Analysis of risk factors leading to anxiety and depression in patients with prostate cancer after castration and the construction of a risk prediction model

BACKGROUND Cancer patients often suffer from severe stress reactions psychologically,such as anxiety and depression.Prostate cancer(PC)is one of the common cancer types,with most patients diagnosed at advanced stages that cannot be treated by radical surgery and which are accompanied by complications such as bodily pain and bone metastasis.Therefore,attention should be given to the mental health status of PC patients as well as physical adverse events in the course of clinical treatment.AIM To analyze the risk factors leading to anxiety and depression in PC patients after castration and build a risk prediction model.METHODS A retrospective analysis was performed on the data of 120 PC cases treated in Xi'an People's Hospital between January 2019 and January 2022.The patient cohort was divided into a training group(n=84)and a validation group(n=36)at a ratio of 7:3.The patients’anxiety symptoms and depression levels were assessed 2 wk after surgery with the Self-Rating Anxiety Scale(SAS)and the Selfrating Depression Scale(SDS),respectively.Logistic regression was used to analyze the risk factors affecting negative mood,and a risk prediction model was constructed.RESULTS In the training group,35 patients and 37 patients had an SAS score and an SDS score greater than or equal to 50,respectively.Based on the scores,we further subclassified patients into two groups:a bad mood group(n=35)and an emotional stability group(n=49).Multivariate logistic regression analysis showed that marital status,castration scheme,and postoperative Visual Analogue Scale(VAS)score were independent risk factors affecting a patient's bad mood(P<0.05).In the training and validation groups,patients with adverse emotions exhibited significantly higher risk scores than emotionally stable patients(P<0.0001).The area under the curve(AUC)of the risk prediction model for predicting bad mood in the training group was 0.743,the specificity was 70.96%,and the sensitivity was 66.03%,while in the validation group,the AUC,specificity,and sensitivity were 0.755,66.67%,and 76.19%,respectively.The Hosmer-Lemeshow test showed aχ^(2) of 4.2856,a P value of 0.830,and a C-index of 0.773(0.692-0.854).The calibration curve revealed that the predicted curve was basically consistent with the actual curve,and the calibration curve showed that the prediction model had good discrimination and accuracy.Decision curve analysis showed that the model had a high net profit.CONCLUSION In PC patients,marital status,castration scheme,and postoperative pain(VAS)score are important factors affecting postoperative anxiety and depression.The logistic regression model can be used to successfully predict the risk of adverse psychological emotions.

Changes in aortic endothelium ultrastructure in male rats following castration, replacement with testosterone and administration of 50α-reductase inhibitor

Aim： To investigate the relationship between low androgen level and ultrastructure of vascular endothelium. Methods： Forty-eight male Sprague-Dawley rats were randomly divided into four groups： group A, normal rats with sham castration; group B, castrated rats; group C, castrated rats given testosterone （T） undecanoate; and group D, intact rats treated with 5α-reductase inhibitor. After 10 weeks of treatment or castration, rats in different groups were killed and serum T, free T （FT） and dihydrotestosterone （DHT） were measured. The aortic endothelia were scanned under electron microcopy and the Vascular Endothelium Structure Score （VESS） was computed. Results： Serum T and FT concentrations of rats in group B were significantly lower than those of the other three groups （P 〈 0.01）; DHT concentrations of group D rats were significantly decreased （P 〈 0.01 ） when compared with those of groups A and C. Rats in groups B and D rats （with low androgen levels） had obvious damage to their endothelial surfaces, which appeared crimpled, rough, adhesive and ruptured, and had high destruction of VESS. Conclusion： These results suggest that low concentrations of T and DHT are associated with ultrastructural damage of the aortic endothelia in male rats.

Efficacy of maximal androgen blockade versus castration alone in the treatment of advanced prostate cancer： a retrospective clinical experience from a Chinese medical centre

In this retrospective study, we evaluated and compared the efficacy and toxicities of maximal androgen blockade （MAB） versus castration alone in Chinese patients with advanced prostate cancer. From 1996 to 2004, 608 patients with advanced prostate cancer were included in the study. Patients were retrospectively divided into two groups according to different therapeutic regimens. Of the 608 patients, 300 patients were treated with MAB （castration plus nonsteroidal antiandrogens） and the remaining 308 were treated with castration alone. The 2- and 5-year overall survival rates of these patients were 73.7% and 56%, respectively. Multivariate analysis showed that, in patients with metastatic prostate cancer, MAB was associated with not only the improvement of progression-free survival （PFS） （increased by 10 months） but also a 20.6% reduction in mortality risk compared with castration alone. In contrast, the efficacy of MAB was not superior to castration alone for patients with nonmetastatic prostate cancer. Interestingly, among patients with MAB, those using bicalutamide had a longer PFS than those using flutamide; this was especially so in patients with metastatic prostate cancer. Almost all of the toxicities due to the hormone therapy were mild to moderate and manageable. To conclude, in China, hormone therapies, including MAB and castration alone, have been standard treatments for advanced prostate cancer. For patients with nonmetastatic prostate cancer, castration alone might be adequately practical and efficient. In patients with metastatic prostate cancer, however, MAB has superior efficacy over castration alone. It is clear that MAB should be considered the first-line standard treatment for patients with metastatic prostate cancer.

Ailanthone:a new potential drug for castration-resistant prostate cancer

Prostate cancer (PCa) is the most common male cancer [1, 2]. PCa initially depends on androgen receptor (AR) signaling for growth and survival. Androgen deprivation therapy causes a temporary reduction in PCa tumor burden, but the tumor eventually develops into castrationresistant prostate cancer (CRPC) with the ability to grow again in the absence of androgens [3]. Mechanisms of CRPC progression include AR amplification and overexpression [4], AR gene rearrangement promoting synthesis of constitutively-active truncated AR splice variants (ARVs) [4], and induction of intracrine androgen metabolic enzymes [3]. Current anti-androgen therapies including MDV3100 (Enzalutamide) and abiraterone have focused on the androgen-dependent activation of AR through its ligand-binding domain (LBD), but do not provide a continuing clinical benefit for patients with CRPC and presumably fail due to multiple mechanisms including the expression of AR-Vs lacking the LBD [5]. These AR-Vs signal in the absence of ligand and are therefore resistant to LBD-targeting AR antagonists or agents that repress androgen biosynthesis [6].

Effects of castration and testosterone replacement on veno-occlusion during penile erection in the rat

Aim: To determine if androgens directly regulate veno-occlusion or if androgens act indirectly to maintain the penilestructures which control outflow. Methods: Using CASTRATE and TESTO rats, measurement was made of meanarterial pressure (MAP), intracavernosal pressure (CCP), and intracavernosal flow (CCF) during erection resultingfrom stimulation of the autonomic innervation of the penis. CCP and CCF were also measured during saline infusioninto the cavernosal sinuses before and after treatment with sodium nitroprusside (SNP, a nitric oxide donor drag) tofully relax cavernosal smooth muscle. Penile tissue was also collected to measure the content of α actin and proline andhydroxyproline to determine if brief withdrawal of androgenic support led to changes in the number of smooth musclecells or the collagen content of the tissue. Results: Infusion of saline into the cavernosal sinuses demonstrated thatveno-occlusion was defective in CASTRATE rats while reno-occlusion was fully functional in TESTO animals.Furthermore, veno-occlusion could be induced in CASTRATE rats if they were first treated with SNP. Thisobservation suggests that failure of veno-occlusion in the CASTRATE rats is due to a deficiency in the production of NOresulting in a reduction in the degree of relaxation of the penile smooth muscle. The measurements of smooth muscleα actin and proline and hydroxyproline content of collagen showed that both were unaffected by castration and that thebasic structure of the penis did not degenerate after one week without androgenic support. Conclusion: Theseresults can be interpreted to mean that androgens control the veno-occlusive mechanism indirectly via a NO dependentmechanism and not by maintaining the structures of the penis which are essential to reno-occlusion.

Current paradigms and evolving concepts in metastatic castration-resistant prostate cancer

Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer （mCRPC）. The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents （sipuleuceI-T, cabazitaxel and abiraterone） with distinct mechanisms of action. Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.

Apoptosis in rat erectile tissue induced by castration

Aim: To investigate the effect of androgen on the structure of corpus cavernosum. Methods: Thirty mature rats wererandomized into 3 groups, i.e., simple castration, castration with testosterone (T) supplementation and sham-operatedcontrols. One week after operation, the animals were sacrificed and corpora cavenosa harvested. Apoptosis was detect-ed with the in situ end labeling (ISEL) techniques and DNA fragment analysis. Results: The apoptotic rate was4.19 % in the simple castrated rats, 0.2 % in castrated rats supplemented with T and 0.14 % in the controls. Signifi-cant difference was found between the simple castrates and other two groups (P < 0.01). When comparing the T-sup-plementation group with the controls, there was no statistical difference (P > 0.05). Conclusion: Castration inducedapoptosis in rat corpus cavernosum, that could be prevented by T supplementation. It suggests that androgen plays animportant role in maintaining the structure of corpus cavernosum. (Asian J Androl 1999 Dec; 1: 181-185)

Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer

The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit androgen signaling such as enzalutamide and abiraterone.Unfortunately,it is estimated that up to 30%of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug.Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered.Androgen receptor(AR)mutations,expression of AR-V7(or other constitutively active androgen receptor variants),intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1,Member C3(AKR1C3)are among the many mechanisms associated with resistance to anti-androgens.In regards to the taxanes,one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1(ABCB1).Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies.For instance,targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment.ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel.A more thorough understanding of how drug resistance develops will lead to improved treatment strategies.This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.

Castration-induced expression of caspase-1 in epithelia of accessory sex organs in male rats

Aim: As an attempt to clarify the molecular basis of castration-induced apoptosis, this study was undertaken todemonstrate the expression of caspase-1 in male accessory sex organs of rats. Methods and results; cDNA of ratcaspase-1 was cloned by reverse transcription-polymerase chain reaction from the ventral prostates. The open readingframe predicts 402 amino acids, which shows more than 91% and 63% identity to those of mouse and human, respec-tively. Northern analyses demonstrated the presence of castration-induced up-regulation of the 1.6 kb transcript in theventral prostate and the seminal vesicles. Finally, the authors demonstrated the caspase-1 transcripts in the epithelia ofthese tissues by in situ hybridization analyses. Conclusion; Castration induces the expression of caspase-1 tran-scripts in the epithelia of ventral prostate and seminal vesicle. These observations suggest a possible role of caspase-1 inapoptosis in male accessory sex organs.

Early and delayed castrations confer a similar survival advantage in TRAMP mice

The most appropriate time to introduce androgen deprivation therapy for prostate cancer remains controversial. Our aim was to evaluate the effects of early versus delayed surgical castration on prostate cancer progression and survival in the transgenic adenocarcinoma of the mouse prostate （TRAMP） model. TRAMP mice were randomly divided into three groups： the early castration group （on which castration was performed at the age of 4 weeks）, the delayed castration group （on which castration was performed when abdominal tumours could be palpated）, and the sham-castrated group. Mice were monitored daily throughout their lives until cancer-related death or the develop- ment of an obviously moribund appearance, at which time the individual mouse was killed. Androgen receptor expression in prostate tumours was also evaluated. The results shows that the average lifespan in early castration, delayed castration and sham-castrated groups were 54.1 weeks, 59.9 weeks and 39.1 weeks, respectively. Both early castration and delayed castration conferred a statistically significant survival advantage when compared with the sham-castrated group （P 〈 0.001）. However, the difference in lifespan between the early castration group and the delayed castration group was not statistically significant （P = 0.85）. The increase in lifespan in the TRAMP mice that received either early or delayed castration correlated with lower G/B value （genitourinary tract weight/body weight） at death than the sham-castrated mice. In conclusion, early and delayed castrations in TRAMP mice pro- longed survival to a similar extent. This finding may provide a guide for clinical practice in prostate cancer therapy.

Novel flutamide regulated genes in the rat veritral prostate： differential modulation of their expression by castration and flutamide treatments

Aim： To identify flutamide regulated genes in the rat ventral prostate. Methods： Total RNA from ventral prostates of control and flutamide treated rats were isolated. Differentially expressed transcripts were identified using differential display reverse transcriptase polymerase chain reaction. The effect of castration on the expression of flutamideregulated transcripts was studied. Results： We have identified β2-microglobulin, cytoplasmic FMR1 interacting protein 2 and pumilio 1 as flutamide induced and spermine binding protein and ribophorin Ⅱ as flutamide repressed targets in the rat ventral prostate. Although flutamide treatment caused an induction of pumilio 1 rnRNA, castration had no effect. Conclusion： Castration and flutamide treatments exert differential effects on gene expression. Flutamide might also have direct AR independent effects, which might have implications in the emergence of androgen independent prostate cancer and the failure of flutamide therapy.

Time-dependent effects of castration on the bladder function and histological changes in the bladder and blood vessels

We examined the effect of androgens on bladder blood flow （BBF）, bladder function and histological changes in castrated male rats. Male Wistar rats were classified into unoperated group （control group）, groups castrated at the age of 8weeks （group 8wPC） and groups castrated at the age of 4weeks （group 4wPC）. Each rat was used at the age of 20weeks. BBF was measured using fluorescent microspheres. Bladder cystometry was performed without anesthesia or restraint; the bladder was first irrigated with saline and then with 0.25% acetic acid （AA） solution. Maximum voiding pressure and voiding interval were measured. The bladder and lilac artery were histologically examined for differences in smooth muscle and quantity of collagen fiber to analyze the effect of castration on the smooth muscle content. No differences were noted in BBF following castration. The voiding intervals for all groups were shortened （P 〈 0.001） following AA irrigation. No significant difference was noted in the maximum voiding pressure. Histological changes were observed in bladder and lilac artery. Smooth muscle/collagen ratio at the bladder was lower in groups 8wPC and 4wPC compared to the control group （P 〈 0.01）, while that at the lilac artery was decreased in group 4wPC compared to the control group （P〈 0.001）. In conclusion, our findings indicate that castration does not alter BBF, but leads to histological changes in the bladder as well as its associated blood vessels.

IL13Rα1 prevents a castration resistant phenotype of prostate cancer by targeting hexokinase 2 for ubiquitin-mediated degradation

Objective:Androgen deprivation therapy(ADT)is still the principal treatment option for prostate cancer(PCa).In addition to reactivation of androgen receptor signaling,the resistance of PCa to apoptosis during ADT also contributes to castration resistant PCa(CRPC).A previous study reported that gene transfer of IL-13Rα2 into PCa cells sensitized the cells to the IL-13R-targeted cytotoxin IL13Rα1,leading to apoptosis.Compared with IL-13Rα2,IL13Rα1 is more constitutively expressed in PCa cells,but its function in PCa remains to be established.Methods:We determined the role and expression of IL13Rα1 in PCa cancer cells using western blotting,flow cytometry,and cell proliferation assays.Co-immunoprecipitation and mass spectrometry were used to identify the proteins that interacted with IL13Rα1,to elucidate its function.Results:In this study,we showed that IL13Rα1 was selectively suppressed in androgen-deprived PCa cells and that its suppression tended to be associated with poor prognoses of PCa patients.IL13Rα1 overexpression promoted apoptosis and inhibited tumor growth under androgen-deprived or castrated conditions(P<0.01).Mechanistically,IL13Rα1 recruited and facilitated ubiquitin protein ligase E3C-mediated ubiquitination and degradation of hexokinase 2(HK2),resulting in glycolytic inhibition and eventually leading to PCa cell apoptosis.Furthermore,our data revealed that mutated ataxia-telangiectasia kinase phosphorylated and facilitated the selective ubiquitin proteasome-mediated degradation of HK2.Notably,IL13Rα1-overexpressing PCa cells were more susceptible to apoptosis and exhibited reduced tumor growth after exposure to the HK2 inhibitor,2-deoxy-D-glucose(P<0.01).Conclusions:Our data identified a tumor suppressor role for IL13Rα1 in preventing the resistance of PCa cells to apoptosis during androgen deprivation by inhibiting glycolysis.IL13Rα1-mediated signaling involving HK2 may therefore provide a novel treatment target and strategy for CRPC.

HIGH-INTENSITY FOCUSED ULTRASOUND CASTRATION FOR BREAST CANCER PATIENTS

Objective: To evaluate the safety and efficacy of external high-intensity focused ultrasound(HIFU) castration for breast cancerous patients after mastectomy if they are at a high risk of recurrence. Methods: We recruited 52 consecutive patients with primary operable breast cancer who were treated with mastectomy with excision of regional lymph nodes. Patients were positive for ER and PR immuno- cytochemical staining, node-positive, un-menopause, over 40 years old and were divided into two groups randomly. For castration, 26 patients received one or two times of HIFU treatment within five days, and the other patients received radiotherapy with DT 18Gy/9 f/11days. During and after the treatment, local changes and systemic response of the patients were observed. Results: After 1 month treatment, levels of serum E1 and E2 were significantly decreased compared to before treatment in HIFU groups (P<0.01 and P<0.001). The same changes were occurred in radiotherapy(RT) groups (P<0.05 and P<0.01). The levels of serum E1 or E2 in RT groups were higher than in HIFU groups (P<0.05). The symptom distribution of 慶limacteric syndrome?of HIFU groups were significantly different from RT groups (P<0.01). The follow-up time was 4 months. The incidence of amenorrhea was 100% in all patients. No serious complications were seen. The temperature, pulse, blood pressure, and respiratory rate of the patients were almost normal. Conclusion: We have shown that the use of HIFU in the castrating of patients with breast cancer is feasible, safe and effective. This technology may provide a rapid noninvasive alterative to conventional bilateral oophorectomy or RT castration.

Real-world evaluation of upfront docetaxel in metastatic castrationsensitive prostate cancer

BACKGROUND The majority of patients with newly diagnosed metastatic prostate cancer(PC)initially respond to androgen deprivation therapy(ADT)and are classified as metastatic castration-sensitive PC(mCSPC).Following months to years of ADT,the disease tends to become resistant to ADT.Recent randomized phase-III trials demonstrated a survival benefit with the addition of upfront docetaxel to ADT in mCSPC.Following its implementation in routine care,this combined treatment strategy requires more detailed evaluation in a real-world setting.AIM To assess the real-world outcome and safety of upfront docetaxel treatment in mCSPC.METHODS A multicenter retrospective cohort study in the Southeast Health Care Region of Sweden was performed.This region includes approximately 1.1 million citizens and the oncology departments of Linköping,Jönköping,and Kalmar.All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included.The primary endpoint was progression-free survival(PFS)at 12 mo,and the secondary endpoints were PFS at 24 mo,overall survival(OS),treatment intensity,adverse events,and unplanned hospitalizations.Exploratory analyses on potential prognostic parameters were performed.RESULTS Ninety-four patients were eligible and formed the study cohort.PFS at 12 and 24 mo was 75%(95%CI:66–84)and 58%(46–70),respectively.OS at 12 and 24 mo was 93%(87–99)and 86%(76–96).A total of 91%of patients(n=86)were given docetaxel according to the standard protocol of 75 mg/m2 every 3 wk(6 cycles),while 9%(n=8)received a modified protocol of 50 mg/m2 every 2 wk(9 cycles).The average overall dose intensity for those commencing standard treatment was 91%.Univariate Cox regression analyses show that baseline PSA>180 vs<180 and the presence of distant metastases vs locoregional lymph node metastases were only negative prognostic factors(HR 2.86,95%CI:1.39–5.87,P=0.0041 and 3.36,95%CI:1.03–10.96,P=0.045).Following multivariate analysis,statistical significance remained for PSA(2.51,95%CI:1.21–5.19,P=0.013)but not for metastatic status(2.60,95%CI:0.78–8.65,P=0.12).Febrile neutropenia was recorded in 21%(n=20)of patients,and 26%(n=24)had at least one episode of unplanned hospitalization under and up to 30 d after the treatment course.CONCLUSION Results from this study support the implementation of upfront docetaxel plus ADT as part of the standard of care treatment strategy in mCSPC.

Future Directions in Metastatic Castration Resistant Prostate Cancer (mCRPC): Clinical Rationale and Use of New-Generation Hormonal Therapies

Several recent studies in mCRPC have identified the mechanisms of tumoral growth after the disease becomes unresponsive to standard hormonal therapy. These studies have highlighted the importance of residual intratumoral androgens in maintaining androgen receptor (AR) transcriptional activity in mCRPC [1]. Based on this findings, it has been possible to develop drugs, blocking the key enzyme in the biosynthesis of androgens through the inhibition of cytochrome p450 17 (CYP17) such as Abiraterone Acetate (AA) and drugs which directly target the AR including Enzalutamide (E) and Orteronel. Before this new knowledge, mCRPC treatment benefited from chemotherapy with taxanes. Recently a new taxane, Cabazitaxel (C), was approved in second line setting in association with prednisone. Retrospective analyses have tried to clarify the current role of chemotherapy in mCRPC patients and the right chemotherapy sequence of use of chemotherapy compared to new hormonal agents. Moreover, it would be important to address changes in the endpoints used in clinical trials, based on the stage of disease including the presence tumor-related symptoms, in order to identify the right therapeutic strategy.

Changes in Electrocardiogram Findings during Treatment with Gonadotropin-Releasing Hormone Agonist and Surgical Castration for Prostate Carcinoma

Purpose: To investigate electrocardiogram (ECG) changes after complete androgen blockade (CAB) achieved by either surgical or medical castration and compare the outcomes of the groups. Methods: Sixty-three consecutive men (between 58 - 86 years of age) requiring CAB for prostate cancer were enrolled in the study. Patients with diabetes mellitus, an additional malignancy, coronary heart disease, atrial fibrillation, heart failure or a medical history of cardiac event in the last 12 months were excluded from the study. Additionally, those who were taking medicine affecting heart rate were excluded. The participants were divided into two groups according to their modality of castration. The first group consisted of 35 patients who received bilateral orchiectomy plus anti-androgen medication. The second group contained 28 patients who accepted gonadotropin-releasing hormone (GnRH) plus anti-androgen therapy. After complete examinations and biochemical tests, the ECG leads of the patients were obtained conveniently. This was then repeated at three- and six-month visits. ECG findings (including heart rate, PR, QRS, QT, corrected QT (QTc) intervals and QT dispersion (QTd)) were recorded and analysed statistically. The groups were then compared in terms of pre- and post-treatment ECG outcomes. Results: Both groups revealed similarly lower heart rate and prolonged PR, QRS, QT, corrected QTc and QTd by the end of six months. By the end of three months, all variables had changed significantly in the orchiectomy group, whereas in the GnRH group, they had not. Conclusion: CAB may result in lower heart rate and prolonged QT, a condition associated with fatal cardiac arrhythmia and sudden death. Therefore, patients receiving CAB should be monitored closely for cardiac adverse effects.

A combination of castration with(125)~I brachtherapy in middle and late period prostate cancer

Objective To investigate the therapeutic efficacy of castration with 125 I brachtherapy in middle and late stage prostate cancer. Methods Sixty-six patients with prostate cancer from 2004 to 2009 were analyzed,40 were at clinical stage C and 26 were at clinical stage D,

The role of glutamine metabolism in castration-resistant prostate cancer

Reprogramming of metabolism is a hallmark of tumors,which has been explored for therapeutic purposes.Prostate cancer(PCa),particularly advanced and therapy-resistant PCa,displays unique metabolic properties.Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes.Among the many nutrients,glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa.In addition to amino acid metabolism,glutamine is also widely involved in the synthesis of other macromolecules and biomasses.Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients.This review summarizes the metabolic landscape of PCa,with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa,and suggests novel therapeutic strategies.

Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.