Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells.

Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)-negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.

United in Fight against prOstate cancer (UFO) registry: first results from a large, multi-centre, prospective, longitudinal cohort study of advanced prostate cancer in Asia.

OBJECTIVES: To document the management of advanced prostate cancer including diagnosis, prognosis, treatment, and care, in real-world practice in Asia using the United in Fight against prOstate cancer (UFO) registry. PATIENTS AND METHODS: We established a multi-national, longitudinal, observational registry of patients with prostate cancer presenting to participating tertiary care hospitals in eight Asian countries. A total of 3636 eligible patients with existing or newly diagnosed high-risk localised prostate cancer (HRL), non-metastatic biochemically recurrent prostate cancer (M0), or metastatic prostate cancer (M1), were consecutively enrolled and are being followed-up for 5 years. Patient history, demographic and disease characteristics, treatment and treatment decisions, were collected at first prostate cancer diagnosis and at enrolment. Patient-reported quality of life was prospectively assessed using the European Quality of Life-five Dimensions, five Levels (EQ-5D-5L) and Functional Assessment of Cancer Therapy for Prostate Cancer questionnaires. In the present study, we report the first interim analysis of 2063 patients enrolled from study start (15 September 2015) until 18 May 2017. RESULTS: Of the 2063 enrolled patients, 357 (17%), 378 (19%), and 1328 (64%) had HRL, M0 or M1 prostate cancer, respectively. The mean age at first diagnosis was similar in each group, 56% of all patients had extracapsular extension of their tumour, 28% had regional lymph node metastasis, and 53% had distant metastases. At enrolment, 62% of patients had at least one co-morbidity (mainly cardiovascular disease or diabetes), 91.8% of M1 patients had an Eastern Cooperative Oncology Group performance score of <2 and the mean EQ-5D-5L visual analogue score was 74.6-79.6 across cohorts. Treatment of M1 patients was primarily with combined androgen blockade (58%) or androgen-deprivation therapy (either orchidectomy or luteinising hormone-releasing hormone analogues) (32%). Decisions to start therapy were mainly driven by treatment guidelines and disease progression. Decision to discontinue therapy was most often due to disease progression (hormonal drug therapy) or completion of therapy (chemotherapy). CONCLUSION: In the UFO registry of advanced prostate cancer in Asia, regional differences exist in prostate cancer treatment patterns that will be explored more deeply during the follow-up period; prospective follow-up is ongoing. The UFO registry will provide valuable descriptive data on current disease characteristics and treatment landscape amongst patients with prostate cancer in Asia.

Differential Protein Expression Patterns of HOXA13 and HOXB13 Are Associated with Bladder Cancer Progression.

Bladder cancer is a common urological cancer and has the highest recurrence rate of any cancer. The aim of our study was to profile and characterize the protein expression of homeobox A13 (HOXA13) and homeobox B13 (HOXB13) genes in Malaysian bladder cancer patients. The protein expression of HOXA13 and HOXB13 in formalin-fixed paraffin-embedded (FFPE) bladder cancer tissues was determined by immunohistochemistry (IHC) analysis. The association between HOXA13/HOXB13 protein expression and demographic/clinicopathological characteristics of the bladder cancer patients was determined by chi-square analysis. Approximately 63.6% of the bladder cancer tissues harbored high HOXA13 expression. High HOXA13 expression was significantly associated with non-muscle invasive bladder cancer, lower tumor grade, higher number of lymph node metastases, and recurrence risk. In contrast, low HOXB13 expression (including those with negative expression) was observed in 71.6% of the bladder cancer tissues analyzed. Low HOXB13 expression was significantly associated with muscle-invasive bladder cancer, higher tumor stage, tumor grade, and metastatic risk. Both HOXA13 and HOXB13 protein expression were found to be associated with bladder tumorigenesis. The putative oncogenic and tumor suppressive roles of HOXA13 and HOXB13, respectively, suggest their potential utility as biomarkers in bladder cancer.

Predictive factors of prostate cancer diagnosis with PSA 4.0-10.0 ng/ml in a multi-ethnic Asian population, Malaysia.

OBJECTIVES: To identify the associated factors determining prostate cancer detection using transrectal ultrasound (TRUS)-guided prostate biopsy, within a multi-ethnic Malaysian population with prostate specific antigen (PSA) between 4.0 and 10.0 ng/ml. METHODS: Study subjects included men with initial PSA between 4.0 and 10.0 ng/ml that have undergone 12-core TRUS-guided prostate biopsy between 2009 and 2016. The prostate cancer detection rate was calculated, while potential factors associated with detection were investigated via univariable and multivariable analysis. RESULTS: A total of 617 men from a multi-ethnic background encompassing Chinese (63.5%), Malay (23.1%) and Indian (13.3%) were studied. The overall cancer detection rate was 14.3% (88/617), which included cancers detected at biopsy 1 (first biopsy), biopsy 2 (second biopsy with previous negative biopsy) and biopsy ≥ 3 (third or more biopsies with prior negative biopsies). Indian men displayed higher detection rate (23.2%) and increased risk of prostate cancer development (OR 1.85, 95% CI 1.03-3.32, p < 0.05), compared to their Malay (9.8%) and Chinese (14.0%) counterparts. Multivariable analysis revealed that ethnicity and PSA density (PSAD) are independent factors associated with overall prostate cancer detection rate. A unit increase of PSAD reflected an increase in PSA after controlling for prostate volume. CONCLUSION: Prostate cancer detection in Malaysia is comparatively lower. Our study suggests that ethnicity and PSA density should be considered when recommending first or repeat TRUS-guided prostate biopsy for prostate cancer detection in a multi-ethnic Malaysian population.

Genome-wide copy number analysis reveals candidate gene loci that confer susceptibility to high-grade prostate cancer.

BACKGROUND: Two key issues in prostate cancer (PCa) that demand attention currently are the need for a more precise and minimally invasive screening test owing to the inaccuracy of prostate-specific antigen and differential diagnosis to distinguish advanced vs. indolent cancers. This continues to pose a tremendous challenge in diagnosis and prognosis of PCa and could potentially lead to overdiagnosis and overtreatment complications. Copy number variations (CNVs) in the human genome have been linked to various carcinomas including PCa. Detection of these variants may improve clinical treatment as well as an understanding of the pathobiology underlying this complex disease. METHODS: To this end, we undertook a pilot genome-wide CNV analysis approach in 36 subjects (18 patients with high-grade PCa and 18 controls that were matched by age and ethnicity) in search of more accurate biomarkers that could potentially explain susceptibility toward high-grade PCa. We conducted this study using the array comparative genomic hybridization technique. Array results were validated in 92 independent samples (46 high-grade PCa, 23 benign prostatic hyperplasia, and 23 healthy controls) using polymerase chain reaction-based copy number counting method. RESULTS: A total of 314 CNV regions were found to be unique to PCa subjects in this cohort (P<0.05). A log2 ratio-based copy number analysis revealed 5 putative rare or novel CNV loci or both associated with susceptibility to PCa. The CNV gain regions were 1q21.3, 15q15, 7p12.1, and a novel CNV in PCa 12q23.1, harboring ARNT, THBS1, SLC5A8, and DDC genes that are crucial in the p53 and cancer pathways. A CNV loss and deletion event was observed at 8p11.21, which contains the SFRP1 gene from the Wnt signaling pathway. Cross-comparison analysis with genes associated to PCa revealed significant CNVs involved in biological processes that elicit cancer pathogenesis via cytokine production and endothelial cell proliferation. CONCLUSION: In conclusion, we postulated that the CNVs identified in this study could provide an insight into the development of advanced PCa.

Cardiovascular Risk Factors and Ethnicity Are Independent Factors Associated with Lower Urinary Tract Symptoms.

OBJECTIVES: To determine the lower urinary tract symptoms (LUTS) profile and factors affecting its degree of severity including cardiovascular risk profile, age, ethnicity, education level and prostate volume in a multiethnic Asian setting. MATERIALS AND METHODS: We conducted a cross-sectional study of 1021 men aged 40-79 years with no clinical evidence of prostate cancer, prostate surgery or 5α-reductase inhibitor treatment of known prostate conditions. The severity of LUTS was assessed using the International Prostate Symptom Score (IPSS). Potential factors associated with LUTS including age, ethnicity, education, history of hypertension, diabetes and hypercholesterolemia, height, weight, and prostate volume were evaluated using univariable and multivariable analyses. RESULTS: There were 506 (50%) men found to have moderate-to-severe LUTS attaining an IPSS above 7. Overall, nocturia (45.5%) was the most frequently reported symptom. Multivariable analysis showed that age, ethnicity, prostate volume and history of hypertension and hypercholesterolemia were independent factors associated with severity of LUTS (p < 0.05). Considering individual lower urinary tract symptoms, we found a strong association of storage symptom with history of hypertension and hypercholesterolemia. Malay men were significantly bothered by post micturition symptom compared to their Chinese and Indian counterparts. Stratified analyses of LUTS demonstrated a mutually exclusive cardiovascular risk factors profile defined by ethnicity. CONCLUSION: Severity of LUTS varies between different ethnicities across all age groups. In addition to age and prostate volume, ethnicity and cardiovascular risk factors including hypertension and hypercholesterolemia may also need to be taken into account in managing men with LUTS.

Oral drug treatments in patients with erectile dysfunction and multiple comorbidities: a retrospective observational study.

OBJECTIVE: To investigate factors associated with demographic/clinical characteristics and drug selection in patients with erectile dysfunction (ED). The prevalence of ED is increasing worldwide. Studies have shown that ED is associated with age, lifestyle and comorbidities. However, the factors associated with patient characteristics as well as drug selection are incompletely understood. SETTING: A tertiary medical centre in Kuala Lumpur, Malaysia. PARTICIPANTS: A total of 219 patients (range 23-80 years) who had received phosphodiesterase type-5 (PDE-5) inhibitors as ED treatment were evaluated. INCLUSION CRITERIA: Adult patients aged ≥18 years, diagnosed with ED, and prescribed with sildenafil, tadalafil or vardenafil. EXCLUSION CRITERIA: Patients diagnosed with ED but who did not receive any PDE-5 inhibitor, or those with missing data. PRIMARY AND SECONDARY OUTCOME MEASURES: Factors associated with demographic and clinical characteristics as well as drug selection were assessed. RESULTS: Ischaemic heart disease (p=0.025), benign prostatic hyperplasia (p<0.001), obesity (p=0.005), lower urinary tract symptoms (LUTS) (p=0.006) and α-blockers (p<0.001) were significantly associated with elderly patients with ED. Additionally, LUTS (p=0.038) and α-blockers (p=0.008) were significantly associated with the selection of PDE-5 inhibitor. CONCLUSIONS: These data showed that elderly patients with ED were significantly associated with comorbidities and α-blockers, whereas LUTS and α blockers were associated with drug selection.

Anxiety Status and its Relationship with General Health Related Quality of Life among Prostate Cancer Patients in Two University Hospitals in Kuala Lumpur, Malaysia.

BACKGROUND: This study aimed to determine the prevalence of anxiety among prostate cancer patients, and to ascertain the association between stress status, socio-demographic, medical and surgical illness, current urinary problem and cancer status with general health-related quality of life (HRQOL) among these patients. METHODS: A hospital based, cross sectional study was conducted at Surgical Clinic, University Malaya Medical Centre (UMMC) and Universiti Kebangsaan Malaysia Medical Centre (UKMMC) using universal sampling. RESULT: A total of 193 patients were recruited. The prevalence of anxiety was 25.4% (95%CI: 19.2 - 31.6). The anxiety ratings were mild anxiety (10.4%), moderate anxiety (13.6%) and severe anxiety (1.6%). The total quality of life among stress group was 59.2 ± 14.7 and among non-stress group was 73.9 ± 12.7. There was a significant negative weak correlation between anxiety score and total quality of life (rs=-0.534, P<0.001). In multivariable analysis, there was a significant difference in the total quality of life (QOL) among anxiety status [adj. mean diff. = -9.1 (95%CI: -15.2, -4.7)]. The adjusted mean difference was associated by age category of the patients (P<0.001); living partner (P<0.001); intermittency (P=0.035) and problem of hematuria during micturition (P=0.005). CONCLUSION: The prevalence of anxiety among prostate cancer was moderately high. Treating the urination problem as well as encouraging living with spouse/family may improve the quality of life among anxiety condition of these patients.

Impact of applied progressive deep muscle relaxation training on the level of depression, anxiety and stress among prostate cancer patients: a quasi-experimental study.

BACKGROUND: The aim of this study was to determine the impact of applied progressive muscle relaxation training on the levels of depression, anxiety and stress among prostate cancer patients. MATERIALS AND METHODS: A quasi-experimental study was conducted at the University Malaya Medical Centre (UMMC) and Universiti Kebangsaan Malaysia Medical Centre (UKMMC) over six months. Prostate cancer patients from UMMC received the intervention and patients from UKMMC were taken as controls. The level of depression, anxiety and stress were measured using Depression, Anxiety Stress Scales - 21 (DASS-21). RESULTS: A total of 77 patients from the UMMC and 78 patients from the UKMMC participated. At the end of the study, 90.9% and 87.2% of patients from the UMMC and UKMMC groups completed the study respectively. There were significant improvements in anxiety (p<0.001, partial ?2=0.198) and stress (p<0.001, partial ?2=0.103) at the end of the study in those receiving muscle training. However, there was no improvement in depression (p=0.956). CONCLUSIONS: The improvement in anxiety and stress showed the potential of APMRT in the management of prostate cancer patients. Future studies should be carried out over a longer duration to provide stronger evidence for the introduction of relaxation therapy among prostate cancer patients as a coping strategy to improve their anxiety and stress.

General health related quality of life and associated factors among prostate cancer patients in two tertiary medical centers in Kuala Lumpur, Malaysia: a cross-sectional study.

Measurement of quality of life among prostate cancer patients helps the health care providers to understand the impact of the disease in the patients' own perspective. The main aim of this study is to measure the quality of life among prostate cancer patients at University Malaya Medical Center (UMMC) and Universiti Kebangsaan Malaysia Medical Centre (UKMMC) and to ascertain the association factors for physical coefficient summary (PCS) and mental coefficient summary (MCS). A hospital based, cross sectional study using the Short Form-36 (SF-36) questionnaire was conducted over a period of 6 months. A total of 193 respondents were recruited. Their total quality of life score was 70.1± 14.7 and the PCS score was lower compared to MCS. The factors associated for PCS were: age, living partner, renal problem, urinary problem of intermittency, dysuria and hematuria. Factors associated for MCS were: age, living partner, renal problem, presenting prostatic specific antigen and urinary problem of intermittency and dysuria. Our prostate cancer patients had moderate quality of life in the physical health components but their mental health was less affected.