Моlecular mechanisms of initiation of carcinogenesis in the testis.

In this review, literature data on the study of precancerous changes in testicular tissue and molecular changes, as well as the influence of environmental factors that can initiate carcinogenesis, were analyzed and summarized for the future determination of early diagnosis of germ cell tumors of the testis and the development of preventive measures. The review also discusses the significant new changes presented in the Fourth Edition of the World Health Organization Classification of Urogenital Tumors, published in 2016, and modern concepts of the etiology and pathogenesis of these diseases. Among the environmental factors that can initiate carcinogenesis, the most noteworthy are the biological effects of low doses of ionizing radiation, such as the effect of radiation-induced genome instability, which increases the risk of carcinogenesis, the "bystander effect", and chronic oxidative stress. Disruption of ubiquitin-proteasomal proteolysis, impaired molecular-level components of the blood-testis barrier, and impaired regulatory action of TGF-ß on the cell cycle can play a crucial role in the pathogenesis of male infertility and the initiation of carcinogenesis in the testis. The effect of low doses of ionizing radiation as an additional etiological factor leads to changes in the structural, as well as molecular, components of the testis, including epigenetic changes, which can be characterized as environmental pathomorphosis, which leads to impaired spermatogenesis and increased risk of malignancy. Summarizing the literature review data, we can state that patients with blocked spermatogenesis, in which atypical germ cell neoplasia in situ cells are detected in testicular tissue, constitute a group at increased risk of testicular carcinogenesis. The presence of additional etiological factors, such as chronic low doses of ionizing radiation, can initiate the progression of carcinogenesis in the testicle.

[IMMUNOHISTOCHEMICAL EXPRESSION OF UBIQUITIN PROTEIN IN PERITUMORAL TISSUE OF PATIENTS WITH TESTICULAR GERM CELL TUMORS].

For the purpose of definition of features immunohistochemical expression of protein Ubiquitin in peritumoral testicular tissue, which can be characterised as precancerous changes, the 40 patients with testicular germ cell tumors are investigated. In peritumoral testicular tissue in patients with disturbance of spermatogenesis. which make 95 %, it is taped: intensifying in seminiferous tubules of ubiquitination processes, testifying about intensive proteolysis of considerable quantity of the damaged intracellular proteins, occurrence of atypical germ cells (TIN), which differ from normal spermatogenesis cells authentically lower of nuclear and cytoplasmatic expression of protein Ubiquitin, and also disturbance of ubiquitination processes in Leydig cells in the form of intensifying of cytoplasmatic expression and total disappearance of nuclear expression of protein Ubiquitin. The received results testify to the important role of structural and functional disturbances of ubiquitin-proteolysis system components at the initial stages of testicular tissue carcinogenesis.

[Changes of peritumoral testicular tissue in patients with germ cell tumors].

For the purpose of definition of characteristic morphological changes of testicular tissue which to be surveyed as precancerous, the peritumoral tissue at 40 patients with testicular germ cell tumors (TGCT) which has been spent orchiectomy is investigated and the diagnosis according to classification TNM is established. In peritumoral tissue in 95% patients with testicular germ cell tumors disturbance of spermatogenesis, characteristic for the secretory form of male infertility, are taped. Occurrence of atypical germ cells (TIN) in semen tubules, which were defined in 60% of cases, and overexpressed hyperplasia of Leydig cells of interstition, defined in 82.5% of cases--the typical changes of peritumoral testicular tissue which can be characterised as precancerous changes. Patients with the secretory form of male infertility whith atypical germ cells (TIN) in semen tubules and the overexpressed hyperplasia of Leydig cells, make hight risk group of development of testicular cancer and demand a dispensary observation.

Microvessel density is high in clear-cell renal cell carcinomas of Ukrainian patients exposed to chronic persistent low-dose ionizing radiation after the Chernobyl accident.

During the 25-year period subsequent to the Chernobyl accident, the morbidity of malignant renal tumors in Ukraine has increased from 4.7 to 10.7 per 100,000 of the total population. Recent studies of our group have shown that increases in morbidity, aggressiveness, and proliferative activity of renal cell carcinomas (RCCs), especially clear-cell renal cell carcinoma (CCRCC), in Ukrainian patients continuously inhabiting the radio-contaminated areas could be explained by specific molecular changes influenced by the so-called "chronic persistent low-dose ionizing radiation" (CPLDIR) exposure. This study aimed to examine the role of angiogenesis in CCRCC carcinogenesis associated with CPLDIR in patients living more than 20 years in cesium 137 ((137)Cs) contaminated areas after the Chernobyl accident in Ukraine. Paraffin-embedded specimens of 106 CCRCs were studied: Control cases were 18 tumors from Spanish patients (group 1), 25 tumors from Ukrainian patients from so-called clean areas without known radio-contamination (group 2), and 63 tumors from Ukrainian patients from radio-contaminated areas (group 3). For intratumoral microvessel density (MVD) determination, anti-CD31 antibody was used. A computerized image analysis program was used to quantitatively calculate the vascular density. Seventy-three percent of group 3 and 72 % of group 2 CCRCCs displayed the highest MVD. A striking increase in MVD was seen in group 3 CCRCCs, in comparison with groups 1 and 2 (p < 0.001). The majority of the hot spot vessels in group 3 was poorly differentiated. Moreover, MVD values for total vessels as well as for capillaries and tumor grade were strongly correlated. When we compared only tumor-node-metastasis tumor stages I and II, the differences remained statistically significant (p < 0.1). The ratio of the average total vessels and capillaries in the Ukrainian groups combined was 1.65:1 in comparison to the Spanish group. Our results provide evidence that CPLDIR exposure increases MVD (particularly capillary) in CCRCCs and is associated with a higher histological grade.

Correlation between histological type and immunohistochemical profile of prostate cancer and gleason scale gradation.

AIM: To evaluate the characteristics of prostate cancer (PC) morphogenesis, taking into consideration the role of proliferation and apoptosis in tumor cells. METHODS: p53, p16INK4a, Bcl-2 and Ki-67 proteins expression was analyzed by immunohistochemistry in paraffin embedded sections of biopsy specimens from PC patients. The level of tissue immunoreactivity was evaluated by semi-quantitative method with estimation of 100% colored cells content over 1000 cells in one specimen. Patients were divided into three groups in accordance to Gleason scale gradation: group 1 - with Gleason scale < 5 (n = 13); group 2 - with Gleason scale > 5 and < 8 (n = 8); group 3 - with the highest Gleason scale > 8 (n = 6). RESULTS: Upon histological examination of prostate biopsy specimens, it was found that in the first group in 6 out of 13 (46%) cases small acinic cell PC developed on the background of chronic prostatitis with PIA (proliferative inflammatory atrophy) locus, frequently in combination with prostatic intraepithelial neoplasia (PI) locus. Hyperchromic epithelial cells in PIA locus were characterized by nuclear expression of p53 and Ki67 proteins, and cytoplasmic expression of Bcl-2. The precancerous foci in the PIN and PIA in the biopsy specimens of the second group of PC patients were found in 2 out of 8 (25%) cases of large and small acinic cell adenocarcinoma observations. The expression level of p53, p16INK4a, Bcl-2 proteins and especially Ki67 protein adequately increased in tumors of group 2 in comparison with group 1. Group 3 comprised of patients with Gleason scale > 8, predominantly solid structures or scirrhus of PC, which were characterized by the highest nuclear expression of p53, p16INK4a and Ki-67, and also by overexpression of cytoplasmic Bcl-2. CONCLUSIONS: Obtained results showed the direct correlation between patients' Gleason scale, and the expression level of p53, p16INK4a, Bcl-2 proteins and, particularly, Ki67 marker of proliferating cells in PC tumor cells.

[Clinical and immunological studies of the therapeutical effect of cytokines combined with 5-fluorouracil in metastatic kidney cancer]. / Kliniko-immunologicheskoe izuchenie lechebnogo vozdeistviia tsitokinov v sochetanii s 5-ftoruratsilom pri metastaziruiushchem rake pochki.

The authors present the results of a six-year clinicoimmunological study of a therapeutic effect of cytkins combined with 5-fluoruracyl in metastatic renal-cell carcinoma. Two therapeutic regiments have been used: rhIFN-a + 5-FU and rhIL-2 + RHifn-A + 5-FU. In cytokin-sensitive patients, both therapy protocols vrs conventional therapeutic alternatives (cytostatics, hormones, irradiation) have been shown to increase the frequency of achievement of remission by objective scoring and life span of the patients. There was an improvement in patients on having received the complex with IL-2 but a higher therapeutic effect appeared to be accompanied by substantial side effects. Recommendatory measures well-targeted to those patients with metastatic renal-cell carcinoma who are to be placed on cytokinotherapy are presented together with immunological indices to monitor the treatments administered and prognosis.

Prostatic intraepithelial neoplasia and apoptosis in benign prostatic hyperplasia before and after the Chernobyl accident in Ukraine.

The prevalence of prostatic intraepithelial neoplasia (PIN) in men who underwent surgery for benign prostatic hyperplasia (BPH) before and after the Chernobyl nuclear accident was studied. BPH samples were obtained by adenomectomy from 45 patients operated in 1984 before the accident (Group I), and 47 patients from the low contaminated Kiev City (Group II) and 76 from high contaminated area (Group III) operated between 1996 and 1998. Their BPH samples were examined histologically and immunohistochemically. The incidences of prostatic intraepithelial neoplasia (PIN) and high grade PIN (HGPIN) were 15.5 and 11.1% in Group I, 29.8 and 14.9% in Grpoup II, and 35. 5 and 19.7% in Group III. The difference between the incidences of PIN in Group I and III is significant (p<0.02). There was increased apoptosis in areas of PIN in Group II and III as compared to Group I (p<0.001). Since apoptosis has been shown to be associated with ionizing radiation and it is now found to be associated with PIN in patients diagnosed after the Chernobyl nuclear accident, this suggests that long-term low dose internal ionizing radiation potentially may cause prostate cancer.

[The immunohistochemical determination of p53 and of proliferating cell nuclear antigen in the epithelial nuclei of benign prostatic hyperplasia following the accident at the Chernobyl Atomic Electric Power Station]. / Imunohistokhimichne vyznachennia p53 ta proliferatyvnoho klitynnoho iadernohoantyhena v iadrakh epiteliiu dobroiakisnoï hiperplaziï peredmikhurovoï zalozy pislia avariï na ChAES.

With the purpose of studying into the morphogenesis and proliferous activity of the prostatic epithelium under a long-term exposure to low doses of ionizing radiation there have been conducted comparative histological and immunohistochemical (expression of p53 and proliferous cellular nuclear antigen-PCNA) investigations designed to study benign prostatic hyperplasia in patients living in those Ukraine territories affected by radionuclide contamination (group III), residents of Kiev (group II), and patients having been operated on before the Chernobyl accident, having constituted the control group I. It has been found out that the incidence of prostatic intraepithelial neoplasia (PIN), the level of nuclear expression of proteins p53 (in the PIN epithelium) and PCNA (in the epithelium of both benign prostatic hyperplasia and PIN) of patients in groups II and III are by far higher as compared with those in group I. The stroma of benign prostatic hyperplasia in patients of groups II and III was clearly different from that in the control group in that the former was characterized by apparent phenomena of hyalinosis, sclerosis, fibrosis, and extensive inflammatory infiltration, which changes can be explained by a long-term systematic exposure of prostatic tissue to low doses of ionizing radiation.

[The prognostic importance of the immunohistochemical study of protein p53 in transitional-cell bladder tumors]. / Prognosticheskoe znachenie immunogistokhimicheskogo issledovaniia belka p53 v perekhodno-kletochnykh opukholiakh mochevogo puzyria.

In an immunohistochemical investigation designed to study a mutated p53 protein in transitional-cell tumours (n = 44) we succeeded in identifying the presence of two types of transitional-cell tumours of human urinary bladder, such as p53 immunopositive and p53 immunonegative transitional-cell tumours. Thus, the results of the immunohistochemical investigation into the protein p53 were found out to directly correlate with the clinical course of transitional-cell tumours, that are held to be of great differential-diagnostic and prognostic significance.

[The morphogenic characteristics of human transitional-cell bladder tumors in Ukraine after the accident at the Chernobyl Atomic Electric Power Station]. / Osobennosti morfogeneza perekhodno-kletochnykh opukholei mochevogo puzyria cheloveka v Ukraine posle avarii na ChAES.

A study made into the morphogenesis of transitional cell tumors of human urinary bladder in 226 patients before the Chernobyl Nuclear Power Plant breakdown (I period of investigation) and 608 patients and majority of whom have been living in those regions of Ukraine affected by contamination with radionuclides as a result of the Chernobyl accident (II period of investigation) revealed decline in the prevalence of transitional cell papillomas, younger age of patients, greater incidence of invasive varieties of moderately differentiated, poorly differentiated (high-grade) transitional cell carcinoma, an unusual frequency of transitional cell carcinoma presenting with foci of multilayer planocellular metaplasia, lymphoidocellular infiltration, recurrent inflammation, foci of necrosis and hemorrhages.

[Plasma myoglobin and continuous hemofiltration in patients with rhabdomyolysis and acute kidney failure]. / Mioglobin plazmy i postoiannaia gemofil'tratsiia u bol'nykh s rabdomiolizom i ostroi pochechnoi nedostatochnost'iu.

Plasma and filtrate levels of myoglobin, specific antibodies and immune complexes were measured by radioimmunoassay or enzyme immunoassay in patients with rhabdomyolysis and acute renal failure on continuous hemofiltration (CHF). 14 of them had crush syndrome, 7 had other forms of rhabdomyolysis. 11 patients died (52%) because of the underlying disease or its complications. Rhabdomyolysis was associated with marked and long-lasting myoglobinemia. Early amputation and restoration of diuresis combined with CHF resulted in a fall in myoglobin content. CHF provided elimination of large amounts of myoglobin with filtrate. In rhabdomyolysis in all cases there appeared specific antibodies and circulating immune complexes.

[Ultrastructural changes in the hemato-testicular barrier in the pathogenesis of infertility]. / Izmeneniia ul'trastruktury gematotestikuliarnogo bar'era v patogeneze besplodiia.

An ejaculate and biopsy specimen of the testes from 162 patients with infertility of different etiology were studied. General regularities were established of development of pathospermy on the ultrastructural level in diseases of urogenital genesis. Development of infertility appear to be conditioned by consecutive interrelated processes of changes in the structure of different components of the hemato-testicular barrier. Changes in the capillary structure and primary with respect to disorders in other elements of the hemato-testicular barrier. Changes in the germinal system appear to occur secondary to the trophic abnormalities. In the hemomicrocirculatory bed of the testes, structural changes were at their greatest in the venular link.

[Apoptosis and cancer]. / Apoptoz i rak.

Apoptosis is a form of cell death in which the cell actively participates by providing molecules that are directly or indirectly involved in the process and by providing energy for the process to proceed. Apoptosis is a fundamental process which is controlled at the genetic and molecular levels, and as such can be analyzed, understood and manipulated. Cell death in which there is a chromatin condensation prior to damage of cytoplasmic organelles and to disruption of the cell membrane is apoptotic. Apoptosis plays an important role in the regulation of tissue growth, the inhibition of transformation in normal cell and in the control of cancer. A failure of blockade of the apoptotic mechanism is a prerequisite for cancer. Currently, it may not be practical to treat patients with antisense oligonucleotides that target antiapoptosis genes, although such treatments may become available in the future.

[Various immunohistochemical markers of precancer and variants of prostate cancer]. / Nekotorye immunokhistokhimicheskie markery predraka i razlichnykh variantov raka predstatel'noi zhelezy.

The prostates of 45 patients with benign hyperplasia, precancer and carcinoma of the prostate were studied using histochemical and immunohistochemical methods. The correlation between the expression of the prostatic specific antigen and prostatic acid phosphatase according to the histological type of tumor and the level of differentiation of the prostatic intraepithelial neoplasia (PIN) was established. PIN is connected with acinar glandular epithelium. It occupies an intermediate position between well differentiated non-invasive carcinoma and large-acinar carcinoma. Cytospecificity of these antigens may be used as markers of premalignant lesions for differential diagnosis of precancerous processes in the prostate. Immunohistochemical properties of PIN may be used for revealing groups of a high risk.

[Fibronectin and its significance in pyelonephritis]. / Fibronektin i ego znachenie pri pielonefrite.

Fibronectin levels were measured by enzyme immunoassay in 68 patients with pyelonephritis and 10 patients with chronic cystitis. The patients with chronic cystitis, acute and chronic non-obstructive pyelonephritis exhibited significantly high average blood fibronectin levels, whereas those with chronic obstructive pyelonephritis displayed the levels slightly different from those observed in healthy individuals. Hypofibronectinemia was detected in 23.3% of patients with chronic pyelonephritis. Preincubation of the neutrophils isolated from pyelonephritis patients with fibronectin increased the initially low phagocytic capacity without enhancing their metabolic activity. In experimental pyelonephritis, administration of exogenous fibronectin was demonstrated to contribute to a rapid bacterial elimination from the kidneys, to decrease the intensity of an inflammatory response, to prevent renal histostructural lesions, to enhance the functional activity of immunocompetent cells and to stabilize their membranes. The findings may serve the basis for using fibronectin in clinical practice as a promising agent to treat pyelonephritis.

[The morphological characteristics of the nephrotic form of glomerulonephritis in children at puberty]. / Morfologicheskaia kharakteristika nefroticheskoi formy glomerulonefrita u detei pubertatnogo vozrasta.

67 children (from 3 to 18 years of age) and 26 adults (19-30-year-olds) with nephrotic or mixed forms of glomerulonephritis (GN) are studied. The most severe and pleiomorphic forms of GN are found in children of 12 to 15 years of age: mesangio-capillary, mesangial proliferative, extracapillary proliferative GN with "half-moon" structures, sclerosing GN. Pronounced disturbances of the vimentine content and distribution in the basal lamina, of i.v. type collagen, fibronectin in combination with its damage under the influence of various immune deposits (particularly subepithelial ones) are found in these patients.

[Endoscopic removal of isolated gastrinoma of the duodenum after Billroth II gastric resection]. / Endoskopicheskoe udalenie izolirovannoi gastrinomy dvenadsatiperstnoi kishki posle rezektsii zheludka po Bil'rot-II.

Duodenal carcinoma is a rare disease and is encountered in no more than 10% of cases of the Zollinger-Ellison syndrome. The article discusses a rare case in which an isolated duodenal gastrinoma was removed endoscopically with subsequent recovery from the Zollinger-Ellison syndrome. Study of the serum gastrin concentration with provocative tests allowed the Zollinger-Ellison syndrome to be diagnosed and the radicality of duodenal gastrinoma removal to be controlled. Retrograde duodenoscopy conducted after resection of the gastric stump by the Billroth II method localized the source of hypergastrinemia and made possible radical removal of the duodenal gastrinoma, which was confirmed by normalization of the blood serum gastrin concentration. The work includes a brief literature reference on the subject.

[Alterations of nucleoli and nucleolar organizers in proliferative cystitis and transitional cell carcinoma of the urinary bladder]. / Izmeneniia iadryshek i iadryshkovykh organizatorov pri proliferativnykh tsistitakh i perekhodnokletochnom rake mochevogo puzyria.

The values of the nucleolar and granular rates as well as the number of Ag-granules were increased during the process of malignancy of transitional epithelium in proliferative chronic cystitis and transitional cell bladder carcinoma, including invasive tumours at both ultrastructural and light microscopic levels. The results may serve as additional criteria in the assessment of the risk of bladder mucosa malignancy and prognosis of the transitional cell bladder carcinoma.

[The clinico-morphological aspects of aspermia]. / Kliniko-morfologicheskie aspekty aspermii.

The clinico-morphologic, clinico-endocrinologic, and morpho-endocrinologic parallels were studied in 126 males with aspermia who underwent genitography and biopsy of the testes. On the basis of the findings, the structure of male sterility in aspermia was exactly identified and the differential diagnostic value of certain values was established; a correlation between the blood follitropine content and the degree of spermatogenesis inhibition in testicular aspermia was revealed in particular. Testosterone excreted in the urine and circulating in blood plasma is reduced by more than three times in this case, while the plasma estradiol level increases 1.5 times. Obturation aspermia accounts for 12.7% and testicular aspermia for 87.3% of all cases of aspermia. Further search for clinico-laboratory and laboratory differential diagnostic criteria in aspermia is necessary. The modern methods of treatment are ineffective.