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F1000Research 2023To report the ocular surface and meibomian gland changes in polycystic ovarian syndrome (PCOS) women taking hormone supplementation. Case series. Three women (27 ±...
To report the ocular surface and meibomian gland changes in polycystic ovarian syndrome (PCOS) women taking hormone supplementation. Case series. Three women (27 ± 11 years) already diagnosed with PCOS presented with dry eye symptoms (mean OSDI, 37.5) for a mean duration of 13 months and were taking hormonal supplements for a mean duration of 60 ± 11 months. The hormonal supplements included oral estrogen (n=3), oral progesterone (n=3), antiandrogen cyproterone (n=1) and isotretinoin (n=1). Ocular surface evaluation revealed mean NIBUT of 9.9 ± 1.6 seconds and mean TMH of 0.27 ± 0.05 mm, assessed non-invasively using Oculus keratograph 5M (K5M). Meibography (K5M) showed near total loss of all meibomian glands (n=8/12 eyelids) with residual ghost glands in all four eyelids of two patients, and gland shortening alone in one patient. The gland morphology did not change following intense thermal pulsation treatment or cessation of hormonal therapy. Near-total irreversible meibomian gland loss was seen in two young PCOS women taking hormonal supplements. Collaboration between ophthalmologists and gynecologists is advisable for early detection and better understanding of dry eye disease (DED) progression in these patients.
PubMed: 38948507
DOI: 10.12688/f1000research.139229.1 -
ACS Omega Jun 2024Prostate cancer (PCa) is the second most common cancer in males worldwide. Androgen deprivation therapy (ADT) is the primary treatment method used for PCa. Although more... (Review)
Review
Prostate cancer (PCa) is the second most common cancer in males worldwide. Androgen deprivation therapy (ADT) is the primary treatment method used for PCa. Although more effective androgen synthesis and antiandrogen inhibitors have been developed for clinical practice, hormone resistance increases the incidence of ADT-insensitive prostate cancer and poor prognoses. The tumor microenvironment (TME) has become a research hotspot with efforts to identify treatment targets based on the characteristics of the TME to improve prognosis. Herein, we introduce the basic characteristics of the PCa TME and the side effects of traditional prostate cancer treatments. We further highlight the emergence of novel nanotherapy strategies, their therapeutic mechanisms, and their effects on the PCa microenvironment. With further research, clinical applications of nanotherapy for PCa are expected in the near future. Collectively, this Review provides a valuable resource regarding the various nanotherapy types, demonstrating their broad clinical prospects to improve the quality of life in patients with PCa.
PubMed: 38947792
DOI: 10.1021/acsomega.4c03055 -
BJU International Jun 2024To assess the association between achievement of prostate-specific antigen (PSA) levels ≤0.2 ng/mL (henceforth 'ultralow') and clinical outcomes in patients in the...
Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) study: ultralow prostate-specific antigen decline with apalutamide plus androgen-deprivation therapy.
OBJECTIVE
To assess the association between achievement of prostate-specific antigen (PSA) levels ≤0.2 ng/mL (henceforth 'ultralow') and clinical outcomes in patients in the 'Targeted Investigational Treatment Analysis of Novel Anti-androgen' (TITAN) study (ClinicalTrials.gov Identifier NCT02489318) with metastatic castration-sensitive prostate cancer (mCSPC).
PATIENTS AND METHODS
Patients in the TITAN study with mCSPC were randomised to 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy. This post hoc analysis assessed the achievement of a PSA level of 0.2->0.02 ng/mL ('ultralow one' [UL1]) and ≤0.02 ng/mL ('ultralow two' [UL2]) vs >0.2 ng/mL with apalutamide treatment and its association with radiographic progression-free survival (rPFS), overall survival (OS), time to castration-resistant PC (TTCRPC), and time to PSA progression (TTPP). The landmark analysis and Kaplan-Meier methods were used.
RESULTS
By 3 months, more patients achieved UL1 and UL2 with apalutamide (38% and 23%) vs placebo (15% and 5%). In the apalutamide-treated patients, UL2 vs PSA >0.2 ng/mL at landmark 3 months was associated with significantly longer rPFS (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.14-0.54), OS (HR 0.24, 95% CI 0.13-0.43), TTCRPC (HR 0.2, 95% CI 0.11-0.38), and TTPP (HR 0.11, 95% CI 0.04-0.27; nominal P values all <0.001); this association was also observed but less pronounced for UL1. Similar findings were observed at 6 months. Early onset of decline to UL2 by 3 months was associated with improved survival vs PSA >0.2 ng/mL anytime (HR 0.12, 95% CI 0.06-0.22; P < 0.001) in apalutamide-treated patients.
CONCLUSIONS
In this post hoc analysis of TITAN, patients with the deepest PSA decline derived the greatest benefit. These results extend our findings of apalutamide efficacy in the overall TITAN population, underscoring the clinical value of PSA kinetics as a marker for treatment efficacy.
PATIENT SUMMARY
Patients with metastatic prostate cancer that is sensitive to ongoing hormonal treatment benefited significantly from the addition of apalutamide compared with placebo. Those who achieved rapid and deep PSA reduction had the greatest survival benefit.
PubMed: 38940282
DOI: 10.1111/bju.16449 -
The Lancet. Oncology Jul 2024
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Antineoplastic Combined Chemotherapy Protocols; Androgen Antagonists; Neoplasm Metastasis; Treatment Outcome; Androgen Receptor Antagonists
PubMed: 38936382
DOI: 10.1016/S1470-2045(24)00335-8 -
International Journal of Molecular... Jun 2024Aging (senescence) is an unavoidable biological process that results in visible manifestations in all cutaneous tissues, including scalp skin and hair follicles....
Aging (senescence) is an unavoidable biological process that results in visible manifestations in all cutaneous tissues, including scalp skin and hair follicles. Previously, we evaluated the molecular function of adenosine in promoting alopecia treatment in vitro. To elucidate the differences in the molecular mechanisms between minoxidil (MNX) and adenosine, gene expression changes in dermal papilla cells were examined. The androgen receptor (AR) pathway was identified as a candidate target of adenosine for hair growth, and the anti-androgenic activity of adenosine was examined in vitro. In addition, ex vivo examination of human hair follicle organ cultures revealed that adenosine potently elongated the anagen stage. According to the severity of alopecia, the ratio of the two peaks (terminal hair area/vellus hair area) decreased continuously. We further investigated the adenosine hair growth promoting effect in vivo to examine the hair thickness growth effects of topical 5% MNX and the adenosine complex (0.75% adenosine, 1% penthenol, and 2% niacinamide; APN) in vivo. After 4 months of administration, both the MNX and APN group showed significant increases in hair density (MNX + 5.01% ( < 0.01), APN + 6.20% ( < 0.001)) and thickness (MNX + 5.14% ( < 0.001), APN + 10.32% ( < 0.001)). The inhibition of AR signaling via adenosine could have contributed to hair thickness growth. We suggest that the anti-androgenic effect of adenosine, along with the evaluation of hair thickness distribution, could help us to understand hair physiology and to investigate new approaches for drug development.
Topics: Alopecia; Humans; Male; Receptors, Androgen; Adenosine; Hair Follicle; Signal Transduction; Minoxidil; Female; Animals; Hair
PubMed: 38928239
DOI: 10.3390/ijms25126534 -
Clinical Proteomics Jun 2024Tumorigenesis and progression of prostate cancer (PCa) are indispensably dependent on androgen receptor (AR). Antiandrogen treatment is the principal preference for...
BACKGROUND
Tumorigenesis and progression of prostate cancer (PCa) are indispensably dependent on androgen receptor (AR). Antiandrogen treatment is the principal preference for patients with advanced PCa. However, the molecular characteristics of PCa with antiandrogen intervention have not yet been fully uncovered.
METHODS
We first performed proteome analysis with 32 PCa tumor samples and 10 adjacent tissues using data-independent acquisition (DIA)- parallel accumulation serial fragmentation (PASEF) proteomics. Then label-free quantification (LFQ) mass spectrometry was employed to analyze protein profiles in LNCaP and PC3 cells.
RESULTS
M-type creatine kinase CKM and cartilage oligomeric matrix protein COMP were demonstrated to have the potential to be diagnostic biomarkers for PCa at both mRNA and protein levels. Several E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) were significantly altered in PCa and PCa cells under enzalutamide treatment, and these proteins might reprogram proteostasis at protein levels in PCa. Finally, we discovered 127 significantly varied proteins in PCa samples with antiandrogen therapy and further uncovered 4 proteins in LNCaP cells upon enzalutamide treatment.
CONCLUSIONS
Our research reveals new potential diagnostic biomarkers for prostate cancer and might help resensitize resistance to antiandrogen therapy.
PubMed: 38918720
DOI: 10.1186/s12014-024-09490-9 -
Critical Reviews in Oncology/hematology Jun 2024Genitourinary cancers (GUCs) encompass malignancies affecting the urinary and reproductive systems, including renal cell carcinoma (RCC), urothelial carcinoma (UC), and... (Review)
Review
CONTEXT
Genitourinary cancers (GUCs) encompass malignancies affecting the urinary and reproductive systems, including renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer (PC). With the rapidly evolving therapeutic domain of these cancers, cutaneous adverse events (AEs) remain among the most observed toxicities.
OBJECTIVE
To explore the dermatologic AEs linked to novel GUC treatments, their underlying pathophysiology, clinical presentations, and risk factors.
EVIDENCE ACQUISITION
A narrative review of the literature from PubMed and Embase databases was conducted. The search strategy included dermatologic/cutaneous adverse events, risk factors, and pathophysiology in conjunction with the following classes of therapies; immune checkpoint inhibitors (ICIs), antiangiogenic therapies, enfortumab vedotin (EV), erdafitinib, and androgen receptor antagonists (ARAs).
EVIDENCE SYNTHESIS
Maculopapular rash, pruritus, and alopecia are present among the five classes of therapies. ICIs demonstrate the highest incidence of severe drug AEs including Steven Johnson syndrome/toxic epidermal necrolysis. Unique cutaneous AEs present with specific therapies including hand-foot skin reaction and subungual splinter hemorrhage with antiangiogenic drugs, stomatitis/mucositis and onycholysis with erdafitinib. Incidence and type of cutaneous AE also differed within therapies in the same class as seen with apalutamide displaying the highest risk of cutaneous AEs within ARAs. Risk factors for development of cutaneous AEs can be general to therapies, or specific, and include age, immune status, BMI, and gender.
CONCLUSIONS
Dermatologic AEs may impact patients' quality of life and increase the tendency to dose reduce, hold or discontinue life-saving therapies, underscoring the need for vigilant monitoring, early recognition, and collaborative management between medical oncologists, pharmacists, dermatologists and other specialists.
PubMed: 38906514
DOI: 10.1016/j.critrevonc.2024.104420 -
Science Advances Jun 2024Androgen deprivation therapy (ADT) for prostate cancer is associated with an increased risk of dementia, including Alzheimer's disease (AD). The mechanistic connection...
Androgen deprivation therapy (ADT) for prostate cancer is associated with an increased risk of dementia, including Alzheimer's disease (AD). The mechanistic connection between ADT and AD-related cognitive impairment in patients with prostate cancer remains elusive. We established a clinically relevant prostate cancer-bearing AD mouse model to explore this. Both tumor-bearing and ADT induce complex changes in immune and inflammatory responses in peripheral blood and in the brain. ADT disrupts the integrity of the blood-brain barrier (BBB) and promotes immune cell infiltration into the brain, enhancing neuroinflammation and gliosis without affecting the amyloid plaque load. Moreover, treatment with natalizumab, an FDA-approved drug targeting peripheral immune cell infiltration, reduces neuroinflammation and improves cognitive function in this model. Our study uncovers an inflammatory mechanism, extending beyond amyloid pathology, that underlies ADT-exacerbated cognitive deficits, and suggests natalizumab as a potentially effective treatment in alleviating the detrimental effects of ADT on cognition.
Topics: Animals; Alzheimer Disease; Male; Cognitive Dysfunction; Mice; Brain; Humans; Blood-Brain Barrier; Disease Models, Animal; Androgen Antagonists; Prostatic Neoplasms; Natalizumab; Plaque, Amyloid
PubMed: 38905345
DOI: 10.1126/sciadv.adn8709 -
The British Journal of General Practice... Jun 2024Prostate Cancer (PCa) is the commonest cancer in the UK. Androgen deprivation therapy (ADT) is a mainstay of treatment. It increases fragility fractures causing a huge... (Observational Study)
Observational Study
BACKGROUND
Prostate Cancer (PCa) is the commonest cancer in the UK. Androgen deprivation therapy (ADT) is a mainstay of treatment. It increases fragility fractures causing a huge burden to patients and the NHS. As men live longer with PCa, many require prolonged ADT. Reducing fracture risks and improving cancer survivorship is becoming increasingly important. Primary care plays an important role.
AIM
To evaluate how fracture risk of PCa patients taking ADT (PCa-ADT) was assessed and managed in primary care.
METHOD
A retrospective multi-practice database study. PCa patients were identified using SNOMED codes from five sociodemographically diverse practices (registered population 49 400). Data were extracted by hand-searching records, including hospital letters, and included: demographics; a 10-year fragility fracture score (FRAX); NOGG intervention threshold; DEXA requests; and use of bisphosphonates.
RESULTS
Of the 261 PCa patients identified, 6% were Black African/Caribbean and 89% White British. Half had been prescribed ADT, 28% being current users. No fracture risk assessment was documented for any patients. ADT current users had significantly increased FRAX scores for both major osteoporotic fractures (MOF) (9.61%±1.12%) and hip fracture (HF) (5.30%±1.02%) compared with PCa patients without ADT (7.08%±0.57% [MOF] and 3.06%±0.46% [HF], <0.001). For ADT current users, 39% showed intermediate fracture risk (NOGG amber), warranting a DEXA scan, with only 30% performed. Patients in more affluent areas received more DEXA scans and bisphosphonate treatment.
CONCLUSION
Osteoporosis is underdiagnosed and undertreated in men with PCa-ADT, especially in those with deprived backgrounds. There is an unmet need to manage the fracture prevention in this population.
Topics: Humans; Male; Prostatic Neoplasms; Androgen Antagonists; Retrospective Studies; Aged; Risk Assessment; Osteoporotic Fractures; Primary Health Care; Bone Density Conservation Agents; United Kingdom; Middle Aged; Diphosphonates; Databases, Factual; Absorptiometry, Photon; Osteoporosis; Aged, 80 and over; Risk Factors
PubMed: 38902070
DOI: 10.3399/bjgp24X737637 -
Cancer Letters Jun 2024With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a...
With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.
PubMed: 38901665
DOI: 10.1016/j.canlet.2024.217068