Prostate-Specific Membrane Antigen (PSMA) Expression in Tumor-Associated Neovasculature Is an Independent Prognostic Marker in Patients with Ovarian Cancer

Prostate-specific membrane antigen (PSMA) is present in the tumor-associated neovasculature of many cancer types. Current data in ovarian cancer are limited and controversial; thus, the aim of this study was to investigate PSMA expression in a larger and homogenous patient cohort. This might lead to further studies investigating the use of imaging and therapeutic modalities targeting PSMA. Eighty patients with advanced stage high-grade serous ovarian cancers were included. Using immunohistochemistry, PSMA and CD31, a marker for endothelial cells, were examined in whole tissue sections. Percentage and intensity of PSMA expression were determined in the neovasculature. Expression levels were correlated with clinicopathological parameters and survival. Low (≤10%), medium (20–80%), and high (≥90%) PSMA expression was found in 14, 46, and 20 ovarian cancer samples, respectively. PSMA expression was confined to tumor-associated neovasculature and significantly correlated with progression-free (HR 2.24, 95% CI 1.32–3.82, p = 0.003) and overall survival (HR 2.73, 95% CI 1.41–5.29, p = 0.003) in multivariate models, considering age, FIGO stage, and residual disease. This is the first study showing a clinical relevance for PSMA in patients with ovarian cancer. PSMA was detected in the vast majority of cancer samples and showed an impact on survival

The Phenotypic Characterization of the Human Renal Mononuclear Phagocytes Reveal a Co-Ordinated Response to Injury.

Mammalian tissues contain networks of mononuclear phagocytes (MPh) that sense injury and orchestrate the response to it. In mice, this is affected by distinct populations of dendritic cells (DC), monocytes and macrophages and recent studies suggest the same is true for human skin and intestine but little is known about the kidney. Here we describe the analysis of MPh populations in five human kidneys and show they are highly heterogeneous and contain discrete populations of DC, monocytes and macrophages. These include: plasmacytoid DC (CD303+) and both types of conventional DC-cDC1 (CD141+ cells) and CD2 (CD1c+ cells); classical, non-classical and intermediate monocytes; and macrophages including a novel population of CD141+ macrophages clearly distinguishable from cDC1 cells. The relative size of the MPh populations differed between kidneys: the pDC population was bi-modally distributed being less than 2% of DC in two kidneys without severe injury and over 35% in the remaining three with low grade injury in the absence of morphological evidence of inflammation. There were profound differences in the other MPh populations in kidneys with high and low numbers of pDC. Thus, cDC1 cells were abundant (55 and 52.3%) when pDC were sparse and sparse (12.8-12.5%) when pDC were abundant, whereas the proportions of cDC2 cells and classical monocytes increased slightly in pDC high kidneys. We conclude that MPh are highly heterogeneous in human kidneys and that pDC infiltration indicative of low-grade injury does not occur in isolation but is part of a co-ordinated response affecting all renal DC, monocyte and macrophage populations

Pathology & Oncology Research / Molecular Profiling of Thymoma and Thymic Carcinoma : Genetic Differences and Potential Novel Therapeutic Targets

Thymoma and thymic carcinoma are thymic epithelial tumors (TETs). We performed a molecular profiling to investigate the pathogenesis of TETs and identify novel targets for therapy. We analyzed 37 thymomas (18 type A, 19 type B3) and 35 thymic carcinomas. The sequencing of 50 genes detected nonsynonymous mutations in 16 carcinomas affecting ALK, ATM, CDKN2A, ERBB4, FGFR3, KIT, NRAS and TP53. Only two B3 thymomas had a mutation in noncoding regions of the SMARCB1 and STK11 gene respectively. Three type A thymomas harbored a nonsynonymous HRAS mutation. Fluorescence in situ hybridization detected in 38 % of carcinomas a CDKN2A, in 32 % a TP53 and in 8 % an ATM gene deletion, whereas only one B3 thymoma exhibited a CDKNA deletion, and none of the type A thymomas showed a gene loss. Sequencing of the total miRNA pool of 5 type A thymomas and 5 thymic carcinomas identified the C19MC miRNA cluster as highly expressed in type A thymomas, but completely silenced in thymic carcinomas. Furthermore, the miRNA cluster C14MC was downregulated in thymic carcinomas. Among non-clustered miRNAs, the upregulation of miR-21, miR-9-3 and miR-375 and the downregulation of miR-34b, miR-34c, miR-130a and miR-195 in thymic carcinomas were most significant. The expression of ALK, HER2, HER3, MET, phospho-mTOR, p16INK4A, PDGFRA, PDGFRB, PD-L1, PTEN and ROS1 was investigated by immunohistochemistry. PDGFRA was increased in thymic carcinomas and PD-L1 in B3 thymomas and thymic carcinomas. In summary, our results reveal genetic differences between thymomas and thymic carcinomas and suggest potential novel targets for therapy.(VLID)354444

Chronic Hepatitis E is associated with cholangitis

Background and Aims Sporadic hepatitis E is an emerging indigenous disease in Europe induced by genotype 3 of the virus. While the disease takes an acute self-limited course in immunocompetent individuals, under immunocompromised conditions chronic hepatitis E might develop. The histology of chronic hepatitis E has not been described in detail systematically. Methods Liver biopsies from 19 immunosuppressed patients with chronic hepatitis E were collected: 17 were organ transplant recipients, one had a CD4-deficiency and one had received steroid therapy because of ulcerative colitis. Biopsies were processed with standard stains. Evaluation of histologic activity and fibrosis was performed according to Ishak. Additionally, immunohistochemistry with antibodies directed against open reading frame 2 and 3 of the virus was performed and liver biopsies were tested for hepatitis E virus RNA. Results Biochemical data showed an increase in alanine transaminase, aspartate transaminase, gamma-glutamyl transferase and total bilirubin. Histopathology displayed typical features of chronic hepatitis with mild to moderate activity. The number of polymorphonuclear leucocytes was considerably increased and all patients had a florid cholangitis that presented as a destructive form in five of them. Hepatocytes and bile duct epithelia stained positive for hepatitis E virus by immunohistochemistry. Conclusions Chronic hepatitis E in immunocompromised individuals runs a similar course as hepatitis B and C and shows similar histopathology. However, the presence of destructive cholangitis in some cases accompanied by an increased number of polymorphonuclear leucocytes is markedly different. Immunohistochemically the virus is present in bile duct epithelia, seemingly the cause for cholangitis

Absolute count and relative percentage of Dendritic cell subtype in histological sections.

<p>Absolute count and relative percentage of Dendritic cell subtype in histological sections.</p

Localization of the DC subtypes in kidney cortex.

<p>Histological sections from CDN (case 5) and RTN (case 1) adjacent to those used for FACS were stained with CD303, CD141 and CD1c in order to localize the DC subtype and count their absolute number. CD303 expressing pDC (double staining with CD68 in brown) are rare in the renal cortex of the donor nephrectomy specimens (CDN) whereas CD141⁺ cells (arrows) were more common and CD1c⁺ cells (arrows) were easily detectable. There were three-to seven-fold more pDC (arrows) in the tumour nephrectomies (RTN) compared to the donor kidneys, but rarely any CD141 expressing cells (arrows).</p

Monocytes derived macrophages in inflamed kidney.

<p>The proportion of CD14 positive cells that express CD16 cells is greater in kidneys with low numbers of pDC than in those with high numbers of pDC, and includes both CD14^int CD16⁺ and CD14⁺CD16⁺(central panel). The addition of 25F9, a marker for monocyte derived infiltrating macrophages and the active phagocytic marker CD68 reveals that the expanded population includes CD14 positive macrophages in addition to non-classical and intermediate monocytes, as it shown also by the scatter plot property. In here the plots of the kidney n° 2 are shown, similar results were obtained with the kidneys n° 1 and 3.</p

CD141 positive cells in human kidney.

<p>Two distinct populations of CD11c⁺ CD11b^- (upper panels) and CD11c^- CD11b⁺ (lower panels) express the cDC1 marker CD141. CD11c⁺ CD141⁺ cells have the typical dendritic cell shape and high expression of HLA-DR but are negative for DC-SIGN. These characteristics identify them as cDC1 cells. The CD11b⁺ CD141⁺ have similar granularity to macrophages and express DC-SIGN together with HLA-DR. In here the plots of the kidney n° 5 are shown, similar results were obtained with the kidney n° 4. (b) In here the CD141 positive cells, plots of the kidney n°2 characterized by high numbers of infiltrating pDC are shown similar results were obtained with the kidneys n° 1 and 3.</p