ADT Group Research Articles

Synergistic Role of Aerobic Training and Resveratrol on AMPK/PGC1-α/SIRT1 Pathway in the Hippocampus of Rats with Alzheimer's Disease

Background: Alzheimer's disease symptoms indicate that increased Aβ leads to central nervous system dysfunction. Exercise reduces Aβ deposition through the AMPK signaling pathway. Additionally, resveratrol (RSV) has neuroprotective effects related to cognitive decline. Objectives: This study investigated the effects of aerobic training and RSV on the AMPK/PGC-1α/SIRT1 pathway in the hippocampus of Alzheimer's rats. Methods: Thirty-five male Wistar rats were divided into five groups: Normal (NO), Alzheimer's (AD), Alzheimer's-training (ADT), Alzheimer's-resveratrol (ADRSV), and Alzheimer's-training-resveratrol (ADTRSV). The supplement groups received 20 mg of RSV (per kg of body weight) orally during the intervention period. The aerobic exercise program, which included running on a treadmill at speeds of 6 - 18 meters per minute, was performed 5 days a week for eight weeks. Results: Alzheimer's induction caused a significant decrease in the expression of AMPK/PGC-1α/SIRT1 (P = 0.0001). Exercise and RSV significantly increased the expression of AMPK/PGC-1α/SIRT1 in AD rats (P < 0.05). Additionally, significant increases in the expression of AMPK, PGC-1α, and SIRT1 were observed in the ADTRSV group compared to the ADT group (P = 0.034, P = 0.020, and P = 0.038, respectively) and ADRSV (P = 0.026, P = 0.021, and P = 0.021). Conclusions: AD induction was associated with decreased AMPK/PGC-1α/SIRT1 expression. Aerobic exercise and RSV consumption can reverse this decrease. Given the crucial role of this signaling pathway in hippocampal function, alterations in these indicators following physical activity and RSV use may partially mitigate Alzheimer's disease complications.

Highlighting the effects of high-intensity interval training on the changes associated with hypertrophy, apoptosis, and histological proteins of the heart of old rats with type 2 diabetes

T2DM is known to cause disturbances in glucose homeostasis and negative changes in the heart muscle, while aging and diabetes are recognized risk factors for CVD. Given this, our study aims to investigate a method for controlling and managing CVDs induced by T2DM in elderly populations. To achieve this, we categorized 40 rats into 5 groups, including HAD (n = 8), HA (n = 8), AD (n = 8), AHT (n = 8), and ADT (n = 8). The exercise protocol consisted of eight weeks of HIIT (three sessions per week) performed at 90–95% of maximal speed. Following cardiac tissue extraction, we assessed the levels of IGF-1, PI3K, and AKT proteins using Western blot technique, and analyzed the histopathological variations of the heart tissue using H&E, Sudan Black, and Masson’s trichrome tissue staining. The histological findings from our study demonstrated that T2DM had a significant impact on the development of pathological hypertrophy and fibrosis in the heart tissue of elderly individuals. However, HIIT not only effectively controlled pathological hypertrophy and fibrosis, but also induced physiological hypertrophy in the AHT and ADT groups compared to the HA and AD groups. Results from Sudan Black staining indicated that there was an increase in lipid droplet accumulation in the cytoplasm of cardiomyocytes and their nuclei in the HA and AD groups, while the accumulation of lipid droplets decreased significantly in the AHT and ADT groups. In both the AHT group and the ADT group, a single HIIT session led to a reduction in collagen fiber accumulation and fibrotic frameworks. Our research also revealed that diabetes caused a significant elevation in the levels of IGF-1, PI3K, and AKT proteins, but after eight weeks of HIIT, the levels of these proteins decreased significantly in the training groups. Overall, our findings suggest that HIIT may be a suitable non-pharmacological approach for improving histological and physiological changes in elderly individuals with T2DM. However, we recommend further research to examine the impact of HIIT training on both healthy and diseased elderly populations.

Optimal treatment strategy and prognostic analysis for hypopharyngeal squamous-cell carcinoma patients with T3-T4 or node-positive: A population-based study

PurposeTo explore the optimal treatment strategy and relevant prognostic analysis for hypopharyngeal squamous-cell carcinoma patients (HSCC) with T3-T4 or node-positive. Methods and materialsFrom 2004 to 2018, data for 2574 patients from the Surveillance, Epidemiology, and End Results database (SEER) and 66 patients treated at our center from 2013 to 2022 with T3-T4 or N + HSCC were collected. Patients in the SEER cohort were randomly assigned to the training set or validation set at a 7:3 ratio. Variables with statistically significant (P < 0.05) in univariate COX regression analysis or clinical significance were included in the multivariate COX regression model and subsequently used to construct the nomogram. ResultsThe 3-year OS (52.9%vs44.4%, P < 0.01) and 3-year CSS rate (58.7%vs51.5%, P < 0.01) rates in the surgery combined with postoperative adjuvant therapy (S + ADT) group were superior to the radiotherapy combined with chemotherapy (CRT) group. The multivariate Cox regression analysis of the training group showed that age, race, marital status, primary site, T stage, N stage, and treatment modalities were correlated with OS and CSS. Based on those variables, we constructed nomograms for OS and CSS. Both the internal and external validation showed high prediction accuracy of the nomogram. ConclusionAmong patients with T3-T4 or node-positive, S + ADT was associated with superior OS and CSS compared to those treated with primary CRT, while the survival rate in the CRT group was comparable to S + ADT group in T2-T3 disease. The internal and external verification shows that the prognostic model has good discrimination ability and accuracy.

Assessment of oligometastasis status of prostate cancer following combined robot-assisted radical prostatectomy and androgen deprivation versus androgen deprivation therapy alone using PSA percentage decline rate.

To compare the tumor control in prostate cancer patients with oligo-metastasis following combined robot-assisted radical prostatectomy and androgen deprivation versus androgen deprivation therapy alone based on total prostate-specific antigen (tPSA) assessment. Medical data of a total of 18 prostate cancer patients with oligometastasis administered in The First Affiliated Hospital of Nanchang University from March 2017 to March 2018 were prospectively collected. 10 patients received a combined therapy of robot-assisted radical prostatectomy and pharmaceutical androgen deprivation (RARP+ADT group), while 8 patients received pharmaceutical androgen deprivation therapy alone (ADT group). Then demographic characteristics, prostate volume, tumor characteristics and tPSA data were analysised and compared. Statistical analysis was performed using t-test for continuous variables and Pearson chi-square test or Fisher's exact test for categorical variables. No significant difference was found in patients' age (p = 0.075), prostate volume (p = 0.134) and number of bone metastasis (p = 0.342). Pre-treatment Gleason score was significantly lower in RA group (p = 0.003). Patients in RARP+ADT group had significantly lower pre-treatment tPSA (p = 0.014), while no statistical difference was noted in reexamined tPSA (p = 0.140) on follow-up. No statistical difference was noted in tPSA decline rates (declined tPSA value per day) in RARP+ADT and ADT group (8.1 ± 4.7 verse 7.5 ± 8.0 ng/ml/d, p = 0.853). However, tPSA percentage decline rate (declined tPSA percentage per day) was significantly higher in RARP+ADT group (11.6 ± 1.5%/d verses 2.9 ± 2.2%/d, p< 0.001). Immediate urinary continence was achieved in 9 patients (90%) upon removal of urethral catheter on post-operative day 7 in RARP+ADT group. ADT alone and in combination with RARP both provide effective tumor control in patients suffering from prostate cancer with oligometastasis. ADT combined with RARP exhibited significant advantage in PSA percentage decline rate without compromising patients' urinary continence. Long-term tumor control requires further follow-up.

Magnetic Resonance-Guided Adaptive Radiation Therapy for Prostate Cancer: The First Results from the MOMENTUM study—An International Registry for the Evidence-Based Introduction of Magnetic Resonance-Guided Adaptive Radiation Therapy

Magnetic resonance (MR)-guided radiation therapy (MRgRT) is a new technique for treatment of localized prostate cancer (PCa). We report the 12-month outcomes for the first PCa patients treated within an international consortium (the MOMENTUM study) on a 1.5T MR-Linac system with ultrahypofractionated radiation therapy. Patients treated with 5×7.25 Gy were identified. Prostate specific antigen-level, physician-reported toxicity (Common Terminology Criteria for Adverse Events [CTCAE]), and patient-reported outcomes (Quality of Life Questionnaire PR25 and Quality of Life Questionnaire C30 questionnaires) were recorded at baseline and at 3, 6, and 12 months of follow-up (FU). Pairwise comparative statistics were conducted to compare outcomes between baseline and FU. The study included 425 patients with localized PCa (11.4% low, 82.0% intermediate, and 6.6% high-risk), and 365, 313, and 186 patients reached 3-, 6-, and 12-months FU, respectively. Median prostate specific antigen level declined significantly to 1.2 ng/mL and 0.1 ng/mL at 12 months FU for the nonandrogen deprivation therapy (ADT) and ADT group, respectively. The peak of genitourinary and gastrointestinal CTCAE toxicity was reported at 3 months FU, with 18.7% and 1.7% grade ≥2, respectively. The QLQ-PR25 questionnaire outcomes showed significant deterioration in urinary domain score at all FU moments, from 8.3 (interquartile range [IQR], 4.1-16.6) at baseline to 12.4 (IQR, 8.3-24.8; P=.005) at 3 months, 12.4 (IQR, 8.3-20.8; P=.018;) at 6 months, and 12.4 (IQR, 8.3-20.8; P=.001) at 12 months. For the non-ADT group, physician- and patient-reported erectile function worsened significantly between baseline and 12 months FU. Ultrahypofractionated MR-guided radiation therapy for localized PCa using a 1.5T MR-Linac is effective and safe. The peak of CTCAE genitourinary and gastrointestinal toxicity was reported at 3 months FU. Furthermore, for patients without ADT, a significant increase in CTCAE erectile dysfunction was reported at 12 months FU. These data are useful for educating patients on expected outcomes and informing study design of future comparative-effectiveness studies.

Docetaxel chemotherapy plus androgen-deprivation therapy in high-volume disease metastatic hormone-sensitive prostate cancer in Chinese patients: an efficacy and safety analysis

ObjectiveTo investigate the efficacy and safety of docetaxel chemotherapy combined with androgen-deprivation therapy for patients with high-volume disease metastatic hormone-sensitive prostate cancer.Methods153 cases of high-volume disease metastatic hormone-sensitive prostate cancer in Minhang Hospital between January 2018 and December 2019 were analyzed retrospectively, including the number of patients, age, initial PSA level, Gleason score, TNM stage and ECOG score. 90 patients in the endocrine therapy group received continuous ADT, and 63 patients in the combined chemotherapy group received docetaxel plus ADT. The progression-free survival time (time from initiation of prostate cancer treatment to progression to CRPC), PSA response rate, and adverse reactions were compared between the two groups.ResultsAll 153 cases were closely followed up for a period of 12.3–35.3 months, with a median follow-up time of 23.5 months. The median time to reach the lowest point of PSA in the two groups was 6.3 months and 7.9 months (P = 0.018) in the combination chemotherapy group and the ADT group alone, with 27 (42.9%) and 12 (13.3%) cases in the two groups Within 12 months of treatment, PSA decreased to below 0.2 ng/ml (P = 0.02), and progression-free survival was 16.9 months (6.5–28.5 months) and 11.2 months (4.3–22.7 months) in the two groups. (P < 0.001). There were 18 cases (28.6%) and 54 cases (60%) in the two groups with disease progression (P < 0.001). There were 6 cases (9.5%) and 15 cases (16.7%) in the combination chemotherapy group and the ADT group died of prostate cancer and related complications, respectively. All 63 cases in the combined chemotherapy group completed 6 cycles of chemotherapy. 39 (61.9%) cases experienced varying degrees of neutropenia, of which 12 (19%) experienced grade 3–4 neutropenia, with 6 cases (9.5%) developed febrile neutropenia. 30 cases (47.6%) had toxic reactions in the digestive system, and 3 case (4.3%) had grade 3 liver dysfunction. 27 cases (42.8%) had skin and mucosal toxicity. 9 cases (14.3%) had mild fluid retention. No blood and digestive toxicity were observed in the ADT group. 33 cases (52.4%) and 48 (53.3%) of the two groups had symptoms of afternoon hot flashes and fatigue, (P = 0.961).ConclusionDocetaxel chemotherapy combined with endocrine therapy could be one of effective treatments for delaying castration resistance of HVD-mHSPC, which could prolong PFS effectively and obtain a higher PSA response rate, high safety under close monitoring, and controllable adverse reactions.

Stereotactic Radiotherapy for Lesions Detected via 68Ga-Prostate-specific Membrane Antigen and 18F-Fluorodexyglucose Positron Emission Tomography/Computed Tomography in Patients with Nonmetastatic Prostate Cancer with Early Prostate-specific Antigen Progression on Androgen Deprivation Therapy: A Prospective Single-center Study

BackgroundDual-tracer positron emission tomography/computed tomography (PET/CT) with a 68Ga-labelled prostate-specific membrane antigen (PSMA) ligand and 18F-fluorodeoxyglucose (FDG) improves detection of metastatic heterogeneity and burden in patients with nonmetastatic prostate cancer (nmPCa). However, there is limited prospective evidence regarding its impact on the efficacy of stereotactic body radiotherapy (SBRT). ObjectiveTo evaluate metastasis-free survival (MFS) and toxicity after SBRT to dual-tracer PET/CT-detected metastases in patients with nmPCa and early prostate-specific antigen (PSA) progression on androgen deprivation therapy (ADT; PSA ≤2 ng/ml). Design, setting, and participantsPatients were prospectively screened using dual-tracer PET/CT between April 2019 and October 2020. SBRT was recommended for patients with five or fewer nonvisceral metastases (SBRT group). Patients without detectable metastases (N−/M− group) and those who refused SBRT (ADT group) continued to receive ADT. Patients were followed with conventional imaging. InterventionSBRT to each PET/CT-detected metastasis. Outcome measurements and statistical analysisKaplan-Meier methods were used to determine MFS. Toxicity was evaluated using Common Terminology Criteria for Adverse Event v4.0. Results and limitationsSeventy-four consecutive patients were screened. The median PSA and PSA doubling time were 0.59 ng/ml and 4.56 mo, respectively. Overall, 54 patients had metastases and 17 had PSMA-/FDG+ disease. Seven patients were excluded from the MFS analysis, including two with a history of abiraterone treatment and five with more than five metastases. The median follow-up was 21.4 mo. The ADT group had shorter MFS than the SBRT group (11.0 mo vs not reached; hazard ratio [HR] 4.69, 95% confidence interval [CI] 2.92–25.0; p < 0.001) and the N−/M− group (11.0 mo vs not reached; HR 8.78, 95% CI 4.04–40.30; p < 0.001). There was no significant difference in median MFS between the SBRT group and the N−/M− group (p = 0.261). A PSA response >90% was achieved by 86% of patients in the SBRT group. There were no grade ≥3 adverse events after SBRT. The nonrandomized design is the major study limitation. ConclusionsDual-tracer PET/CT-guided SBRT delivered superior local control rates in comparison to ADT alone and had minimal toxicity. Patient summaryWe investigated metastasis-targeted radiotherapy for patients with up to five prostate cancer metastases detected with two different radioisotope scans. Our results show that this approach yields promising metastasis-free survival and low toxicity.

Cardiovascular toxicities of androgen deprivation therapy in Asian men with localized prostate cancer after curative radiotherapy: a registry-based observational study

BackgroundAndrogen deprivation therapy (ADT) and radiotherapy (RT) are the mainstay treatment for localized prostate cancer and recurrence after surgery. Cardiovascular (CV) toxicity of ADT is increasingly recognized, and the risk relates to pre-existing risk factors and ADT modalities. Despite ethnic differences in the prevalence of CV risk factors and variations of CV mortality, data on ADT-related cardiotoxicities in the Asian population remain inconclusive. Our registry-based study investigated ADT-related major adverse cardiovascular events (MACE) after primary or salvage RT.MethodsOur study combined two prospectively established registry databases from National Cancer Center Singapore and National Heart Center Singapore. The primary endpoint is time to first MACE after treatment. MACE is defined as myocardial infarction, stroke, unstable angina, or cardiovascular death. Two types of propensity score adjustments, including ADT propensity score as a covariate in the multivariable regression model and propensity score weighting, were applied to balance baseline features and CV risk factors between RT alone and RT + ADT groups.ResultsFrom 2000 to 2019, 1940 patients received either RT alone (n = 494) or RT + ADT (n = 1446) were included. After a median follow-up of 10 years (RT) and 7.2 years (RT+ ADT), the cumulative incidence of MACE at 1, 3 and 9 years was 1.2, 5 and 16.2% in RT group, and 1.1, 5.2 and 17.6% in RT + ADT group, respectively. There were no differences in the incidence of MACE between 2 groups (HR 1.01, 95% CI 0.78–1.30, p = 0.969). Pre-treatment CV risk factors were common (80%), and CV disease (15.9%) was the second leading cause of death after prostate cancer (21.1%). On univariate analysis, older age, Indians and Malays, pre-existing CV risk factors, and history of MACE were associated with higher MACE risk. After propensity score adjustments, there remained no significant differences in MACE risk between RT + ADT and RT group on multivariable analysis.ConclusionsIn our registry-based study, ADT is not associated with increased risk of major cardiovascular events among Southeast Asian men with prostate cancer after curative radiotherapy.

Androgen-deprivation therapy and cognitive decline in the NEON-PC prospective study during the COVID-19 pandemic

BackgroundAndrogen-deprivation therapy (ADT) has been associated with cognitive decline, but results are conflicting. This study describes changes in cognitive performance in patients with prostate cancer, according to ADT, during the first year after prostate cancer diagnosis.Patients and methodsPatients with prostate cancer treated at the Portuguese Institute of Oncology of Porto (n = 366) were evaluated with the Montreal Cognitive Assessment (MoCA), before treatment and after 1 year. All baseline evaluations were performed before the coronavirus disease 2019 (COVID-19) pandemic and 69.7% of the 1-year assessments were completed after the first lockdown. Cognitive decline was defined as the decrease in MoCA from baseline to the 1-year evaluation below 1.5 standard deviations of the distribution of changes in the whole cohort. Participants scoring below age- and education-specific normative reference values in the MoCA were considered to have cognitive impairment. Age- and education-adjusted odds ratios (aORs) were computed for the association between ADT and cognitive outcomes.ResultsMean MoCA scores increased from baseline to the 1-year evaluation (22.3 versus 22.8, P < 0.001). Cognitive decline was more frequent in the ADT group, and even more after the onset of the COVID-19 pandemic (aOR 6.81 versus 1.93, P for interaction = 0.233). The 1-year cumulative incidence of cognitive impairment was 6.9% (9.1% before and 3.7% after the pandemic onset), which was higher among patients receiving ADT, but only after the pandemic (aOR 5.53 versus 0.49, P for interaction = 0.044).ConclusionsADT was associated with worse cognitive performance of patients with prostate cancer, mostly among those evaluated after the first COVID-19 lockdown.

Effect of androgen deprivation therapy on bone mineral density in patients with prostate cancer.

Objectives:To access the effects of acute and chronic Androgen Deprivation Therapy on Bone Marrow Density and related bone markers; to compare the bone loss among the patients who terminated GnRH use and control group (not given ADP therapy at all) with the ones with acute or chronic Androgen Deprivation Therapy.Methods:A cross-sectional study was conducted in the Oncology Department of Nishtar Medical University & Hospital Multan for one year. Bone mineral density of the entire body, 1/3rd distal radius, ultra-distal forearm, femoral neck, and lumbar spine, was measured in 40 patients diagnosed with non-metastatic prostate cancer at baseline for the duration of six months. They were categorized into four groups: (i) acute ADT (less than six months of treatment; (ii) chronic ADT (greater than six months of treatment; (iii) former ADT; and (iv) no ADT (placebo groups). Quantitative measures of bone metabolism marker, including C-terminal cross-linking telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) was done.Results:The cross-sectional analysis showed that BMD dropped significantly in more in patients with former ADT or control groups as compared to chronic ADT. At the 6th month assessment, a significant decline in ultra-distal forearm BMD was demonstrated in patients from both acute and chronic ADT groups (4.05% and 2.54%, P = .001 and .016, respectively). Total body BMD was significantly reduced among those on acute treatment (2.91%, p=0.022). In the former ADT group, a significant increase of BMD was observed in the femoral neck and lumbar spine bones (1.60 % and 2.85%, P = .001 and .0064, respectively). The difference of changes in BMD of the acute and chronic groups was not significant. The levels of PINP and CTX levels were significantly increased in an chronic and acute group than in placebo or former ADT groups.Conclusion:Chronic and acute ADT users experience similar changes in BMD levels but reversibility of BMD can be achieved on withdrawal of treatment. Similarly disturbed bone metabolism markers come back in range on withdrawal of treatment.

Modulation of Long-Term Potentiation by Gamma Frequency Transcranial Alternating Current Stimulation in Transgenic Mouse Models of Alzheimer's Disease.

Transcranial alternating current stimulation (tACS) is a neuromodulation procedure that is currently studied for the purpose of improving cognitive function in various diseases. A few studies have shown positive effects of tACS in Alzheimer’s disease (AD). However, the mechanism underlying tACS has not been established. The purpose of this study was to investigate the mechanism of tACS in five familial AD mutation (5xFAD) mouse models. We prepared twenty 4-month-old mice and divided them into four groups: wild-type mice without stimulation (WT-NT group), wild-type mice with tACS (WT-T group), 5xFAD mice without stimulation (AD-NT group), and 5xFAD mice with tACS (AD-T group). The protocol implemented was as follows: gamma frequency 200 μA over the bilateral frontal lobe for 20 min over 2 weeks. The following tests were conducted: excitatory postsynaptic potential (EPSP) recording, Western blot analysis (cyclic AMP response element-binding (CREB) proteins, phosphorylated CREB proteins, brain-derived neurotrophic factor, and parvalbumin) to examine the synaptic plasticity. The EPSP was remarkably increased in the AD-T group compared with in the AD-NT group. In the Western blot analysis, the differences among the groups were not significant. Hence, tACS can affect the long-lasting enhancement of synaptic transmission in mice models of AD.

Comparison of the wound-healing efficacy of gelatin sponge dressings and that of artificial dermis using atelocollagen in a rat cranial periosteal defect model.

In oral surgery, tissue loss may occur in some cases, resulting in bone exposure and subsequent wound infection and possible scar formation during secondary healing. In this study, Terudermis® Artificial Dermis (AD-T), a dermal defect graft made from processed bovine dermis collagen and gelatin sponge (GS) were used as dressings on 100-mm2 wounds with exposed bone on the heads of rats. For the control group, the wound was left exposed. The wound-healing efficacy of the treatment was compared macroscopically and histologically among the three groups at 1, 2, and 4 weeks after surgery. Complete wound healing was achieved faster in the AD-T group than in the GS group, and osteoblasts appeared on the bone surface, indicating accelerated bone remodeling. Furthermore, in the AD-T group, there was an increased production of newly formed blood vessels, fibroblasts and osteoblasts positive for anti-cortactin antibodies, which are believed to contribute to wound healing. Our findings suggest that AD-T is better than GS as a wound dressing material.

PD57-11 IDENTIFICATION OF THE BEST CANDIDATES FOR PSMA PET/CT AMONG PATIENTS EXPERIENCING BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY

You have accessJournal of UrologyProstate Cancer: Localized: Surgical Therapy IV (PD57)1 Sep 2021PD57-11 IDENTIFICATION OF THE BEST CANDIDATES FOR PSMA PET/CT AMONG PATIENTS EXPERIENCING BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY Giorgio Gandaglia, Daniele Robesti, Nicola Fossati, Giuseppe Rosiello, Francesco Barletta, Elio Mazzone, Simone Scuderi, Vito Cucchiara, Umberto Capitanio, Andrea Necchi, Andrea Salonia Milan, Italy, Pierre I Karakiewicz, Montreal, Canada, Francesco Montorsi, and Alberto Briganti Giorgio GandagliaGiorgio Gandaglia More articles by this author , Daniele RobestiDaniele Robesti More articles by this author , Nicola FossatiNicola Fossati More articles by this author , Giuseppe RosielloGiuseppe Rosiello More articles by this author , Francesco BarlettaFrancesco Barletta More articles by this author , Elio MazzoneElio Mazzone More articles by this author , Simone ScuderiSimone Scuderi More articles by this author , Vito CucchiaraVito Cucchiara More articles by this author , Umberto CapitanioUmberto Capitanio More articles by this author , Andrea NecchiAndrea Necchi More articles by this author , Andrea Salonia Milan, ItalyAndrea Salonia Milan, Italy More articles by this author , Pierre I Karakiewicz, Montreal, CanadaPierre I Karakiewicz, Montreal, Canada More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , and Alberto BrigantiAlberto Briganti More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002091.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although PSMA PET/CT is recommended in the biochemical recurrence (BCR) setting after radical prostatectomy (RP), its impact on clinical management is unclear. This is particularly true when considering prostate cancer (PCa) patients at low risk of metastases who could be managed with salvage radiotherapy (sRT) alone. We aimed at assessing when PSMA PET/CT could be safely avoided or postponed METHODS: 182 patients evaluated with PSMA PET/CT for BCR after RP between 2016 and 2020 were evaluated. The outcome was a distant metastasis (i.e., retroperitoneal, skeletal or visceral) at PSMA PET/CT. Multivariable logistic regression analyses assessed predictors of distant spots (i.e., pathological stage, grade group, sRT and ADT). The model based on the regression coefficients was internally validated. An interaction analysis tested whether the association between PSA at PET/CT and distant spots varied according to the risk calculated using the model. Patients were stratified according to the model-derived risk (<30 vs. ≥30%) and the rate of distant spots at PET/CT was plotted against PSA values RESULTS: Median PSA at PET/CT scan was 0.7 ng/ml. Overall, 76 (41.5%) and 57 (31.1%) had grade group 4-5 and seminal vesicle invasion (SVI). Overall, 60 (32.8%) and 24 (13.1%) patients received sRT and ADT before PSMA PET/CT. Overall, 59 (32.2%) patients had distant spots at PSMA PET/CT. Concomitant ADT (Hazard Ratio [HR]: 5.5; p=0.02), SVI (HR:3.5; p=0.005) and grade group 4-5 (HR:3.7; p=0.01) predicted distant spots at PET/CT (AUC: 80%). The rate of distant positive spots in men with grade group 1-3, no SVI and no ADT (n=34, 18.6%) was 12%. This increased to 41% in patients with adverse factors (p<0.001). The impact of PSA values at PSMA PET/CT varied according to the novel risk score (p=0.03 by interaction test). While in men with a calculated risk <30% increasing PSA values at PSMA PET/CT did not impact on the risk of distant metastases at PSMA PET/CT, in those with worse characteristics it increased according to PSA levels. CONCLUSIONS: The use of PSMA PET/CT can be safely avoided or postponed in individuals with grade group 1-3, no SVI and who did not receive previous salvage therapies. These patients can be considered candidates to sRT without a previous PSMA PET/CT. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1014-e1014 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Giorgio Gandaglia More articles by this author Daniele Robesti More articles by this author Nicola Fossati More articles by this author Giuseppe Rosiello More articles by this author Francesco Barletta More articles by this author Elio Mazzone More articles by this author Simone Scuderi More articles by this author Vito Cucchiara More articles by this author Umberto Capitanio More articles by this author Andrea Necchi More articles by this author Andrea Salonia Milan, Italy More articles by this author Pierre I Karakiewicz, Montreal, Canada More articles by this author Francesco Montorsi More articles by this author Alberto Briganti More articles by this author Expand All Advertisement Loading ...

Steroid Hormone Biosynthesis Metabolism Is Associated With Fatigue Related to Androgen Deprivation Therapy for Prostate Cancer.

BackgroundAndrogen deprivation therapy (ADT) is a cornerstone treatment for prostate cancer. Despite the clinical benefits, ADT is associated with multiple adverse effects including fatigue. The goal of the study was to examine metabolomic changes to better understand cancer-related fatigue specific to ADT treatment.MethodsA total of 160 plasma samples collected from participants with (+ADT, n = 58) or without neoadjuvant ADT (−ADT, n = 102) prior to radiation therapy for treatment of non-metastatic localized prostate cancer were included in the study. Fatigue and sleep-related impairment were measured using the Patient Reported Outcomes Measurement Information System. Plasma metabolites were identified and measured using untargeted ultrahigh-performance liquid chromatography/mass spectrometry metabolomics analyses. Partial least square discriminant analysis was used to identify discriminant metabolite features, and the diagnostic performance of selected classifiers was quantified using AUROC curve analysis. Pathway enrichment analysis was performed using metabolite sets enrichment analyses.FindingsSteroid hormone biosynthesis pathways, including androstenedione metabolism as well as androgen and estrogen metabolism, were overrepresented by metabolites that significantly discriminated samples in the +ADT from the −ADT group. Additional overrepresented metabolic pathways included amino acid metabolism, glutathione metabolism, and carnitine synthesis. Of the metabolites that were significantly different between the groups, steroid hormone biosynthesis metabolites were most significantly correlated with fatigue severity. Sleep-related impairment was strongly correlated with fatigue severity and inversely correlated with ADT-induced reduction in androsterone sulfate.ConclusionsPatients with non-metastatic prostate cancer receiving neoadjuvant ADT prior to radiation therapy reported relatively more severe fatigue. Increased fatigue in this population may be attributable to sleep-related impairment associated with alterations in steroid hormone biosynthesis. Findings in this study provide a basis for further research of changes in sleep patterns and their role in this specific subcategory of cancer-related fatigue caused by the treatment.

PCN20 Can Real-World Data Replicate RCT Results? A Retrospective Comparative Effectiveness Study Of Docetaxel In Metastatic Hormone Sensitive Prostate Cancer Using German Claims Data

Using real-world evidence to evaluate medical interventions is largely debated. Taking metastatic hormone-sensitive prostate cancer (mHSPC) as an example, we aimed to compare the real-world overall survival advantage of docetaxel over ADT monotherapy with the efficacy results from the CHAARTED trial. This was a retrospective observational study using German claims data. We identified mHSPC patients between 01/01/2014-31/12/2018, replicating the inclusion and exclusion criteria of the CHAARTED trial. Patients treated with docetaxel in combination with ADT at first line (docetaxel group) were compared with patients treated with ADT monotherapy (ADT group). Patients were matched using propensity score matching (PSM), and overall survival after start of therapy was compared between the two matched cohorts. Of 39,932 prostate cancer patients, 2,354 were mHSPC patients. Of these, 69 were included in the docetaxel group and 616 in the ADT group. After PSM, 56 patients were included in each group with no significant differences in baseline characteristics. Compared to patients in the CHAARTED trial, real-world patients included in the study were older (median age 68 years compared to 63 in the trial). Median survival was shorter for real-world patients (28.7 months in the ADT group, 36.7 months in the docetaxel group; median follow-up: 19.1 months) compared to patients in the trial (44 months in the ADT group, 57.6 months in the docetaxel group; median follow-up: 28.9 months). The hazard ratio was 0.58 (95% CI, 0.30-1.10) using real world data, compared to 0.61 (95% CI, 0.47-0.80) in the trials. Overall survival was shorter in the real-world compared to the trial, but the effect size was comparable despite differences in patient characteristics. While unobservable patient characteristics, low sample size, and regional bias are limitations of the study, results suggest that real-world data have the potential to replicate and complement results from CHAARTED.

Temperature Dependence of Structural Dynamics at the Catalytic Cofactor of [FeFe]-hydrogenase.

[FeFe]-hydrogenases are nature's blueprint for efficient hydrogen turnover. Understanding their enzymatic mechanism may improve technological H2 fuel generation. The active-site cofactor (H-cluster) consists of a [4Fe-4S] cluster ([4Fe]H), cysteine-linked to a diiron site ([2Fe]H) carrying an azadithiolate (adt) group, terminal cyanide and carbon monoxide ligands, and a bridging carbon monoxide (μCO) in the oxidized protein (Hox). Recently, the debate on the structure of reduced H-cluster states was intensified by the assignment of new species under cryogenic conditions. We investigated temperature effects (4-280 K) in infrared (IR) and X-ray absorption spectroscopy (XAS) data of [FeFe]-hydrogenases using fit analyses and quantum-chemical calculations. IR data from our laboratory and literature sources were evaluated. At ambient temperatures, reduced H-cluster states with a bridging hydride (μH-, in Hred and Hsred) or with an additional proton at [4Fe]H (Hred') or at the distal iron of [2Fe]H (Hhyd) prevail. At cryogenic temperatures, these species are largely replaced by states that hold a μCO, lack [4Fe]H protonation, and bind an additional proton at the adt nitrogen (HredH+ and HsredH+). XAS revealed the atomic coordinate dispersion (i.e., the Debye-Waller parameter, 2σ2) of the iron-ligand bonds and Fe-Fe distances in the oxidized and reduced H-cluster. 2σ2 showed a temperature dependence typical for the so-called protein-glass transition, with small changes below ∼200 K and a pronounced increase above this "breakpoint". This behavior is attributed to the freezing-out of larger-scale anharmonic motions of amino acid side chains and water species. We propose that protonation at [4Fe]H as well as ligand rearrangement and μH- binding at [2Fe]H are impaired because of restricted molecular mobility at cryogenic temperatures so that protonation can be biased toward adt. We conclude that a H-cluster with a μCO, selective [4Fe]H or [2Fe]H protonation, and catalytic proton transfer via adt facilitates efficient H2 conversion in [FeFe]-hydrogenase.

Anodal Transcranial Direct Current Stimulation Can Improve Spatial Learning and Memory and Attenuate Aβ42 Burden at the Early Stage of Alzheimer's Disease in APP/PS1 Transgenic Mice.

Alzheimer’s disease (AD) is an irreversible progressive neurodegenerative disease. Intervention in the early stage of AD is a new path for AD treatment that is being explored. The behavioral and pathological effects of anodal transcranial direct current stimulation (AtDCS) at the early stage of AD in the mouse model, amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice, were investigated based on our previous studies. Thirty-three 6-month-old male APP/PS1 mice were randomly divided into the model group (AD group), model + sham stimulation group (ADST group) and stimulation group (ADT group). Eleven 6-month-old male C57 wild-type mice were randomly selected as a control group (CTL group). The ADT group received 10 AtDCS sessions. The Morris water maze (MWM) task and novel object recognition (NOR) task were used to test mouse memory. Nissl staining, Western blot (WB), immunohistochemistry and immunofluorescence staining of β-amyloid (Aβ42), glial fibrillary acidic protein (GFAP) and NF200 were conducted for pathological analysis. The ADT group and the CTL group had a shorter escape latency and more platform-region crossings than the AD group and ADST group in the MWM. There was no significant difference in the discrimination index among the groups in the NOR task. Pathological analysis showed visible differences between the AD group and ADT group. This study revealed that early-stage APP/PS1 transgenic mice did not show recognition memory impairment. AtDCS effectively improved spatial learning and memory in the early-stage APP/PS1 transgenic mouse model of AD, alleviating Aβ burden and having a protective effect on neurons. AtDCS could improve AD-related symptoms by activating many glial cells to promote the degradation and clearance of Aβ or directly affecting production and degradation of Aβ to reduce glial activation. AtDCS is an effective means of early intervention in the early stage of AD.

A drug potency signature links progression of chronic lymphocytic leukemia to mitochondria-related stress responses and metabolic reprogramming under hypoxia

Chronic lymphocytic leukemia (CLL) cells change their metabolic program between normoxia and hypoxia, possibly affecting cytotoxic drug potency by altering mitochondria-related cell stress responses (MRCSR) including mitophagy, mitochondrial biogenesis, and mitochondrial proteostasis. We evaluated in CLL cells from nine patients, the single and multiple-combined drug potency of arsenic trioxide (ATO), valproic acid (VPA), vincristine (VCR) and MG132 as four pharmacological sensors influencing mitochondrial apoptosis, mitochondrial biogenesis, mitophagy, and mitochondrial proteostasis respectively, under normoxia and hypoxia to force hypoxia-induced metabolic reprogramming (HMR). Untreated cells from all patients remained viable under O2 levels below 0.5% for 72 h. We obtained 21 measures of drug potency and interaction at 50% effect level that we denoted drug potency signature (DPS). Using the comparative DPS between normoxia and hypoxia, two non-supervised classification algorithms discriminated CLL patients with active disease (ADT) and stable disease (NAD) and showed complete consistency with their clinical characteristics. In ADT group under hypoxia, the potency of MG132 was increased, the interaction of ATO + VPA and ATO + VPA + VCR shifted towards antagonism, and ATO + VPA + VCR + MG132 shifted towards synergism, indicating a prominent role of mitochondrial proteostasis. Classification of patients based on DPS, depended on the contrasting response of drugs under hypoxia and normoxia, owing to HMR. Using these drugs as pharmacological sensors, we linked the metabolic arrangement of CLL cells under hypoxia, to potency of drugs targeting MRCSR, and to the clinical features of individual patients, therefore providing new sources of data on disease progression, drug response and risk prognosis.

Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches.

Androgen deprivation therapy alone has been the standard of care for metastatic hormone sensitive prostate cancer for the last 75 years. This review focuses on recent trials and mechanisms which highlight the new paradigm of combining androgen deprivation therapy with other agents, changing the treatment of patients with prostate cancer who have advanced disease. We searched the peer reviewed literature on the PubMed® and Web of Science® databases through January 2018 using the key words, "metastatic hormone sensitive prostate cancer," "metastatic castration sensitive prostate cancer," "docetaxel," "abiraterone" and "senescence in cancer." ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings were also evaluated. Recently published, phase III trials using androgen deprivation therapy combinations for metastatic hormone sensitive prostate cancer can be broadly grouped into chemohormonal studies (docetaxel) or trials of androgen signaling inhibitors. The CHAARTED (Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) studies showed a survival advantage when combining androgen deprivation therapy with chemotherapy, as well as increased time to progression to castration resistant status. The abiraterone arm of the STAMPEDE and LATITUDE trials, which analyzed combining androgen deprivation therapy with abiraterone, revealed improved overall and progression-free survival. Androgen deprivation therapy generates a number of phenotypes in resistant cancer cells, including quiescence, autophagy and cellular senescence. Senescent cells represent a metabolic target for synergistic lethality with drugs such as metformin. Ongoing trials are under way to examine the effect of combining newer antiandrogens and novel drugs with androgen deprivation therapy in patients with metastatic hormone sensitive prostate cancer. Combination therapy has evolved as the standard of care for metastatic hormone sensitive prostate cancer. The ideal combination is tailored to patients after individualized counseling taking into account general health and comorbid illness status.

Oncological and peri-surgical outcomes of radical prostatectomy for non-metastatic prostate cancer with prostate-specific antigen level of 50 ng/ml or greater

The role of radical prostatectomy in treating non-metastatic prostate cancer patients with high prostate-specific antigen levels remains unclear. We evaluated the feasibility and oncological outcomes of radical prostatectomy in non-metastatic prostate cancer patients with prostate-specific antigen levels of 50 ng/ml or higher. This retrospective study included 31 patients who were diagnosed as very high-risk prostate cancer (clinical stage of any T, N0-1 M0 and PSA levels ≥50 ng/ml) and underwent radical prostatectomy either as a monotherapy or as a component of multimodal therapy (RP group). Surgery-related complications were investigated. Time to castration-resistant prostate cancer, cancer-specific survival, and overall survival were estimated using the Kaplan-Meier method. A total of 47 patients with very high-risk prostate cancer who were treated with androgen deprivation therapy without local therapy served as a control group (ADT group). Survivals were compared between RP group and ADT group in exploratory analyses. The median pretreatment prostate-specific antigen was 87 ng/ml and 100 ng/ml in the RP and ADT groups, respectively (P = 0.67). Surgical complications of Clavien-Dindo Grade 3 were documented in nine patients (29%). Ten-year castration-resistant prostate cancer-free, cancer-specific and overall survivals were 78%, 81% and 77% in RP group, respectively, and they were significantly better than those of ADT group (54%, P = 0.006; 54%, P = 0.006 and 38%, P < 0.001). Exploratory multivariate analysis identified radical prostatectomy as the only significant factor associated with a better cancer-specific survival (hazard ratio: 0.25, P = 0.006). Radical prostatectomy is feasible for non-metastatic prostate cancer patients with prostate-specific antigen levels of 50 ng/ml or higher. Radical prostatectomy is a viable option for select patients with non-metastatic, very high-risk prostate cancer.