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Hereditary Leiomyomatosis and Renal Cell Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
RCC appears as a solitary and unilateral lesion of 2.3–20 cm in size with partial cystic area, and occasionally as multifocal or bilateral lesions. It frequently invades capsular and perinephric adipose tissue as well as renal vein and vena cava. Abdominal CT scan helps reveal hypodensity lesion in the kidney, while contrast enhanced CT shows homogenous or nonhomogenous and less enhanced mass. Histologically, RCC is composed of neoplastic cells organized in papillary, tubulopapillary, solid, cystic tubulocystic, vacuolated/cribriform, or mixed pattern. The most common RCC type linked to HLRCC is papillary predominated type 2, which demonstrates large tumor cells with eosinophilic cytoplasm, pseudostratified nuclei containing prominent inclusion-like eosinophilic nucleoli, and perinucleolar clearing/haloes (Figure 31.3c) [28]. Immunohistochemically, tumor cells stain positive for S-(2-succino)-cysteine (2SC), PAX8, CD10, vimentin, cytokeratin 8/18, HIF-1a, and GLUT1 but show reduced expression of FH. Other RCC types (e.g., tubulopapillary RCC, collecting-duct RCC, clear cell RCC, unclassified RCC, oncocytic tumor, cystic tumor, angiomyolipoma, and Wilms tumor) may also be observed. Besides RCC, solitary or multifocal renal cysts or tubular cells with hobnail patterns in the renal parenchyma adjacent to the main tumor may be present [29].
Adult Stem Cells for Intervertebral Disc Repair
Published in Raquel M. Gonçalves, Mário Adolfo Barbosa, Gene and Cell Delivery for Intervertebral Disc Degeneration, 2018
Esther Potier, Delphine Logeart-Avramoglou
As IVD is considered as a fibrocartilaginous tissue, most of the aforementioned studies used major markers of chondrocytic cells (i.e., gene expression of Sox9, type II collagen, and aggrecan and glycosaminoglycan synthesis) to characterize stem cell discogenic differentiation. Hyaline cartilage and NP, however, have a distinct embryological origin and display significant differences in tissue composition. For instance, the ratio of glycosaminoglycans to collagens is much higher, both at the protein and at the gene levels, in NP than in hyaline cartilage (e.g., 27:1 for young, human NP vs. 5:1 for articular cartilage at the protein level) (Clouet et al. 2009; Minogue et al. 2010a; Mwale, Roughley, and Antoniou 2004). Using chondrocyte markers to characterize NP-differentiated stem cell is somewhat an oversimplification, and it is therefore difficult to conclude on the true efficacy of the proposed differentiation protocols. Accordingly, recent efforts have been undertaken to identify more specific markers of healthy NP cells. So far, no specific marker has been found, but immunohistological analyses have shown that young, human NPs exhibit high expression of cytokeratin-8/-18/-19 (Rutges et al. 2010; Stosiek, Kasper, and Karsten 1988; Weiler et al. 2010). Microarray investigations confirmed that these markers are much highly expressed in NP than in articular cartilage or in AF, as described in Table 4.5. Interestingly, these studies also revealed a high expression of Brachyury (T) in NP cells, an unequivocal marker of a notochordal origin. Table 4.5 discloses the recommendations for the phenotyping of young, healthy NP cells established in 2015 by the Spine Research Interest Group at the 2014 Annual ORS Meeting (Risbud et al. 2015).
Circulating Tumor Cells in Individualizing Breast Cancer Therapy
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
James M. Reuben, Massimo Cristofanilli
The only assay approved by the U.S. Food and Drug Administration is the CellSearch™ system (Veridex, LLC, Warren, New Jersey, U.S.). With this assay, a small sample of peripheral blood is allowed to react with ferrofluids coated with antibodies to EpCAM. Next, the sample is processed through a magnetic field to retain the EpCAM-positive cells, while the EpCAM-negative cells, primarily of hematopoietic origin, are eluted from the column and discarded. Thereafter, the enriched EpCAM-positive cells are allowed to react with the nucleic acid dye 4',6-doamidino-2-phenylindole (DAPI), monoclonal antibodies specific for leukocytes (anti-CD45 antibodies conjugated with allophycocyanin), and epithelial cells (phycoerythrin-conjugated antibodies to cytokeratin 8, 18, and 19) and analyzed by the CellSpotter™ Analyzer (Veridex). The CellSpotter Analyzer is a semiautomated fluorescence-based microscopy system that enables computer-generated reconstruction of cellular images. The analyzer interrogates each cell image to determine if it meets the very stringent requirements of an algorithm to be classified as a CTC. The algorithm insures that a CTC expresses EpCAM and not leukocyte lineage-specific antigens (represented by CD45), exhibits cytoplasmic expression of cytokeratin, and contains a nucleus that binds DAPI. Absence of any of these characteristics disqualifies a cell image as a CTC. In identifying CTCs, the procedure identifies cell objects that possess some, but not all, of the required characteristics to be a CTC and are labeled as “unclassified” objects (24). The stringent criteria of CellSearch for identifying a CTC are laudable; however, the merits of the assay continue to be debated as it minimizes the scientific or clinical significance of unclassified objects.
Histopathological evaluation of prostate specimens after thermal ablation may be confounded by the presence of thermally-fixed cells
Published in International Journal of Hyperthermia, 2019
Mikael Anttinen, Eemil Yli-Pietilä, Visa Suomi, Pietari Mäkelä, Teija Sainio, Jani Saunavaara, Lauri Eklund, Roberto Blanco Sequeiros, Pekka Taimen, Peter J. Boström
Specific to prostate tissue, two other in vivo studies and one in vitro study have reported thermally-fixed cells in human prostates after thermal ablation, and one additional in vivo study reported findings in canine prostates. In both in vivo human studies, cytokeratin 8 staining was utilized for detecting non-viable dead tissue [16,36]. Van Leenders et al. [16] demonstrated an apparent concordance between cytokeratin 8-negative prostate tissue inside ablated area and ultrastructural electron microscopy changes consistent with necrosis. Based on our results and the conclusions of these studies, cytokeratin 8, as detected by Cam5.2 antibody, appears more sensitive for detection of necrosis than H&E staining, identifying cells that are non-viable despite retaining normal morphologic features on H&E. Following transurethral ultrasound ablation in canine prostates, Boyes et al. [17] observed a TFZ located in the central area of the CNZ where the highest temperature is likely to occur, and more prominent when large target boundaries result in faster temperature rise and higher temperatures enabling formation of thermal fixation. In our study, a distinct TFZ was distinguishable in only one patient, but was similarly located within the CNZ in the region with the highest maximum temperature. This patient also had the most rapid temperature rise among the six study patients, possibly related to a large intended treatment volume as suggested by Boyes et al. [17].
Optimizing cancer immunotherapy: Is it time for personalized predictive biomarkers?
Published in Critical Reviews in Clinical Laboratory Sciences, 2018
Milena Music, Ioannis Prassas, Eleftherios P. Diamandis
Proteomics is the large-scale study of proteins, encompassing their abundance, function, structure and interactions with other proteins and molecules [5]. There are several well-established methods of screening for autoantibody responses in cancer patients undergoing immunotherapy. An early example of the use of proteomics to efficiently screen for autoantibodies was demonstrated by Canelle et al. [68]. The study presented a method for screening and identifying the antigens recognized by autoantibodies in patients with breast cancer and in healthy volunteers. A combination of two-dimensional gel electrophoresis, image analysis and mass spectrometry was performed to identify antigens that elicited a humoral immune response in tested sera. These antigens included cytokeratin 8 and cytokeratin 18, which have previously been shown to induce autoantibody production in patients with hepatocellular carcinoma. One of the observations made in the study was that human serum contains IgG autoantibodies that are independent of cancer status and are highly conserved between individuals.
Tumor-infiltrating lymphocytes from human prostate tumors reveal anti-tumor reactivity and potential for adoptive cell therapy
Published in OncoImmunology, 2019
Sharon Yunger, Assaf Bar El, Li-at Zeltzer, Eddie Fridman, Gil Raviv, Menachem Laufer, Jacob Schachter, Gal Markel, Orit Itzhaki, Michal J Besser
From patient PS-002 onwards, we tried to establish primary prostate cancer cultures. Of 172 initiated fragments, we observed an adherent monolayer of outgrowing cells with typical morphological characteristics of epithelial cells in 85 fragments (49%) (Supplementary Fig. S6). Interestingly, 55 of 85 (64%) epithelial cell containing cultures gave also rise to TIL (Supplementary Table S4). Primary prostate cancer cultures were grown with keratinocyte serum-free medium (KSFM) supplemented with epidermal growth factor (EGF) and bovine pituitary extract (BPE) combined with poly-D-lysine or collagen type I coated plates. Prostate cancer cultures were established from seven of seven patients (PS-002-008). The tumor cells grew for 3 to 4 passages. Phenotype characterization of the cells showed the absence of the fibroblasts marker CD90 and high expression of the epithelial markers cytokeratin 5 (CK5, basal marker, 81%) and cytokeratin 8 (CK8, luminal marker, 91%). In most PCa cultures, CK5 and CK8 were co-expressed (above 80%) indicating an intermediate phenotype.30 Prostatic origin was verified by the expression of prostate-specific membrane antigen (PSMA) and androgen receptor (AR). Representative flow cytometric plots are illustrated in Figure 2a and data summarized for all patients in Figure 2b–d. Due to the presence of tumor cells in the resected tissues (Supplementary Fig. S2), one can assume that the obtained cultures are carcinoma cells. High CK5 and CK8 expressions were described as markers of malignant cells28,34,35 although no specific markers exists, which definitively distinguish between tumor cells and non-tumor prostate epithelium.