hormone sensitive
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2022 ◽  
Vol 23 (1) ◽  
pp. 559
Author(s):  
Iris Stoltenborg ◽  
Fiona Peris-Sampedro ◽  
Erik Schéle ◽  
Marie V. Le May ◽  
Roger A. H. Adan ◽  
...  

The availability of Cre-based mouse lines for visualizing and targeting populations of hormone-sensitive cells has helped identify the neural circuitry driving hormone effects. However, these mice have limitations and may not even be available. For instance, the development of the first ghrelin receptor (Ghsr)-IRES-Cre model paved the way for using the Cre-lox system to identify and selectively manipulate ghrelin-responsive populations. The insertion of the IRES-Cre cassette, however, interfered with Ghsr expression, resulting in defective GHSR signaling and a pronounced phenotype in the homozygotes. As an alternative strategy to target ghrelin-responsive cells, we hereby utilize TRAP2 (targeted recombination in active populations) mice in which it is possible to gain genetic access to ghrelin-activated populations. In TRAP2 mice crossed with a reporter strain, we visualized ghrelin-activated cells and found, as expected, much activation in the arcuate nucleus (Arc). We then stimulated this population using a chemogenetic approach and found that this was sufficient to induce an orexigenic response of similar magnitude to that induced by peripheral ghrelin injection. The stimulation of this population also impacted food choice. Thus, the TRAPing of hormone-activated neurons (here exemplified by ghrelin-activated pathways) provides a complimentary/alternative technique to visualize, access and control discrete pathways, linking hormone action to circuit function.


2022 ◽  
Vol 11 (1) ◽  
pp. 257
Author(s):  
Francis P. Young ◽  
Therese M. Becker ◽  
Mohammed Nimir ◽  
Thomas Opperman ◽  
Wei Chua ◽  
...  

Androgen Receptor (AR) alterations (amplification, point mutations, and splice variants) are master players in metastatic castration resistant prostate cancer (CRPC) progression and central therapeutic targets for patient management. Here, we have developed two multiplexed droplet digital PCR (ddPCR) assays to detect AR copy number (CN) and the key point mutation T877A. Overcoming challenges of determining gene amplification from liquid biopsies, these assays cross-validate each other to produce reliable AR amplification and mutation data from plasma cell free DNA (cfDNA) of advanced prostate cancer (PC) patients. Analyzing a mixed PC patient cohort consisting of CRPC and hormone sensitive prostate cancer (HSPC) patients showed that 19% (9/47) patients had AR CN amplification. As expected, only CRPC patients were positive for AR amplification, while interestingly the T877A mutation was identified in two patients still considered HSPC at the time. The ddPCR based analysis of AR alterations in cfDNA is highly economic, feasible, and informative to provide biomarker detection that may help to decide on the best follow-up therapy for CRPC patients.


2022 ◽  
pp. 41-45
Author(s):  
Sh. G. Khakimova ◽  
G. G. Khakimova ◽  
G. A. Khakimov ◽  
J. B. Sadullaev

Currently, there is no consensus on the place of prostatectomy in the complex treatment of patients with metastatic prostate cancer. A description of a clinical case of complex treatment and observation of a patient with prostate cancer with an unfavorable baseline prognosis and the presence of bone metastases with a good clinical result is presented.


2022 ◽  
Vol Volume 14 ◽  
pp. 89-101
Author(s):  
Giulia Marvaso ◽  
Stefania Volpe ◽  
Matteo Pepa ◽  
Mattia Zaffaroni ◽  
Giulia Corrao ◽  
...  

2021 ◽  
Vol 9 (4) ◽  
pp. 70-86
Author(s):  
K. M. Nyushko ◽  
V. M. Perepukhov ◽  
B. Ya. Alekseev

Introduction. In recent years, interest in the use of radical prostatectomy (RPE) as one of the components of a multimodal approach in patients with lymphogenous disseminated and metastatic prostate cancer (PCa) has grown significantly. At the same time, the dearth of large randomized trials does not make it possible to use this technique in wide clinical practice outside of clinical trials.Purpose of the study. To evaluate the effectiveness of multimodal therapy using combined chemo-hormonal, surgical and radiation therapy in patients with primary oligometastatic hormone-sensitive PCa.Material and methods. The study included 48 patients with primary oligometastatic prostate cancer who received combination treatment within the internal one-research-center protocol. At the first stage, all patients underwent combined drug therapy with docetaxel (75 mg/m2 intravenously every 3 weeks for 6 courses) and degarelix. Patients who had a decrease in PSA level ≤ 2 ng/ml and registered stabilization of the disease according to radiological examination were treated surgically through RPE with extended pelvic and retroperitoneal lymph node dissection. Radiation therapy was performed only in patients with the presence of bone lesions at a dose of 50-70 Gy to the location of bone metastases in the stage 3 plan of combined multimodal therapy.Results. PCa biochemical relapse was verified in 27 (56.3%) patients during the median follow-up of 10 months. The average time to PSA increase was 9.0 ± 5.7 months (from 1 to 24 months), median — 7 months, Six-month PSA relapse-free survival (PSA-RFS) was 61.2 ± 7.5%; 1-year PSA-RFS — 38.0 ± 8.6%. The average duration before the initiation of hormonal therapy was 12 ± 6.1 months (from 3 to 27 months), median: 10 months. Six-month survival before the drug administration was 72.6 ± 6.8%; twelve-month survival: 40.9 ± 8.7%. About 40% of patients with oligometastatic PCa had no signs of progression and did not receive any other drug therapy for 12 months after completion of protocol treatment.Conclusions. Analysis of the study results demonstrates satisfactory oncological outcomes of the studied treatment option in patients with newly diagnosed oligometastatic hormone-sensitive PCa, as well as a low likelihood of side effects and complications. Nevertheless, it is necessary to continue conducting larger and more structured randomized trials to determine the possibility of applying this therapeutic approach in clinical practice.


Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 8
Author(s):  
Christian Thomas ◽  
Martin Baunacke ◽  
Holger H. H. Erb ◽  
Susanne Füssel ◽  
Kati Erdmann ◽  
...  

For decades, mono androgen deprivation therapy (ADT) has been the gold standard for metastatic hormone-sensitive prostate cancer (mHSPC) treatment. Several studies have been published within the last seven years demonstrating a significant survival advantage by combination treatment with standard ADT plus docetaxel or androgen receptor-axis-targeted therapy (ARAT) compared to ADT monotherapy. As a result, overall survival can be prolonged by at least 18 months. Recently published congress data of the PEACE-1 study suggests that in the future, triple therapy might be the new gold standard. In addition to this study, which has shown that triple treatment with standard ADT plus docetaxel plus abiraterone is superior to standard ADT plus docetaxel, several other phase III triple therapy studies are currently ongoing. The different modes of action that are investigated reach from AR-targeting over mitotic inhibition and immunotherapy to PARP and AKT inhibition. In this review we will explore if triple therapy has the potential to be the new standard for mHSPC treatment in the near future.


2021 ◽  
Vol 23 (1) ◽  
pp. 4
Author(s):  
Zachery R. Reichert ◽  
Tadas Kasputis ◽  
Srinivas Nallandhighal ◽  
Sophia M. Abusamra ◽  
Amy Kasputis ◽  
...  

The substantial biological heterogeneity of metastatic prostate cancer has hindered the development of personalized therapeutic approaches. Therefore, it is difficult to predict the course of metastatic hormone-sensitive prostate cancer (mHSPC), with some men remaining on first-line androgen deprivation therapy (ADT) for several years while others progress more rapidly. Improving our ability to risk-stratify patients would allow for the optimization of systemic therapies and support the development of stratified prospective clinical trials focused on patients likely to have the greatest potential benefit. Here, we applied a liquid biopsy approach to identify clinically relevant, blood-based prognostic biomarkers in patients with mHSPC. Gene expression indicating the presence of CTCs was greater in CHAARTED high-volume (HV) patients (52% CTChigh) than in low-volume (LV) patients (23% CTChigh; * p = 0.03). HV disease (p = 0.005, q = 0.033) and CTC presence at baseline prior to treatment initiation (p = 0.008, q = 0.033) were found to be independently associated with the risk of nonresponse at 7 months. The pooled gene expression from CTCs of pre-ADT samples found AR, DSG2, KLK3, MDK, and PCA3 as genes predictive of nonresponse. These observations support the utility of liquid biomarker approaches to identify patients with poor initial response. This approach could facilitate more precise treatment intensification in the highest risk patients.


2021 ◽  
Vol 11 ◽  
Author(s):  
Naoki Matsumura ◽  
Kazutoshi Fujita ◽  
Mitsuhisa Nishimoto ◽  
Yutaka Yamamoto ◽  
Ken Kuwahara ◽  
...  

This study aimed to compare the effects of abiraterone acetate plus prednisone (AAP) with androgen deprivation therapy (ADT) with those of combined androgen blockade (CAB) therapy in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). This study retrospectively identified 163 patients with high-risk mHSPC at Kindai University and affiliated hospitals between January 2014 and December 2020. Kaplan-Meier analysis was used to summarize progression-free survival (PFS) and overall survival (OS). Multivariate Cox proportional hazard modeling was used to identify the prognostic factors in the overall cohort. Propensity score matching was used to adjust the clinical characteristics, and log-rank test was applied to these propensity score–matched cohorts. Seventy-four patients who received AAP with ADT and 89 patients who received CAB were included in this study. The median follow-up duration was 27 months (range, 2–89 months). The median PFS and OS were not reached by the AAP+ADT group and 15 and 79 months, respectively, in the CAB group. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) score and AAP+ADT were significant prognostic factors for PFS, whereas ECOG PS score, visceral metastasis, and AAP+ADT were significant prognostic factors for OS. The 2-year PFS was 76.1% in the AAP+ADT group and 38.6% in the CAB group (P < 0.0001), and the 2-year OS was 90.2% in the AAP+ADT group and 84.8% in the CAB group (P = 0.015). In conclusion, AAP+ADT had better PFS and OS than CAB in patients with high-risk mHSPC.


Author(s):  
Martin R. Stockler ◽  
Andrew J. Martin ◽  
Ian D. Davis ◽  
Haryana M. Dhillon ◽  
Stephen D. Begbie ◽  
...  

PURPOSE We previously reported that enzalutamide improved overall survival when added to standard of care in metastatic, hormone-sensitive prostate cancer. Here, we report its effects on aspects of health-related quality of life (HRQL). METHODS HRQL was assessed with the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire and QLM-PR25 at weeks 0, 4, 12, and then every 12 weeks until progression. Scores from week 4 to 156 were analyzed with repeated measures modeling to calculate group means and differences. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in fatigue, physical function, cognitive function, or overall health and quality of life (OHQL). HRQL scores range from 0 (lowest possible) to 100 (highest possible). RESULTS HRQL was assessed in 1,042 of 1,125 participants (93%). Differences in means favored control over enzalutamide for fatigue (5.2, 95% CI, 3.6 to 6.9; P < .001), cognitive function (4.0, 95% CI, 2.5 to 5.5; P < .001), and physical function (2.6, 95% CI, 1.3 to 3.9; P < .001), but not OHQL (1.2, 95% CI, −0.2 to 2.7; P = .1). Deterioration-free survival rates at 3 years, and log-rank P values comparing the whole distributions, favored enzalutamide over control for OHQL (31% v 17%; P < .0001), cognitive function (31% v 20%; P = .001), and physical function (31% v 22%; P < .001), but not fatigue (24% v 18%; P = .16). The effects of enzalutamide on HRQL were independent of baseline characteristics. CONCLUSION Enzalutamide was associated with worsening of self-reported fatigue, cognitive function, and physical function, but not OHQL. Enzalutamide was associated with improved deterioration-free survival for OHQL, physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL.


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