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Prostate cancer is one of the most frequent cancers in men. Although several treatment options exist, their clinical effectiveness is still not satisfactory. One the possible reason of such situation might be the presence of myeloid-derived suppressor cells (MDSC) and their pro-turnorigenic activity. MDSC possess irnmunosuppressive ability and in many studies were shown to support tumor development and progression. In this study we addressed the question whether commonly used therapies of prostate cancer affect the level of MDSC populations in the patients' blood. We compared the level of granulocytic (Gr-MDSC), monocytic (Mo-MDSC) and early stage MDSC (eMDSC) in the blood of patients at different clinical stage and different tumor grading scores, who underwent either surgery or hormonal therapy alone or were given a combined treatment, including e.g. radiotherapy. The obtained results showed that the level of Gr-MDSC was significantly lower in all treated patients comparing to untreated group. On the other hand, surgery or hormonal therapy alone did not affect the level of Mo-MDSC. These results were independent of the PSA level, the tumor grading and clinical stage of the patients. In conclusion, we suggest that Mo-MDSC should be considered as a potential therapy target in the course of prostate cancer treatment to enhance its anti-tumor effectiveness.

The progress in translational cancer research relies on access to well-characterized samples from a representative number of patients and controls. The rationale behind our biobanking are explorations of post-zygotic pathogenic gene variants, especially in non-tumoral tissue, which might predispose to cancers. The targeted diagnoses are carcinomas of the breast (via mastectomy or breast conserving surgery), colon and rectum, prostate, and urinary bladder (via cystectomy or transurethral resection), exocrine pancreatic carcinoma as well as metastases of colorectal cancer to the liver. The choice was based on the high incidence of these cancers and/or frequent fatal outcome. We also collect age-matched normal controls. Our still ongoing collection originates from five clinical centers and after nearly 2-year cooperation reached 1711 patients and controls, yielding a total of 23226 independent samples, with an average of 74 donors and 1010 samples collected per month. The predominant diagnosis is breast carcinoma, with 933 donors, followed by colorectal carcinoma (383 donors), prostate carcinoma (221 donors), bladder carcinoma (81 donors), exocrine pancreatic carcinoma (15 donors) and metachronous colorectal cancer metastases to liver (14 donors). Forty percent of the total sample count originates from macroscopically healthy cancer-neighboring tissue, while contribution from tumors is 12%, which adds to the uniqueness of our collection for cancer predisposition studies. Moreover, we developed two program packages, enabling registration of patients, clinical data and samples at the participating hospitals as well as the central system of sample/data management at coordinating center. The approach used by us may serve as a model for dispersed biobanking from multiple satellite hospitals. Our biobanking resource ought to stimulate research into genetic mechanisms underlying the development of common cancers. It will allow all available “-omics” approaches on DNA-, RNA-, protein- and tissue levels to be applied. The collected samples can be made available to other research groups.

The aim of the study was to evaluate prognosis for biochemical recurrence (BR) by analysing the pathological and biological characteristics of prostate cancer (PCa) after radical prostatectomy (RP). There were 130 men with clinically localized PCa in whom pretreatment serum PSA level and Ki-67, prostate specific membrane antigen (PSMA), glucose transporter-1 (GLUT-1), vascular endothelial growth factor (VEGF), microvessel density (MVD) and human telomerase reverse transcriptase (hTERT) proteins expression, based on number of immunohistochemically positive cells (labelling index), were retrospectively studied. In order to assess the prognostic significance of analysed variables in univariate and multivariate Cox analysis, patients were dichotomized based on cut-off points chosen by receiver operating characteristic (ROC) curves. There were 83 males (63.8%) at pT stage 1–2 and 47 (36.1%) at pT stage 3–4, respectively, with median (range) age of 62.8 years (49–77), and median follow-up of 78.5 months (12–148). In 42 (32.3%) men BR was found. In univariate analysis, tumour biological features: PSA ≤ 8 ng/mL (p = 0.006), Ki-67LI ≤ 12.7% (p = 0.015), VEGFLI>11.0% (p = 0.030), and hTERTLI>6.7% (p = 0.016), but not clinicopathological parameters, appeared to be positive prognosticators for BRFS. In the Cox analysis, Ki-67 lost its significance, and clinicopathological parameters appeared to be nonsignificant. The independent negative prognostic factors for BRFS were: PSA > 8.0 ng/mL, (Hazard ratio = 2.75, p = 0.003), GLUT-1 > 19.1% (HR = 2.1, p = 0.032), VEGF≤11.0% (HR = 1, p = 0.024) and hTERT≤6.7% (HR = 1, p = 0.017). High PSA level, and GLUT-1 expression and lower VEGF and nuclear hTERT expression may indicate the great role of hypoxia in BR induction in PCa.

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.

Funder: Kjell och Märta Beijers Stiftelse (SE), Funder: Hjärnfonden; doi: http://dx.doi.org/10.13039/501100003792, Funder: Cancerfonden; doi: http://dx.doi.org/10.13039/501100002794, Funder: Vetenskapsrådet; doi: http://dx.doi.org/10.13039/501100004359, Funder: Alzheimerfonden; doi: http://dx.doi.org/10.13039/501100008599, Funder: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse (SE), Funder: Science for Life Laboratory (SE), Funder: Fundacja na rzecz Nauki Polskiej (PL), Funder: Uppsala University, Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.

BackgroundMosaic loss of chromosome Y (LOY) is the most common somatic mutation and is associated with all-cause mortality, non-haematological cancers and Alzheimer’s disease among other outcomes. The predominant method used for estimating LOY is the intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic scale. Here we describe a new way to convert the LOY mosaicism into a non-logarithmic scale, which instead represents the percentage of affected cells.MethodsWe compared three independent LOY readouts from matched samples, generated by SNP-array, whole genome sequencing and droplet digital PCR. The SNP-array standardization was derived from this comparison and was applied in analyses of serially collected samples from a large cohort of aging men. The sampling was performed up to five times, spanning up to 22 years.ResultsWe observed a higher correlation between the LOY measurements from SNP-array and the two other readouts when using the standardized, instead of the logarithmic, SNP-array data. We also observed a pronounced intra-individual variation of changes in the frequency of LOY within individual males over time.ConclusionsDescribing LOY measurements generated from SNP-arrays in percentage of cells without the Y chromosome makes comparisons to WGS and ddPCR measurements more precise and easier to interpret. This standardization could be applied to the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated disease and outcomes. Additionally, the frequency of LOY in this study changed profoundly within men over time, likely as a result of aberrant clonal expansions.

BACKGROUND Contrast enhanced spectral mammography (CESM) is a new method of breast cancer diagnosis in which an iodinated contrast agent is injected and dual-energy mammography is obtained in multiple views of the breasts. The aim of this study was to compare the degree of enhancement on CESM with lesion characteristics on mammography (MG) and lesion histology in women with suspicious breast lesions. MATERIAL AND METHODS The degree of enhancement on CESM (absent, weak, medium, or strong) was compared to lesion characteristics on MG (mass, mass with microcalcifications, or microcalcifications alone) and histology (infiltrating carcinoma, intraductal carcinoma, or benign) to compare sensitivity of the two modalities and to establish correlations that might improve diagnostic accuracy. RESULTS Among 225 lesions identified with CESM and MG, histological evaluation revealed 143 carcinomas (127 infiltrating, 16 intraductal) and 82 benign lesions. This is the largest cohort investigated with CESM to date. The sensitivity of CESM was higher than that of MG (100% and 90%, respectively, p=0.010). Medium or strong enhancement on CESM and the presence of a mass on MG was the most likely indictor of malignancy (55.1% p=0.002). Among benign lesions, 60% presented as enhancement on CESM (were false-positive), and most frequently as medium or weak enhancement, together with a mass on MG (53%, p=0.047). Unfortunately, the study did not find combinations of MG findings and CESM enhancement patterns that would be helpful in defining false-positive lesions. We observed systematic overestimation of maximum lesion diameter on CESM compared to histology (mean difference: 2.29 mm). CONCLUSIONS Strong or medium enhancement on CESM and mass or mass with microcalcifications on MG were strong indicators of malignant transformation. However, we found no combination of MG and CESM characteristics helpful in defining false-positive lesions.

The incidence of ovarian carcinoma in Poland is 11.2/100,000. It is the second most common cancer of the genital tract....

Amyloidosis is a heterogeneous group of protein misfolding diseases caused by extracellular deposition of abnormal beta-fibrils resistant to proteolysis. The most common type is light-chain amyloidosis (AL amyloidosis) which can be systemic or localized. Localized amyloidosis mostly affects the respiratory airways, genitourinary tract, gastrointestinal system or skin. We present diagnostic and therapeutic approach in a 25-year-old female patient diagnosed with urinary bladder amyloidosis. The main complaint was macroscopic hematuria occurring periodically for 2 years. Abdominal and pelvic computed tomography revealed single 25-mm-thick soft-tissue lesion of the left bladder wall. Histopathological examination of the lesion biopsied during transurethral resection of bladder tumor showed amyloid deposits with strong positive immunostaining for transthyretin, weaker for light chain (AL) and weak for serum amyloid A (AA). Serum protein electrophoresis and immunofixation did not reveal monoclonal protein. X-rays of flat bones presented without lytic lesions. There were no amyloid deposits both in trephine biopsy and subcutaneous fat biopsy. Primary systemic AL amyloidosis was excluded. According to the results of (99m)Tc-DPD scintigraphy and genetic analysis of transthyretin gene (TTR), the ATTRm amyloidosis was also excluded. Consultative histopathological analysis of the bladder biopsy made in the National Amyloidosis Center in London revealed amyloid deposits stained to lambda light chains, confirming the diagnosis of localized AL lambda bladder amyloidosis. The patient was qualified for surgical treatment. Partial resection of the bladder wall with no need for left ureter transplantation was performed. Primary localized bladder amyloidosis is a very rare entity. In the diagnostic approach the most important is the exclusion of primary systemic amyloidosis due to a completely different treatment method.

Introduction: Soft tissue sarcoma accounts for 1% of malignant neoplasms detected in adult patients in Poland. Their primary localization in...

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 theSCARB1gene (OR=1.688, 95% CI: 1.104–2.582,P=0.016) and a haplotype inVDRcomprising 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 inGNAS1was implicated in a strong synergistic interaction withBIRC5. This effect was part of a model suggested by multifactor dimensionality reduction method including also a synergy betweenGNAS1andSCARB1(P=0.036). Significance ofGNAS1-SCARB1interaction was further confirmed by logistic regression (P=0.041), which also indicated involvement ofSCARB1in additional interaction withEPAS1(P=0.008) as well as revealing interactions betweenGNAS1andEPAS1(P=0.016),GNAS1andMC1R(P=0.031),GNAS1andVDR(P=0.032), andMC1RandVDR(P=0.035).

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. Electronic supplementary material The online version of this article (doi:10.1007/s10456-017-9540-2) contains supplementary material, which is available to authorized users.

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

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, βhCG, 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.