MCPIP1 contributes to clear cell renal cell carcinomas development.

Monocyte Chemoattractant protein-induced protein 1 (MCPIP1), also known as Regnase-1, is encoded by the ZC3H12a gene, and it mediates inflammatory processes by regulating the stability of transcripts coding for proinflammatory cytokines and controlling activity of transcription factors, such as NF-κB and AP1. We found that MCPIP1 transcript and protein levels are strongly downregulated in clear cell renal cell carcinoma (ccRCC) samples, which were derived from patients surgically treated for renal cancer compared to surrounded normal tissues. Using Caki-1 cells as a model, we analyzed the role of MCPIP1 in cancer development. We showed that MCPIP1 expression depends on the proteasome activity; however, hypoxia and hypoxia inducible factor 2 alfa (HIF2α) are key factors lowering MCPIP1 expression. Furthermore, we found that MCPIP1 negatively regulates HIF1α and HIF2α levels and in the case of the last one, the mechanism is based on the regulation of the half time of transcript coding for HIF2α. Enhanced expression of MCPIP1 in Caki-1 cells results in a downregulation of transcripts encoding VEGFA, GLUT1, and IL-6. Furthermore, MCPIP1 decreases the activity of mTOR and protein kinase B (Akt) in normoxic conditions. Taken together, MCPIP1 contributes to the ccRCC development.

Post-Irradiation Bladder Syndrome After Radiotherapy of Malignant Neoplasm of Small Pelvis Organs: An Observational, Non-Interventional Clinical Study Assessing VESIcare®/Solifenacin Treatment Results.

BACKGROUND Radiotherapy is explicitly indicated as one of the excluding factors in diagnosing overactive bladder syndrome (OAB). Nevertheless, symptoms of OAB such as urgent episodes, incontinence, pollakiuria, and nocturia, which are consequences of irradiation, led us to test the effectiveness of VESIcare®/Solifenacin in patients demonstrating these symptoms after radiation therapy of small pelvis organs due to malignant neoplasm. MATERIAL AND METHODS We conducted an observatory clinical study including 300 consecutive patients with symptoms of post-irradiation bladder; 271 of those patients completed the study. The observation time was 6 months and consisted of 3 consecutive visits taking place at 12-week intervals. We used VESIcare® at a dose of 5 mg a day. Every sixth patient was examined urodynamically at the beginning and at the end of the observation period, with an inflow speed of 50 ml/s. RESULTS We noticed improvement and decline in the average number of episodes a day in the following parameters: number of micturitions a day (-36%, P<0.01), nocturia (-50%, P<0.01), urgent episodes (-41%, P<0.03), and episodes of incontinence (-43%, P<0.01). The patients' quality of life improved. The average maximal cystometric volume increased by 34 ml (21%, p<0.01), average bladder volume of "first desire" increased by 42 ml (49%, P<0.01), and average detrusor muscle pressure at maximal cystometric volume diminished by 9 cmH2O (-36%, P<0.03). CONCLUSIONS The substance is well-tolerated. Solifenacin administered long-term to patients with symptoms of OAB after radiotherapy of a malignant neoplasm of the small pelvis organs has a daily impact in decreasing number of urgent episodes, incontinence, pollakiuria, and nocturia.

Correlation between CT perfusion and clinico-pathological features in prostate cancer: a prospective study.

BACKGROUND: The aim of the study was to assess the correlation between computed tomography perfusion (PCT) parameters and PSA levels, Gleason score, and pTNM stage in patients with prostate cancer (PCa). MATERIAL/METHODS: One hundred twenty-five patients with localized PCa were prospectively enrolled in the study. All patients were diagnosed due to suspicious prostate findings and elevated PSA serum levels and underwent PCT followed by core biopsy and radical prostatectomy. Blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability-surface (PS) area product were computed in the suspected PCa area and normal prostatic tissue. Core biopsy followed by prostatectomy was performed 2-4 weeks after PCT. Correlation between PCT findings and PSA levels, Gleason score, and pTNM stage were analyzed. RESULTS: The mean age of patients was 64 years. All patients had elevated PSA levels (mean value 6.2 ng/ml). Nineteen patients (15.9%) were at low risk of recurrence, 91 (76.5%) were at moderate risk, and 9 (7.6%) were at high risk according to National Comprehensive Cancer Network criteria. PCa was visible on PCT as focal peripheral CT enhancement in 119 out of 125 patients (sensitivity 95.2%). Significant correlations between BV, BF, and PS values and PSA level were found (p<0.05), as well as a trend for difference between BV, BF, and PS in poorly and moderately differentiated tumors (according to Gleason score) in comparison with highly differentiated PCa (p<0.08). The analysis also revealed a correlation between mean perfusion values and BV, MTT, PS, and pTNM cancer stage (p<0.04). CONCLUSIONS: Our study suggests that in low- and intermediate- risk patients, PCT parameters correlate with PSA values, Gleason score, and pTNM stage and can be useful for initial tumor staging.

Histopathological assessment of residual retroperitoneal mass removed in patients after chemotherapy for non-seminomatous germ cell tumours of the testis.

Between 1990 and 1999, 182 men were treated for non-seminomatous germ cell testicular tumours. In 24 of them after chemotherapy a residual retroperitoneal mass was removed. In 14 of them additional immunohistochemical (IHC) examinations using antibodies against cytokeratins, vimentin, PLAP, CD30, AFP, ßhCG, p53, and MIB-1 were performed. We compared the results of those additional studies with the results of routine histopathological examination. Histological assessment revealed most frequently (ca. 54% of cases) non-neoplastic lesions, i.e. fibro-cystic, necrotic or inflammatory tumours and lymphatic tissue. In about 33% of cases, surviving live neoplastic cells were found.

Value of perfusion CT parameters, microvessl density and VEGF expression in differentiation of benign and malignant prostate tumours.

The purpose of this study was to assess the correlation between parameters evaluated using computed tomography perfusion (CTP) and microvessel density (MVD), the vascular endothelial growth factor labelling index (VEGFLI), as well as known clinicopathological indicators of tumour malignancy, in non-advanced prostatic cancer. We included 110 patients with early stage prostate cancer who were subjected to CT examinations followed by radical prostatectomy between 2007 and 2011 (in this analysis we included only patients diagnosed with CT). Both in affected and in healthy tissue the following perfusion parameters were assessed: blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability-surface area product (PS). After surgery in the resected prostate tumour tissue the MVD and VEGFLI were assessed. The mean BF and PS values were significantly higher in carcinomas with high histological grade (p = 0.02). The sensitivity, specificity and accuracy of the threshold BF value, for the distinction between malignant and healthy prostate tissue, were: 67%, 54% and 59% respectively. For BV sensitivity was 71%, specificity was 52%, and accuracy was 48%. Microvessel density significantly correlated with BV, MTT and PS (p < 0.05), while VEGFLI did not correlate with any of the perfusion parameters. Our results suggest that BF and PS might be helpful in discrimination between benign and malignant prostate tissue, while the positive correlation between BV, MTT, PS and MVD might suggest their potential utility in assessment of cancer angiogenesis.

Mucinous breast cancer - clinical characteristics and treatment results in patients treated at the Oncology Centre in Kraków between 1952 and 2002.

AIM OF THE STUDY: To present the characteristics and clinical outcomes in 94 patients with mucinous breast cancer treated at the Oncology Centre in Krakow between 1952 and 2002. MATERIAL AND METHODS: Stage I or II carcinomas were found in 66 patients (69.4%) of the presented group and in the remaining 28 patients (29.8%) stage III disease was diagnosed. In 27 cases regional lymph nodes were involved. All patients had been treated with surgery: mastectomy (90 patients) or breast-conserving treatment (4 patients). Radiotherapy was administered in 14 patients, adjuvant chemo-therapy in 14 patients, and endocrine therapy in 39 patients. RESULTS: The maximum follow-up was 257 months. Ten-year survival was as follows: 75.7% (overall survival), 82.5% (disease-free survival). During the follow-up, 4 patients developed local recurrence, 5 patients developed metastases. Second primary cancer was found in 8 patients. CONCLUSIONS: The presented results confirm the good prognosis in patients treated for mucinous breast cancer. The diagnosis of early-stage breast cancer based on mammography can allow breast-conserving treatment.

[Apocrine breast cancer in the material from Cancer Centre in Krakow. Clinical features and treatment results in patients treated between 1952 and 2002]. / Apokrynowy rak piersi w materiale Centrum Onkologii w Krakowie. Cechy kliniczne i wyniki leczenia chorych w latach 1952-2002.

UNLABELLED: Apocrine breast cancer is a rare type of neoplasm and accounts for approximately 0.3-4% of all breast cancers. It most frequently diagnosed in women over the age of 50. OBJECTIVES: The purpose of the study was to present the clinical characteristics and treatment outcomes of 53 patients treated from apocrine breast cancer at the Oncology Center in Kraków between 1955 and 2002.. MATERIAL AND METHODS: Stage I or II carcinomas were found in 37 patients (69.8%) of the study group and 16 patients (30.2%) were classified as stage II. Node metastases were observed in 27 patients (50.9%). Surgery constituted the primary method of treatment and was used in all patients. Forty-nine patients underwent mastectomy and 4 underwent breast conserving surgery Post-operative radiotherapy was given to 16 patients. Chemotherapy and hormonal therapy were also used--in 20 and 26 cases, respectively. RESULTS: The follow-up period in the study group was maximum 207 months. The 10-year survival rates were as follows: 75.9% (overall survival) and 58.1% (disease-free survival). It was shown that positive lymph nodes highly affected symptoms-free free survival. During follow-up, 7 patients developed local recurrence, 16 patients developed distant metastases. Second primary malignancies were found in 5 patients. CONCLUSIONS: Our findings confirm good prognosis in patients treated for apocrine breast cancer similar to invasive ductal carcinoma.

Total number of lymph nodes and number of metastatic lymph nodes harvested during radical mastectomy did not influence early postoperative drainage volume.

OBJECTIVES: We aimed at evaluation of the influence of the extent of axillary lymph node dissection, measured by the total number of lymph nodes harvested, on the drainage volume. We also looked at the lymph node positivity (N+) and the number of metastatic axillary lymph nodes as a potential prognostic factors in this regard. MATERIAL AND METHODS: We have analysed the data of 63 patients (F/M: 62/1) with breast cancer who underwent radical modified mastectomy in 2008-2009 in the single department of surgical oncology RESULTS: We observed no significant correlation between the 1) total number of axillary lymph nodes harvested during lymphadenectomy 2) presence of metastatic lymph nodes (node positive disease), 3) number of metastatic axillary lymph nodes and: drainage volume on the day of surgery drainage volume on three consecutive postoperative days and drainage volume from the day of surgery to drain removal. CONCLUSION: The extent of axillary lymph node dissection, measured by the total number of lymph nodes excised, did not influence drainage volume after radical modified mastectomy Neither total number of metastatic lymph nodes excised nor the node positivity (N+) were associated with increased drainage volume after mastectomy with axillary dissection.

Prevalence of frailty syndrome in urological patients undergoing major elective surgical procedure due to malignancy.

Introduction: The group of elderly urological patients is growing. A majority of urological operations is performed in this group. The current model of preoperative assessment is developed to be effective in younger groups of patients but not in the elderly. Frailty syndrome has been confirmed to be an effective risk stratification tool in many surgical settings. It can be diagnosed using a variety of screening tools, but the only objective tool is comprehensive geriatric assessment (CGA). However it is time consuming, difficult and to our best knowledge, has not been attempted in Polish urological patients. Material and methods: We assessed the prevalence of frailty in elderly urological patients undergoing surgery due to malignancy using CGA and screening tests. A total of 68 patients over 65 years of age qualified to elective major urological surgery underwent the preoperative assessment including use of traditional tools (medical history, physical examination, ASA score), CGA and frailty-screening tests. The 30-day postoperative complications rate using the Clavien-Dindo scale was also evaluated. Results: The mean age of patients was 71 years. The most common procedures were radical prostatectomy (47.1%), radical nephrectomy (36.6%) and radical cystectomy (11.8%). The prevalence of frailty was 39.7% using CGA and 4.4-10.3% using screening tests. The complication rate was significantly higher in frail individuals when using CGA. Conclusions: Frailty is common in urological elderly patients. The CGA is a time-consuming but reliable tool to diagnose frailty syndrome and predict complications. Screening tests can be useful for selecting patients who should undergo CGA but their predictive value is low.

Biomarkers of epithelial-mesenchymal transition in localized, surgically treated clear-cell renal cell carcinoma.

INTRODUCTION: It has been suggested that the metastatic potential of neoplastic cells can be predicted on the basis of their biological features, including expression of proteins involved in the epithelial to mesenchymal transition (EMT). Therefore, the purpose of this work was to (1) evaluate the expression of EMT markers: ZEB2, vimentin, N-cadherin, TWIST, PTEN, survivin, E-cadherin, Ki-67 and GLUT-1, (2) assess mutation status of two genes: PIK3CA and KRAS, and (3) investigate the potential relationships between the studied biomarkers and clinicopathological factors in clear-cell renal cell carcinoma (ccRCC). MATERIAL AND METHODS: Tumor tissue samples (embedded in paraffin blocks) from 159 patients undergoing radical nephrectomy were analyzed. Proteins expression was evaluated immunohistochemically. DNA mutations were analyzed on DNA isolated from tumor tissue and amplified by real-time PCR detection using suitable fluorescent labeled TaqMan assays. RESULTS: One hundred and seven men and 52 women of mean age of 63.1years were enrolled. Fifty four cancers at pTNM stage I-II and 98 at pTNM III-IV stage were diagnosed. There were 30 Fuhrman grade G1, 61 Fuhrman G2, 49 Fuhrman G3 and 19 Fuhrman G4 tumors. A negative correlation between ZEB2 (p = 0.047, r = -0.172) or E-cadherin expression (p = 0.027, r = -0.191) and TNM was observed. Positive association between grade and Ki-67 (p < 0.001), survivin (p < 0.001), vimentin (p < 0.001) immunoreactivity and negative association between TWIST expression (p = 0.029) or PTEN expression (p = 0.013) were found. Ki-67 expression was positively correlated with survivin (p < 0.001, r = 0.617), vimentin (p = 0.001, r = 0.251) and N-cadherin (p = 0,009, r = 0.207) immunoreactivity which can suggest tumor aggressiveness. TWIST was negatively correlated with E-cadherin (p < 0.001, r = -0.284), vimentin (p < 0.001, r = -0.297) and N-cadherin (p < 0.002, r = -0.241). ZEB2 was not associated with ccRCC grade but was negatively correlated with E-cadherin (p = 0.055, r= -0.153) and PTEN (p = 0.006). GLUT-1 expression was inversely linked to E-cadherin expression (p = 0.022, r= -0.182). Mutations in PIK3CA and KRAS genes were not found in any of the studied ccRCC tumors. CONCLUSIONS: Low-grade tumors showed higher expression of ZEB2 and TWIST proteins than high-grade tumors, which can suggest that EMT in ccRCC begins at early stages of tumor development and, therefore, evaluation of these proteins, together with other biomarkers, may be useful for assessment of the tumor metastatic potential.

Variants of SCARB1 and VDR Involved in Complex Genetic Interactions May Be Implicated in the Genetic Susceptibility to Clear Cell Renal Cell Carcinoma.

The current data are still inconclusive in terms of a genetic component involved in the susceptibility to renal cell carcinoma. Our aim was to evaluate 40 selected candidate polymorphisms for potential association with clear cell renal cell carcinoma (ccRCC) based on independent group of 167 patients and 200 healthy controls. The obtained data were searched for independent effects of particular polymorphisms as well as haplotypes and genetic interactions. Association testing implied position rs4765623 in the SCARB1 gene (OR = 1.688, 95% CI: 1.104-2.582, P = 0.016) and a haplotype in VDR comprising positions rs739837, rs731236, rs7975232, and rs1544410 (P = 0.012) to be the risk factors in the studied population. The study detected several epistatic effects contributing to the genetic susceptibility to ccRCC. Variation in GNAS1 was implicated in a strong synergistic interaction with BIRC5. This effect was part of a model suggested by multifactor dimensionality reduction method including also a synergy between GNAS1 and SCARB1 (P = 0.036). Significance of GNAS1-SCARB1 interaction was further confirmed by logistic regression (P = 0.041), which also indicated involvement of SCARB1 in additional interaction with EPAS1 (P = 0.008) as well as revealing interactions between GNAS1 and EPAS1 (P = 0.016), GNAS1 and MC1R (P = 0.031), GNAS1 and VDR (P = 0.032), and MC1R and VDR (P = 0.035).

S-phase fraction and menopausal status as the most important prognostic factors of disease-free survival for node negative patients with breast cancer. A prospective study.

The aim of our study was to determine a prognostic value of DNA flow cytometry measurements performed on fresh breast cancer tissues, separately for patients' groups defined by nodal status, with special attention to histological type of tumor. Between 1993 and 1996 samples from 677 patients were analyzed and 457 cases were included in the survival analysis. Two-hundred and nine patients from them were node negative (N0). The median time of follow-up was 74 months. In multivariate analysis of disease-free survival (DFS), S-phase fraction (SPF) and menopausal status were found to be independent prognostic parameters for N0 group. A combination of this factors allowed us to distinguish three groups different in respect of the risk of recurrence. Our results showed that: 1. SPF and menopausal status could be prognostically valuable factors for DFS in N0 breast cancer patients; 2. prognostic value of SPF and ploidy should be evaluated separately for each histological type of breast cancer.

The role of CD44v3 expression in female breast carcinomas.

CD44-protein and its isoforms are the multifunctional cell adhesion molecules participating in cell-cell and cell-matrix interactions. In this study we estimated the frequency of CD44-expression as well as two of its variants (CD44v3 and CD44v5) in female breast cancer. Among 75 breast carcinomas studied, 23 (44.2%) presented strong membrane reaction with monoclonal antibody against antigen CD44. The immunocytochemical reaction to CD44v3 and CD44v5 were observed in 16 (21.3%) and 50 (66.75%) cases, respectively. The presence of CD44v3 antigen on the surface of breast cancer cells significantly correlated with ER expression (0.0430) and the lack of p53 protein (p=0.0252), and also with the percentage of T cells in the total population of lymphocytes infiltrating the primary tumor (TILs) (p=0.0248). What is more important, the reaction to CDv3 significantly correlated with the presence of metastases to the lymph nodes (p=0.0385).

Perfusion CT is a valuable diagnostic method for prostate cancer: a prospective study of 94 patients.

PURPOSE: The aim of this study is to assess the usefulness of perfusion computer tomography (pCT) in prostate cancer (PCa) diagnostics. MATERIALS AND METHODS: 94 patients with biopsy-proven PCa were enrolled in the study. Dynamic pCT of the prostate gland was performed for 50 seconds after an intravenous injection of contrast medium. Blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface area product (PS) were computed in the suspected PCa area and in normal prostatic tissue. RESULTS: PCa was visible in pCT in 90 of the 94 examined patients as a focal peripheral CT enhancement. When PCa was located in the peripheral zone (PZ), it was visible on perfusion maps, mostly showing an early peak followed by wash-out. The average values of all perfusion parameters were higher for tumour than for normal prostate tissue (p < 0.000). BV and BF were dependent on tumour grade expressed by the Gleason score (GS). All PCa cases were divided into groups, according to histological grade, as low (GS ≤ 6), medium (GS = 7), and high (GS > 7). In high-grade PCa, the mean BF value was significantly higher (p = 0.001) than the mean value of BF low- and medium-grade PCa (p = 0.011). Similar results were obtained regarding the mean values of BV; the more aggressive the cancer grade, the higher the mean BV value (p = 0.04). CONCLUSION: CT quantitative perfusion imaging allows PCa to be distinguished from normal prostate tissue. The highest values for BF and BV were observed in the most aggressive PCa grade.

Prognostic factors of overall survival in renal cancer patients - single oncological center study.

INTRODUCTION: The clinical course of renal cancer remains difficult to predict. Attempts to appoint new independent prognostic factors (IPFs) and comparisons of already identified ones among populations are inevitable to develop more effective prognostic instruments. The aim of this study was to evaluate IPFs of overall survival in a given population of patients with renal cancer. MATERIALS AND METHODS: Retrospective analysis of 148 patients with renal cancer treated at the Oncological Institute in Cracow from 2000 to 2007 was performed. Mean follow-up was 51 months. Using the log-rang test, a group of clinicopathological and biochemical features was analyzed in respect to their influence on overall survival. Results were presented as Kaplan-Meier curves. Final identification of IPFs was made by multivariate Cox regression analysis. RESULTS: Overall survival rate at 1, 2, and 5-year follow-up was 58.8%, 38.2%, and 21.4%, respectively. The set of identified IPFs consisted of performance status, smoking history, hemoglobin concentration, anatomical staging, tumor grade, and the presence of microvascular invasion. It was confirmed that only nephrectomy increases significantly overall survival. CONCLUSIONS: Apart from smoking history, the role of all other IPFs identified in our study is well documented in the literature. Smoking history seems to be a new IPF with strong negative impact on survival in patients with RCC.

The intraoperative assessment of the effectiveness of computed tomography in the detection of the residual mass of the retroperitoneal space in patients with nonseminoma testicular tumors after chemotherapy.

BACKGROUND: The incidence of testicular tumors in Poland accounts for 2.4 new cases per 100.000 men a year. When investigating the incidence with regard to age, we may notice three age ranges with the highest incidence rate: babyhood, 25-40 years of age, and age of about 60 years. A routine examination in patients with testicular cancer after the first course of chemotherapy is computed tomography of the retroperitoneal space which aims to exclude the presence of residual masses and to assess the effectiveness of the treatment. AIM OF THE STUDY: The assessment of the effectiveness of computed tomography in the intraoperative investigation of patients with nonseminoma testicular tumors after chemotherapy. MATERIAL/METHOD: This detailed retrospective analysis included 182 men with nonseminoma testicular tumor treated at the Center of Oncology in Cracow, between the yeas 1990-1999. Men with tumors in stage from IA to IIC made up 79.68% of the patients. Twenty patients after chemotherapy, with residual masses in the retroperitoneal cavity revealed in computed tomography, underwent retroperitoneal lymphadenectomy. The investigation was carried out with GE CT spiral scanner before and after intravenous contrast administration. CONCLUSIONS: Computed tomography is a method of a satisfactory sensitivity in the assessment of residual masses in the retroperitoneal cavity in postchemotherapy patients, as concerns the location of the tumor, its size, number of foci, and the fact whether it can be operated on or not. Together with tumor markers, it allows for a precise qualification to retroperitoneal lymphadenectomy of residual masses in postchemotherapy patients.