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2. Germline variation at 8q24 and prostate cancer risk in men of European ancestry (vol 9, 4616, 2018)

Author

Matejcic, M, Saunders, EJ, Dadaev, T, Brook, MN, Wang, K, Sheng, X, Al Olama, AA, Schumacher, FR, Ingles, SA, Govindasami, K, Benlloch, S, Berndt, SI, Albanes, D, Koutros, S, Muir, K, Stevens, VL, Gapstur, SM, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Pashayan, N, Schleutker, J, Wolk, A, West, C, Mucci, L, Kraft, P, Cancel-Tassin, G, Sorensen, KD, Maehle, L, Grindedal, EM, Strom, SS, Neal, DE, Hamdy, FC, Donovan, JL, Travis, RC, Hamilton, RJ, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Bensen, JT, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Khaw, K-T, Cannon-Albright, LA, Pandha, H, Thibodeau, SN, Schaid, DJ, Wiklund, F, Chanock, SJ, Easton, DF, Eeles, RA, Kote-Jarai, Z, Conti, DV, Haiman, CA, Henderson, BE, Stern, MC, Thwaites, A, Guy, M, Whitmore, I, Morgan, A, Fisher, C, Hazel, S, Livni, N, Cook, M, Fachal, L, Weinstein, S, Freeman, LEB, Hoover, RN, Machiela, MJ, Lophatananon, A, Carter, BD, Goodman, P, Moya, L, Srinivasan, S, Kedda, M-A, Yeadon, T, Eckert, A, Eklund, M, Cavalli-Bjoerkman, C, Dunning, AM, Sipeky, C, Hakansson, N, Elliott, R, Ranu, H, Giovannucci, E, Turman, C, Hunter, DJ, Cussenot, O, Orntoft, TF, Lane, A, Lewis, SJ, Davis, M, Key, TJ, Brown, P, Kulkarni, GS, Zlotta, AR, Fleshner, NE, Finelli, A, Mao, X, Marzec, J, MacInnis, RJ, Milne, R, Hopper, JL, Aguado, M, Bustamante, M, Castano-Vinyals, G, Gracia-Lavedan, E, Cecchini, L, Stampfer, M, Ma, J, Sellers, TA, Geybels, MS, Park, H, Zachariah, B, Kolb, S, Wokolorczyk, D, Lubinski, J, Kluzniak, W, Nielsen, SF, Weisher, M, Cuk, K, Vogel, W, Luedeke, M, Logothetis, CJ, Paulo, P, Cardoso, M, Maia, S, Silva, MP, Steele, L, Ding, YC, De Meerleer, G, De Langhe, S, Thierens, H, Lim, J, Tan, MH, Ong, AT, Lin, DW, Kachakova, D, Mitkova, A, Mitev, V, Parliament, M, Jenster, G, Bangma, C, Schroder, FH, Truong, T, Koudou, YA, Michael, A, Kierzek, A, Karlsson, A, Broms, M, Wu, H, Aukim-Hastie, C, Tillmans, L, Riska, S, McDonnell, SK, Dearnaley, D, Spurdle, A, Gardiner, R, Hayes, V, Butler, L, Taylor, R, Papargiris, M, Saunders, P, Kujala, P, Talala, K, Taari, K, Bentzen, S, Hicks, B, Vogt, A, Hutchinson, A, Cox, A, George, A, Toi, A, Evans, A, Van der Kwast, TH, Imai, T, Saito, S, Zhao, S-C, Ren, G, Zhang, Y, Yu, Y, Wu, Y, Wu, J, Zhou, B, Pedersen, J, Lobato-Busto, R, Manuel Ruiz-Dominguez, J, Mengual, L, Alcaraz, A, Pow-Sang, J, Herkommer, K, Vlahova, A, Dikov, T, Christova, S, Carracedo, A, Tretarre, B, Rebillard, X, Mulot, C, Adolfsson, J, Stattin, P, Johansson, J-E, Martin, RM, Thompson, IM, Chambers, S, Aitken, J, Horvath, L, Haynes, A-M, Tilley, W, Risbridger, G, Aly, M, Nordstrom, T, Pharoah, P, Tammela, TLJ, Murtola, T, Auvinen, A, Burnet, N, Barnett, G, Andriole, G, Klim, A, Drake, BF, Borre, M, Kerns, S, Ostrer, H, Zhang, H-W, Cao, G, Lin, J, Ling, J, Li, M, Feng, N, Li, J, He, W, Guo, X, Sun, Z, Wang, G, Guo, J, Southey, MC, FitzGerald, LM, Marsden, G, Gomez-Caamano, A, Carballo, A, Peleteiro, P, Calvo, P, Szulkin, R, Llorca, J, Dierssen-Sotos, T, Gomez-Acebo, I, Lin, H-Y, Ostrander, EA, Bisbjerg, R, Klarskov, P, Roder, MA, Iversen, P, Holleczek, B, Stegmaier, C, Schnoeller, T, Bohnert, P, John, EM, Ost, P, Teo, S-H, Gamulin, M, Kulis, T, Kastelan, Z, Slavov, C, Popov, E, Van den Broeck, T, Joniau, S, Larkin, S, Esteban Castelao, J, Martinez, ME, Van Schaik, RHN, Xu, J, Lindstrom, S, Riboli, E, Berry, C, Siddiq, A, Canzian, F, Kolonel, LN, Le Marchand, L, Freedman, M, Cenee, S, Sanchez, M, and Commission of the European Communities

Subjects
Multidisciplinary Sciences, Science & Technology, MD Multidisciplinary, Science & Technology - Other Topics, PRACTICAL Consortium
Abstract

Correction to: Nature Communications; https://doi.org/10.1038/s41467-018-06863-1, published online 5 November 2018.

Published
2019

3. Macrophageal infiltration and microvessel density in laryngeal carcinoma: study of 52 cases

Author

POPOV, T.M., DIKOV, T., GORANOVA, T.E., STANCHEVA, G., KANEVA, R.P., TODOROV, S., STOYANOV, O., RANGACHEV, J., MARINOV, T., POPOVA, D.P., MITEV, V.I., and KONOV, D.

Subjects
Basic Research in Otorhinolaryngology, Macrophage count, Neovascularization, Pathologic, Microvessels, Humans, CD31, Laryngeal carcinoma, Neoplasm Recurrence, Local, Micro-vessel density, Prognosis, CD68, Immunohistochemistry, Laryngeal Neoplasms
Abstract

Angiogenesis is one of the six originally constituted hallmarks of cancer that has been extensively studied in the last two decades. The aim of our study is to assess the microvessel and macrophageal density in laryngeal carcinoma and its clinicopathological correlations. We immunohistochemically assessed microvessel density (CD34) and macrophage count (CD68) using microarray techniques and then looked for clinicopathological correlations. The mean micro-vessel density in the study group was 14.27 ± 12.92 vessels in a ×200 field with a mean macrophageal infiltration density of 5.19 ± 4.32. Median microvessel density was significantly higher in patients with metastasis than in patients without metastasis. Additionally, linear regression established that macrophageal infiltration density could predict microvessel density in laryngeal carcinoma. We found no association between either factor and recurrence rate or other clinical characteristics. Our study adds additional data to a problem that has been widely studied during the last two decades, even if controversies in this area still remain.L'angiogenesi è uno dei sei principali meccanismi alla base del cancro, ed è stato studiato approfonditamente negli ultimi 20 anni. L'obiettivo del presente studio è stato quello di determinare sia la densità capillare sia l'infiltrato macrofagico nei campioni di carcinoma laringeo e di determinarne la correlazione con gli aspetti clinici e patologici. Sia la densità capillare (CD34) sia l'infiltrato macrofagico (CD68) sono stati determinati con metodiche immunoistochimiche mediante microarray. Il nostro campione ha mostrato una densità capillare media di 14,27 ± 12,92 vasi su campo ingrandito a 200×, e l'infiltrato macrofagico medio è stato di 5,19 ± 4,32. La densità capillare si è dimostrata superiore nei pazienti metastatici. Inoltre uno studio di regressione lineare ha mostrato che l'entità dell'infiltrato macrofagico poteva predire la densità capillare del campione di carcinoma laringeo preso in esame. Non abbiamo invece individuato una correlazione fra ambo i fattori studiati e l'incidenza delle recidive o gli altri fattori clinici presi in esame. Il nostro studio aggiunge dati ad un problema che per quanto studiato a fondo negli ultimi 20 anni resta nella sostanza controverso.

Published
2015

4. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Author

Gusev, A, Shi, H, Kichaev, G, Pomerantz, M, Li, F, Long, HW, Ingles, SA, Kittles, RA, Strom, SS, Rybicki, BA, Nemesure, B, Isaacs, WB, Zheng, W, Pettaway, CA, Yeboah, ED, Tettey, Y, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Chokkalingam, AP, John, EM, Murphy, AB, Signorello, LB, Carpten, J, Leske, MC, Wu, S-Y, Hennis, AJM, Neslund-Dudas, C, Hsing, AW, Chu, L, Goodman, PJ, Klein, EA, Witte, JS, Casey, G, Kaggwa, S, Cook, MB, Stram, DO, Blot, WJ, Eeles, RA, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Southey, MC, Fitzgerald, LM, Gronberg, H, Wiklund, F, Aly, M, Henderson, BE, Schleutker, J, Wahlfors, T, Tammela, TLJ, Nordestgaard, BG, Key, TJ, Travis, RC, Neal, DE, Donovan, JL, Hamdy, FC, Pharoah, P, Pashayan, N, Khaw, K-T, Stanford, JL, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Maier, C, Vogel, W, Luedeke, M, Herkommer, K, Kibel, AS, Cybulski, C, Wokolorczyk, D, Kluzniak, W, Cannon-Albright, L, Teerlink, C, Brenner, H, Dieffenbach, AK, Arndt, V, Park, JY, Sellers, TA, Lin, H-Y, Slavov, C, Kaneva, R, Mitev, V, Batra, J, Spurdle, A, Clements, JA, Teixeira, MR, Pandha, H, Michael, A, Paulo, P, Maia, S, Kierzek, A, Conti, DV, Albanes, D, Berg, C, Berndt, SI, Campa, D, Crawford, ED, Diver, WR, Gapstur, SM, Gaziano, JM, Giovannucci, E, Hoover, R, Hunter, DJ, Johansson, M, Kraft, P, Le Marchand, L, Lindstrom, S, Navarro, C, Overvad, K, Riboli, E, Siddiq, A, Stevens, VL, Trichopoulos, D, Vineis, P, Yeager, M, Trynka, G, Raychaudhuri, S, Schumacher, FR, Price, AL, Freedman, ML, Haiman, CA, Pasaniuc, B, Cook, M, Guy, M, Govindasami, K, Leongamornlert, D, Sawyer, EJ, Wilkinson, R, Saunders, EJ, Tymrakiewicz, M, Dadaev, T, Morgan, A, Fisher, C, Hazel, S, Livni, N, Lophatananon, A, Pedersen, J, Hopper, JL, Adolfson, J, Stattin, P, Johansson, J-E, Cavalli-Bjoerkman, C, Karlsson, A, Broms, M, Auvinen, A, Kujala, P, Maeaettaenen, L, Murtola, T, Taari, K, Weischer, M, Nielsen, SF, Klarskov, P, Roder, A, Iversen, P, Wallinder, H, Gustafsson, S, Cox, A, Brown, P, George, A, Marsden, G, Lane, A, Davis, M, Tillmans, L, Riska, S, Wang, L, Rinckleb, A, Lubiski, J, Stegmaier, C, Pow-Sang, J, Park, H, Radlein, S, Rincon, M, Haley, J, Zachariah, B, Kachakova, D, Popov, E, Mitkova, A, Vlahova, A, Dikov, T, Christova, S, Heathcote, P, Wood, G, Malone, G, Saunders, P, Eckert, A, Yeadon, T, Kerr, K, Collins, A, Turner, M, Srinivasan, S, Kedda, M-A, Alexander, K, Omara, T, Wu, H, Henrique, R, Pinto, P, Santos, J, Barros-Silva, J, and Consortium, PRACTICAL

Subjects
urologic and male genital diseases
Abstract

Although genome-wide association studies have identified over 100 risk loci that explain ~33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Published
2016

5. Extranodal marginal zone B-cell lymphoma arising in chronic myeloid leukaemia successfully treated with tyrosine kinase inhibitor: a case report

Author

Mihaylov, G, Varbanova, V, Stoeva, V, and Dikov, T

Subjects
hemic and lymphatic diseases, Case Report, respiratory tract diseases
Abstract

Background: Chronic myelogenous leukemia (CML) is a hematological malignancy that originates in an abnormal pluripotent bone marrow stem cell. CML is consistently associated with the expression of the BCR-ABL1 fusion gene, generated by the t(9;22) chromosomal translocation, thus creating the Philadelphia chromosome, a target for protein tyrosine kinase inhibitor (TKI) therapy. There is no published data, demonstrating increased risk for development of second cancers, associated with the exposure to TKIs.

Published
2016

6. FIRST REPORT OF CANINE MAMMARY GLAND GRANULAR CELL TUMOUR: CASE DESCRIPTION AND REVIEW OF THE LITERATURE.

Author

DIMOV, D., DIKOV, T., DIMITROVA, L., FILIPOV, C., and RAYCHEV, I.

Subjects
*MAMMARY glands, *LITERATURE reviews, *TUMORS, *ENOLASE, *CELLS
Abstract

The case of a 5-year-old intact female Pitbull Terrier with a granular cell tumour (GCT) of the mammary gland is presented. The dog was admitted for surgical removal of a non-painful lump assumed to be a fibroadenoma. Histological and immunohistochemical findings leading to the diagnosis consisted of polygonal tumour cells with well-defined cell borders and granular cytoplasm, staining positively with neuron-specific enolase (NSE) and protein S100 and negatively for cytokeratin AE1-AE3. Some important points in the diagnostic and therapeutic approach to this uncommon neoplasm are discussed. To our best knowledge this is the first case of such tumour in the mammary gland described in the veterinary literature. [ABSTRACT FROM AUTHOR]

Published
2019
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18. Unraveling the Complex Molecular Interplay and Vascular Adaptive Changes in Hypertension-Induced Kidney Disease.

Author

Gaydarski L, Dimitrova IN, Stanchev S, Iliev A, Kotov G, Kirkov V, Stamenov N, Dikov T, Georgiev GP, and Landzhov B

Abstract

Angiogenesis, the natural mechanism by which fresh blood vessels develop from preexisting ones, is altered in arterial hypertension (AH), impacting renal function. Studies have shown that hypertension-induced renal damage involves changes in capillary density (CD), indicating alterations in vascularization. We aimed to elucidate the role of the apelin receptor (APLNR), neuronal nitric oxide synthase (nNOS), and vascular endothelial growth factor (VEGF) in hypertension-induced renal damage. We used two groups of spontaneously hypertensive rats aged 6 and 12 months, representing different stages of AH, and compared them to age-matched normotensive controls. The kidney tissue samples were prepared through a well-established protocol. All data analysis was conducted with a dedicated software program. APLNR was localized in tubular epithelial cells and the endothelial cells of the glomeruli, with higher expression in older SHRs. The localization of nNOS and VEGF was similar. The expression of APLNR and nNOS increased with AH progression, while VEGF levels decreased. CD was lower in young SHRs compared to controls and decreased significantly in older SHRs in comparison to age-matched controls. Our statistical analysis revealed significant differences in molecule expression between age groups and varying correlations between the expression of the three molecules and CD.

Published
2024
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19. Death Following Methyl Alcohol Intoxication: Gross Autopsy and Histological Findings.

Author

Mileva B, Dikov T, Goshev M, Georgieva M, Tsranchev II, Angelov M, Alexandrov A, Ateriya N, and Ivanova V

Abstract

Methanol, or wood alcohol, is a clear liquid with a weak odor, slightly sweeter than ethanol, which is easily accessible. The last makes it a product of choice for intentional self-harm, severe intoxication, or even suicide. Accidental ingestion and homicidal usage are not exclusions. We present and discuss the case of a man in his 20s who was in continuous alcoholic intoxication until he finally abused with methanol and was admitted to a hospital, where he died six days later. When it comes to intoxication, there are often no apparent findings that could help in determining the cause and manner of death. The last is especially important in cases of delayed death when the toxicology results are negative., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Mileva et al.)

Published
2024
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20. Death Following a Skiing Incident: Severe Exsanguination Due to Rupture of the Left Renal Artery.

Author

Mileva B, Goshev M, Dikov T, Georgieva M, Valcheva M, Tsranchev II, Alexandrov A, and Ivanova V

Abstract

With the growing popularity of winter sports, it is necessary to pay more attention to the types of traumatic injuries that a person can sustain in various incidents related to their practice. We present a case in which an adult man died as a result of a collision with a tree while skiing. Although the deaths are associated with different types and severity of craniocerebral injuries in the majority of the cases, here we are dealing with an abdominal injury with rupture of the stomach, pancreas, and left renal artery. The exact localization of the resulting traumatic injuries and the mechanism of their occurrence were examined. Both macroscopic autopsy findings (gross pathology) and histologically proven ones are presented and described. Presenting this case, we want to raise awareness of the different types of injuries received while skiing, as well as to emphasize the possibility of death in the absence of visible external injuries over the victim's body., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Mileva et al.)

Published
2024
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21. Mixed Eccrine Cutaneous Tumor with Folliculo-Sebaceous Differentiation: Case Report and Literature Review.

Author

Kisova D, Dikov T, Ivanova V, Stoyanov H, and Yordanova G

Subjects
Female, Humans, Middle Aged, Biopsy, Cell Differentiation, Confusion, Skin Neoplasms diagnosis, Adenoma, Pleomorphic
Abstract

Background/Introduction: Cutaneous mixed tumor is a rare benign neoplasm that exhibits a wide range of metaplastic changes and differentiation in the epithelial, myoepithelial, and stromal components, which is often confused with various other skin lesions. Case report: We present an unusual case of a 58-year-old woman with a mixed tumor of the upper lip, previously misdiagnosed as adnexal carcinoma on a preoperative biopsy. The excision biopsy shows a well-circumscribed lesion composed of various cells and structures featuring folliculo-sebaceous differentiation embedded in a prominent chondromyxoid stroma. The immunohistochemical study proves the various lineages of differentiation and classifies the neoplasm as the less common eccrine subtype of cutaneous mixed tumor. Discussion: The common embryologic origin of the folliculo-sebaceous apocrine complex leads to a great histological variety of cellular components of mixed tumors and the formation of structures that resemble established types of adnexal neoplasms, which could be a diagnostic pitfall, especially on a small incision biopsy.

Published
2023
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23. The potential role of mast cells and fibroblast growth factor-2 in the development of hypertension-induced renal damage.

Author

Stanchev S, Landzhov B, Kotov G, Stamenov N, Dikov T, and Iliev A

Subjects
Animals, Blood Pressure physiology, Collagen metabolism, Hypertension metabolism, Immunohistochemistry, Male, Rats, Rats, Inbred SHR, Fibroblast Growth Factor 2 metabolism, Hypertension complications, Kidney metabolism, Kidney pathology, Mast Cells metabolism
Abstract

Hypertension-induced renal injury is a multifactorial process which plays a crucial role in the development of chronic kidney disease. Multiple studies have demonstrated that interstitial rather than glomerular changes correlate better with renal functional capacity. Recent evidence indicates that mast cells and cell signaling proteins such as fibroblast growth factor-2 may contribute to the progression of interstitial changes under hypertensive conditions. The aim of our study was to determine the localization of mast cells in the renal cortex and report on the changes in their number, to analyze the distribution of fibroblast growth factor-2, to assess the extent of renal fibrosis and to evaluate renal damage and correlate it with the changes in the number of mast cells in a model of hypertension-induced renal injury by comparing two age groups of spontaneously hypertensive rats. We used 6- and 12-month-old animals. A light microscopic study was conducted on sections stained with hematoxylin and eosin, periodic acid-Schiff stain, Mallory's trichrome method and toluidine blue. For the immunohistochemical study we used monoclonal antibodies against mast cell tryptase and fibroblast growth factor-2 and a polyclonal antibody against c-kit. The expression of fibroblast growth factor-2 was assessed semi-quantitatively. The number of mast cells was evaluated on toluidine blue-, tryptase- and c-kit-stained sections, as well as double-stained sections and a comparative statistical analysis with the Mann-Whitney test was conducted between the two age groups. Our results showed that mast cells were located mainly in the peritubular and perivascular areas and were absent in the region of the renal corpuscles. Their number increased significantly in 12-month-old animals. Immunostaining for tryptase, c-kit and double staining for both molecules yielded identical results. The immunohistochemical expression of fibroblast growth factor-2 increased in the kidneys of older animals, as did the percentage of collagen fibers. In addition, we described more severe renal damage in 12-month-old spontaneously hypertensive rats and noted a positive correlation in both age groups between the number of mast cells on the one hand and glomerular sclerosis index and tubulointerstitial damage index, on the other. The results obtained in the present study support the pivotal role of mast cells in the development of hypertension-induced kidney damage., Competing Interests: Declarations of Competing Interest None., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Published
2020
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24. Cultured Cells Isolated from CNS Indolent B-Cell Lymphoma Have Characteristics of Mesenchymal Stem Cells: A Clinical Case and Scientific Research.

Author

Tumagelova-Yuzeir K, Ivanova-Todorova E, Naydenov E, Velikova T, Krasimirova E, Belemezova K, Dikov T, Penkov M, Nachev S, Genova M, and Kyurkchiev D

Abstract

The case report presented here describes the culturing and characterization of mesenchymal stem cells (MSCs) isolated from a primary indolent B-cell lymphoma, located in the CNS of an immunocompetent patient. The presence of such cells in the tumor mass can further elucidate the pathogenesis of the disease and reveal possible future approaches for its treatment. We present a case report of a 61-year-old immunocompetent woman who had an episode of confusion with numbness in the right leg and the right arm, slurred and dysarthric speech and urine incontinence. The peripheral blood tests were normal. The neurological examination demonstrated a latent hemi-paresis of the right side, aphasia, discrete hypertension and bradypsychia. The ophthalmologic examination revealed left quadranopsia. Computed tomography and magnetic resonance imaging of the brain showed a 3.5 × 2.9 cm infiltrative neoplastic lesion involving the left temporal parenchyma. The morphological features and the immunophenotyping of the lymphoid cell composition were consistent with low-grade (indolent) B-lymphocyte non-Hodgkin's lymphoma of CNS. Cells, isolated from the resected tumor mass, were cultured in vitro in medium containing 10% fetal bovine serum (FBS) and characterized by their morphology, growth, phenotype, clonogenicity and osteogenic differentiation. It was apparent that the cultured cells isolated from the indolent B- cell lymphoma located in the CNS have the basic characteristics of mesenchymal stem cells. The presence of MSCs is described for the very first time in such type of tumor. The well-known immunosuppressive properties of the MSCs may represent another mechanism favouring the tumor growth.

Published
2018

25. Diffuse Xanthogranulomatous Cholecystitis: Master of Disguise.

Author

Neychev V, Ivanova V, Dikov T, and Todorov G

Abstract

A 67-year-old woman presented with clinical symptoms, radiological findings, and preoperative work-up highly suggestive of advanced stage IV carcinoma of the gallbladder (CG). An extended cholecystectomy with the excision of adjacent liver segments and loco-regional lymphadenectomy was performed. Final pathology results revealed diffuse xanthogranulomatous cholecystitis (XG) with ruptured Rokitansky-Aschoff sinuses with tumor-resembling adenomyosis without atypical or malignant cells. There was a reactive inflammatory and fatty degeneration of the adjacent hepatic tissue and a nonspecific inflammatory reaction of the enlarged periportal lymph nodes. The main concern in the management of patients with mass-forming XG is that this benign condition shares strikingly similar clinical, imaging, biochemical, and intraoperative features with advanced CG, which has one of the poorest overall survival rates. Misdiagnosis is not uncommon, which causes significant distress for patients and their families and, in some cases, may result in erroneous treatment. Although the presence of some preoperative imaging findings and/or intraoperative frozen section biopsies may be helpful in suspecting XG, definitive diagnosis is usually delayed until the final pathology result that may come as a surprise. Increasing awareness of this rare, insidious disease will contribute to a better understanding of its biology and natural history and, eventually, help improve management., Competing Interests: The authors have declared that no competing interests exist.

Published
2018
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26. Histologic subtypes of ovarian carcinoma: selected diagnostic and classification problems in Bulgaria: is low hospital volume an issue?

Author

Ivanova V, Dikov T, and Dimitrova N

Subjects
Adenocarcinoma diagnosis, Adenocarcinoma pathology, Bulgaria, Female, Health Facility Size, Humans, Logistic Models, Middle Aged, Patient Care, Carcinoma diagnosis, Carcinoma pathology, Ovarian Neoplasms diagnosis, Ovarian Neoplasms pathology
Abstract

Purpose: To provide an overview of the morphologic subtypes of ovarian carcinomas in Bulgaria in relation to current healthcare organization using Bulgarian National Cancer Registry data. Further, we investigated hospital volume as a factor influencing the quality of care for patients with ovarian cancer., Methods: Bulgarian National Cancer Registry ovarian carcinoma data were retrieved (2009-2011) and distribution of histologic types was analyzed. Cases were divided and compared with respect to main treatment: no surgery, surgery at hospitals dealing with ≥30 ovarian cancer patients/year (high volume), and surgery at hospitals dealing with <30 ovarian cancer patients/year (low volume). We then estimated the odds of being diagnosed with adenocarcinoma and carcinoma not otherwise specified (NOS) vs specified morphologies (serous, endometrioid, clear cell, and mucinous), including age, grade, stage, and hospital volume, in a logistic regression model., Results: A total of 2,041 ovarian carcinomas were distributed as follows: serous 47.7%, mucinous 11.9%, endometrioid 5.8%, clear cell 1.8%, and adenocarcinoma and carcinoma NOS 32.5%. More than half of cancer patients (n = 1,100, 53.9%) were surgically treated in low-volume hospitals and they had a larger proportion of cases with adenocarcinoma and carcinoma NOS: 33.3%, in comparison with 24.0% in high-volume hospitals (p<0.0001). The odds of being diagnosed with unspecified morphology, assumed as a proxy of suboptimal quality of care, are higher for patients surgically treated in low-volume hospitals (odds ratio 1.50 [95% confidence interval 1.21-1.87]) compared with high-volume hospitals after adjustment for age, stage, and grade., Conclusions: The results of our study may serve policymakers and healthcare professionals when optimizing diagnosis and treatment of ovarian cancer in Bulgaria.

Published
2017
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27. A rare case with synchronous gastric gastrointestinal stromal tumor, pancreatic neuroendocrine tumor, and uterine leiomyoma.

Author

Arabadzhieva E, Yonkov A, Bonev S, Bulanov D, Taneva I, Vlahova A, Dikov T, and Dimitrova V

Subjects
Biomarkers, Tumor metabolism, Female, Gastrectomy, Gastrointestinal Stromal Tumors diagnostic imaging, Gastrointestinal Stromal Tumors metabolism, Gastrointestinal Stromal Tumors pathology, Humans, Hysterectomy, Immunohistochemistry, Intestinal Neoplasms diagnostic imaging, Intestinal Neoplasms metabolism, Intestinal Neoplasms pathology, Leiomyoma diagnostic imaging, Leiomyoma metabolism, Leiomyoma pathology, Middle Aged, Neoplasms, Multiple Primary diagnostic imaging, Neoplasms, Multiple Primary metabolism, Neoplasms, Multiple Primary pathology, Neuroendocrine Tumors diagnostic imaging, Neuroendocrine Tumors metabolism, Neuroendocrine Tumors pathology, Omentum surgery, Pancreas surgery, Pancreatic Neoplasms diagnostic imaging, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Stomach Neoplasms diagnostic imaging, Stomach Neoplasms metabolism, Stomach Neoplasms pathology, Tomography, X-Ray Computed, Ultrasonography, Uterine Neoplasms diagnostic imaging, Uterine Neoplasms metabolism, Uterine Neoplasms pathology, Gastrointestinal Stromal Tumors surgery, Intestinal Neoplasms surgery, Leiomyoma surgery, Neoplasms, Multiple Primary surgery, Neuroendocrine Tumors surgery, Pancreatic Neoplasms surgery, Splenectomy, Stomach Neoplasms surgery, Uterine Neoplasms surgery
Abstract

Background: Although gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, they comprise less than 1% of all gastrointestinal tumors. Neuroendocrine tumors (NET) of the gastro-enteropancreatic system are also rare, representing about 2% of all gastrointestinal neoplasms. Pancreatic localization of NET is extremely uncommon-these tumors are only 1-5% of all pancreatic cancers., Case Presentation: We describe an unusual case with triple tumor localization-a gastric tumor, a formation in the pancreas, which involves the retroperitoneal space, and a uterine leiomyoma. The exact diagnosis was confirmed with immunohistochemical study after surgical treatment of the patient. Distal pancreatic resection, splenectomy, partial gastrectomy, omentectomy, and hysterectomy were performed. The histological examination proved an epithelioid type of gastric GIST. Immunostaining showed focal positive expression of c-kit and no mitotic figures per 50 HPF. Histology of the pancreatic and retroperitoneal formation proved a well-differentiated NET with origin from the islets of Langerhans. The immunohistochemical study demonstrated co-expression of chromogranin A and synaptophysin., Conclusions: This is the fourth case published so far of a patient with synchronous pancreatic NET and gastric GIST. The main objective of the study is to present a unique case because we have not found any reports for coexistence of the described three types of neoplasm, as in our patient, and we hope that it will be valuable in the future investigations about the genesis, diagnosis, and treatment of these types of tumors.

Published
2016
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28. Extranodal marginal zone B-cell lymphoma arising in chronic myeloid leukaemia successfully treated with tyrosine kinase inhibitor: a case report.

Author

Mihaylov G, Varbanova V, Stoeva V, and Dikov T

Abstract

Background: Chronic myelogenous leukemia (CML) is a hematological malignancy that originates in an abnormal pluripotent bone marrow stem cell. CML is consistently associated with the expression of the BCR-ABL1 fusion gene, generated by the t(9;22) chromosomal translocation, thus creating the Philadelphia chromosome, a target for protein tyrosine kinase inhibitor (TKI) therapy.  There is no published data, demonstrating increased risk for development of second cancers, associated with the exposure to TKIs., Case Report: We report a case of a primary extranodal marginal zone B-cell lymphoma (EMZBCL), diagnosed in a 53-year-old woman with CML receiving treatment with TKI the preceding seven years. Both diagnoses were confirmed by cytological/histological examination. Regarding CML, complete hematological, cytogenetic, and molecular remission was achieved by imatinib therapy. Regarding EMZBCL complete remission with an anthracycline-based polychemotherapy was achieved, while the patient was on continuous treatment with imatinib. Currently, the patient is in major molecular response for CML (151 months) and also in complete remission for EMZBCL (60 months)., Conclusion: We report this case as we consider that any secondary neoplasia developing in patients treated with TKIs should be reported for assessment and further detailed analyzes. Hippokratia 2016, 20(3): 241-243.

Published
2016

29. A rare case of IgG4-related disease: a gastric mass, associated with regional lymphadenopathy.

Author

Bulanov D, Arabadzhieva E, Bonev S, Yonkov A, Kyoseva D, Dikov T, and Dimitrova V

Subjects
Autoimmune Diseases diagnosis, Biopsy, Female, Humans, Lymphadenopathy diagnosis, Middle Aged, Stomach Diseases diagnosis, Autoimmune Diseases immunology, Immunoglobulin G immunology, Lymph Nodes pathology, Lymphadenopathy immunology, Rare Diseases, Stomach Diseases immunology
Abstract

Background: IgG4-related disease (IgG4-RD) is a newly recognized disorder, characterized by massive IgG4+ lymphocyte and plasma cell infiltration, storiform fibrosis, causing enlargement, nodules or thickening of the various organs, simultaneously or metachronously. Involvement of the gastrointestinal tract is very rare and can be presented as a diffuse wall thickening or polyp or mass-like lesion. Up to now, there have been reported only a few cases of isolated gastric IgG4-RD., Case Presentation: We present an unusual case of IgG4-RD of the stomach with involvement of the regional lymph nodes, clinically manifested as a gastric cancer with related pyloric stenosis. The patient underwent distal gastrectomy, omentectomy and lymph node dissection. The postoperative serum IgG4 level was increased. The diagnosis was confirmed by immunohistochemical study., Conclusions: In the most of the reported cases there was not sufficient data about the regional lymph nodal status, although the majority of the patients had been operated with presumptive diagnosis of gastric neoplasm. Our case is rare and valuable because it presents a gastric IgG4-related lesion larger than all previously reported in literature, and IgG4-related lymphadenopathy, confirmed histologically, which contributes to better knowledge of the disease.

Published
2016
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30. Polymorphisms in androgen metabolism genes AR, CYP1B1, CYP19, and SRD5A2and prostate cancer risk and aggressiveness in Bulgarian patients.

Author

Kachakova D, Mitkova A, Popov E, Beltcheva O, Vlahova A, Dikov T, Christova S, Mitev V, Slavov C, and Kaneva R

Subjects
3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Aromatase, Case-Control Studies, Cytochrome P-450 CYP1B1, Genetic Predisposition to Disease, Genotype, Humans, Male, Membrane Proteins, Prostatic Neoplasms, Receptors, Androgen, Polymorphism, Genetic
Abstract

Background/aim: The aim of our study was to elucidate the role of polymorphisms in AR, CYP1B1, CYP19, and SRD5A2 genes for prostate cancer (PC) development in Bulgarian patients., Materials and Methods: We genotyped 246 PC patients and 261 controls (155 with benign prostate hyperplasia and 107 healthy population controls) using direct sequencing, PCR-RFLP, SSCP, and fragment analysis., Results: The allele and genotype frequencies of most of the studied variants did not differ significantly between cases and controls. Increased frequencies of the C/C genotype and C allele of rs1056837 in CYP1B1, and genotype 7/8 of the (TTTA)n repeat polymorphism in CYP19, were observed in patients in comparison with controls.The 8/9 and the 7/12 genotypes of (TTTA)n in CYP19 showed suggestive evidence for association with decreased prostate cancer risk and the risk for aggressive disease, respectively. The haplotype analysis revealed 2 CYP1B1 haplotypes associated with PC risk reduction., Conclusion: Some CYP1B1 haplotypes and genotypes of the CYP19 (TTTA)n repeat appeared to be associated with disease risk or aggressiveness in Bulgarian PC patients. In contrast, the SRD5A2 polymorphisms (V89L and (TA)n repeat), the CAG repeat in AR, and the Arg264Cys variant in CYP19A1 are most likely not implicated in prostate carcinogenesis.

Published
2016
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31. Relative quantitative expression of hypoxia-inducible factor-1α, -2α and -3α, and vascular endothelial growth factor A in laryngeal carcinoma.

Author

Popov TM, Goranova T, Stancheva G, Kaneva R, Dikov T, Chalakov I, Rangachev J, Konov D, Todorov S, Stoyanov O, and Mitev V

Abstract

The aim of the present study was to determine the relative quantitative expression of hypoxia-inducible factor (HIF)-1α, -2α and -3α, and VEGF-A in laryngeal carcinoma. A total of 63 patients with carcinoma of the larynx were enrolled in the study. Total RNA was isolated from fresh, frozen normal and tumor tissues of each patient, and quantitative polymerase chain reaction was performed. HIF-1α was upregulated in the majority of patients (44 patients; 69.84%). By contrast, only 7 (11.11%) patients from the whole group displayed HIF-2α overexpression, while the HIF-3α isoform was silenced in the majority of patients (48 patients, 76.19%). A small group of 5 (7.94%) patients exhibited significant overexpression of the HIF-3α isoform. VEGF-A expression was significantly higher (P<0.05) in patients with upregulated HIF-1α (2.72±1.41 RQ) compared with patients without upregulated HIF-1α (1.86±1.46 RQ). There was a moderate positive correlation between mRNA expression levels of HIF-1α and VEGF-A (r s =0.392; P<0.005). To the best of our knowledge, this study is first to report quantitative data with regard to the expression of all three HIF isoforms in malignant neoplasms. The findings suggest the existence of specific phenotypes of HIF expression in laryngeal carcinoma, where the HIF switch is absent.

Published
2015
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32. Combinations of serum prostate-specific antigen and plasma expression levels of let-7c, miR-30c, miR-141, and miR-375 as potential better diagnostic biomarkers for prostate cancer.

Author

Kachakova D, Mitkova A, Popov E, Popov I, Vlahova A, Dikov T, Christova S, Mitev V, Slavov C, and Kaneva R

Subjects
Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Diagnosis, Differential, Gene Expression Regulation, Neoplastic, Humans, Male, MicroRNAs genetics, Middle Aged, Prognosis, Prostatic Hyperplasia blood, Prostatic Hyperplasia diagnosis, Prostatic Hyperplasia genetics, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics, ROC Curve, Reverse Transcriptase Polymerase Chain Reaction, Young Adult, Biomarkers, Tumor blood, MicroRNAs blood, Prostate-Specific Antigen blood, Prostatic Neoplasms blood
Abstract

In the current study, expression levels of let-7c, miR-30c, miR-141, and miR-375 in plasma from 59 prostate cancer (PC) patients with different clinicopathological characteristics and two groups of controls: 16 benign prostatic hyperplasia (BPH) samples and 11 young asymptomatic men (YAM) were analyzed to evaluate their diagnostic and prognostic value in comparison to prostate-specific antigen (PSA). miR-375 was significantly downregulated in 83.5% of patients compared to BPH controls and showed stronger diagnostic accuracy (area under the curve [AUC]=0.809, 95% CI: 0.697-0.922, p=0.00016) compared with PSA (AUC=0.710, 95% CI: 0.559-0.861, p=0.013). Expression levels of let-7c showed potential to distinguish PC patients from BPH controls with AUC=0.757, but the result did not reach significance. Better discriminating performance was observed when combinations of studied biomarkers were used. Sensitivity of 86.8% and specificity of 81.8% were reached when all biomarkers were combined (AUC=0.877) and YAM were used as calibrators. None of the studied microRNAs (miRNAs) showed correlation with clinicopathological characteristics. PSA levels were significantly correlated with the Gleason score, tumor stage, and lymph node metastasis with Spearman correlation coefficients: 0.612, 0.576, and 0.458. In conclusion, the combination of the studied circulating plasma miRNAs and serum PSA has the potential to be used as a noninvasive diagnostic biomarker for PC screening outperforming the PSA testing alone.

Published
2015
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33. NPM1 Gene Type A Mutation in Bulgarian Adults with Acute Myeloid Leukemia: A Single-Institution Study.

Author

Balatzenko G, Spassov B, Stoyanov N, Ganeva P, Dikov T, Konstantinov S, Hrischev V, Romanova M, Toshkov S, and Guenova M

Abstract

Objective: Mutations of the nucleophosmin (NPM1) gene are considered as the most frequent acute myeloid leukemia (AML)-associated genetic lesion, reported with various incidences in different studies, and type A (NPM1-A) is the most frequent type. However, since most series in the literature report on the features of all patients regardless of the type of mutation, NPM1-A(+) cases have not been well characterized yet. Therefore, we evaluated the prevalence of NPM1-A in Bulgarian AML patients and searched for an association with clinical and laboratory features., Materials and Methods: One hundred and four adults (51 men, 53 women) were included in the study. NPM1-A status was determined using allele-specific reverse-transcription polymerase chain reaction with co-amplification of NPM1-A and β-actin and real-time quantitative TaqMan-based polymerase chain reaction. Patients received conventional induction chemotherapy and were followed for 13.2±16.4 months., Results: NPM1-A was detected in 26 (24.8%) patients. NPM1-A mutation was detected in all AML categories, including in one patient with RUNX1-RUNX1T1. There were no differences associated with the NPM1-A status with respect to age, sex, hemoglobin, platelet counts, percentage of bone marrow blasts, splenomegaly, complete remission rates, and overall survival. NPM1-A(+) patients, compared to NPM1-A(-) patients, were characterized by higher leukocyte counts [(75.4±81.9)x109/L vs. (42.5±65.9)x109/L; p=0.049], higher frequency of normal karyotype [14/18 (77.8%) vs. 26/62 (41.9%); p=0.014], higher frequency of FLT3-ITD [11/26 (42.3%) vs. 8/77 (10.4%); p=0.001], and lower incidence of CD34(+) [6/21 (28.8%) vs. 28/45 (62.2%); p=0.017]. Within the FLT3-ITD(-) group, the median overall survival of NPM1-A(-) patients was 14 months, while NPM1-A(+) patients did not reach the median (p=0.10)., Conclusion: The prevalence of NPM1-A mutation in adult Bulgarian AML patients was similar to that reported in other studies. NPM1-A(+) patients were characterized by higher leukocyte counts, higher frequency of normal karyotypes and FLT3-ITD, and lower incidence of CD34(+), supporting the idea that the specific features of type A mutations might contribute to the general clinical and laboratory profile of NPM1(+) AML patients.

Published
2014
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34. Evaluation of the clinical value of the newly identified urine biomarker HIST1H4K for diagnosis and prognosis of prostate cancer in Bulgarian patients.

Author

Kachakova D, Mitkova A, Popov E, Beltcheva O, Vlahova A, Dikov T, Hristova S, Mitev V, Slavov C, and Kaneva R

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Case-Control Studies, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Grading, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Prostate-Specific Antigen blood, Prostatic Hyperplasia genetics, Prostatic Hyperplasia urine, Prostatic Neoplasms genetics, Prostatic Neoplasms urine, Real-Time Polymerase Chain Reaction, Young Adult, Biomarkers, Tumor urine, DNA Methylation, Histones genetics, Promoter Regions, Genetic genetics, Prostatic Hyperplasia diagnosis, Prostatic Neoplasms diagnosis
Abstract

Purpose: Searching for diagnostic and prognostic biomarkers for prostate cancer (PC) is main public health priority. DNA methylation in body fluids is a stable, easily detectable and promising PC biomarker. The major advantages of urine-based assays are their noninvasive nature and the ability to monitor PC with heterogeneous foci. The aim of this study was to determine the diagnostic value of the recently identified candidate PC biomarker HIST1H4K., Methods: We investigated DNA methylation of HIST1H4K in urine samples from 57 PC patients, 29 controls with benign prostatic hyperplasia (BPH) and 50 young asymptomatic men (YAM) by MethyLight real-time PCR., Results: The frequency of HIST1H4K promoter hypermethylation significantly discriminated PC patients from YAM (AUC =0.763; 95% CI 0.672-0.839; p<0.0001), but did not show any statistical difference between PC patients and BPH controls (AUC=0.513, 95% CI 0.402-0.622; p=0.8255). HIST1H4K could not outperform the prostatic specific antigen (PSA) in our sample (AUC=0.785; 95% CI 0.679-0.870; p<0.0001). Methylation of HIST1H4K showed significant correlation with aging (r=0.5418; p<0.0001), but with no other clinicopathological characteristics., Conclusion: The results suggest that the promoter hypermethylation of HIST1H4K is rather due to aging than related to prostate carcinogenesis. To elucidate this observation analysis of larger samples is needed.

Published
2013

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