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European Urology Oncology May 2024Mutations in the speckle-type POZ (SPOP) gene are frequently identified in prostate cancer (PC); yet, prognostic implications for affected patients remain unclear.... (Review)
Review
CONTEXT
Mutations in the speckle-type POZ (SPOP) gene are frequently identified in prostate cancer (PC); yet, prognostic implications for affected patients remain unclear. Limited consensus exists regarding tailored treatments for SPOP-mutant (SPOPmut) PC.
OBJECTIVE
To elucidate the prognostic and predictive significance of SPOP mutations across distinct PC stages and treatments.
EVIDENCE ACQUISITION
A systematic literature search of PubMed, Embase, and Scopus was conducted up to January 29, 2024. The meta-analysis included studies comparing survival outcomes between SPOPmut and SPOP wild-type (SPOPwt) PC.
EVIDENCE SYNTHESIS
From 669 records, 26 studies (including five abstracts) were analyzed. A meta-analysis of metastasis-free survival in localized (hazard ratio [HR]: 0.72, 95% confidence interval [CI]: 0.59-0.88; p < 0.01) and overall survival (OS) in metastatic PC (HR: 0.64, 95% CI: 0.53-0.76; p < 0.01) showed a favorable prognosis for patients with SPOPmut PC. In metastatic settings, SPOP mutations correlated with improved progression-free survival (PFS) and OS in patients undergoing androgen deprivation therapy ± androgen receptor signaling inhibitor (HR: 0.51, 95% CI: 0.35-0.76, p < 0.01, and HR: 0.60, 95% CI:0.46-0.79, p < 0.01, respectively). In metastatic castration-resistant PC, only abiraterone provided improved PFS and OS to patients with SPOP mutations compared with patients with SPOPwt, but data were limited. SPOP mutations did not correlate with improved PFS (p = 0.80) or OS (p = 0.27) for docetaxel.
CONCLUSIONS
Patients with SPOPmut PC seem to exhibit superior oncological outcomes compared with patients with SPOPwt. Tailored risk stratification and treatment approaches should be explored in such patients.
PATIENT SUMMARY
Speckle-type POZ (SPOP) mutations could be a favorable prognostic factor in patients with prostate cancer (PC) and may also predict better progression-free and overall survival than treatment with hormonal agents. Therefore, less intensified treatments omitting chemotherapy for patients with SPOP-mutant PC should be explored in clinical trials.
PubMed: 38704358
DOI: 10.1016/j.euo.2024.04.011 -
Fertility and Sterility Sep 2016This systematic review identified 45 original published research articles related to oil and gas extraction activities and human reproductive endpoints. Reproductive... (Review)
Review
This systematic review identified 45 original published research articles related to oil and gas extraction activities and human reproductive endpoints. Reproductive outcomes were categorized as [1] birth outcomes associated with maternal exposure, [2] semen quality, fertility, and birth outcomes associated with adult paternal exposure, [3] reproductive cancers, and [4] disruption of human sex steroid hormone receptors. The results indicate there is moderate evidence for an increased risk of preterm birth, miscarriage, birth defects, decreased semen quality, and prostate cancer. The quality of the evidence is low and/or inadequate for stillbirth, sex ratio, and birth outcomes associated with paternal exposure, and testicular cancer, female reproductive tract cancers, and breast cancer, and the evidence is inconsistent for an increased risk of low birth weight; therefore, no conclusions can be drawn for these health effects. There is ample evidence for disruption of the estrogen, androgen, and progesterone receptors by oil and gas chemicals, which provides a mechanistic rationale for how exposure to oil and gas activities may increase the health risks we have outlined. The results from this systematic review suggest there is a negative impact on human reproduction from exposure to oil and gas activities. Many of the 45 studies reviewed identified potential human health effects. Most of these studies focused on conventional oil and gas activities. Few studies have been conducted to evaluate the impact of unconventional oil and gas operations on human health. The impact of unconventional oil and gas activities may be greater than that of conventional activity, given that unconventional activities employ many of the same approaches and use dozens of known endocrine-disrupting chemicals in hydraulic fracturing.
Topics: Abnormalities, Drug-Induced; Cell Line, Tumor; Endocrine Disruptors; Environmental Exposure; Female; Fertility; Genital Neoplasms, Female; Genital Neoplasms, Male; Humans; Hydraulic Fracking; Infertility; Male; Maternal Exposure; Natural Gas; Oil and Gas Fields; Oil and Gas Industry; Paternal Exposure; Petroleum; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Receptors, Steroid; Reproduction; Risk Assessment; Risk Factors; Spermatozoa
PubMed: 27568524
DOI: 10.1016/j.fertnstert.2016.07.1099 -
Minerva Urologica E Nefrologica = the... Feb 2018To evaluate the available evidence on the standard diagnosis and management of men with metastatic castration resistant prostate cancer (mCRPC), and providing the timely... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
To evaluate the available evidence on the standard diagnosis and management of men with metastatic castration resistant prostate cancer (mCRPC), and providing the timely update on new pharmacological treatments.
EVIDENCE ACQUISITION
A systematic literature search from from January 2000 until March 2017 was performed by combining the following MESH terms: castrate resistant prostate cancer, abiraterone, enzalutamide, 223radium, sipuleucel-T, docetaxel, cabazitaxel, resistance mechanisms, resistance to androgen deprivation, androgen receptor (AR) mutations, amplifications, splice variants, and AR alterations. We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA).
EVIDENCE SYNTHESIS
In the few last years the introduction of new treatment modalities as abiraterone or enzalutamide have significantly change our prospective in mCRPC management increasing patients survival and quality of life. The standard imaging modalities to define the presence of regional or distant metastasis or the different resistant mechanisms to the available treatments are still an issue of debate, however several studies are ongoing to define the standard of care and to reduce treatments' resistance. Data from ongoing phase III trials are awaited to introduce in clinical new effective treatments that can be used in patients resistant to abiraterone/enzalutamide or more probably in a different phase of the disease.
CONCLUSIONS
Castration resistant prostate cancer is now the key issue in prostate cancer management and research. Our challenge in the near future will be to identify the right treatment or better the right combination and sequencing of treatments that should be used in patients with mCRPC or even with advanced prostate cancer.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Quality of Life
PubMed: 28707844
DOI: 10.23736/S0393-2249.17.02976-9 -
Frontiers in Oncology 2023At present, androgen deprivation therapy (ADT) is still the standard regimen for patients with metastatic and locally advanced prostate cancer (PCa). The level of...
BACKGROUND
At present, androgen deprivation therapy (ADT) is still the standard regimen for patients with metastatic and locally advanced prostate cancer (PCa). The level of androgen receptor splice variant-7 (AR-V7) in men with castration-resistant prostate cancer (CRPC) has been reported to be elevated compared with that in patients diagnosed with hormone-sensitive prostate cancer (HSPC).
AIM
Herein, we performed a systematic review and cumulative analysis to evaluate whether the expression of AR-V7 was significantly higher in patients with CRPC than in HSPC patients.
METHODS
The commonly used databases were searched to identify the potential studies reporting the level of AR-V7 in CRPC and HSPC patients. The association between CRPC and the positive expression of AR-V7 was pooled by using the relative risk (RR) with the corresponding 95% confidence intervals (CIs) under a random-effects model. For detecting the potential bias and the heterogeneity of the included studies, sensitivity analysis and subgroup analysis were performed. Publication bias was assessed Egger's and Begg's tests. This study was registered on PROSPERO (ID: CRD42022297014).
RESULTS
This cumulative analysis included 672 participants from seven clinical trials. The study group contained 354 CRPC patients, while the other group contained 318 HSPC patients. Pooled results from the seven eligible studies showed that the expression of positive AR-V7 was significantly higher in men with CRPC compared to those with HSPC (RR = 7.55, 95% CI: 4.61-12.35, < 0.001). In the sensitivity analysis, the combined RRs did not change substantially, ranging from 6.85 (95% CI: 4.16-11.27, < 0.001) to 9.84 (95% CI: 5.13-18.87, < 0.001). In the subgroup analysis, a stronger association was detected in RNA hybridization (RISH) measurement in American patients, and those studies were published before 2011 (all < 0.001). There was no significant publication bias identified in our study.
CONCLUSION
Evidence from the seven eligible studies demonstrated that patients with CRPC had a significantly elevated positive expression of AR-V7. More investigations are still warranted to clarify the association between CRPC and AR-V7 testing.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42022297014.
PubMed: 36865799
DOI: 10.3389/fonc.2023.1053111 -
ESMO Open Oct 2022Androgen-deprivation therapy (ADT) historically represented the milestone for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). Recently, combining... (Meta-Analysis)
Meta-Analysis Review
Addition of androgen receptor-targeted agents to androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis.
BACKGROUND
Androgen-deprivation therapy (ADT) historically represented the milestone for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). Recently, combining androgen receptor-targeted agents (ARTA) or docetaxel with ADT significantly improved clinical outcomes in this setting. The efficacy of the combined use of an ARTA with docetaxel and ADT (triplet), however, was unknown, and often conflicting data derived from subgroup analysis of randomized phase III trials. In order to better define the benefits and risks of the triplet in mHSPC, we carried out a systematic review and meta-analysis of available clinical trials.
METHODS
A literature search with no data restriction using Medline/PubMed, the Cochrane Library, and American Society of Clinical Oncology/European Society for Medical Oncology (ASCO/ESMO) Meeting abstracts was carried out up to April 2022. The meta-analysis was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statements. Overall survival (OS) was the primary endpoint; progression-free survival (PFS) and safety were secondary endpoints. For OS and PFS, summary hazard ratios (HRs) were calculated; for safety, risk ratio (RR) was assessed. Random- or fixed-effects models were used, depending on studies heterogeneity.
RESULTS
Five randomized clinical trials fulfilled the prespecified inclusion criteria. The triplet significantly improved OS (fixed-effect, HR = 0.74; P < 0.00001) and PFS (fixed-effect; HR = 0.50 for clinical PFS, HR = 0.49 for radiological PFS; P < 0.0001) compared with docetaxel plus ADT. We did not show heterogeneity between treatment efficacy and the disease burden, metachronous versus synchronous presentation, concomitant versus sequential strategy. Compared with docetaxel + ADT, the triplet did not increase the risk of adverse events (AEs) (RR = 1.00, P = 0.27 for any-grade AEs; RR = 1.13, P = 0.14 for severe AEs), except for severe hypertension (RR = 1.73, P = 0.001).
CONCLUSIONS
Emerging evidence supports the combination of an ARTA plus docetaxel and ADT in mHSPC patients. Given the availability of several strategies in this setting, clinical characteristics and drug safety profile may help clinicians select the appropriate treatment for mHSPC patients who are more likely to benefit from treatment intensification.
Topics: Male; Humans; Docetaxel; Androgen Antagonists; Prostatic Neoplasms; Androgens; Receptors, Androgen; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents
PubMed: 36152486
DOI: 10.1016/j.esmoop.2022.100575 -
European Urology Oncology Feb 2024The addition of androgen receptor signalling inhibitors (ARSIs) to standard androgen deprivation therapy (ADT) has improved survival outcomes in patients with advanced... (Review)
Review
Risk of Fractures and Falls in Men with Advanced or Metastatic Prostate Cancer Receiving Androgen Deprivation Therapy and Treated with Novel Androgen Receptor Signalling Inhibitors: A Systematic Review and Meta-analysis of Randomised Controlled Trials.
CONTEXT
The addition of androgen receptor signalling inhibitors (ARSIs) to standard androgen deprivation therapy (ADT) has improved survival outcomes in patients with advanced prostate cancer (PCa). Advanced PCa patients have a higher incidence of osteoporosis, compounded by rapid bone density loss upon commencement of ADT resulting in an increased fracture risk. The effect of treatment intensification with ARSIs on fall and fracture risk is unclear.
OBJECTIVE
To assess the risk of falls and fractures in men with PCa treated with ARSIs.
EVIDENCE ACQUISITION
A systematic review of EMBASE, MEDLINE, The Cochrane Library, and The Health Technology Assessment Database for randomised control trials between 1990 and June 2023 was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analyses guidance. Risk ratios were estimated for the incidence of fracture and fall events. Subgroup analyses by grade of event and disease state were conducted.
EVIDENCE SYNTHESIS
Twenty-three studies were eligible for inclusion. Fracture outcomes were reported in 17 studies (N = 18 811) and fall outcomes in 16 studies (N = 16 537). A pooled analysis demonstrated that ARSIs increased the risk of fractures (relative risk [RR] 2.32, 95% confidence interval [CI] 2.00-2.71; p < 0.01) and falls (RR 2.22, 95% CI 1.81-2.72; p < 0.01) compared with control. A subgroup analysis demonstrated an increased risk of both fractures (RR 2.13, 95% CI 1.70-2.67; p < 0.01) and falls (RR 2.19, 95% CI 1.53-3.12; p < 0.0001) in metastatic hormone-sensitive PCa patients, and an increased risk of fractures in the nonmetastatic (RR 2.27, 95% CI 1.60-3.20; p < 0.00001) and metastatic castrate-resistant (RR 2.85, 95% CI 2.16-3.76; p < 0.00001) settings. The key limitations include an inability to distinguish fragility from pathological fractures and potential for a competing risk bias.
CONCLUSIONS
Addition of an ARSI to standard ADT significantly increases the risk of fractures and falls in men with prostate cancer.
PATIENT SUMMARY
We found a significantly increased risk of both fractures and falls with a combination of novel androgen signalling inhibitors and traditional forms of hormone therapy.
PubMed: 38383277
DOI: 10.1016/j.euo.2024.01.016 -
Diagnostics (Basel, Switzerland) Feb 2021Bladder cancer (BCa) is an endocrine-related tumour and the activation of androgen signalling pathways may promote bladder tumorigenesis. We summarized the available... (Review)
Review
Inhibition of Androgen Signalling Improves the Outcomes of Therapies for Bladder Cancer: Results from a Systematic Review of Preclinical and Clinical Evidence and Meta-Analysis of Clinical Studies.
Bladder cancer (BCa) is an endocrine-related tumour and the activation of androgen signalling pathways may promote bladder tumorigenesis. We summarized the available preclinical and clinical evidence on the implications of the manipulation of androgen signalling pathways on the outcomes of BCa therapies. A systematic review was performed in December 2020. We included papers that met the following criteria: original preclinical and clinical research; evaluating the impact of androgen signalling modulation on the outcomes of BCa therapies. Six preclinical and eight clinical studies were identified. The preclinical evidence demonstrates that the modulation of androgen receptor-related pathways has the potential to interfere with the activity of the Bacillus Calmette Guerin, doxorubicin, cisplatin, gemcitabine, and radiotherapy. The relative risk of BCa recurrence after transurethral resection of the bladder tumour (TURBT) is significantly lower in patients undergoing therapy with 5 alpha reductase inhibitors (5-ARIs) or androgen deprivation therapy (ADT) (Relative risk: 0.50, 95% CI: 0.30-0.82; = 0.006). Subgroup analysis in patients receiving 5-ARIs revealed a relative risk of BCa recurrence of 0.46 (95% CI: 0.22-0.95; = 0.040). A significant negative association between the ratio of T1 BCa patients in treated/control groups and the relative risk of BCa recurrence was observed. Therapy with 5-ARIs may represent a potential strategy aimed at reducing BCa recurrence rate, mainly in patients with low stage disease. Further studies are needed to confirm these preliminary data.
PubMed: 33672461
DOI: 10.3390/diagnostics11020351 -
Cancer Cell International 2020Accumulating evidence suggests androgen receptor splice variant 7 (AR-V7) may be associated with the prognosis of castration-resistant prostate cancer (CRPC) received... (Review)
Review
BACKGROUND
Accumulating evidence suggests androgen receptor splice variant 7 (AR-V7) may be associated with the prognosis of castration-resistant prostate cancer (CRPC) received novel hormonal therapy while its characteristic and prognosis value in hormonal sensitive prostate cancer is unclear.
METHODS
We aimed to evaluate the prognostic role of AR-V7 by progression free survival (PFS) and overall survival (OS) in hormonal sensitive prostate cancer (HSPC), and the AR-V7-positive-proportion difference in HSPC and CRPC. A search of PubMed, Embase, and the Web of Science was performed using the keywords prostate cancer, prostate tumor, prostate neoplasm, prostate carcinoma; AR-V7, AR3, androgen receptor splicing variant-7, or androgen receptor-3. Seventeen trials published due December 2019 were enrolled.
RESULTS
AR-V7-positive proportion in CRPC was significantly larger than newly diagnosed prostate cancer (PCa) (odds ratio [OR] 7.06, 95% confidence interval [CI] 2.52-19.83, P < 0.001). Subgroup analyses indicated significantly higher AR-V7-positive proportion in CRPC derived from RNA in situ hybridization (OR 65.23, 95% CI 1.34-3171.43, P = 0.04), exosome RNA (OR 3.88, 95% CI 0.98-15.39, P = 0.05) and tissue RNA (OR 10.89, 95% CI 4.13-28.73, P < 0.001). AR-V7-positive patients had a significantly shorter PFS than those who were AR-V7-negative treated with first-line hormonal therapy (hazard ratio [HR] 3.63, 95% CI 1.85-7.10, P < 0.001) and prostatectomy (HR 2.49, 95% CI 1.33-4.64, P = 0.004). OS (HR 5.59, 95% CI 2.89-10.80, P < 0.001) were better in AR-V7-negative than AR-V7-positive HSPC patients treated with first-line hormonal therapy. The limitations of our meta-analysis were differences in study sample size and design, AR-V7 detection assay, and disease characteristics.
CONCLUSION
AR-V7-positive proportion was significantly higher in CRPC than that in newly diagnosed PCa. AR-V7 positive HSPC patients portend worse prognosis of first-line hormonal therapy and prostatectomy. Additional studies are warranted to confirm these findings.
PubMed: 32390764
DOI: 10.1186/s12935-020-01229-4 -
International Review of Psychiatry... Oct 2018There are several biological factors that might play a role in physiological response to opioids and/or the onset of problematic opioid use; however, sex-based...
There are several biological factors that might play a role in physiological response to opioids and/or the onset of problematic opioid use; however, sex-based differences in non-analgesic opioid-based effects are poorly understood. The goal of this review is to provide a current analysis of the pre-clinical literature on sex-based differences in response to endogenous and exogenous opioids, including the interplay between sex hormones and opioid receptor-mediated neuronal activity and associated behaviours. A systematic search was performed on the following terms within PubMed between March and April 2018: 'opioid oestrogen', 'opioid progesterone', 'opioid oestradiol', and 'opioid testosterone'. Pre-clinical research on the non-analgesic, sex-based effects of opioids is disparate, both in terms of methodology and outcomes, which prohibits a cohesive summary of the results. Themes from the pre-clinical literature suggest that opioid receptor binding, coupling, and density vary as a function of hormone exposure. Findings also suggest that interactions between endogenous opioid and stress systems may differ between males and females as a function of ovarian hormones. Given the current opioid-related public health crisis, there is a pressing need to increase systematic pre-clinical and clinical research on sex-based differences in opioid-effects and opioid use disorder.
Topics: Analgesics, Opioid; Animals; Gonadal Steroid Hormones; Humans; Models, Animal; Receptors, Opioid; Sex Characteristics
PubMed: 30522374
DOI: 10.1080/09540261.2018.1514295 -
Frontiers in Pharmacology 2023To conduct a systematic review and network meta-analysis (NMA) to compare the efficacy of currently available combination therapies in patients with metastatic...
To conduct a systematic review and network meta-analysis (NMA) to compare the efficacy of currently available combination therapies in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Qualified publications were searched in the PubMed, Embase, and Cochrane CENTRAL databases. Overall survival (OS) and radiographic progression-free survival (rPFS) were indirectly compared and assessed using NMA and the surface under the cumulative ranking curve, respectively. Adverse events (AEs) were also compared. Eighteen publications from 12 trials were analyzed in the NMA. In the overall population, triplet therapy was ranked first for OS (hazard ratio [HR]: 0.57, 95% credible interval [CrI]: 0.48-0.67) and rPFS (HR: 0.33, 95% CrI:0.26-0.41) compared with androgen deprivation therapy (ADT) with or without standard non-steroidal antiandrogen. In high-volume mHSPC, triplet therapy was also ranked first in OS (HR, 0.57; 95% CrI:0.44-0.75) and rPFS(HR, 0.29; 95% CrI: 0.23-0.37). Specifically, abiraterone triplet therapy was ranked first in OS (HR, 0.52; 95% CrI:0.38-0.72) and rPFS (HR, 0.28; 95% CrI:0.21-0.38) among all therapies. ADT plus rezvilutamide was ranked first among doublet therapies (OS: HR, 0.58; 95% CrI:0.44-0.77; rPFS: HR, 0.44; 95% CrI:0.33-0.58). In low-volume mHSPC, doublet and triplet therapies were ranked first in OS (HR:0.68, 95% CrI:0.58-0.80) and rPFS (HR:0.37, 95% CrI:0.25-0.55), respectively. ADT plus apalutamide was ranked first in OS among all therapies (HR:0.53, 95% CrI:0.35-0.79), whereas enzalutamide triplet therapy was ranked first in rPFS (HR:0.27, 95% CrI:0.15-0.51). ADT plus rezvilutamide showed a relatively lower incidence of AE among all therapies (OR:1.00, 95% CrI:0.31-3.15), and a lower risk of specific AEs among doublet therapies, particularly regarding seizure (OR, 0.29; 95% CrI:0.01-8.18) and fatigue (OR, 0.96; 95% CrI:0.63-1.46). Docetaxel-based doublet or triplet therapies significantly increased the risk of any AEs or grade ≥3 AEs. Triplet therapy was the best treatment option for the overall population. In high-volume mHSPC, triplet therapy and ADT plus rezvilutamide had the greatest potential to benefit patients. Patients with low-volume mHSPC were most likely to benefit from ADT plus androgen receptor-targeted agents. Triplet therapy was associated with a higher risk of AEs than the other therapies. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022375347, identifier PROSPERO:CRD42022375347.
PubMed: 37153773
DOI: 10.3389/fphar.2023.1148021