Introduction of novel agents for the management of advanced prostate cancer provides a range of treatment options with notable benefits for men with metastatic castration-resistant prostate cancer ...(mCRPC). At the same time, understanding of optimal patient selection, effective sequential use, and development of resistance patterns remains incomplete.
To review current systemic therapies and recent advances in drug development for mCRPC and strategies to aid in patient selection and optimal sequencing.
A literature review of PubMed/Medline, Cochrane Library, Current Contents Medicine, Web of Science, Clinical Trial.Gov, WHO-ICTRP (January 2004–November 2017), and the proceedings of major international meetings (2015/2016/2017) was performed in November 2017.
In the last few years, several new options for treatment of mCRPC have shown a survival benefit in phase III trials besides docetaxel:abiraterone, enzalutamide, cabazitaxel, radium-223, and sipuleucel-T. Radium-223 and denosumab have increased options in management of bone metastases. Currently, novel agents such as next-generation androgen receptor (AR) axis-targeting treatments, immunotherapeutics, or therapies targeting other oncogenic and genomic pathways, particularly poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors and PD-1 inhibitors, are under clinical investigation. With increasing treatment options for mCRPC, information on how to personalize management and how to select and sequence existing therapies is beginning to emerge, as are predictive biomarkers (homologous repair mutations, mismatch repair mutations, AR splice variant 7). Finally, early use of active agents in the castration-sensitive state will likely also change the clinical management of the disease when it becomes castrate resistant.
The emergence of new drugs for mCRPC has improved treatment options dramatically. Currently, systemic treatment options for mCRPC include hormonal therapy, chemotherapy, immunotherapy, and radionuclide therapy as well as bone-modifying agents and palliative or supportive measures. Further, new genetically targeted agents (PARP inhibitors and PD-1 inhibitors) are on the horizon for certain subsets of biomarker-selected patients. The best strategies for patient selection and optimal sequential use to achieve the longest cumulative survival improvement and to prevent early resistance remain unclear.
The current literature and proceedings from relevant congresses related to available systemic agents for the treatment of metastatic castration-resistant prostate cancer, including novel genetically targeted therapies, including poly(adenosine diphosphate–ribose) polymerase inhibitors and PD-1 inhibitors, were reviewed. Current therapies and ongoing developments are discussed.
In the last few years, new therapeutics for the treatment of metastatic castration-resistant prostate cancer have increased survival substantially. While promising novel agents are currently under trial, including genetically targeted therapies (poly(adenosine diphosphate–ribose) polymerase inhibitors and PD-1 inhibitors), further clinical and translational research in predictive biomarkers is needed to optimize treatment selection and sequencing strategies for existing drugs.
For clear cell renal cell carcinoma (ccRCC) risk-dependent diagnostic and therapeutic algorithms are routinely implemented in clinical practice. Artificial intelligence-based image analysis has the ...potential to improve outcome prediction and thereby risk stratification. Thus, we investigated whether a convolutional neural network (CNN) can extract relevant image features from a representative hematoxylin and eosin-stained slide to predict 5-year overall survival (5y-OS) in ccRCC. The CNN was trained to predict 5y-OS in a binary manner using slides from TCGA and validated using an independent in-house cohort. Multivariable logistic regression was used to combine of the CNNs prediction and clinicopathological parameters. A mean balanced accuracy of 72.0% (standard deviation SD = 7.9%), sensitivity of 72.4% (SD = 10.6%), specificity of 71.7% (SD = 11.9%) and area under receiver operating characteristics curve (AUROC) of 0.75 (SD = 0.07) was achieved on the TCGA training set (n = 254 patients / WSIs) using 10-fold cross-validation. On the external validation cohort (n = 99 patients / WSIs), mean accuracy, sensitivity, specificity and AUROC were 65.5% (95%-confidence interval CI: 62.9–68.1%), 86.2% (95%-CI: 81.8–90.5%), 44.9% (95%-CI: 40.2–49.6%), and 0.70 (95%-CI: 0.69–0.71). A multivariable model including age, tumor stage and metastasis yielded an AUROC of 0.75 on the TCGA cohort. The inclusion of the CNN-based classification (Odds ratio = 4.86, 95%-CI: 2.70–8.75, p < 0.01) raised the AUROC to 0.81. On the validation cohort, both models showed an AUROC of 0.88. In univariable Cox regression, the CNN showed a hazard ratio of 3.69 (95%-CI: 2.60–5.23, p < 0.01) on TCGA and 2.13 (95%-CI: 0.92–4.94, p = 0.08) on external validation. The results demonstrate that the CNN’s image-based prediction of survival is promising and thus this widely applicable technique should be further investigated with the aim of improving existing risk stratification in ccRCC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human cancers almost ubiquitously harbor epigenetic alterations. Although such alterations in epigenetic marks, including DNA methylation, are potentially heritable, they can also be dynamically ...altered. Given this potential for plasticity, the degree to which epigenetic changes can be subject to selection and act as drivers of neoplasia has been questioned. We carried out genome-scale analyses of DNA methylation alterations in lethal metastatic prostate cancer and created DNA methylation "cityscape" plots to visualize these complex data. We show that somatic DNA methylation alterations, despite showing marked interindividual heterogeneity among men with lethal metastatic prostate cancer, were maintained across all metastases within the same individual. The overall extent of maintenance in DNA methylation changes was comparable to that of genetic copy number alterations. Regions that were frequently hypermethylated across individuals were markedly enriched for cancer- and development/differentiation-related genes. Additionally, regions exhibiting high consistency of hypermethylation across metastases within individuals, even if variably hypermethylated across individuals, showed enrichment for cancer-related genes. Whereas some regions showed intraindividual metastatic tumor heterogeneity in promoter methylation, such methylation alterations were generally not correlated with gene expression. This was despite a general tendency for promoter methylation patterns to be strongly correlated with gene expression, particularly at regions that were variably methylated across individuals. These findings suggest that DNA methylation alterations have the potential for producing selectable driver events in carcinogenesis and disease progression and highlight the possibility of targeting such epigenome alterations for development of longitudinal markers and therapeutic strategies.
Abstract Background Despite recent improvements, radical cystectomy (RC) is still associated with adverse rates for 90-d mortality. Objective To validate the performance of the Isbarn nomogram ...incorporating age and postoperative tumor characteristics for predicting 90-d RC mortality in a multicenter series and to generate a new nomogram based strictly on preoperative parameters. Design, setting, and participants Data of 679 bladder cancer (BCa) patients treated with RC at 18 institutions in 2011 were prospectively collected, from which 597 patients were eligible for final analysis. Intervention RC for BCa. Outcome measurements and statistical analysis An established prediction tool, the Isbarn nomogram, was applied to our cohort. For the purpose of external validation, model discrimination was measured using the receiver operating characteristics–derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities. Univariable and multivariable logistic regression models were fitted to assess the impact of preoperative characteristics on 90-d mortality. Results and limitations The 30-, 60-, and 90-d mortality rates in the development cohort ( n = 597) were 2.7%, 6.7%, and 9.0%, respectively. The Isbarn nomogram predicted individual 90-d mortality with an accuracy of 68.6%. Our preoperative multivariable model identified age (odds ratio OR:1.052), American Society of Anesthesiologists score (OR: 2.274), hospital volume (OR: 0.982), clinically lymphatic metastases (OR: 4.111), and clinically distant metastases (OR: 7.788) (all p < 0.05) as independent predictors of 90-d mortality (predictive accuracy: 78.8%). Our conclusions are limited by the lack of an external validation of the preoperative model. Conclusions The Isbarn nomogram was validated with moderate discrimination. Our newly developed model consisting of preoperative characteristics might outperform existing models. Our model might be particularly suitable for preoperative patient counseling. Patient summary The current report validated an established nomogram predicting 90-d mortality in patients with bladder cancer after radical cystectomy (RC). We developed a new prediction tool consisting of strictly preoperative parameters, thus allowing clinicians an optimal consultation for RC candidates.
Radiomics may increase the diagnostic accuracy of medical imaging for localized and metastatic RCC (mRCC). A systematic review and meta-analysis was performed. Doing so, we comprehensively searched ...literature databases until May 2020. Studies investigating the diagnostic value of radiomics in differentiation of localized renal tumors and assessment of treatment response to ST in mRCC were included and assessed with respect to their quality using the radiomics quality score (RQS). A total of 113 out of 1098 identified studies met the criteria and were included in qualitative synthesis. Median RQS of all studies was 13.9% (5.0 points, IQR 0.25-7.0 points), and RQS increased over time. Thirty studies were included into the quantitative synthesis: For distinguishing angiomyolipoma, oncocytoma or unspecified benign tumors from RCC, the random effects model showed a log odds ratio (OR) of 2.89 (95%-CI 2.40-3.39,
< 0.001), 3.08 (95%-CI 2.09-4.06,
< 0.001) and 3.57 (95%-CI 2.69-4.45,
< 0.001), respectively. For the general discrimination of benign tumors from RCC log OR was 3.17 (95%-CI 2.73-3.62,
< 0.001). Inhomogeneity of the available studies assessing treatment response in mRCC prevented any meaningful meta-analysis. The application of radiomics seems promising for discrimination of renal tumor dignity. Shared data and open science may assist in improving reproducibility of future studies.
Objectives
To explore men’s onset and burden of lower limb lymphedema (LLL) after radical prostatectomy (RP) with pelvic lymph node dissection (PLND).
Patients and methods
A cross-sectional ...survey-based study was conducted nation-wide and web-based in Germany. Part 1 included 15 multidisciplinary compiled questions with three questions from the Short Form 12 Health Survey (SF-12) and the WHO activity recommendation and part 2 included the validated German Lymph-ICF-Questionnaire (Lymph-ICF-LL). Subgroup comparisons and simple regression analyses were used to identify factors associated with therapy and burden of LLL, followed by multiple regression analyses to explain variance in impairment in the patients’ daily life.
Results
Fifty-four patients completed the survey. Median time of LLL-onset was reported with 2.0 (0.5–9.75) months after RP. Nineteen patients (35.2%) reported bilateral lymphedema, 28 (51.9%) the use of individually fitted compression stockings (CS), 25 (46.3%) of manual lymphatic drainage (LD), and 26 (48.1%) complete regression. The Lymph-ICF-LL revealed a higher total burden for patients with an active LLL compared to complete regression (total score: 25.5 vs. 11.9,
p
= 0.01) especially for “physical function” (28.3 vs. 12.9,
p
< 0.01) and “mental function” (26.2 vs. 6.7,
p
< 0.01). In multiple linear regression analysis, a higher BMI (β = 0.28), lower subjective general health (β = -0.48), and active lymphedema (β = 0.28) were significant predictors of higher reported impairments in the Lymph-ICF-LL, accounting for 45.4% of variance.
Conclusion
Men with LLL after RP with PLND report a significant burden in daily life. Basic therapy needs to be offered early. Postoperative onset of LLL is variable, which should be considered when assessing complications after RP.
Endothelial cells derived from human induced pluripotent stem cells (hiPSC-ECs) provide a new opportunity for mechanistic research on vascular regeneration and drug screening. However, functions of ...hiPSC-ECs still need to be characterized. The objective of this study was to investigate electrophysiological and functional properties of hiPSC-ECs compared with primary human cardiac microvascular endothelial cells (HCMECs), mainly focusing on ion channels and membrane receptor signaling, as well as specific cell functions. HiPSC-ECs were derived from hiPS cells that were generated from human skin fibroblasts of three independent healthy donors. Phenotypic and functional comparison to HCMECs was performed by flow cytometry, immunofluorescence staining, quantitative reverse-transcription polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), tube formation, LDL uptake, exosome release assays and, importantly, patch clamp techniques. HiPSC-ECs were successfully generated from hiPS cells and were identified by endothelial markers. The mRNA levels of KCNN2, KCNN4, KCNMA1, TRPV2, and SLC8A1 in hiPSC-ECs were significantly higher than HCMECs. AT1 receptor mRNA level in hiPSC-ECs was higher than in HCMECs. AT2 receptor mRNA level was the highest among all receptors. Adrenoceptor ADRA2 expression in hiPSC-ECs was lower than in HCMECs, while ADRA1, ADRB1, ADRB2, and G-protein GNA11 and Gai expression were similar in both cell types. The expression level of muscarinic and dopamine receptors CHRM3, DRD2, DRD3, and DRD4 in hiPSC-ECs were significantly lower than in HCMECs. The functional characteristics of endothelial cells, such as tube formation and LDL uptake assay, were not statistically different between hiPSC-ECs and HCMECs. Phenylephrine similarly increased the release of the vasoconstrictor endothelin-1 (ET-1) in hiPSC-ECs and HCMECs. Acetylcholine also similarly increased nitric oxide generation in hiPSC-ECs and HCMECs. The resting potentials (RPs), ISK1–3, ISK4 and IK1 were similar in hiPSC-ECs and HCMECs. IBK was larger and IKATP was smaller in hiPSC-ECs. In addition, we also noted a higher expression level of exosomes marker CD81 in hiPSC-ECs and a higher expression of CD9 and CD63 in HCMECs. However, the numbers of exosomes extracted from both types of cells did not differ significantly. The study demonstrates that hiPSC-ECs are similar to native endothelial cells in ion channel function and membrane receptor-coupled signaling and physiological cell functions, although some differences exist. This information may be helpful for research using hiPSC-ECs.
Innate immune memory allows macrophages to adequately respond to pathogens to which they have been pre-exposed. To what extent different pattern recognition receptors, cytokines and resolution ...signals influence innate immune memory needs further elucidation. The present study assessed whether lipopolysaccharide (LPS) tolerance in monocytes and macrophages is affected by these factors. Human CD14
cells were isolated from peripheral blood, stimulated by LPS and re-stimulated after 3 days of resting. Hereafter, immune-responsive gene 1 (IRG-1), heme oxygenase 1 (HO-1), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) expression were assessed. Our study revealed the following findings: (1) While pre-stimulation with the Toll-like receptor 4 ligand LPS inhibits the induction of IRG-1, TNF-α and IL-6 expression, pre-stimulation with TLR 1/2 ligands only affects cytokine production but not IRG-1 expression upon subsequent TLR4 engagement. (2) Prior TNF-α stimulation does not affect LPS tolerance but rather increases LPS-mediated cytokine expression. (3) Dimethyl itaconate (DMI) inhibits the expression of IRG-1 in a dose-dependent manner but does not affect TNF-α or IL-6 expression. (4) Docosahexaenoic acid (DHA) partly inhibits IRG-1 expression in monocytes but not in M
and M
polarized macrophages. LPS tolerance is not affected in these cells by DHA. The data presented in this study partly corroborate and extend previous findings on innate immune memory and warrant further studies on LPS tolerance to gain a better understanding of innate immune memory at the molecular level.
Perioperative cisplatin-based chemotherapy (CBC) can improve the outcome of patients with muscle-invasive bladder cancer (MIBC), but it is still to be defined which patients benefit. Mutations in DNA ...damage response genes (DDRG) can predict the response to CBC. The value of DDRG expression as a marker of CBC treatment effect remains unclear.
RNA expression of the nine key DDRG (
,
,
,
,
,
,
,
, and
) was assessed by qRT-PCR in a cohort of 61 MICB patients (median age 66 y, 48 males, 13 females) who underwent radical cystectomy in a tertiary care center. The results were validated in the The Cancer Genome Atlas (TCGA) cohort of MIBC (
= 383). Gene expression was correlated with disease-free survival (DFS) and overall survival (OS). Subgroup analyses were performed in patients who received adjuvant cisplatin-based chemotherapy (ACBC) (Mannheim
= 20 and TCGA
= 75).
Low expression of
was associated with low DFS in both the Mannheim and the TCGA cohorts (Mannheim:
= 0.039; TCGA:
= 0.017). This was especially apparent in subgroups treated with ACBC (Mannheim:
= 0.0059; TCGA:
= 0.012). Several other genes showed an influence on DFS in the Mannheim cohort (
,
,
) where low expression was associated with poor DFS (
< 0.05 for all). This finding was not fully supported by the data in the TCGA cohort, where high expression of
and
correlated with poor DFS.
Low expression of
correlated with decreased DFS in the Mannheim and the TCGA cohort. This effect was especially pronounced in the subset of patients who received ACBC, making it a promising indicator for response to ACBC on the level of gene expression.
Introduction Muscle invasive bladder cancer (MIBC) remains a prevalent cancer with limited therapeutic options, obviating the need for innovative therapies. The epidermal growth factor receptor ( ...EGFR ) is a linchpin in tumor progression and presents a potential therapeutic target in MIBC. Additionally, the EGFR ligands AREG and EREG have shown associations with response to anti-EGFR therapy and improved progression-free survival in colorectal carcinoma. Materials and methods We investigated the prognostic significance of EGFR , AREG , and EREG in MIBC. Gene expression and copy number analyses were performed via qRT-PCR on tissue samples from 100 patients with MIBC who underwent radical cystectomy at the University Hospital Mannheim (MA; median age 72, interquartile range IQR 64–78 years, 25% female). Results were validated in 361 patients from the 2017 TCGA MIBC cohort (median age 69, IQR 60–77 years, 27% female), in the Chungbuk and MDACC cohort. Gene expressions were correlated with clinicopathologic parameters using the Mann-Whitney test, Kruskal-Wallis- test and Spearman correlation. For overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) gene expression was analyzed with Kaplan-Meier and Cox-proportional hazard models. Results Significant gene expression differences in EGFR , AREG , and EREG could be detected in all cohorts. In the TCGA cohort, EGFR expression was significantly elevated in patients with EGFR amplification and KRAS wildtype. High AREG expression independently predicted longer OS (HR = 0.35, CI 0.19 - 0.63, p = 0.0004) and CSS (HR = 0.42, CI 0.18 – 0.95, p = 0.0378) in the MA cohort. In the TCGA cohort, high EGFR , AREG , and EREG expression correlated with shorter OS ( AREG : HR = 1.57, CI 1.12 – 2.20, p = 0.0090) and DFS ( EGFR : HR = 1.91, CI 1.31 – 2.8, p = 0.0008). EGFR amplification was also associated with reduced DFS. Discussion High EGFR and EREG indicate worse survival in patients with MIBC. The prognostic role of AREG should further be investigated in large, prospective series. Divergent survival outcomes between the four cohorts should be interpreted cautiously, considering differences in analysis methods and demographics. Further in vitro investigations are necessary to elucidate the functional mechanisms underlying the associations observed in this study.
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