Involvement of Lipophagy and Chaperone-Mediated Autophagy in the Pathogenesis of Non-Alcoholic Fatty Liver Disease by Regulation of Lipid Droplets.

Non-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of lipids in the form of lipid droplets in more than 5% of hepatocytes. It is regarded as a range of diverse pathologies, including simple steatosis and steatohepatitis. The structural characteristics of lipid droplets, along with their protein composition, mainly including perilipins, have been implicated in the etiology of the disease. These proteins have garnered increasing attention as a pivotal regulator since their levels and distinct expression appear to be associated with the progression from simple steatosis to steatohepatitis. Perilipins are target proteins of chaperone-mediated autophagy, and their degradation is a prerequisite for lipolysis and lipophagy to access the lipid core. Both lipophagy and chaperone-mediated autophagy have significant implications on the development of the disease, as evidenced by their upregulation during the initial phases of simple steatosis and their subsequent downregulation once steatosis is established. On the contrary, during steatohepatitis, the process of chaperone-mediated autophagy is enhanced, although lipophagy remains suppressed. Evidently, the reduced levels of autophagic pathways observed in simple steatosis serve as a defensive mechanism against lipotoxicity. Conversely, in steatohepatitis, chaperone-mediated autophagy fails to compensate for the continuous generation of small lipid droplets and thus cannot protect hepatocytes from lipotoxicity.

Antigen-presenting cells in ocular surface diseases.

PURPOSE: To review the role of antigen-presenting cells (APC) in the pathogenesis of ocular surface diseases (OSD). METHODS: A thorough literature search was performed in PubMed database. An additional search was made in Google Scholar to complete the collected items. RESULTS: APCs have the ability to initiate and direct immune responses and are found in most lymphoid and non-lymphoid tissues. APCs continuously sample their environment, present antigens to T cells and co-ordinate immune tolerance and responses. Many different types of APCs have been described and there is growing evidence that these cells are involved in the pathogenesis of OSD. OSD is a complex term for a myriad of disorders that are often characterized by ocular surface inflammation, tear film instability and impairment of vision. CONCLUSIONS: This review summarizes the current knowledge concerning the immunotopographical distribution of APCs in the normal ocular surface. APCs appear to play a critical role in the pathology of a number of conditions associated with OSD including infectious keratitis, ocular allergy, dry eye disease and pterygium.

Autologous platelet-rich plasma (PRP) effect on intervertebral disc restoration: an experimental rabbit model.

PURPOSE: Platelet-rich plasma (PRP) treatment for intervertebral disc (IVD) repair and tissue engineering technologies have been the target of intense research with promising results. The purpose of this study was to investigate the effect of only one intradiscal injection of PRP in the degenerated rabbit IVD and to assess the restoration process over a 6-week follow-up period. METHODS: The L3-L4 and L4-L5 discs of 18 adult female rabbits were injured, according to an established degenerative model, with an 18-gauge needle, and classified into two groups: In the discs of group A rabbits, after needle puncture, an intradiscal injection of autologous PRP growth factors was performed, using a 27-gauge needle, and in the discs of the control group (group B), the same procedure was followed by intradiscal injection of normal saline. The PRP preparation was carried out aseptically, after blood collection from the same rabbit. RESULTS: During the 6 weeks, there was a noteworthy progression of degeneration process in group B, whereas the grade of degeneration was significantly lower in group A, both for annulus fibrosus (AF) and for nucleus pulposus (NP). The intervertebral disc regeneration and reversal process of the lesions are obvious on 45 days after the injury, in group A. The hematoxylin and eosin histology grading score and the expression of collagen type II in NP and inner layer of AF were the markers better mirroring the degeneration and restoration process. CONCLUSION: PRP intradiscal treatment in degenerative disc disease provokes the maintenance of the disc's basic morphological characteristics with restoration being evident early after injury.

Decreased DNA Disruption in the Porcine Neocortex with Erythromycin Preconditioning during Prolonged Hypothermic Circulatory Arrest: Evidence for Neuroprotection.

BACKGROUND AND AIM OF THE STUDY: We have previously reported that the neocortex is selectively vulnerable to injury in an acute porcine model of hypothermic circulatory arrest (HCA) at 18°C. In view of recent evidence showing that pharmacologic preconditioning with a single dose of erythromycin induces tolerance against transient global cerebral ischemia in rats, we hypothesized that erythromycin would reduce the number of apoptotic neurons in the neocortex in an acute porcine model of HCA at 18°C. METHODS: Fourteen piglets underwent 75 min of HCA at 18°C following pretreatment with erythromycin (25 mg/kg, IV) (n = 8) or vehicle (Normal Saline 0.9%) (n = 6), applied 12 hr before arrest. Three served as normal controls. After gradual rewarming to a temperature of 36°C, treatment animals were sacrificed and brains were perfusion-fixed and cryopreserved. Neuronal apoptosis after HCA was observed morphologically with hematoxylin and eosin staining, and characterized by in situ DNA fragmentation using terminal deoxynucleotidyl-transferase-mediated biotin-dUTP nick end-labeling (TUNEL) histochemistry. RESULTS: Pre-ischemic conditioning with a single dose of the antibiotic erythromycin reduced neuronal apoptosis in the neocortex of the porcine brain. TUNEL-positive cells indicating DNA fragmentation and neuronal injury were significantly greater in the neocortex of animals treated with 18°C HCA (2.55 ± 1.17) compared to animals undergoing HCA after erythromycin preconditioning (1.76 ± 0.91) (p ≤ 0.001). CONCLUSIONS: These results suggest that cerebral protection during HCA may be achieved with erythromycin pharmacological preconditioning in the porcine model.

Complex cystic liver lesions: classification, diagnosis, and management.

Cystic liver disease has been increasingly reported in the literature, with a prevalence as high as 15-18%. Hepatic cysts are usually discovered incidentally, while their characterization and classification rely on improved imaging modalities. Complex cystic liver lesions comprise a wide variety of novel, re-introduced, and re-classified clinical entities. This spectrum of disorders ranges from non-neoplastic conditions to benign and malignant tumors. Their clinicopathological features, prognostic factors, and oncogenic pathways are incompletely understood. Despite representing a heterogeneous group of disorders, they can have similar clinical and imaging characteristics. As a result, the diagnosis and management of complex liver cysts can become quite challenging. Furthermore, inappropriate diagnosis and management can lead to high morbidity and mortality. In this review, we aim to offer up-to-date insight into the diagnosis, classification, and management of the most common complex cystic liver lesions.

Ten-year clinical outcome, toxicity and compliance of dose-dense sequential adjuvant administration of cyclophosphamide & epirubicin followed by docetaxel in patients with early breast cancer: A hellenic cooperative oncology group observational study (HE 10/10) with concurrent investigation of significance of tumor infiltrating lymphocytes.

BACKGROUND: Dose-dense sequential (dds) chemotherapy has changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a currently widely used chemotherapeutic regimen. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8+ lymphocytes were also evaluated in the same cohort. PATIENTS AND METHODS: Totally, 1054 patients were prospectively enrolled in the current study with 1024 patients being eligible, while adequate tissue was available for 596 of them. TILs, CD8+ lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8+ lymphocytes in tumor stroma (sCD8) as well as the total number of CD8+ lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry. RESULTS: Within a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. Importantly, the 10-year DFS and OS rates were 78.4% (95% CI 75.0-81.5) and 81.7% (95% CI 79.0-84.1), respectively. Interestingly, higher CD8+ T cells as well as TILs in the tumor microenvironment were associated with an improved long-term survival outcome. CONCLUSIONS: In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of TILs and infiltrating CD8+ lymphocytes in BC patients with early-stage disease.

The Role of Oxidative Stress and Cellular Senescence in the Pathogenesis of Metabolic Associated Fatty Liver Disease and Related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) represents a worryingly increasing cause of malignancy-related mortality, while Metabolic Associated Fatty Liver Disease (MAFLD) is going to become its most common cause in the next decade. Understanding the complex underlying pathophysiology of MAFLD-related HCC can provide opportunities for successful targeted therapies. Of particular interest in this sequela of hepatopathology is cellular senescence, a complex process characterised by cellular cycle arrest initiated by a variety of endogenous and exogenous cell stressors. A key biological process in establishing and maintaining senescence is oxidative stress, which is present in multiple cellular compartments of steatotic hepatocytes. Oxidative stress-induced cellular senescence can change hepatocyte function and metabolism, and alter, in a paracrine manner, the hepatic microenvironment, enabling disease progression from simple steatosis to inflammation and fibrosis, as well as HCC. The duration of senescence and the cell types it affects can tilt the scale from a tumour-protective self-restricting phenotype to the creator of an oncogenic hepatic milieu. A deeper understanding of the mechanism of the disease can guide the selection of the most appropriate senotherapeutic agent, as well as the optimal timing and cell type targeting for effectively combating HCC.

The Role of Macroautophagy and Chaperone-Mediated Autophagy in the Pathogenesis and Management of Hepatocellular Carcinoma.

Hepatocarcinogenesis is a long process with a complex pathophysiology. The current therapeutic options for HCC management, during the advanced stage, provide short-term survival ranging from 10-14 months. Autophagy acts as a double-edged sword during this process. Recently, two main autophagic pathways have emerged to play critical roles during hepatic oncogenesis, macroautophagy and chaperone-mediated autophagy. Mounting evidence suggests that upregulation of macroautophagy plays a crucial role during the early stages of carcinogenesis as a tumor suppressor mechanism; however, it has been also implicated in later stages promoting survival of cancer cells. Nonetheless, chaperone-mediated autophagy has been elucidated as a tumor-promoting mechanism contributing to cancer cell survival. Moreover, the autophagy pathway seems to have a complex role during the metastatic stage, while induction of autophagy has been implicated as a potential mechanism of chemoresistance of HCC cells. The present review provides an update on the role of autophagy pathways in the development of HCC and data on how the modulation of the autophagic pathway could contribute to the most effective management of HCC.

Investigation of prognostic biomarkers in patients with urothelial carcinoma treated with platinum-based regimens.

BACKGROUND: Bladder cancer (BC) is a heterogeneous malignancy with dismal outcome. PATIENTS AND METHODS: Mutations in genes, altered or linked to platinum sensitivity in BC, were examined in 66 patients' tumors along with tumor infiltrating lymphocytes (TILs) density and MMR, PD-L1 and CD8 protein expression, as well as basal and luminal subtypes, defined by protein expression of markers, including CK5/6 and GATA3 or CK20, respectively. RESULTS: 41 tumors harbored mutations, mainly in TP53 (38%), ARID1A (17%) and the DNA damage response and repair (DDR) genes ERCC2 (17%) and BRCA2 (15%). Mutations in other DDR relevant genes were also present. Age showed unfavorable prognosis for overall survival (HR=1.07, P = 0.026); no benefit was seen for patients with TP53, ARID1A, ERCC2 or BRCA2 mutations or mutations in 1 or more DDR genes. PD-L1 status positively correlated with stromal (rho=0.46, P < 0.001) and intratumoral (rho=0.53, P < 0.001) CD8 expression or TILs (rho=0.29, P = 0.018); none associated with overall survival (OS). A statistically significant difference was observed between PD-L1 status and immunohistochemistry (IHC)­based subtypes, with tumors classified as luminal (GATA3+ and/or CK20+ and CK5/6-) showing lower PD-L1 expression relative to basal (CK5/6+ and GATA3- and/or CK20-) (median value 0 vs. 2.5, P = 0.029). Concerning OS, no statistically significant difference was seen among patients with basal or luminal tumors. CONCLUSION: No association was seen herein between DDR mutations, TILs, PD-L1, CD8 expression or IHC-based subtypes and patient survival; these observations warrant validation within a larger cohort.

Association between CD8+ Tumor Infiltrating Lymphocytes and the Clinical Outcome of Patients with Operable Breast Cancer Treated with Adjuvant Dose-Dense Chemotherapy-A 10 Year Follow-Up Report of a Hellenic Cooperative Oncology Group Observational Study.

Tumor-infiltrating lymphocytes (TILs) contribute to breast cancer (BC) prognosis. We investigated the prognostic impact of CD8+ TILs in patients with early breast cancer treated with adjuvant chemotherapy in a large observational clinical trial. Along with a 10 year follow-up, considering the efficacy and safety, we report the results of the translational part of our study. We examined the patients' tumors for total (t), stromal (s), and intratumoral (i) CD8 lymphocyte density (counts/mm2) on tissue-microarray cores. The impact of CD8+ TILs counts on DFS and OS, and its correlation with breast cancer subtypes and standard clinicopathological parameters, were investigated, along with efficacy and safety data. Among the 928 eligible patients, 627 had available CD8+ data. Of which, 24.9% had a high expression of sCD8, iCD8, and total CD8, which were correlated with higher Ki67, TILs density, ER/PgR negativity, and higher histological grade. The 5year DFS and OS rates were 86.1% and 91.4%, respectively. Patients with high iCD8 and tCD8 had longer DFS and OS compared to those with low counts/mm2 (DFS: HR = 0.58, p = 0.011 and HR = 0.65, p = 0.034 and OS: HR = 0.63, p = 0.043 and HR = 0.58, p = 0.020, respectively). Upon adjustment for clinicopathological parameters, iCD8 and tCD8 retained their favorable prognostic significance for DFS and OS, whereas high sCD8 was only prognostic for DFS. Menopausal status, tumor size, and nodal status retained their prognostic significance in all examined multivariate models. CD8+ TILs, and especially their intratumoral subset, represent a potential favorable prognostic factor in early BC.

Autophagy and Exosomes: Cross-Regulated Pathways Playing Major Roles in Hepatic Stellate Cells Activation and Liver Fibrosis.

Chronic liver injury, regardless of the underlying disease, results in gradual alteration of the physiological hepatic architecture and in excessive production of extracellular matrix, eventually leading to cirrhosis Liver cellular architecture consists of different cell populations, among which hepatic stellate cells (HSCs) have been found to play a major role in the fibrotic process. Under normal conditions, HSCs serve as the main storage site for vitamin A, however, pathological stimuli lead to their transdifferentiation into myofibroblast cells, with autophagy being the key regulator of their activation, through lipophagy of their lipid droplets. Nevertheless, the role of autophagy in liver fibrosis is multifaceted, as increased autophagic levels have been associated with alleviation of the fibrotic process. In addition, it has been found that HSCs receive paracrine stimuli from neighboring cells, such as injured hepatocytes, Kupffer cells, sinusoidal endothelial cells, which promote liver fibrosis. These stimuli have been found to be transmitted via exosomes, which are incorporated by HSCs and can either be degraded through lysosomes or be secreted back into the extracellular space via fusion with the plasma membrane. Furthermore, it has been demonstrated that autophagy and exosomes may be concomitantly or reciprocally regulated, depending on the cellular conditions. Given that increased levels of autophagy are required to activate HSCs, it is important to investigate whether autophagy levels decrease at later stages of hepatic stellate cell activation, leading to increased release of exosomes and further propagation of hepatic fibrosis.

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.

VL30 retrotransposition is associated with induced EMT, CSC generation and tumorigenesis in HC11 mouse mammary stem­like epithelial cells.

Retrotransposons copy their sequences via an RNA intermediate, followed by reverse transcription into cDNA and random insertion, into a new genomic locus. New retrotransposon copies may lead to cell transformation and/or tumorigenesis through insertional mutagenesis. Methylation is a major defense mechanism against retrotransposon RNA expression and retrotransposition in differentiated cells, whereas stem cells are relatively hypo­methylated. Epithelial­to­mesenchymal transition (EMT), which transforms normal epithelial cells into mesenchymal­like cells, also contributes to tumor progression and tumor metastasis. Cancer stem cells (CSCs), a fraction of undifferentiated tumor­initiating cancer cells, are reciprocally related to EMT. In the present study, the outcome of long terminal repeat (LTR)­Viral­Like 30 (VL30) retrotransposition was examined in mouse mammary stem­like/progenitor HC11 epithelial cells. The transfection of HC11 cells with a VL30 retrotransposon, engineered with an EGFP­based retrotransposition cassette, elicited a higher retrotransposition frequency in comparison to differentiated J3B1A and C127 mouse mammary cells. Fluorescence microscopy and PCR analysis confirmed the specificity of retrotransposition events. The differentiated retrotransposition­positive cells retained their epithelial morphology, while the respective HC11 cells acquired mesenchymal features associated with the loss of E­cadherin, the induction of N­cadherin, and fibronectin and vimentin protein expression, as well as an increased transforming growth factor (TGF)­ß1, Slug, Snail­1 and Twist mRNA expression. In addition, they were characterized by cell proliferation in low serum, and the acquisition of CSC­like properties indicated by mammosphere formation under anchorage­independent conditions. Mammospheres exhibited an increased Nanog and Oct4 mRNA expression and a CD44+/CD24­/low antigenic phenotype, as well as self­renewal and differentiation capacity, forming mammary acini­like structures. DNA sequencing analysis of retrotransposition­positive HC11 cells revealed retrotransposed VL30 copies integrated at the vicinity of EMT­, cancer type­ and breast cancer­related genes. The inoculation of these cells into Balb/c mice produced cytokeratin­positive tumors containing pancytokeratin­positive cells, indicative of cell invasion features. On the whole, the findings of the present study demonstrate, for the first time, to the best of our knowledge, that stem­like epithelial HC11 cells are amenable to VL30 retrotransposition associated with the induction of EMT and CSC generation, leading to tumorigenesis.

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.

Adult intradural extramedullary teratoma of the spinal cord: A case presentation.

Teratomas involving the spinal cord are very rare tumors that affect more commonly children than adult. We report a rare case of an intradural extramedullary teratoma arising in the region of conus medullaris in a previously healthy adult patient. The lesion was totally excised and the postsurgical outcome was favorable. Teratomas should be taken into consideration in the differential diagnosis in previously healthy adults with sudden onset of lower back pain or neurological deficits of the lower extremities and with a tumoral lesion of the spinal cord. Total surgical excision is the indicative treatment of choice.

Expression of the O-linked N-acetylglucosamine containing epitope H in normal myometrium and uterine smooth muscle cell tumors.

Epitope H contains an O-linked N-acetylglucosamine (O-GlcNAc) residue in a specific conformation and/or environment recognized by monoclonal antibody H (mAbH). We have previously shown that epitope H is present in more than one polypeptide and in various types of normal and pathological cells. In the present study, we focused on uterine smooth muscle cell tumors and their adjacent normal myometrium to gain further insight into the expression patterns of epitope H in human tissues. The indirect immunoperoxidase method was applied using the mAbH and the monoclonal anti-cytokeratin 8 antibody (AbCK8) in 50 cases of typical uterine leiomyomas and in five cases of uterine leiomyosarcomas, with four cases belonging to Group II A and one to Group III according to Bell et al. [6]. Western immunoblotting was applied using mAbH and AbCK8 in five cases of uterine leiomyomas and their adjacent myometrium. The main results were as follows: (1) epitope H showed intense immunohistochemical expression in 46% (23/50) and moderate expression in 54% (27/50) of uterine leiomyomas, (2) epitope H showed intense immunohistochemical expression in 40% (2/5) and moderate expression in 60% (3/5) of uterine leiomyosarcomas, (3) epitope H showed no difference in the immunohistochemical expression between leiomyomas and their adjacent myometrium and between leiomyosarcomas and their adjacent myometrium, (4) immunohistochemical expression of cytokeratin 8 was not detected in the normal and neoplastic smooth muscle cells, (5) Western immunoblotting showed that in the smooth muscle cells of the myometrium and leiomyomas, epitope H is localized in four polypeptides with molecular weights of 100, 61, 59, and 54 kDa, and (6) Western immunoblotting did not detect cytokeratin 8 in the normal and neoplastic smooth muscle cells. The present results indicate fluctuations of the epitope expression levels in uterine smooth muscle cell tumors and their adjacent myometrium. These fluctuations may be of interest for gaining insight into the pathogenesis of uterine smooth muscle cell tumors, since O-GlcNAc glycosylation is involved in cell cycle and apoptosis pathways and may modify proteins involved in oncogenesis (tumor suppressor proteins and oncoproteins) and proteins with important biological functions such as cytoskeletal proteins, transcription factors, and heat-shock proteins. Furthermore, the present results indicate that cytokeratin 8, without being present in the cells of the myometrium, leiomyomas and leiomyosarcomas, shares its epitope H, which contains its unique sugar O-N-acetylglucosamine residue, with four other unrelated polypeptides produced by the normal and neoplastic smooth muscle cells. This should be considered when using anti-cytokeratin 8 antibodies in immunohistochemistry against smooth muscle cell tumors to avoid false positive immunohistochemical results.

Adamantinoma.

Adamantinoma is one of the rarest low-grade malignant bone tumours, representing less than 1% of them. Fisher in 1913 named this tumour adamantinoma because of its similarity to ameloblastoma of the jaw. It usually arises in the center of long bones, and 97% of all reported cases were in long tubular bones and mainly in the tibial mid shaft (80-85%). Other long bones not uncommonly affected are the humerus, ulna, femur, fibula and radius. Ribs, spine, metatarsal and carpal bones are very rarely affected. The symptoms are not specific but most frequently the patient complains about swelling, redness, pain and sensitivity of the bone where the tumour is located. Young males are more prone to develop adamantinoma than females. The tumour usually spreads to the lungs, the regional lymph nodes, or other bones. Wide tumour excision and limb salvage reconstruction surgery, or an amputation, are the current surgical treatment options. Radiotherapy and chemotherapy have not been shown to be effective modalities of treatment.

Primary lymphomas of bone.

Primary lymphomas of bone are uncommon malignancies. The vast majority of them are non-Hodgkin lymphoma (NHL), whereas primary Hodgkin lymphoma (HL) of bone is extremely rare. Patients with primary NHL of bone commonly present with local bone pain, soft tissue swelling, and a mass or a pathological fracture. There is a slight male preponderance, and most patients are over 45-50 years of age. Primary NHL of bone can arise in any part of the skeleton, but long bones (femurs, tibia) are the most common sites of presentation. Comprehensive immunohistochemical studies are required to establish an accurate histological diagnosis of primary NHL of bone. Most cases of primary NHL of bone are classified as diffuse large B-cell lymphomas (DLBCL) in the World Health Organisation (WHO) classification of hematological malignancies. On full staging evaluation, most patients have disease of stage IE or IIE according to the Ann Arbor system. Several studies indicate that patients with primary NHL of bone have a favorable outcome, especially when treated by combined modality therapy. A number of studies reported that clinical stage is the most important prognostic variable in predicting overall survival. Interestingly, the rare occurrence of primary lymphoma of bone is in contrast with the frequency of plasma cell tumors in bone. This could be due to the fact that, during normal B-cell differentiation, the bone marrow is the normal site of homing of plasma cells which are terminally-differentiated, immunoglobulin-secreting post-germinal center B-cells. In this respect, there is circumstancial evidence that primary NHL of bone may represent tumors of post-germinal center B-cells. The present review summarizes data on the histogenesis of primary NHL of bone in view of the recent histogenetic classification of DLBCL on the basis of the B-cell differentiation gene expression profiles (germinal center vs. post-germinal center B-cell differentiation).

Expression of cathepsin D in urothelial carcinoma of the urinary bladder: an immunohistochemical study including correlations with extracellular matrix components, CD44, p53, Rb, c-erbB-2 and the proliferation indices.

The immunohistochemical Cathepsin D (CD) expression of tumor and stromal cells was investigated in a series of 77 urothelial carcinomas of the urinary bladder with the intention to evaluate its prognostic significance and its contribution to the metastatic potential of bladder cancer. CD expression (clone D13A) was correlated with the expression of extracellular matrix components (collagen type IV, laminin, fibronectin), CD44, p53, pRb, proliferation indices (PCNA and MIB1) as well as with other conventional clininopathological features. CD expression (> 10% of positive tumor cells) was observed in 77.9% of the carcinomas. Stromal CD expression was detected in all cases. Linear collagen type IV and laminin deposit at the tumor-stroma border (in > 25% of the BM) was found in 26% and 57.6% of the cases, respectively. The CD of cancer cells (CCCD) was inversely-correlated with the CD of the stromal cells (p = 0.039), tumor grade (p = 0.0028), tumor stage (p = 0.0046), p53 protein (p = 0.05) and positively-correlated with CD44 (p = 0.002) and pRb (p = 0.05). The stromal cells CD (SCCD) showed a statistically significant positive correlation with tumor grade (p < 0.0001) and stage (p = 0.0001), and the proliferation indices PCNA and MIB1 (p = 0.0001 and p = 0.0002, respectively). These data suggest that both CD of tumor and stromal cells could play important roles in the expansion of urothelial carcinoma of the urinary bladder.