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.

Methylation pattern of the putative tumor-suppressor gene LRRC3B promoter in clear cell renal cell carcinomas.

The leucine rich repeat containing 3B (LRRC3B) gene is a putative tumor suppressor located on human chromosome 3 in the 3p24 region. LRRC3B is frequently altered in colon and gastric cancers and also in leukaemias. In this study we investigated the promoter region methylation as a possible mechanism of LRRC3B gene inactivation in clear cell renal cell carcinomas. We found that the LRRC3B gene promoter was methylated in 43% of clear cell renal carcinoma samples. However, no correlation between DNA methylation and LRRC3B expression was found.

[Task-orientated therapy (target-therapy) directed to patients with renal cell carcinoma].

Two main ways playing a cardinal role in the pathogenesis of metastatic renal cell carcinoma (mRCC) have been identified in recent years, they are following: 1) a way of the mutation of a gene suppressor VHL (Van-Hippel-Lindau), stimulating various types of tyrosine-kinases participating in the development of tumors; 2) mTOR way, where ramapycyn plays a leading role, which effect proliferation and angiogenesis of mRCC. This discovery enabled the development of a new generation of highly effective medications for target-therapy of mRCCC--tyrosine-kinases inhibitors (VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha/PDGFR-beta, Raf-kinases, etc.) sunitimab, sorafenib, pazopanib, axitinib, etc. and mTOR inhibitors--everolimus and temsirolimus as well as monoclonal neutralising antibody VEGF (bevasizumab). The review is devoted to the analysis of antitumor activity, patient tolerance and side effect of these preparations in the system therapy of patients with mRCC.

[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.

Radiation sclerosing proliferative atypical nephropathy of peritumoral tissue of renal-cell carcinomas after the Chernobyl accident in Ukraine.

After the Chernobyl accident, the morbidity of renal-cell carcinomas in Ukraine increased gradually from 4.7 to 7.5 per 100,000 of the total population. Cesium 137 (137Cs) is responsible for 80-90% of the internal radioactivity in people living in radiocontaminated areas of Ukraine, and 90% of 137Cs is eliminated through the kidneys. Histological and immunohistochemical study of proliferating cell nuclear antigen (PCNA) and K-ras protein was performed in peritumoral kidney tissues of 167 Ukrainian patients (groups I-III, according to varying degrees of internal exposure to radiation), and of 85 analog Spanish patients, as a control group. Our data showed in the majority of Ukrainian patients a radiation sclerosing proliferative atypical nephropathy (RSPAN) in association with an increase in the incidences of tubular epithelial nuclear atypia and carcinoma in situ (CIS). Areas of epithelial nuclear atypia and CIS of the cortex and medulla showed significant PCNA expression with means of extent as 12, 14, and 15% of stained nuclei in groups I, II, and III respectively. K-ras expression of the same areas occurred in 67, 87, and 85% of cases in groups I, II, and III respectively. The present study points to a strong relationship between the long term of low-dose radiation exposure of the Ukrainian population and the development of RSPAN as a possible precursor of malignancy. In addition, it confirms the possible initiator, promoter, or progressor role of chronic low-level radiation of renal human carcinogenesis in Ukraine.

Pathology and proliferative activity of renal-cell carcinomas (RCCS) and renal oncocytomas in patients with different radiation exposure after the Chernobyl accident in Ukraine.

During the 13-year period subsequent to the Chernobyl accident, the morbidity of malignant renal tumors in Ukraine has increased from 4. 7 to 7.5 per 100,000 of total population. Cesium 137 ((137)Cs) accounts for 90% of the incorporated radioactivity in the Ukrainian population, which has been exposed to long-term, low dose ionizing radiation and 90% of the more labile pool of ((137)Cs) is excreted via kidneys. The present study was performed to evaluate the histopathological features and the immunohistochemical status of proliferating cell nuclear antigen (PCNA) and K-ras in renal cell carcinomas (RCCs) of 236 Ukrainian patients (groups I to V), which represents a varying degrees of internal exposure to radiation and were operated in 2 different periods of time after the Chernobyl accident. The control group VI of 112 analog patients with RCCs was selected in Spain. The strong significant differences between the Ukrainian and Spanish groups were found in tumoral nuclear grade, in the percentage of sarcomatoid changes, the level of the peritumoral inflammatory response as well as in the peritumoral lesions. The dramatic increase of aggressivity and proliferative activity supported by strong PCNA and K-ras expression of RCCs from Ukrainian groups, associated with chronic radiation nephropathy of peritumoral kidney tissue, showed good correlation with the duration of radiation exposure and confirmed the influence of chronic but regular and sustained low dose of ionizing radiation on renal carcinogenesis of the Ukrainian population.

Increased oxidative stress with gene alteration in urinary bladder urothelium after the Chernobyl accident.

We have previously shown that bladder urothelium of people living in the cesium-137 ((137)Cs)-contaminated areas of Ukraine demonstrates accumulation of stable p53 and p53 mutational inactivation, preferentially through G:C to A:T transition mutations at CpG dinucleotides, with a codon 245 hot spot. In the present study, we analyzed immuno-histochemically the relationship between oxidative stress markers and over-expression of p53 and H-ras in urinary bladder urothelium from 42 men with benign prostatic hyperplasia. Bladder mapping biopsies were obtained from 15 patients from a highly radiocontaminated area (group I), 14 patients from the less contaminated city of Kiev (group II) and 13 patients as a control group from "clean" (without radiocontamination) areas of Ukraine (group III). Irradiation cystitis with multiple foci of severe dysplasia and carcinoma in situ were observed in 15 of 15 (100%, group I) and 9 of 14 (64%, group II) cases, with 4 small transitional-cell carcinomas incidentally detected in groups I and II. Markedly elevated levels of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) and 8-hydroxy-2;-deoxyguanosine (8-OHdG) were noted in these bladder urothelial lesions from groups I and II, accompanied by strong over-expression of p53 and less H-ras expression. These findings support the hypothesis that iNOS, COX-2 and 8-OHdG in bladder urothelium are induced by long-term exposure to low-dose radiation with a close relationship to p53 over-expression that could predispose to bladder carcinogenesis.

Studies on the application of dynamic surface tensiometry of serum and cerebrospinal liquid for diagnostics and monitoring of treatment in patients who have rheumatic, neurological or oncological diseases.

Human biological liquids comprise various surfactants, which adsorb at liquid interfaces and lead to a variation in surface tension. The adsorption processes involving low molecular weight surfactants, proteins and phospholipids play a vital role in the physiological functions of the human organism, especially if large surfaces are involved (e.g., gas exchange in lungs, metabolism of kidneys, liver and brain). Dynamic surface tensiometric studies of biological liquids like serum and cerebrospinal fluid provide surrogate parameters that reflect surface tension phenomena. We provide dynamic surface tension data of serum and cerebrospinal fluid that were collected from healthy volunteers and patients with rheumatic, neurological or oncological diseases. Our studies indicate that dynamic surface tension data are helpful for diagnostic purposes and for monitoring of therapeutic interventions.

Specific p53 gene mutations in urinary bladder epithelium after the Chernobyl accident.

After the Chernobyl accident, the incidence of urinary bladder cancers in the Ukraine population increased gradually from 26.2 to 36.1 per 100,000 between 1986 and 1996. Urinary bladder epithelium biopsied from 45 male patients with benign prostatic hyperplasia living in radiocontaminated areas of Ukraine demonstrated frequent severe urothelial dysplasia, carcinoma in situ, and a single invasive transitional cell carcinoma, combined with irradiation cystitis in 42 cases (93%). No neoplastic changes (carcinoma in situ or transitional cell carcinoma) were found in 10 patients from clean areas (areas without radiocontamination). DNA was extracted from the altered urothelium of selected paraffin-embedded specimens that showed obviously abnormal histology (3 cases) or intense p53 immunoreactivity (15 cases), and mutational analysis of exons 5-8 of the p53 gene was performed by PCR-single-strand conformational polymorphism analysis followed by DNA sequencing. Nine of 17 patients (53%) had one or more mutations in the altered urothelium. Urine sediment samples were also collected from the patients at 4-27 months after biopsy and analyzed by PCR-single-strand conformational polymorphism analysis or yeast functional assay, and identical or additional p53 mutations were found in four of five cases. Interestingly, a relative hot spot at codon 245 was found in five of nine (56%) cases with mutations, and 11 of the 13 mutations determined (73%) were G:C to A:T transitions at CpG dinucleotides, reported to be relatively infrequent (approximately 18%) in human urinary bladder cancers. Therefore, the frequent and specific p53 mutations found in these male patients may alert us to a future elevated occurrence of urinary bladder cancers in the radiocontaminated areas.

Urinary bladder lesions after the Chernobyl accident: immunohistochemical assessment of p53, proliferating cell nuclear antigen, cyclin D1 and p21WAF1/Cip1.

During the 11-year period subsequent to the Chernobyl accident, the incidence of urinary bladder cancer in Ukraine has increased from 26.2 to 36.1 per 100,000 population. Cesium-137 (137Cs) accounts for 80-90% of the incorporated radioactivity in this population, which has been exposed to long-term, low-dose ionizing radiation, and 80% of the more labile pool of cesium is excreted via the urine. The present study was performed to evaluate the histopathological features and the immunohistochemical status of p53, p21WAF1/Cip1, cyclin D1 and PCNA (proliferating cell nuclear antigen) in urinary bladder mucosa of 55 males (49-92 years old) with benign prostatic hyperplasia who underwent surgery in Kiev, Ukraine, in 1995 and 1996. Group I (28 patients) inhabiting radiocontaminated areas of the country, group II (17 patients) from Kiev city with less radiocontamination and a control group III (10 patients) living in so-called "clean" areas of Ukraine were compared. In groups I and II, an increase in multiple areas of moderate or severe dysplasia or carcinoma in situ was seen in 42 (93%) of 45 cases. In addition, two small transitional cell carcinomas were found in one patient in each of groups I and II. Nuclear accumulation of p53, PCNA, cyclin D1, and to a lesser extent p21WAF1/Cip1, was significantly increased in both groups I and II as compared with the control group III, indicating possible transformation events or enhancement of repair activities, that may precede the defect in the regulatory pathway itself, at least in the G1 phase of the cell cycle. Our results suggest that early malignant transformation is taking place in the bladder urothelium of people in the radiocontaminated areas of Ukraine and that this could possibly lead sometime in the future to an increased incidence of urinary bladder cancer.

[The clinico-immunological effects of leukinferon in the treatment of patients with acute suppurative pyelonephritis]. / Kliniko-immunologicheskie éffekty leikinferona pri lechenii bol'nykh s ostrym gnoinym pielonefritom.

A many as 20 patients with acute purulent pyelonephritis were studied for clinical and immunological effects of leukinferone. The above patients were convalescent earlier than control subjects. There were instances where clinical status was not accompanied by shifts in immunity. However, on an average in the group, such parameters as level of lymphocytes, amounts of B-cells, Igs G, A, T-helpers, and Tx/Tc ratio were found to be increased as was activity of EK-cells. Stimulating effects of leukinferone were particularly pronounced in those patients with decreased values for immunological status. A conclusion is reached to the effect that patients with acute pyelonephritis may benefit from those treatments involving the use of the above drug preparation.

[The clinico-immunological effects of T-activin in the combined treatment of patients with acute suppurative pyelonephritis]. / Kliniko-immunologicheskie éffekty T-aktivina v kompleksnom lechenii bol'nykh ostrym gnoinym pielonefritom.

Results were studied of use of T-activin in those clinical settings related to acute inflammatory diseases of the kidneys. There was a positive clinical effect from this preparation in all twenty-eight patients with acute purulent pyelonephritis, accompanied by readjustments in the patients' immune system. A rise to the norm was found to occur in T-helper counts, and accordingly, immunoregulatory index, NK-cell activity, blood microbocydic activity. The in vitro investigations done suggested the need for individual testing of immunocompetent cells of the patient to optimize the therapy.

[The treatment of prostatic adenoma by transurethral microwave therapy]. / Lechenie adenomy predstatel'noi zhelezy metodom transuretral'noi mikrovolnovoi terapii.

Patients with adenoma of the prostate appear to benefit from application of the unit "Prostatron" in one session without anesthesiologic maintenance and under outpatient conditions in the absolute majority of cases, as evidenced by reports from abroad and our own experience gained in the treatment of patients with adenoma of the prostate. This permits it to be recommended for widespread use in urological settings. Clinical, uroflowmetric and ultrasonic monitoring of the urogenital system status in patients with adenoma of the prostate, which is to be delivered in all such patients,--if used in combination with TUMWT,--becomes a means of really active assessment of treatment effectiveness rather than a passive recording of the moment of worsening of the patient' state.

[The radionuclide diagnosis of vasorenal hypertension using an angiotensin-converting enzyme inhibitor]. / Radionuklidnaia diagnostika vazorenal'noi gipertenzii s pomoshch'iu ingibitora angiotenzinprevrashchaiushchego fermenta.

Conventional routine renography and dynamic renoscintigraphy fail to yield sufficient diagnostic criteria in vasorenal hypertension, being associated with 21.5% false negative and 33.3% false positive results. Capoten induces statistically significant functional changes manifested by worsening of time-associated indicators of secretory-excretory function of the kidney, glomerular filtration rate and effective renal plasma flow on the side of the unilateral renal artery stenosis; relative hypotension in this situation leads to a statistically insignificant improvement of functional activity of the contralateral kidney parenchyma.

[Neuroelectromyographic study methods in the complex diagnosis of urinary incontinence in women]. / Neiroélektromiograficheskie metody issledovaniia v kompleksnoi diagnostike nederzhaniia mochi u zhenshchin.

With the purpose of improving a differential diagnosis between stress and urgent forms of UI (urinary incontinence), functional condition was studied of lower urinary tract in 62 women suffering from the above pathologies, using general clinical, urologic and neuroelectromyographic methods. In women suffering from urinary incontinence, a decrease is noted of contractile activity of all the anatomical formations responsible for the continence of urine, and the pattern of the electromyograms recorded permits identification of the form of the pathology. The authors hold the view that the onset of an UI symptom in the majority of the examinees is associated with the degenerative dystrophic lesion of the lumbosacral portion of the spine.

[The clinico-immunological effects of leukinferon in the treatment of patients with acute suppurative pyelonephritis]. / Kliniko-immunologicheskie éffekty leikinferona pri lechenii bol'nykh ostrym gnoinym pielonefritom.

The effect of leukinferon (LKF) administration to 20 patients with acute renal inflammation was evaluated versus the effect of basic therapy given to 19 matched patients. A short course of LKF (3 injections) promoted more rapid discontinuation of the fever, recovery of satisfactory general condition, healing of postoperative wounds. Immunologically, the test subjects exhibited a rise in the previously low levels of lymphocytes, B-cells, T-helpers, IgA and IgG. The proportion of T-lymphocyte subpopulations improved and the activity of EC-cells enhanced. It is thought valid to use LKF in acute renal inflammation and surgical urological affections.

[Primary tumors of the kidney pelvis]. / Pervichnye opukholi lokhanki pochki.

Of 507 patients with renal tumours 36 (7.1%) presented with primary epithelial neoplasms of the renal pelvis. Histological investigation revealed benign papillomas in 3 (8.3%) cases. These patients underwent resection of the renal pelvis along with the tumour. Nephro-ureterectomy was performed in 33 patients, of whom 27 (75%) had it for transitional cell carcinoma, 5 (14%) for squamous cell carcinoma and 1 (2.7%) patient for solid carcinoma of the pelvis. Results of surgical treatment vary with the process stage so that the more advanced the stage, the poorer is the prognosis. High efficiency was shown of nephro-ureterectomy. At 5 years 9 of 13 operated on are alive without signs of metastatic disease.