A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.

BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Photodynamic Therapy: Current Trends and Potential Future Role in the Treatment of Bladder Cancer.

Bladder cancer (BC) is the 10th most common cancer in the world. The therapeutic spectrum of BC is broad and is constantly expanding. Despite the wide clinical use of photodynamic diagnosis (PTD) for BC, PDT has not been sufficiently investigated in the treatment landscape of BC. We performed an online search of the PubMed database using these keywords: photodynamic therapy, bladder cancer, urothelial carcinoma, in vivo, in vitro, cell line, animal model. Reviews, case reports, and articles devoted to photodynamic diagnostics and the photodynamic therapy of tumors other than urothelial carcinoma were excluded. Of a total of 695 publications, we selected 20 articles with clinical data, 34 articles on in vivo PDT, and 106 articles on in vitro data. The results presented in animal models highlight the potential use of PDT in the neoadjuvant or adjuvant setting to reduce local recurrence in the bladder and upper urinary tracts. Possible regimens include the combination of PDT with intravesical chemotherapy for improved local tumor control or the integration of vascular-targeted PDT in combination with modern systemic drugs in order to boost local response. We summarize available evidence on the preclinical and clinical application of PDT for urothelial carcinoma in order to explain the current trends and future perspectives.

Cell-Free Methylated PTGER4 and SHOX2 Plasma DNA as a Biomarker for Therapy Monitoring and Prognosis in Advanced Stage NSCLC Patients.

Notwithstanding some improvement in the earlier detection of patients with lung cancer, most of them still present with a late-stage disease at the time of diagnosis. Next to the most frequently utilized factors affecting the prognosis of lung cancer patients (stage, performance, and age), the recent application of biomarkers obtained by liquid profiling has gained more acceptance. In our study, we aimed to answer these questions: (i) Is the quantification of free-circulating methylated PTGER4 and SHOX2 plasma DNA a useful method for therapy monitoring, and is this also possible for patients treated with different therapy regimens? (ii) Is this approach possible when blood-drawing tubes, which allow for a delayed processing of blood samples, are utilized? Baseline values for mPTGER4 and mSHOX2 do not allow for clear discrimination between different response groups. In contrast, the combination of the methylation values for both genes shows a clear difference between responders vs. non-responders at the time of re-staging. Furthermore, blood drawing into tubes stabilizing the sample allows researchers more flexibility.

Role of Nivolumab in the Modulation of PD-1 and PD-L1 Expression in Papillary and Clear Cell Renal Carcinoma (RCC).

The expression and cellular mechanisms of programmed cell death-1 protein (PD-1) and its ligands (PD-L1 and PD-L2) in renal cancer cells are not well known. Here, we aimed to investigate the response of renal carcinoma subtypes to the immune checkpoint inhibitor nivolumab and its impact on related signaling pathways. All cell lines analyzed (clear cell (cc)RCC (Caki-1, RCC31) and papillary (p)RCC (ACHN, RCC30)) expressed PD-1 and both ccRCC cell lines, and RCC30 expressed PD-L1. Nivolumab treatment at increasing doses led to increased PD-1 levels in analyzed cells and resulted in aggressive behavior of pRCC but diminished this behavior in ccRCC. The analysis of PD-1/PD-L1-associated signaling pathways demonstrated increased AKT activity in Caki-1 and RCC30 cells but decreased activity in ACHN and RCC31 cells, while ribosomal protein S6 remained largely unchanged. Androgen receptors are related to RCC and were predominantly increased in RCC30 cells, which were the only cells that formed nivolumab-dependent spheroids. Finally, all cell lines exhibited a complex response to nivolumab treatment. Since the pRCC cells responded with increased tumorigenicity and PD-1/PD-L1 levels while ccRCC tumorigenicity was diminished, further studies are needed to improve nivolumab-based therapy for renal carcinoma subtypes, especially the identification of response-involved molecular pathways.

Extract from Cucurbita pepo improves BPH symptoms without affecting sexual function: a 24-month noninterventional study.

PURPOSE: To assess the symptoms, quality of life and sexual well-being in patients with lower urinary tract symptoms due to benign prostatic hyperplasia LUTS/BPH treated with pumpkin seed soft extract (PSE) in routine practice. METHODS: This noninterventional study included 130 men treated for up to 24 months. The International Prostate Symptom Score (IPSS) and related quality of life, Aging Males' Symptoms Scale (AMS), and International Index of Erectile Function (IIEF-5) were recorded. Descriptive statistical methods were applied. The mean with 95% confidence interval (CI) was calculated for the primary end point (change in IPSS after 12-month treatment). RESULTS: Analysis at 12 months included 83 patients [mean (SD) age 65.2 (8.7) years and IPSS (15.6 (3.4), IPSS-QoL 3.4 (0.9)]. AMS and IIEF-5 indicated mild or mild to moderate disorder regarding sexual well-being and erectile dysfunction, respectively. After 12 months, the mean IPSS change from baseline was - 4.7 (95% CI - 5.4 to - 3.9), with 83% (95% CI 65.3 to 84.1) and 53% (95% CI 42.3 to 63.7) of the patients achieving reductions by at least 3 and 5 points, respectively. The proportion of patients with IPSS-QoL below 3 points (mostly satisfied) was 11% (9/83) at baseline and rose to 62% (51/83) and 73% (40/55) at 12 and 24 months, respectively. AMS and IIEF-5 scores did not indicate a negative impact on sexual function during treatment. CONCLUSION: In men with a moderate LUTS suggestive of BPH, a low progression risk and an active sex life, treatment with pumpkin seed soft extract provided symptomatic relief, improved IPSS-QoL, and maintained sexual well-being. TRIAL REGISTRATION: DRKS00010729, June 22, 2016.

Strategies for Isolating and Propagating Circulating Tumor Cells in Men with Metastatic Prostate Cancer.

Selecting a well-suited method for isolating/characterizing circulating tumor cells (CTCs) is challenging. Evaluating sensitive and specific markers for prostate cancer (PCa)-specific CTC identification and analysis is crucial. We used the CellCollector EpCAM-functionalized system (CC-EpCAM) and evaluated and developed a PCa-functionalized version (CC-PCa); we then compared CTC isolation techniques that exploit the physical and biological properties of CTCs. We established two cohorts of metastatic PCa patients (mPCa; 15 in cohort 1 and 10 in cohort 2). CTC cultivation experiments were conducted with two capturing methods (Ficoll and ScreenCell). The most sensitive detection rates and highest CTC counts were reached with the CC-PCa and ScreenCell system. Patients with ≥5 CTCs isolated with CC-EpCAM had an overall survival (OS) of 0.93 years, and patients with ≥5 CTCs isolated with CC-PCa had an OS of 1.5 years in cohort 1. Nevertheless, we observed the highest sensitivity and specificity for 24-month survival by the Ficoll with CD45 depletion and ScreenCell system with May-Grunwald Giemsa (MGG) staining. The EpCAM molecule is an essential factor related to OS for CTC isolation based on biological properties in mPCa patients. The best-suited CTC capture system is not limited to one characteristic of cells but adapted to downstream analysis.

Potential Use of CTCs as Biomarkers in Renal Cancer Patients.

We demonstrated that the CellCollector is an appropriate tool for detecting CTCs in RCC patients. We examined EpCAM and MUC1 expression levels in RCC tissues and cell lines and analyzed the detection rate of CTCs in blood samples ex vivo using an anti-EpCAM antibody-covered straight or spiraled CellCollector. Eight matched samples were examined for affinity to the anti-EpCAM vs. anti-EpCAM/anti-MUC1 antibody-covered wire. The use of this combination of antibodies allowed us to classify patients with lung metastasis. Finally, four patients were analyzed in vivo. In conclusion, both straight (ex vivo, in vivo) and spiraled (ex vivo) wires detected CTCs.

Prospective comparative study of postoperative systemic inflammatory syndrome in robot-assisted vs. open kidney transplantation.

PURPOSE: Robot-assisted kidney transplant (RAKT) recently proved to provide functional results similar to the preferred open kidney transplant (OKT), but with inferior wound morbidity. In a comparative prospective study, we explored the systemic inflammatory response syndrome (SIRS) after KT and compared OKT with RAKT. METHODS: Forty-nine patients underwent pre-emptive ABO-compatible kidney transplantations (KT) between January 2017 and December 2018 in 2 centers: 25 RAKT, 24 OKT. Postoperative SIRS was biologically assessed by serum markers (NGAL, CRP and IL-6) measured at: T0 (preoperative/baseline), T1(H1), T2(H6), T3(H12), T4(H24), T5(D2), T6(D3) and T7(D5) after KT. RESULTS: Inflammatory markers + eGFR were assessed in OKT vs. RAKT. IL-6 peak value occurred at H6 and reached ×9 from baseline. CRP peak occurred at H24 and reached ×28 from baseline (All P < 0.05). NGAL decreased after surgery with a plateau (divided by 2 from baseline) from H12 to D5. There was no significant difference in IL-6, CRP and NGAL kinetics and peak values between RAKT and OKT (All P > 0.05). Serum creatinine and eGFR on postoperative days 1, 3 and 7 were similar in RAKT and OKT (All P > 0.05). Delayed graft function was not observed. CONCLUSION: In this exploratory study, the biological evaluation of postoperative SIRS after living-donor kidney transplant revealed no significant difference between OKT and RAKT and similar functional outcomes in the short term. These results highlight the safety of RAKT as an alternative to OKT in this setting.

Association of Circulating Tumor Cells with Inflammatory and Biomarkers in the Blood of Patients with Metastatic Castration-Resistant Prostate Cancer.

The identification of specific biomarkers that recognize the functional drivers of heterogeneity in prostate cancer (PCa) and personalized treatment remain challenging in systemic medicine. Liquid biopsy allows for the detection and analysis of personalized predictive biomarkers in single blood samples and specifies the current stage of cancer. The aim of our preliminary study was to investigate the association between an elevated circulating tumor cell (CTC) count and the levels of inflammatory factors (IL-6 and IL-8) and biomarkers (DKK-1, PSA, sHER2, and CD44) in patients with metastasized castration-resistant PCa (mCPRC) under chemotherapy and those with localized PCa. Such an association could be used as a component of cancer progression monitoring. We compared the sensitivity and specificity of two CTC isolation platforms. Twenty-eight patients (12 mCRPC and 16 localized PCa patients) were enrolled. Over the study period, the CTC detection rates were 84% with CellCollector® and 73.5% with CellSearch® System in mCPRC patients. The CTC counts determined by the CellSearch® System (CTC_CS) were correlated significantly with the DKK-1, sHER-2, and PSA concentrations in mCRPC patients. The CTC counts captured by CellCollector® demonstrated no significant association with the concentrations of the tested blood-based biomarkers. The CTC_CS count (AUC = 0.9 (95% CI: 0.72-1.0)) and the PSA level (AUC = 0.95 (95% CI: 0.83-1.0)) presented approximately the same sensitivity and specificity for the overall survival of mCRPC patients. For better personalized characterization, further research on CTC phenotyping and their interactions with tumor-associated blood-released factors is needed.

Differential Expression of the Androgen Receptor, Splice Variants and Relaxin 2 in Renal Cancer.

BACKGROUND: The role of the androgen receptor (AR) in renal cell carcinoma (RCC) is unclear. We aimed to analyze the expression of AR and its splice variants (SVs) and their correlation with relaxin 2 (RLN2) and cytokines in RCC. METHODS: We investigated the expression of RLN2 and AR variants in 25 clear cell RCC (ccRCC) and 9 papillary (pRCC) tumor tissues and the corresponding controls using quantitative PCR and serum RLN2, testosterone and cytokine levels in matched samples using ELISA and chemiluminescent immunometric assay, respectively. RESULTS: ccRCC tissues but not pRCC tissues more frequently expressed AR and the SVs than did normal tissues. All pRCC samples expressed more AR than did ccRCC samples. The highest expression of all AR variants except AR-V12 was found in low-stage tumors, with dominant expression of AR-V7. In males in the ccRCC cohort, the expression of AR-FL, AR-V1 and AR-V3 was significantly correlated with that of RLN2. The secretion pattern of proinflammatory IL-6 was higher in ccRCC than in pRCC. CONCLUSIONS: The results highlight additional molecular differences between ccRCC and pRCC, suggesting the influence of external factors on the whole kidney or genetic predispositions to developing certain types of renal cancer, and may support further pathological analysis and studies of targeted hormone therapy.

Organ-Specific Monitoring of Solitary Kidney after Living Donation by Using Markers of Glomerular Filtration Rate and Urinary Proteins.

BACKGROUND: Effective follow-up after living kidney donation is important for maintaining the renal function of the donor. We investigated whether the estimated glomerular filtration rate (eGFR) and urinary protein and enzyme levels can provide important information regarding the state of the remaining kidney after donor nephrectomy. METHODS: Seventy-five living donations were included (prospective/retrospective) in the study. The following parameters were measured up to 1 year after donor nephrectomy: serum creatinine and cystatin C as markers of the GFR; the high-molecular-weight urinary proteins as markers of glomerular injury; and the low-molecular-weight urinary proteins and urinary enzymes as markers of tubular function. RESULTS: One year after kidney donation, the creatinine and cystatin C values were 1.38-fold increased than their initial values, while the eGFR was 32% lower. At that time, 38% of donors had a moderate or high risk of CKD progression. The biochemical urinary glomerular and tubular kidney markers examined showed different behaviors. After a transient increase, the glomerular proteins normalized. Conversely, the detection of low-molecular-weight urinary proteins and enzymes reflected mild tubular damage at the end of the study period. CONCLUSIONS: Our findings suggest that for the evaluation of mild tubular damage, low-molecular-weight marker proteins should be included in the urine diagnostic of a personalized living kidney donor follow-up.

In vivo isolation of circulating tumor cells in patients with different stages of prostate cancer.

Circulating tumor cells (CTCs) provide accurate information on the clinical stage of cancer progression. The present study examined the clinical validity and feasibility of a new medical device for the in vivo isolation of CTCs from the blood of patients with prostate cancer (PCa). The GILUPI CellCollector® (DC01) was applied in 188 cases. The CTC/prostate-specific antigen (PSA) profile of each patient was checked for therapeutic monitoring of patients with PCa. The CellCollector, which is a unique in vivo approach for the isolation of CTCs, was compared with the CellSearch® system, which is the current standard. Overall survival (OS) and diagnostic performance were evaluated. By in vivo isolation, 78.9% (56/71) of patients with metastatic disease (PCa-m) and 46.3% (24/53) of patients with localized disease (PCa-l) had ≥1 captured CTC. Kaplan-Meier analysis revealed that patients with PCa-m that had ≥5 CTCs had a significantly different OS compared with those with <5 CTCs (27.5 months vs. 37 months; HR 2.6; 95% CI 0.78-8.3). Patients with a higher number of CTCs at all time-points had the shortest median OS of 25 months (HR 1.9; 95% CI 0.4-11.6). The effectiveness of CTC isolation technologies demonstrated that in 65.7% of the applications, patients with cancer were positive for CTCs using the CellCollector. By contrast, the CellSearch system detected CTCs in 44.4% of applications. In vivo isolation of CTCs demonstrated the clinical viability of the CellCollector, related to the current standard for the isolation of CTCs from patients with PCa. The advantage of the in vivo device is that it overcomes the blood volume limitations of other CTC assays. Furthermore, the present study revealed that the CellCollector was well tolerated, and no adverse events (AEs) or serious AEs were reported.

Contribution and Expression of Organic Cation Transporters and Aquaporin Water Channels in Renal Cancer.

The body homeostasis is maintained mainly by the function of the kidneys, which regulate salt and water balance and excretion of metabolism waste products and xenobiotics. This important renal function is determined by the action of many transport systems, which are specifically expressed in the different parts of the nephron, the functional unit of the kidneys. These transport systems are involved, for example, in the reabsorption of sodium, glucose, and other important solutes and peptides from the primary urine. They are also important in the reabsorption of water and thereby production of a concentrated urine. However, several studies have shown the importance of transport systems for different tumor entities. Transport systems, for example, contributed to the proliferation and migration of cancer cells and thereby on tumor progression. They could also serve as drug transporters that could enable drug resistance by outward transport of, for example, chemotherapeutic agents and other drugs. Although many renal transporters have been characterized in detail with respect to the significance for proper kidney function, their role in renal cancer progression is less known. Here, we describe the types of renal cancer and review the studies that analyzed the role of organic cation transporters of the SLC22-family and of the aquaporin water channel family in kidney tumors.

Position of Circulating Tumor Cells in the Clinical Routine in Prostate Cancer and Breast Cancer Patients.

Prostate cancer and breast cancer are the most common cancers worldwide. Anti-tumor therapies are long and exhaustive for the patients. The real-time monitoring of the healing progression could be a useful tool to evaluate therapeutic response. Blood-based biosources like circulating tumor cells (CTCs) may offer this opportunity. Application of CTCs for the clinical diagnostics could improve the sequenced screening, provide additional valuable information of tumor dynamics, and help personalized management for the patients. In the past decade, CTCs as liquid biopsy (LB) has received tremendous attention. Many different isolation and characterization platforms are developed but the clinical validation is still missing. In this review, we focus on the clinical trials of circulating tumor cells that have the potential to monitor and stratify patients and lead to implementation into clinical practice.

An overview of the ATOMS generations: port types, functionality and risk factors.

BACKGROUND: We report the multicentre comparison of the different port types of the adjustable transobturator male incontinence system (ATOMS, A.M.I., Austria). METHODS: Between 10/09 and 10/16, 383 patients received an ATOMS. Of these, 63% received the inguinal port (IP, 2009-2013), 23% the intraoperative manually connectable scrotal port (SP, 2013-2015), and 14% the pre-connected fully silicone-covered scrotal port (SSP, 2014-2016). During the follow-up period, continence parameters, pain and quality of life ratings and postoperative port-associated complications were evaluated and compared. Statistical analysis was performed with GraphPad Prism 7®, p < 0.05 considered as significant. RESULTS: Regarding preoperative parameters (BMI, ASA score, previous radiotherapy/incontinence surgery, and preoperative 24-h pad count/24-h pad test), no significant differences were found. Regarding perioperative parameters, the mean operative time was significantly shorter for the SP and SSP (IP vs. SP p < 0.0001, IP vs. SSP p = 0.0048, SP vs. SSP p = 0.697). Comparison of the postoperative 24-h pad count, 24-h pad test and uroflowmetry data revealed no significant differences. However, the postoperative ICIQ-SF score was significantly better for the SSP (p = 0.0232) than the SP. A significant difference was also observed in postoperative port-associated complications. According to the Clavien-Dindo classification, we identified one grade I and 29 grade IIIb complications for the IP, 1 grade I and 6 grade IIIb complications for the SP, but only 2 grade IIIb complications for the SSP (IP vs. SP p = 0.0231, IP vs. SSP p = 0.0189 and SP vs. SSP p = 0.0453). CONCLUSION: The SSP shows fewer complications while retaining comparable efficacy.

Expression of GP88 (progranulin) in serum of prostate cancer patients is associated with Gleason scores and overall survival.

BACKGROUND: GP88/Progranulin is a well-recognized cell growth promoter in different cancers, and elevated serum GP88 levels have been described as negative prognostic factor in breast cancer. However, serum levels in prostate cancer (PCa) patients have not yet been studied. MATERIAL AND METHODS: We analyzed serum GP88 levels by enzyme immunosorbent assay and correlated them with clinicopathological parameters in PCa patients. PCa patients were separated into two groups based on the serum GP88 median level (low ≤44.56 ng/mL or high >44.56 ng/mL) and according to their median age (younger ≤66 years or elder patients >66 years). RESULTS: Low serum GP88 levels were more often detected in younger patients and high levels in elder patients (P=0.018; Fisher's exact test). PCa patients were separated into three groups, Gleason score (GS) ≤6; GS=7; and GS≥8. In receiver operating characteristic analyses, we could distinguish GS≤6 from GS=7 [area under the curve (AUC): 0.646; P=0.018] and GS≤6 from GS≥8 (AUC: 0.629; P=0.048) but not GS=7 from GS≥8. For survival analysis, GP88 levels were separated into two groups by an optimized cutoff value of 36.92 ng/mL. Using this GP88 stratification, all PCa patients and younger patients with a low serum GP88 level had a significantly better overall survival compared with patients with higher serum GP88 levels (log-rank test P=0.010 and P=0.024). CONCLUSION: Serum GP88 levels are significantly different depending on age and GS, and they are associated with the prognosis of PCa patients.

Robotic Donor Nephrectomy: Against.

The use of robotic techniques in laparoscopic donor nephrectomy currently tends to involve a longer ischemia time without clear advantages, and the cost of robotic surgery is significantly higher. If only one robot is available, then unnecessary prolongation of cold ischemia time also occurs, as the donor must first be undocked to dock the recipient. The combination of laparoscopic donor nephrectomy with parallel initiation of robot-assisted situs preparation and exposure of the renal vessels appears to be the best current approach to safe and cost-effective donor nephrectomy and subsequent robot-assisted kidney transplantation without wasting any time.

Serum levels of miR-320 family members are associated with clinical parameters and diagnosis in prostate cancer patients.

We studied the association of the serum levels of the microRNA family members miR-320a/-b/-c with clinico-pathological data to assess their applicability as diagnostic biomarker in prostate cancer (PCa) patients. The levels of miR-320a/-b/-c in 3 groups were evaluated by qRT-PCR (145 patients with PCa, 31 patients with benign prostatic hyperplasia (BPH) and 19 healthy controls). The levels of the three family members of miR-320 were directly correlated within each group (P < 0.001), but they differed significantly among the three groups (P < 0.001). The serum levels of the miR-320 family members were significantly increased in older patients compared to younger patients (≤ 66 years vs. > 66 years, P ≤ 0.001). In addition, the levels of all three miR-320 family members were significantly different in patients with low tumor stage compared with those with high tumor stage (miR-320a: P = 0.034; miR-320b: P = 0.006; miR-320c: P = 0.007) and in patients with low serum PSA compared with those with high serum PSA (≤ 4 ng vs. > 4 ng; miR-320a: P = 0.003; miR-320b: P = 0.003; miR-320c: P = 0.006). The levels of these miRNAs were inversely correlated with serum PSA levels. Detection in the serum samples of PCa patients with or without PSA relapse revealed higher levels of miR-320a/-b/-c in the group without PSA relapse before/after radical prostatectomy than in that with PCa relapse. In summary, the differences among the PCa/BPH/healthy control groups with respect to miR-320a/-b/-c levels in conjunction with higher levels in patients without a PSA relapse than in those with a relapse suggest the diagnostic potential of these miRNA-320 family members in PCa patients.