), increased histologic grade (p=0.04) and large tumor size (p=0.026). CONCLUSION: Low levels of tumor and stromal syndecan- 1 expression were associated with adverse histopathological parameters in gastric carcinoma. This suggests that syndecan-1 expression may be helpful for assessing the aggressiveness of gastric carcinomas.

Alterations of p53 and Rb Pathways Are Associated with High Proliferation in Bladder Urothelial Carcinomas.

BACKGROUND/AIM: Since most cancers are associated with alterations of the p53 and Rb pathways, the expression of p53, p21, Rb, p16, p27, cyclin D1, cyclin A, cyclin B1 and Ki67 proteins were analyzed in bladder urothelial carcinomas (BUC). MATERIALS AND METHODS: One hundred twenty-two cases of BUC were studied by immunohistochemistry. RESULTS: The pathways p53/p21 and Rb/p16/cyclin D1 exhibited alterations in 81/115 and 63/84 cases, respectively. Alterations of the p53/p21 and Rb/p16/cyclin D1 pathways were positively correlated with high cyclin A expression. High expression of p53, Ki67, cyclin A and cyclin B1 was inversely correlated with the papillary morphology of the tumor and positively with tumor grade and T-stage. CONCLUSION: The results showed that a) alterations of the p53 and Rb pathways are associated with high proliferation of tumor cells in BUC and b) high expression of cell-cycle proteins is associated with adverse histopathological parameters of these tumors.

Mitochondrial Membrane Dynamics and Inherited Optic Neuropathies.

Inherited optic neuropathies are a genetically diverse group of disorders mainly characterized by visual loss and optic atrophy. Since the first recognition of Leber's hereditary optic neuropathy, several genetic defects altering primary mitochondrial respiration have been proposed to contribute to the development of syndromic and non-syndromic optic neuropathies. Moreover, the genomics and imaging revolution in the past decade has increased diagnostic efficiency and accuracy, allowing recognition of a link between mitochondrial dynamics machinery and a broad range of inherited neurodegenerative diseases involving the optic nerve. Mutations of novel genes modifying mainly the balance between mitochondrial fusion and fission have been shown to lead to overlapping clinical phenotypes ranging from isolated optic atrophy to severe, sometimes lethal multisystem disorders, and are reviewed herein. Given the particular vulnerability of retinal ganglion cells to mitochondrial dysfunction, the accessibility of the eye as a part of the central nervous system and improvements in technical imaging concerning assessment of the retinal nerve fiber layer, optic nerve evaluation becomes critical - even in asymptomatic patients - for correct diagnosis, understanding and early treatment of these complex and enigmatic clinical entities.

Immunohistochemical Study of Vasculogenic Mimicry and Angiogenesis in Melanocytic Tumors of the Eye and the Periocular Area.

BACKGROUND/AIM: The ability of a tumor to grow requires a sufficient blood supply. Microvascular density is considered the standard for assessing the neovasculature. Tumor cell vasculogenic mimicry refers to the formation of tumor cell-lined vessels that contribute to tumor neovascularization. The aim of the present work was to study angiogenesis and vasculogenic mimicry in benign and malignant melanocytic tumors of the eye and the periocular region. PATIENTS AND METHODS: Histological sections from 118 patients were studied. Eighty-eight of the patients had nevi while the remaining 30 had malignant melanomas. Microvascular density was assessed by using antibodies against the endothelial cell markers CD31 and CD34. Vascular-like channels between neoplastic cells, that were not lined by endothelial cells and thus were negative for CD31 and CD34, represented areas of vasculogenic mimicry. RESULTS: Angiogenesis was more pronounced in melanomas compared to melanocytic nevi and was increased in melanomas with high mitotic index and/or epithelioid cell preponderance compared to melanomas with low mitotic index and/or spindle cell predominance. Vasculogenic mimicry was observed in many melanomas, while it was evident in the minority of benign nevi as well. CONCLUSION: The existence of vasculogenic mimicry in benign nevi might have prognostic implications.

Natural Compounds and Neuroprotection: Mechanisms of Action and Novel Delivery Systems.

Neurodegeneration characterizes pathologic conditions, ranging from Alzheimer's disease to glaucoma, with devastating social and economic effects. It is a complex process implicating a series of molecular and cellular events, such as oxidative stress, mitochondrial dysfunction, protein misfolding, excitotoxicity and inflammation. Natural compounds, because of their broad spectrum of pharmacological and biological activities, could be possible candidates for the management of such multifactorial morbidities. However, their therapeutic potential against neurodegenerative diseases has been hampered by their poor bioavailability and subsequent insufficient delivery to the brain. This article provides an overview of the molecular mechanisms through which natural compounds exert their neuroprotective effects, as well as the development of novel natural compound-loaded delivery systems that could improve their neuroavailability.

The Spectrum of Infectious Diseases in Kidney Transplantation: A Review of the Classification, Pathogens and Clinical Manifestations.

Kidney transplantation is the treatment-of-choice for a significant number of patients with end-stage renal disease. Renal transplant recipients (RTRs) benefit from a longer life expectancy, with a better quality of life. Despite, recent accomplishments in the field of kidney transplantation, both short- and long-term, surgical and medical complications still exist. Among these complications, cardiovascular disease, carcinogenesis and infections are the most important. Infectious diseases constitute the most common complications after renal transplantation and the second most common cause of death among RTRs with a functioning graft. Theoretically, all infectious pathogens could cause disease in immunocompromised RTRs, yet among these, one could identify more important ones, such as the Enterobacteriaceae, causing urinary tract infections; pneumonia due to Pneumocystis jirovecii; Candida species which cause invasive fungal infections; herpes viruses; hepatitis viruses and parasites. Early diagnosis and effective treatment are key elements in salvaging both the allograft and the patient. However, clinical manifestations and diagnosis of such infectious diseases are not easily identified due to the altered state of immune response of the RTR. Thus, apart from possessing a deep knowledge of the etiology and the treatment options in each case, transplant physicians should also always remain alert when dealing with RTRs.

Vasculogenic mimicry: lessons from melanocytic tumors.

Tumor cell vasculogenic mimicry refers to the formation of tumor cell-lined vessels that contribute to tumor neovascularization and nutrient and oxygen supply. These tumor cells express many endothelial and stem cell markers, resulting in them having a unique phenotype. This phenomenon is observed in a variety of neoplasms, such as glioblastomas and sarcomas, as well as breast, ovarian, liver and lung carcinomas. It is also evident in melanocytic lesions, regardless of their benign or malignant nature. The biochemical and molecular events that regulate vasculogenic mimicry provide opportunities for development of novel forms of tumor-targeted treatments. Furthermore, the presence of this process in a tumor might have prognostic implications.

Relationships between body composition analysis measures in Greek women and US white women.

We investigated the regional changes in body composition relative to age, in healthy Caucasian women living in the Mediterranean area. Body composition of total and subtotal body was measured, and fat mass (FM) ratios along with FM and lean mass (LM) indices were calculated in 330 women aged 20-85 years, using DXA. Data were compared with the NHANES reference database. Peak bone mineral density and bone mineral content of total body were 1.149 g/cm(2) and 2,209 g and were achieved between ages 41 and 50. Peak %FM of total body, FM index (FMI; FM/height(2)), FM of trunk to legs, and FM of trunk to limbs were 41.5%, 13.69 kg/m(2), 1.623, and 1.14, respectively. Peak %FM and FMI were achieved between 61 and 70 years. Unlike US counterparts, in our series, both FM ratios showed a propensity for women to accrue fat in the trunk following the android pattern of fat distribution. Peak LM index for total body (LMI; LM/height(2)) and limbs (ASMMI; appendicular skeletal muscle mass/height(2)) was 18.08 kg/m(2) and 7.33 kg/m(2), respectively, and was achieved between 61 and 70 years. For Greeks, the ASMMI was greater from 55 years onwards. Greek women have increasing bone mass in early adulthood followed by significant decline during fifties and onwards. Compared with US white women, Greek women have significantly greater truncal fat for all ages, implying a greater risk of obesity-associated diseases. Middle-aged and older Greek women have greater appendicular skeletal muscle mass, which may eliminate the overall risk of sarcopenic obesity.

Real-Time PCR detection and quantitation of Helicobacter pylori clarithromycin-resistant strains in archival material and correlation with Sydney classification.

BACKGROUND: Helicobacter pylori (H. pylori), infects gastric mucosa causing gastritis. Treatment failure is mainly due to certain genetic changes in the peptidyltransferase loop of 23S rRNA of the microorganism. The aim of the study was to evaluate genetic changes in gastric biopsies of H. pylori (+) patients that lead to clarithromycin resistance and to correlate them with histology data. METHODS: A total of 150 H. pylori (+) gastric biopsies were studied, taken before and after eradication therapy from 75 dyspeptic patients divided in 2 groups: group A consisted of 25 H. pylori (+) triple-therapy resistant patients and group B consisted of 50 H. pylori (+) successfully treated patients. Histological classification of the H. pylori (+) gastritis was done according to the Sydney criteria. Genetic material was analyzed with the ClariRes™ RT-PCR bi-probe based assay for the determination of point mutations in the 23S rRNA gene and with a Quantitative-RT-PCR (Q-RT-PCR) method for the quantitation of H. pylori. RESULTS: We showed that in 18/ 25 group A patients certain point mutations of 23S rRNA at sites A2142C, A2142G and A2143G had occurred. Nine of these 18 mutated cases (50%) were characterized as mixed infections. Mixed infections in 2/50 patients of group B were also observed. Using Q-RT-PCR, we found that gastric mucosal density of H. pylori correlates well with bacterial colonization. There was a statistically significant association (P<0.005) between the presence of the detected H. pylori genetic alterations and inflammation, activity and H. pylori density as histologically determined. CONCLUSION: Certain point mutations in H. pylori genome that affect susceptibility to clarithromycin correlate with histological features of gastritis.

Cytogenetic analysis of a low-grade secondary peripheral chondrosarcoma arising in synovial chondromatosis.

Secondary chondrosarcoma is a malignant chondroid tumor arising in a benign precursor. Synovial chondromatosis is a benign chondroid lesion that rarely transforms to chondrosarcoma. We present the case of a 54-year-old male with the diagnosis of low-grade secondary peripheral chondrosarcoma developed in the context of synovial chondromatosis. Cytogenetics revealed a novel aberration t(1;14)(q23.1~24;q24.1~3). Multicolor banding (mBAND) analysis described the chromosomal regions involved in this translocation with a higher detail. Diagnosis of such borderline lesions is very difficult and cytogenetics is helpful in characterizing these tumors.

[Colorectal carcinogenesis]. / La carcinogenèse colorectale.

Colorectal adenocarcinomas were long thought to be an homogeneous entity, in which traditional adenomas of the colon were the best-recognized and most common precursor lesions. Current morphological and molecular data suggest an alternative pathway of colorectal carcinogenesis involving "serrated neoplasia". This pathway seems to be responsible for approximately 10% to 15% of sporadic colorectal adenocarcinomas. These serrated lesions, that may progress to cancer, show relatively distinct histopathological molecular and epigenetic features not commonly seen in traditional adenomas. Key characteristics of the serrated neoplasia pathway include BRAF gene mutations, excess CpG island methylation, and subsequent microsatellite instability. A major challenge for pathologists is to identify these new potential precursor lesions, in order to enable early diagnosis and treatment.

Altered expression of cell cycle and apoptotic proteins in human liver pathologies.

Τhe expression of cell cycle (P53, Ki-67, P21, and P27) and apoptotic proteins (BCL-2 and BAX) was investigated by immunohistochemistry in paraffin-embedded formalin-fixed tissues of normal and pathologic liver. An increased frequency of expression of P21 in cirrhosis and hepatocellular carcinoma (HCC) (p=0.003 and p=0.001 respectively) was found; P27 protein expression was more frequent in hepatitis (p=0.001) and HCC (p=0.003) when compared with normal tissue. BCL-2 protein was markedly more frequent in steatohepatitis (p<0.05) as compared to normal liver, in hepatitis cases (p=0.002) and in metastases (p<0.033). The expression of BAX was more frequent in hepatitis (p=0.001) and cirrhosis (p<0.001). We demonstrated in our study the expression of these proteins at different levels in liver pathologies. These findings have implications for understanding the evolution from liver inflammation to cirrhosis and associated carcinogenesis.

Synchronous presentation of GISTs and other primary neoplasms: a single center experience.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are common mesenchymal neoplasms of the digestive tract and may occasionally arise within the abdomen without gastrointestinal tract connection. GISTs have recently attracted widespread interest because of the development of effective targeted molecular agents against it. While synchronous occurrence of a GIST with a tumor of different histogenesis was thought to be very rare, it is now apparent that they are more common than previously believed. PATIENTS AND METHODS: We report our experience with GISTs and also six cases of GIST coexisting with other primary neoplasms. Using immunohistochemistry and mutational analysis, a possible correlation was investigated. A review of the literature was also conducted. RESULTS: There were no significant differences in the immumohistochemical and molecular profile between single GISTs and GISTs coexisting with other tumors, nor was there any mutational correlation between GISTs and the coexistent tumors of different histogenesis regarding KIT and PDGFRA genes. CONCLUSION: Further molecular biology studies are required in order to investigate thoroughly the simultaneous development of tumors with different histotypes.

Osteonecrosis of the tibial plateau: magnetic resonance imaging appearances with quantitation of lesion size and evidence of a pathogenesis of meniscal injury.

PURPOSE: To determine the magnetic resonance (MR) imaging appearances of osteonecrosis of the tibial plateau and perform quantitative analysis of the extent of the necrotic area. MATERIALS AND METHODS: Twenty-eight patients (34 knees) with osteonecrosis were retrospectively evaluated using MR imaging and other modalities where available. A computerized image analysis program that allowed quantification of the lesion size was used to obtain measurements of the extent of involvement, which were then incorporated into each stage of the disease. RESULTS: The MR imaging findings of osteonecrosis of the tibial plateau included subchondral regions of abnormal signal intensity (n = 28), a double-line sign (n = 11), and fractures (n = 9). Meniscal tears and cartilage abnormalities were disclosed in the affected knee compartment with an equal frequency (n = 17). The size of the necrotic lesion varied among different stages of the disease as follows: 6.8% to 15.7% (stage I); 6.5% to 59.3% (stage II); 23.5% to 61.3% (stage III); and 34.3% to 75% (stage IV). The extent of involvement was greater in stage II than that in stage I (P < 0.001) and in stage IV than that in stage III (P < 0.05), whereas the extent of involvement in stage III was not significantly greater than that in stage II (P > 0.05). CONCLUSIONS: The MR imaging characteristics of osteonecrosis of the tibial plateau are variable. The association of osteonecrosis at this site with meniscal tears and cartilage abnormalities has important implications for pathogenesis of the disease as it relates to physical stress. Quantification of the lesion size provides precise information for optimal staging of the disease.

Serum and tissue selenium levels in gastric cancer patients and correlation with CEA.

BACKGROUND: An inverse relationship between selenium (Se) intake and cancer mortality is evident in humans. MATERIALS AND METHODS: In eighty patients who had been operated on for primary gastric cancer, serum Se and carcinoembryonic antigen (CEA) levels were measured preoperatively using a fluorometric and immunoradiometric assay (IRMA), respectively. RESULTS: The serum Se levels were 43+/-6.3 microg l(-1) in the patient group and 68.7+/-4.5 microg l(-1) in healthy individuals (p<0.001). The serum CEA was 12+/-1.9 U ml(-1) in the gastric cancer patients and 2.1 U ml(-1) in the control group (p<0.001). The Se tissue concentrations were 2,640+/-220 mg g(-1) in excised neoplastic tissue and 685+/-115 mg g(-1) in non-neoplastic tissue (p<0.001). An inverse correlation between Se and CEA serum levels was found (r=-0.782). There was no correlation between serum/tissue Se concentration and disease stage/histological type or gender in the patient group.

Osteochondromas: review of the clinical, radiological and pathological features.

Osteochondroma is the most common benign bone tumor and usually occurs in the metaphyseal region of the long bones. This tumor takes the form of a cartilage-capped bony outgrowth on the surface of the bone. The vast majority (85%) of osteochondromas present as solitary, nonhereditary lesions. Approximately 15% of osteochondromas occur as multiple lesions in the context of hereditary multiple osteochondromas (HMOs), a disorder that is inherited in an autosomal dominant manner. Most lesions appear in children and adolescents as painless, slow-growing masses. However, depending on the location of the osteochondroma, significant symptoms may occur as a result of complications such as fracture, bony deformity, mechanical joint problems and vascular or neurologic compromise. Malignant transformation of osteochondromas can occur later in adulthood but rarely metastasize. The treatment of choice for osteochondroma is surgical unless the skeleton is still immature. Pathogenetic analysis showed that HMOs are caused by mutations in either of two genes: exostosis (multiple)-1 (EXT1), which is located on chromosome 8q24.11-q24.13 or exostosis (multiple)-2 (EXT2), which is located on chromosome 11p11-12. Recently, biallelic inactivation of the EXT1 locus was described in nonhereditary osteochondromas. The EXT1 and EXT2 proteins function in the biosynthesis of heparin sulfate proteoglycans (HSPGs) which are multifunctional proteins involved in several growth signaling pathways in the normal epiphyseal growth plate. Reduced EXT1 or EXT2 expression in osteochondromas is associated with disordered cellular distribution of HSPGs, resulting in defective endochondral ossification which is likely to be involved in the formation of osteochondromas. Here the clinical, radiological, pathological and pathogenetic features and the treatment modalities of osteochondroma are reviewed.

Differential expression of dysadherin in papillary thyroid carcinoma and microcarcinoma: correlation with E-cadherin.

Dysadherin is a novel glycoprotein, with an anti-cell-cell adhesion function. The aim of the present study was to examine the expression of dysadherin in thyroid papillary microcarcinoma (PMC), to associate it with the expression of E-cadherin and to investigate whether there are differences with papillary carcinoma (PC). A statistically significant difference in dysadherin and E-cadherin expression between PC and PMC and a negative correlation between E-cadherin and dysadherin expression regardless of tumor size were noted. Based on these findings it is hypothesized that retained cell-cell adhesion, through maintenance of the E-cadherin adhesion system, in PMC prevents neoplastic cells from dissociating easily from each other and metastasizing. Increased dysadherin expression is possibly one of the post-transcriptional mechanisms responsible for E-cadherin downregulation in thyroid papillary neoplasia.

Immunohistochemical expression of cell-cycle proteins in gastric precancerous lesions.

BACKGROUND: The early indicator for the subject predisposed to gastric cancer is abnormal proliferation of gastric epithelial cells, such as atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia, which have been considered as precancerous lesions of gastric cancer. To determine whether p53 protein, cyclins D1, and D3, and p27(kip1) play a role in the carcinogenesis pathway of gastric cancer, we performed an immunohistochemical study of their expression in gastric precancerous lesions. METHODS: A total of 1 45 endoscopic gastric biopsy specimens of AG, IM, and gastric dysplasia were studied. These molecular markers were localized by immunohistochemistry. RESULTS: P53 was expressed in 15% of cases with gastric dysplasia and not in the pre-dysplastic stages of the gastric mucosa. All cases were concerning high-grade dysplasia. Cyclin D1 protein was almost undetectable in the precancerous lesions of gastric cancer. Cyclin D3 protein overexpression was seen in 10% of biopsies with IM, and 50% of biopsies with gastric dysplasia. High expression of p27(kip1) protein was demonstrated in all cases of chronic gastritis. As atrophy, IM, and dysplasia develop, expression of p27(kip1) protein is suppressed. In total, 15% of dysplastic cases showed no expression of p27(kip1) protein. CONCLUSIONS: (i) P53 mutation must be a late event during the development of gastric cancer. (ii) Cyclin D1 protein overexpression may not play a role in the progression from normal to neoplastic gastric mucosa, while overexpression of cyclin D3 is an earlier event during gastric carcinogenesis, and its role must be further evaluated. (iii) Reduced expression of p27(kip1) is a rather early event in gastric tumorigenesis, before dysplastic changes occur.