BACKGROUND AND OBJECTIVE: Apalutamide (APA) is a treatment for metastatic castration-sensitive prostate cancer (mCSPC). In the ARON-3 study we investigated real-world experiences with APA treatment for mCSPC. METHODS: We retrospectively assessed real-world clinical outcomes for patients with mCSPC treated with APA in the ARON-3 study. Overall survival (OS) was calculated from APA initiation to death from any cause. PSA90 was defined as a prostate-specific antigen decline of ≥90% from baseline, and PSA0.2 as achievement of a PSA level ≤0.2 ng/ml. Data for adverse events were retrospectively collected from electronic and paper charts and categorized according to Common Terminology Criteria for Adverse Events v5.0. KEY FINDINGS AND LIMITATIONS: We included 531 patients with mCSPC treated with APA. High-volume disease was reported for 214 patients (40%), and 56 (11%) had visceral metastases. Median OS was not reached. PSA90 was experienced by 461 patients (87%) and PSA0.2 by 368 (69%). Median OS was significantly longer for patients with PSA90 or PSA0.2 than for subjects without these responses (p < 0.001). The incidence of grade 3-4 fatigue was higher among elderly patients (≥80 yr) than among younger patients (19% vs 5%), but the incidence of other adverse events was comparable between the age groups. CONCLUSIONS AND CLINICAL IMPLICATIONS: APA is an effective and tolerable treatment for mCSPC in the real-world setting. PATIENT SUMMARY: The ARON-3 project collects data for patients with prostate cancer treated in multiple centers worldwide to assess outcomes in the real-world setting. We analyzed data for patients with metastatic hormone-sensitive prostate cancer receiving apalutamide. Our results show that apalutamide is a safe and effective drug in the real-world setting as well as in clinical trials.
- MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádory prostaty rezistentní na kastraci farmakoterapie patologie mortalita MeSH
- prostatický specifický antigen krev MeSH
- protinádorové látky terapeutické užití MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- thiohydantoiny * terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
The 2024 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for chronic kidney disease (CKD) evaluation and management bring important updates, particularly for European laboratories. These guidelines emphasize the need for harmonization in CKD testing, promoting the use of regional equations. In Europe, the European Kidney Function Consortium (EKFC) equation is particularly suited for European populations, particularly compared to the CKD-EPI 2021 race-free equation. A significant focus is placed on the combined use of creatinine and cystatin C to estimate glomerular filtration rate (eGFRcr-cys), improving diagnostic accuracy. In situations where eGFR may be inaccurate or clinically insufficient, the guidelines encourage the use of measured GFR (mGFR) through exogenous markers like iohexol. These guidelines emphasize the need to standardize creatinine and cystatin C measurements, ensure traceability to international reference materials, and adopt harmonized reporting practices. The recommendations also highlight the importance of incorporating risk prediction models, such as the Kidney Failure Risk Equation (KFRE), into routine clinical practice to better tailor patient care. This article provides a European perspective on how these KDIGO updates should be implemented in clinical laboratories to enhance CKD diagnosis and management, ensuring consistency across the continent.
- MeSH
- chronická renální insuficience * diagnóza terapie MeSH
- cystatin C krev MeSH
- hodnoty glomerulární filtrace * MeSH
- klinické laboratoře MeSH
- kreatinin krev MeSH
- lidé MeSH
- směrnice pro lékařskou praxi jako téma * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Evropa MeSH
BACKGROUND: Androgen-receptor signaling inhibitors (ARSIs) significantly improve survival in systemic therapy for advanced/metastatic prostate cancer (PCa) patients; however possible central nervous system (CNS) toxicity is an unaddressed concern. We aimed to assess and compare the incidence of CNS-related adverse events (AEs) secondary to the treatment of PCa patients with different ARSIs. MATERIALS: In August 2023, a comprehensive seach was conducted in three databases for randomized controlled trials (RCTs) of PCa patients receiving ARSIs plus ADT. The primary endpoints included mental impairment, cognitive impairment, seizure, fatigue, and falls. RESULTS: Twenty-six RCTs, comprising 20,328 patients, were included in meta-analyses and network meta-analyses (NMAs). ARSIs increased the risk of mental impairment (RR: 1.72; 95% CI, 1.09-2.71), cognitive impairment (RR: 2.25; 95% CI, 1.78-2.86), seizure (RR: 2.20, 95% CI, 1.09-4.45), fatigue (RR: 1.31, 95% CI, 1.20-1.43), and falls (RR: 2.07, 95% CI, 1.60-2.67) compared to standard of care (SOC). Based on NMAs, Enzalutamide showed a significant increase in risk for all assessed CNS-related AEs, while Abiraterone demonstrated significant risk increases in cognitive impairment, fatigue, and falls. Conversely, Darolutamide did not exhibit significant increases in risk for any CNS-related AEs, except for fatigue. CONCLUSIONS: The addition of ARSIs to ADT increased all examined CNS-related AEs compared to SOC. Each ARSI is associated with a distinct profile of CNS-related AEs. Careful patient selection and monitoring for CNS sequelae is necessary to achieve the best quality of life in patients on ARSI + ADT for PCa.
- MeSH
- antagonisté androgenních receptorů * škodlivé účinky aplikace a dávkování terapeutické užití MeSH
- benzamidy MeSH
- fenylthiohydantoin škodlivé účinky aplikace a dávkování MeSH
- lidé MeSH
- nádory prostaty * farmakoterapie patologie MeSH
- nemoci centrálního nervového systému chemicky indukované MeSH
- nitrily MeSH
- pyrazoly MeSH
- randomizované kontrolované studie jako téma MeSH
- síťová metaanalýza * MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- přehledy MeSH
- systematický přehled MeSH
BACKGROUND AND OBJECTIVE: In prostate cancer treated with androgen deprivation therapy (ADT), the initial sign of treatment resistance is often prostate-specific antigen (PSA) progression, followed by radiographic progression. However, the association between these two forms of progression remains unclear, especially in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with androgen receptor pathway inhibitors. We sought to evaluate the association between radiographic progression, PSA progression, and outcomes of apalutamide therapy in mCSPC. METHODS: We analyzed individual participant-level data for patients randomized within the TITAN trial who experienced radiographic progression during follow-up (N = 326). This study investigated radiographic progression without simultaneous or preceding PSA progression, as defined by the Prostate Cancer Working Group 2 (discordant progression), and explored the association of such progression with radiographic progression-free survival. KEY FINDINGS AND LIMITATIONS: Among the patients who developed radiographic progression, 115 (35.3%) had been treated with apalutamide plus ADT (the apalutamide group) and 211 (64.7%) with placebo plus ADT (the placebo group). Discordant progression occurred in 52.2% of patients (60 of 115) in the apalutamide group and 27.5% (58 of 211) in the placebo group (p < 0.001). A multivariable logistic regression analysis showed that discordant progression was associated with apalutamide treatment. We found evidence of an association between discordant progression and shorter radiographic progression-free survival. CONCLUSIONS AND CLINICAL IMPLICATIONS: This study found that nearly half of the patients with mCSPC treated with apalutamide who experienced radiographic progression developed it without corresponding PSA progression, suggesting that heavy reliance on PSA monitoring may be inadequate for assessing disease activity in this context. PATIENT SUMMARY: In patients who have metastatic castration-sensitive prostate cancer (mCSPC) and are being treated with apalutamide, radiographic images may show cancer progression even if prostate-specific antigen tests indicate no change. This highlights the importance of regular imaging when using apalutamide to manage mCSPC.
- MeSH
- antagonisté androgenů terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádory prostaty rezistentní na kastraci farmakoterapie patologie krev diagnostické zobrazování MeSH
- progrese nemoci * MeSH
- prostatický specifický antigen * krev MeSH
- senioři MeSH
- thiohydantoiny * terapeutické užití MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: The effect of dexmedetomidine on regional splanchnic blood flow remain unclear. OBJECTIVES: We hypothesized, that there is no difference in regional rectal perianastomotic perfusion and oxygenation when using non-opioid dexmedetomidine-isoflurane anesthesia when compared to fentanyl-isoflurane anesthesia. METHODS: Ten female pigs were randomly divided into two groups (Dexmedetomidine, DEX, Fentanyl, FNT). Analgesia was provided by either dexmedetomidine (0.7-1.0 μg/kg/h) or fentanyl (6-10 μg/kg/h). The model of rectosigmoid resection in pigs was used. Two combined Laser Doppler flowmetry (LDF) and oxymetry probes were fixed on the antimesenterial site of the rectosigmoid, one orally and the second distally to resection zone. At the end of the experiment all animals were woken up and extubated. The healing of the anastomosis was controlled seven days after the operation. RESULTS: All experimental animals were hemodynamically stable throughout the experiment. No anastomotic leakage was detected. All animals survived until the seventh postoperative day. In the DEX group the median of the LDF signal on aboral site at the end of experiment was 35% (23-49%), in FNT group the median of the LDF signal was 19% (12-28%), which was statistically significantly lower (p < 0,05). CONCLUSIONS: This study has shown some protective effects of dexmedetomidine-isoflurane based anesthesia on perianastomotic microcirculation when compared to fentanyl-isoflurane based anesthesia.
- MeSH
- anastomóza chirurgická metody MeSH
- anestezie metody MeSH
- dexmedetomidin * farmakologie MeSH
- fentanyl * farmakologie MeSH
- kolorektální chirurgie metody MeSH
- prasata MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Investigation remains incomplete regarding potential variations in the effect of androgen receptor pathway inhibitors, including apalutamide, based on baseline tumor burden in patients with metastatic castration-sensitive prostate cancer (mCSPC). METHODS: The authors analyzed individual participant-level data from 1052 patients with mCSPC who were randomized in the TITAN trial (apalutamide vs. placebo, both with androgen-deprivation therapy). Outcomes included radiographic progression-free survival (PFS), second PFS (PFS2), and overall survival (OS). Multivariable Cox proportional hazards regression models, with and without restricted cubic splines, were used to determine the association between apalutamide benefit and bone metastasis count or visceral metastasis. Subgroup treatment effects were quantified based on inverse probability of treatment weighting-adjusted hazard ratios (HRs). RESULTS: Analysis using restricted cubic splines indicated that apalutamide provided less benefit for PFS2 and OS in patients with fewer bone metastases. The authors also found evidence of a heterogeneous effect of apalutamide on PFS2 and OS between patients with two or less bone metastases and those with three or more bone metastases. In patients who had two or less bone metastases, there was no evidence of a benefit from apalutamide for radiographic PFS (HR, 0.65; 95% confidence interval [CI], 0.35-1.22), PFS2 (HR, 1.18; 95% CI, 0.66-2.12), or OS (HR, 1.05; 95% CI, 0.60-1.83). No evidence of an association was noted between visceral metastasis and apalutamide benefit. CONCLUSIONS: The addition of apalutamide to androgen-deprivation therapy may provide less benefit in patients with mCSPC who have fewer bone metastases. Counting baseline bone metastases may help identify optimal candidates for apalutamide treatment of mCSPC. CLINICAL TRIALS REGISTRATION: NCT02489318 PLAIN LANGUAGE SUMMARY: In an analysis of individual participant data from a trial (the TITAN trial) in patients with metastatic (spreading) castration-sensitive prostate cancer, treatment intensification based on the addition new drugs to standard androgen-deprivation therapy (ADT) was analyzed and compared with the effects in patients who received only standard ADT. Compared with ADT alone, the survival benefit of adding the new drug apalutamide to standard ADT varied according to the number of bone metastases, but no association was observed between the spread of cancer to soft tissues and organs and a survival benefit from adding apalutamide. The results indicate that counting the number of bone metastases may help identify which patients with metastatic castration-sensitive prostate cancer are optimal candidates for treatment intensification with the addition of apalutamide to standard ADT.
- MeSH
- antagonisté androgenních receptorů terapeutické užití MeSH
- antagonisté androgenů terapeutické užití MeSH
- doba přežití bez progrese choroby MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádory kostí sekundární farmakoterapie MeSH
- nádory prostaty rezistentní na kastraci farmakoterapie patologie mortalita MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- thiohydantoiny * terapeutické užití aplikace a dávkování MeSH
- tumor burden * účinky léků MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
Androgen receptor-targeting agents, particularly enzalutamide, show promise in enhancing prostate cancer diagnostic and therapeutic strategies by modulating prostate-specific membrane antigen (PSMA). Methods: A retrospective clinical cohort study investigated 9 men with metastatic castration-resistant prostate cancer on enzalutamide. PSMA PET/CT scans were obtained before and after enzalutamide initiation to assess PSMA expression changes. Lesions and organs at risk were evaluated visually and semiquantitatively. The flare phenomenon was characterized by a significant increase (≥20%) in the SUVmax of existing lesions or the appearance of new PSMA-positive lesions. Results: Exposure to enzalutamide led to a significant PSMA expression increase in 56% of assessed lesions (n = 42), with new lesions detected in 1 patient (11%). PSMA expression in organs at risk remained largely unaffected, indicating a tumor-specific response. Conclusion: Enzalutamide induces PSMA upregulation in metastatic castration-resistant prostate cancer, potentially enhancing diagnostic and therapeutic strategies. Further exploration of the flare phenomenon's clinical implications is warranted.
- MeSH
- antigeny povrchové * metabolismus MeSH
- benzamidy * MeSH
- fenylthiohydantoin * terapeutické užití analogy a deriváty MeSH
- glutamátkarboxypeptidasa II * metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prostaty rezistentní na kastraci * farmakoterapie diagnostické zobrazování metabolismus MeSH
- nitrily * terapeutické užití MeSH
- PET/CT * MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- upregulace * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Glioblastoma is the commonest malignant brain tumor and has a very poor prognosis. Reduced expression of the MGMT gene (10q26.3), influenced primarily by the methylation of two differentially methylated regions (DMR1 and DMR2), is associated with a good response to temozolomide treatment. However, suitable methods for detecting the methylation of the MGMT gene promoter and setting appropriate cutoff values are debated. RESULTS: A cohort of 108 patients with histologically and genetically defined glioblastoma was retrospectively examined with methylation-specific Sanger sequencing (sSeq) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) methods. The DMR2 region was methylated in 29% of samples, whereas DMR1 was methylated in 12% of samples. Methylation detected with the MS-MLPA method using probes MGMT_215, MGMT_190, and MGMT_124 from the ME012-A1 kit (located in DMR1 and DMR2) correlated with the methylation of the corresponding CpG dinucleotides detected with sSeq (p = 0.005 for probe MGMT_215; p < 0.001 for probe MGMT_190; p = 0.016 for probe MGMT_124). The threshold for methylation detection with the MS-MLPA method was calculated with a ROC curve analysis and principal components analysis of the data obtained with the MS-MLPA and sSeq methods, yielding a weighted value of 0.362. Thus, methylation of the MGMT gene promoter was confirmed in 36% of samples. These patients had statistically significantly better overall survival (p = 0.003). CONCLUSIONS: Our results show that the threshold for methylation detection with the MS-MLPA method determined here is useful from a diagnostic perspective because it allows the stratification of patients who will benefit from specific treatment protocols, including temozolomide. Detailed analysis of the MGMT gene promoter enables the more-precise and personalized treatment of patients with glioblastoma.
- MeSH
- CpG ostrůvky genetika MeSH
- DNA modifikační methylasy * genetika MeSH
- dospělí MeSH
- enzymy opravy DNA * genetika MeSH
- glioblastom * genetika farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metylace DNA * genetika MeSH
- nádorové supresorové proteiny * genetika MeSH
- nádory mozku * genetika MeSH
- promotorové oblasti (genetika) * genetika MeSH
- retrospektivní studie MeSH
- sekvenční analýza DNA metody MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- temozolomid terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- validační studie MeSH
Dry skin is a common condition that is experienced by many. Besides being particularly present during the cold season, various diseases exist all year round, leading to localized xerosis. To prevent it, the skin is provided with natural moisturizing factors (NMFs). They are small amino acids or derivatives found in the outermost layer of the skin, the stratum corneum (SC). They are often claimed to be highly efficient humectants, increasing the water content to maintain the fluidity of the skin. However, alternative mechanisms have been proposed, suggesting that NMFs themselves may act as lipid mobility amplifiers. This work aims at investigating the role of three NMFs, namely, urea (URE), glycerol (GLY), and urocanic acid/urocanate (UCA/UCO) in SC in silico models, considering two different levels of humidity. Molecular dynamic simulations showed an increase in the diffusion of different lipid components, mainly free fatty acids (FFAs) and ceramide acyl chain moieties, in the presence of either high water content or NMFs. The membrane properties were modified, as seen by an increased thickness and greater lateral stiffness. All NMFs exhibited a similar impact, whereas UCA revealed slight differences according to its charged state. By studying NMF-water intermolecular interactions, we highlighted the role of NMF as a regulator of membrane perturbations while ensuring membrane fluidity. This role allows NMFs to prevent destabilization of the skin membrane in the presence of high water content. This study, performed at an atomistic resolution, highlighted a strong H-bond network between lipids involving mainly ceramides but also all other components. This network can be modified in the presence of a high water concentration or NMFs, resulting in modifications of membrane properties, rationalizing hydration effects.
- MeSH
- glycerol * chemie MeSH
- kůže * chemie metabolismus MeSH
- kyselina urokanová chemie metabolismus MeSH
- lidé MeSH
- močovina * chemie MeSH
- simulace molekulární dynamiky * MeSH
- voda * chemie MeSH
- vodíková vazba * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
SIGNIFICANCE STATEMENT: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. More than 1500 patients were collated in an international longitudinal study to revise the ANCA kidney risk score. The score showed satisfactory performance, mimicking the original study (Harrell's C=0.779). In the development cohort of 959 patients, no additional parameters aiding the tool were detected, but replacing the GFR with creatinine identified an additional cutoff. The parameter interstitial fibrosis and tubular atrophy was modified to allow wider access, risk points were reweighted, and a fourth risk group was created, improving predictive ability (C=0.831). In the validation, the new model performed similarly well with excellent calibration and discrimination ( n =480, C=0.821). The revised score optimizes prognostication for clinical practice and trials. BACKGROUND: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. A retrospective international longitudinal cohort was collated to revise the ANCA renal risk score. METHODS: The primary end point was ESKD with patients censored at last follow-up. Cox proportional hazards were used to reweight risk factors. Kaplan-Meier curves, Harrell's C statistic, receiver operating characteristics, and calibration plots were used to assess model performance. RESULTS: Of 1591 patients, 1439 were included in the final analyses, 2:1 randomly allocated per center to development and validation cohorts (52% male, median age 64 years). In the development cohort ( n =959), the ANCA renal risk score was validated and calibrated, and parameters were reinvestigated modifying interstitial fibrosis and tubular atrophy allowing semiquantitative reporting. An additional cutoff for kidney function (K) was identified, and serum creatinine replaced GFR (K0: <250 μ mol/L=0, K1: 250-450 μ mol/L=4, K2: >450 μ mol/L=11 points). The risk points for the percentage of normal glomeruli (N) and interstitial fibrosis and tubular atrophy (T) were reweighted (N0: >25%=0, N1: 10%-25%=4, N2: <10%=7, T0: none/mild or <25%=0, T1: ≥ mild-moderate or ≥25%=3 points), and four risk groups created: low (0-4 points), moderate (5-11), high (12-18), and very high (21). Discrimination was C=0.831, and the 3-year kidney survival was 96%, 79%, 54%, and 19%, respectively. The revised score performed similarly well in the validation cohort with excellent calibration and discrimination ( n =480, C=0.821). CONCLUSIONS: The updated score optimizes clinicopathologic prognostication for clinical practice and trials.
- MeSH
- ANCA-asociované vaskulitidy * diagnóza MeSH
- atrofie MeSH
- fibróza MeSH
- kreatinin MeSH
- ledviny MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- protilátky proti cytoplazmě neutrofilů * MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH