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Background: This study aims to test the effect of the 10 most common nonurological primary cancers (skin, rectal, colon, lymphoma, leukemia, pancreas, stomach, esophagus, liver, lung) on overall mortality (OM) after secondary prostate cancer (PCa). Material and Methods: Within the Surveillance, Epidemiology, and End Results (SEER) database, patients with 10 most common primary cancers and concomitant secondary PCa (diagnosed 2004–2016) were identified and were matched in 1:4 fashion (age, year at diagnosis, race/ethnicity, treatment type, TNM stage) with primary PCa controls. OM was compared between secondary and primary PCa patients and was stratified according to primary cancer type, as well as according to time interval between primary cancer vs. secondary PCa diagnoses. Results: We identified 24,848 secondary PCa patients (skin, n = 3,871; rectal, n = 798; colon, n = 3,665; lymphoma, n = 2,583; leukemia, n = 1,102; pancreatic, n = 118; stomach, n = 361; esophagus, n = 219; liver, n = 160; lung, n = 1,328) vs. 531,732 primary PCa patients. Secondary PCa characteristics were less favorable than those of primary PCa patients (PSA and grade), and smaller proportions of secondary PCa patients received active treatment. After 1:4 matching, all secondary PCa exhibited worse OM than primary PCa patients. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis and subsequent secondary PCa. Conclusion: Patients with secondary PCa are diagnosed with less favorable PSA and grade. Even after matching for PCa characteristics, secondary PCa patients still exhibit worse survival. However, the survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary cancer diagnosis.
Objective: We aimed to assess the correlation between serum prostate-specific antigen (PSA) and tumor burden in prostate cancer (PCa) patients undergoing radical prostatectomy (RP), because estimation of tumor burden is of high value, e.g., in men undergoing RP or with biochemical recurrence after RP. Patients and Methods: From January 2019 to June 2020, 179 consecutive PCa patients after RP with information on tumor and prostate weight were retrospectively identified from our prospective institutional RP database. Patients with preoperative systemic therapy (n=19), metastases (cM1, n=5), and locally progressed PCa (pT4 or pN1, n=50) were excluded from analyses. Histopathological features, including total weight of the prostate and specific tumor weight, were recorded by specialized uro-pathologists. Linear regression models were performed to evaluate the effect of PSA on tumor burden, measured by tumor weight after adjustment for patient and tumor characteristics. Results: Overall, median preoperative PSA was 7.0 ng/ml (interquartile range [IQR]: 5.41–10) and median age at surgery was 66 years (IQR: 61-71). Median prostate weight was 34 g (IQR: 26–46) and median tumor weight was 3.7 g (IQR: 1.8–7.1), respectively. In multivariable linear regression analysis after adjustment for patients and tumor characteristics, a significant, positive correlation could be detected between preoperative PSA and tumor weight (coefficient [coef.]: 0.37, CI: 0.15–0.6, p=0.001), indicating a robust increase in PSA of almost 0.4 ng/ml per 1g tumor weight. Conclusion: Preoperative PSA was significantly correlated with tumor weight in PCa patients undergoing RP, with an increase in PSA of almost 0.4 ng/ml per 1 g tumor weight. This might help to estimate both tumor burden before undergoing RP and in case of biochemical recurrence.
Accumulating evidence suggests that iron homeostasis is disturbed in tumors. We aimed at clarifying the distribution of iron in renal cell carcinoma (RCC). Considering the pivotal role of macrophages for iron homeostasis and their association with poor clinical outcome, we investigated the role of macrophage-secreted iron for tumor progression by applying a novel chelation approach. We applied flow cytometry and multiplex-immunohistochemistry to detect iron-dependent markers and analyzed iron distribution with atomic absorption spectrometry in patients diagnosed with RCC. We further analyzed the functional significance of iron by applying a novel extracellular chelator using RCC cell lines as well as patient-derived primary cells. The expression of iron-regulated genes was significantly elevated in tumors compared to adjacent healthy tissue. Iron retention was detected in tumor cells, whereas tumor-associated macrophages showed an iron-release phenotype accompanied by enhanced expression of ferroportin. We found increased iron amounts in extracellular fluids, which in turn stimulated tumor cell proliferation and migration. In vitro, macrophage-derived iron showed pro-tumor functions, whereas application of an extracellular chelator blocked these effects. Our study provides new insights in iron distribution and iron-handling in RCC. Chelators that specifically scavenge iron in the extracellular space confirmed the importance of macrophage-secreted iron in promoting tumor growth
Introduction and Objectives: Surgical techniques such as preservation of the full functional-length of the urethral sphincter (FFLU) have a positive impact on postoperative continence rates. Thereby, data on very early continence rates after radical prostatectomy (RP) are scarce. The aim of the present study was to analyze very early continence rates in patients undergoing FFLU during RP.
Materials and Methods: Very early-continence was assessed by using the PAD-test within 24 h after removal of the transurethral catheter. The PAD-test is a validated test that measures the amount of involuntary urine loss while performing predefined physical activities within 1 h (e.g., coughing, walking, climbing stairs). Full continence was defined as a urine loss below 1 g. Mild, moderate, and severe incontinence was defined as urine loss of 1–10 g, 11–50 g, and >50 g, respectively.
Results: 90 patients were prospectively analyzed. Removal of the catheter was performed on the 6th postoperative day. Proportions for no, mild, moderate and severe incontinence were 18.9, 45.5, 20.0, and 15.6%, respectively. In logistic regression younger age was associated with significant better continence (HR 2.52, p = 0.04), while bilateral nerve-sparing (HR 2.56, p = 0.057) and organ-confined tumor (HR 2.22, p = 0.078) showed lower urine loss, although the effect was statistically not significant. In MVA, similar results were recorded.
Conclusion: Overall, 64.4% of patients were continent or suffered only from mild incontinence at 24 h after catheter removal. In general, reduced urine loss was recorded in younger patients, patients with organ-confined tumor and in patients with bilateral nerve sparing. Severe incontinence rates were remarkably low with 15.6%.
Introduction: MRI-targeted biopsy (TB) increases overall prostate-cancer (PCa) detection-rates and decreases the risk of insignificant PCa detection. However, the impact of these findings on the definite pathology after radical prostatectomy (RP) is under debate.
Materials and Methods: Between 01/2014 and 12/2018, 366 patients undergoing prostate biopsy and RP were retrospectively analyzed. The correlation between biopsy Gleason-score (highest Gleason-score in a core) and the RP Gleason-score in patients undergoing systematic biopsy (SB-group) (n = 221) or TB+SB (TB-group, n = 145) was tested using the ISUP Gleason-group grading (GGG, scale 1–5). Sub analyses focused on biopsy GGG 1 and GGG ≥ 2.
Results: Proportions of biopsy GGG 1–5 in the SB-group and TB-group were 24.4, 37.6, 19, 10.9, 8.1% and 13.8, 43.4, 24.2, 13.8, 4.8%, respectively (p = 0.07). Biopsy and pathologic GGG were concordant in 108 of 221 (48.9%) in SB- and 74 of 145 (51.1%) in TB-group (p = 0.8). Gleason upgrading was recorded in 33.5 and 31.7% in SB- vs. TB-group (p = 0.8). Patients with biopsy GGG 1 undergoing RP showed an upgrading in 68.5%(37/54) in SB- and 75%(15/20) in TB-group (p = 0.8). In patients with biopsy GGG ≥ 2 concordance increased for both biopsy approaches (54.5 vs. 55.2% for SB- vs. TB-group, p = 0.9).
Discussion: Irrespective of differences in PCa detection-rates between TB- and SB-groups, no significant differences in GGG concordance and upgrading between patients of both groups undergoing biopsy, followed by RP, were recorded. Concordance rates increased in men with biopsy GGG ≥ 2. TB seems to detect more patients with PCa without a difference in concordance with final pathology.
The antitumor effect of curcumin in urothelial cancer cells is enhanced by light exposure in vitro
(2019)
The natural compound curcumin exerts antitumor properties in vitro, but its clinical application is limited due to low bioavailability. Light exposure in skin and skin cancer cells has been shown to improve curcumin bioavailability; thus, the object of this investigation was to determine whether light exposure might also enhance curcumin efficacy in bladder cancer cell lines. RT112, UMUC3, and TCCSUP cells were preincubated with low curcumin concentrations (0.1-0.4 μg/ml) and then exposed to 1.65 J/cm2 visible light for 5 min. Cell growth, cell proliferation, apoptosis, cell cycle progression, and cell cycle regulating proteins along with acetylation of histone H3 and H4 were investigated. Though curcumin alone did not alter cell proliferation or apoptosis, tumor cell growth and proliferation were strongly blocked when curcumin was combined with visible light. Curcumin-light caused the bladder cancer cells to become arrested in different cell phases: G0/G1 for RT112, G2/M for TCCSUP, and G2/M- and S-phase for UMUC3. Proteins of the Cdk-cyclin axis were diminished in RT112 after application of 0.1 and 0.4 μg/ml curcumin. Cell cycling proteins were upregulated in TCCSUP and UMUC3 in the presence of 0.1 μg/ml curcumin-light but were partially downregulated with 0.4 μg/ml curcumin. 0.4 μg/ml (but not 0.1 μg/ml) curcumin-light also evoked late apoptosis in TCCSUP and UMUC3 cells. H3 and H4 acetylation was found in UMUC3 cells treated with 0.4 μg/ml curcumin alone or with 0.1 μg/ml curcumin-light, pointing to an epigenetic mechanism. Light exposure enhanced the antitumor potential of curcumin on bladder cancer cells but by different molecular action modes in the different cell lines. Further studies are necessary to evaluate whether intravesical curcumin application, combined with visible light, might become an innovative tool in combating bladder cancer.
This study was designed to investigate whether epigenetic modulation by histone deacetylase (HDAC) inhibition might circumvent resistance towards the mechanistic target of rapamycin (mTOR) inhibitor temsirolimus in a prostate cancer cell model. Parental (par) and temsirolimus-resistant (res) PC3 prostate cancer cells were exposed to the HDAC inhibitor valproic acid (VPA), and tumor cell adhesion, chemotaxis, migration, and invasion were evaluated. Temsirolimus resistance was characterized by reduced binding of PC3res cells to endothelium, immobilized collagen, and fibronectin, but increased adhesion to laminin, as compared to the parental cells. Chemotaxis, migration, and invasion of PC3res cells were enhanced following temsirolimus re-treatment. Integrin α and β receptors were significantly altered in PC3res compared to PC3par cells. VPA significantly counteracted temsirolimus resistance by down-regulating tumor cell–matrix interaction, chemotaxis, and migration. Evaluation of integrin expression in the presence of VPA revealed a significant down-regulation of integrin α5 in PC3res cells. Blocking studies demonstrated a close association between α5 expression on PC3res and chemotaxis. In this in vitro model, temsirolimus resistance drove prostate cancer cells to become highly motile, while HDAC inhibition reversed the metastatic activity. The VPA-induced inhibition of metastatic activity was accompanied by a lowered integrin α5 surface level on the tumor cells.
The mechanistic target of the rapamycin (mTOR) inhibitor, temsirolimus, has significantly improved the outcome of patients with renal cell carcinoma (RCC). However, development of temsirolimus-resistance limits its effect and metastatic progression subsequently recurs. Since integrin α7 (ITGA7) is speculated to promote metastasis, this investigation was designed to investigate whether temsirolimus-resistance is associated with altered ITGA7 expression in RCC cell lines and modified tumor cell adhesion and invasion. Caki-1, KTCTL-26, and A498 RCC cell lines were driven to temsirolimus-resistance by exposing them to temsirolimus over a period of 12 months. Subsequently, adhesion to human umbilical vein endothelial cells, to immobilized fibronectin, or collagen was investigated. Chemotaxis was evaluated with a modified Boyden chamber assay and ITGA7 expression by flow cytometry and western blotting. Chemotaxis significantly decreased in temsirolimus-sensitive cell lines upon exposure to low-dosed temsirolimus, but increased in temsirolimus-resistant tumor cells upon reexposure to the same temsirolimus dose. The increase in chemotaxis was accompanied by elevated ITGA7 at the cell surface membrane with simultaneous reduction of intracellular ITGA7. ITGA7 knock-down significantly diminished motility of temsirolimous-sensitive cells but elevated chemotactic activity of temsirolimus-resistant Caki-1 and KTCTL-26 cells. Therefore, ITGA7 appears closely linked to adhesion and migration regulation in RCC cells. It is postulated that temsirolimus-resistance is associated with translocation of ITGA7 from inside the cell to the outer surface. This switch forces RCC migration forward. Whether ITGA7 can serve as an important target in combatting RCC requires further investigation.
Background: Does the dogma of nephron sparing surgery (NSS) still stand for large renal masses? Available studies dealing with that issue are considerably biased often mixing imperative with elective indications for NSS and also including less malignant variants or even benign renal tumors. Here, we analyzed the oncological long-term outcomes of patients undergoing elective NSS or radical tumor nephrectomy (RN) for non-endophytic, large (≥7cm) clear cell renal carcinoma (ccRCC).
Methods: Prospectively acquired, clinical databases from two academic high-volume centers were screened for patients from 1980 to 2010. The query was strictly limited to patients with elective indications. Surgical complications were retrospectively assessed and classified using the Clavien-Dindo-classification system (CDS). Overall survival (OS) and cancer specific survival (CSS) were analyzed using the Kaplan-Meier-method and the log-rank test.
Results: Out of in total 8664 patients in the databases, 123 patients were identified (elective NSS (n = 18) or elective RN (n = 105)) for ≥7cm ccRCC. The median follow-up over all was 102 months (range 3–367 months). Compared to the RN group, the NSS group had a significantly longer median OS (p = 0.014) and median CSS (p = 0.04).
Conclusions: In large renal masses, NSS can be performed safely with acceptable complication rates. In terms of long-term OS and CSS, NSS was at least not inferior to RN. Our findings suggest that NSS should also be performed in patients presenting with renal tumors ≥7cm whenever technically feasible. Limitations include its retrospective nature and the limited availability of data concerning long-term development of renal function in the two groups.
Although the mechanistic target of rapamycin (mTOR) inhibitor, everolimus, has improved the outcome of patients with renal cell carcinoma (RCC), improvement is temporary due to the development of drug resistance. Since many patients encountering resistance turn to alternative/complementary treatment options, an investigation was initiated to evaluate whether the natural compound, sulforaphane (SFN), influences growth and invasive activity of everolimus-resistant (RCCres) compared to everolimus-sensitive (RCCpar) RCC cell lines in vitro. RCC cells were exposed to different concentrations of SFN and cell growth, cell proliferation, apoptosis, cell cycle, cell cycle regulating proteins, the mTOR-akt signaling axis, adhesion to human vascular endothelium and immobilized collagen, chemotactic activity, and influence on surface integrin receptor expression were investigated. SFN caused a significant reduction in both RCCres and RCCpar cell growth and proliferation, which correlated with an elevation in G2/M- and S-phase cells. SFN induced a marked decrease in the cell cycle activating proteins cdk1 and cyclin B and siRNA knock-down of cdk1 and cyclin B resulted in significantly diminished RCC cell growth. SFN also modulated adhesion and chemotaxis, which was associated with reduced expression of the integrin subtypes α5, α6, and β4. Distinct differences were seen in RCCres adhesion and chemotaxis (diminished by SFN) and RCCpar adhesion (enhanced by SFN) and chemotaxis (not influenced by SFN). Functional blocking of integrin subtypes demonstrated divergent action on RCC binding and invasion, depending on RCC cell sensitivity to everolimus. Therefore, SFN administration could hold potential for treating RCC patients with established resistance towards everolimus.