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Glutathione-S-transferases (GST) enzymes detoxify xenobiotics and are implicated in response to anticancer therapy. This study evaluated the association of GST theta 1 (GSTT1), GSTT2, and GSTT2B with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) response in non-muscle-invasive bladder cancer treatment. In vitro assessments of GSTT2 knockout (KO) effects were performed using cell lines and dendritic cells (DCs) from GSTT2KO mice. Deletion of GSTT2B, GSTT1, and single-nucleotide polymorphisms in the promoter region of GSTT2 was analysed in patients (n = 205) and healthy controls (n = 150). Silencing GSTT2 expression in MGH cells (GSTT2BFL/FL) resulted in increased BCG survival (p < 0.05) and decreased cellular reactive oxygen species. In our population, there are 24.2% with GSTT2BDel/Del and 24.5% with GSTT2BFL/FL. With ≤ 8 instillations of BCG therapy (n = 51), 12.5% of GSTT2BDel/Del and 53.8% of GSTT2BFL/FL patients had a recurrence (p = 0.041). With ≥9 instillations (n = 153), the disease recurred in 45.5% of GSTT2BDel/Del and 50% of GSTT2BFL/FL. GSTT2FL/FL patients had an increased likelihood of recurrence post-BCG therapy (HR 5.5 [1.87-16.69] p < 0.002). DCs from GSTT2KO mice produced three-fold more IL6 than wild-type DCs, indicating a robust inflammatory response. To summarise, GSTT2BDel/Del patients respond better to less BCG therapy and could be candidates for a reduced surveillance regimen.
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Vacuna BCG , Glutatión Transferasa , Inmunoterapia , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunología , Humanos , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Animales , Ratones , Vacuna BCG/uso terapéutico , Inmunoterapia/métodos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Línea Celular Tumoral , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ratones Noqueados , Mycobacterium bovisRESUMEN
Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are important hepatic transporters. We previously identified OATP1B3 being critically implicated in the disposition of abiraterone. We aimed to further investigate the effects of abiraterone on the activities of OATP1B1 and OATP1B3 utilizing a validated endogenous biomarker coproporphyrin I (CP-I). We utilized OATP1B-transfected cells to characterize the inhibitory potential of abiraterone against OATP1B-mediated uptake of CP-I. Inhibition constant (Ki) was incorporated into our physiologically based pharmacokinetic (PBPK) modeling to simulate the systemic exposures of CP-I among cancer populations receiving either our model-informed 500 mg or clinically approved 1000 mg abiraterone acetate (AA) dosage. Simulated data were compared with clinical CP-I concentrations determined among our 9 metastatic prostate cancer patients receiving 500 mg AA treatment. Abiraterone inhibited OATP1B3- but not OATP1B1-mediated uptake of CP-I in vitro, with an estimated Ki of 3.93 µM. Baseline CP-I concentrations were simulated to be 0.81 {plus minus} 0.26 ng/mL, and determined to be 0.72 {plus minus} 0.16 ng/mL among metastatic prostate cancer patients, both of which were higher than those observed for healthy subjects. PBPK simulations revealed an absence of OATP1B3-mediated interaction between abiraterone and CP-I. Our clinical observations confirmed that CP-I concentrations remained comparable to baseline levels up to 12 weeks post 500 mg AA treatment. Using CP-I as an endogenous biomarker, we identified the inhibition of abiraterone on OATP1B3 but not OATP1B1 in vitro, which was predicted and observed to be clinically insignificant. We concluded that the interaction risk between AA and substrates of OATP1Bs is low. Significance Statement We utilized the endogenous biomarker coproporphyrin I (CP-I) and identified abiraterone as a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B3 in vitro. Subsequent physiologically based pharmacokinetic (PBPK) simulations and clinical observations suggested an absence of OATP1B-mediated interaction between abiraterone and CP-I among prostate cancer patients. This multi-pronged study concluded that the interaction risk between abiraterone acetate and substrates of OATP1Bs is low, demonstrating the application of PBPK-CP-I modelling in predicting OATP1B-mediated interaction implicating abiraterone.
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Interleukin-12 (IL-12) holds significant potential in cancer therapy; however, its clinical applicability is hindered by dose-limiting toxicity. Delivery of the IL-12 gene directly to tumours for constitutive IL-12 expression is a possible strategy to enhance its effectiveness while minimizing systemic toxicity. In this study, we investigate the potential of red blood cell-derived extracellular vesicles (RBCEVs) as a carrier for Il-12 plasmid delivery. We demonstrate that RBCEVs can be loaded with minicircle plasmid encoding IL-12 and delivered to MB49 bladder cancer cells for IL-12 expression. The expression of transgenes from minicircles was significantly higher than from the parental plasmids. RBCEV-mediated IL-12 expression stimulated immune responses in mouse splenocytes. Intratumoral delivery of Il-12 plasmid-loaded RBCEVs suppressed bladder cancer tumour growth, stimulated immune responses and promoted immune cell infiltration. In conclusion, our study demonstrates the promising potential of RBCEVs as an effective, safe and redosable nucleic acid drug delivery platform for IL-12.
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AIM: The aim of the third Asia-Pacific Advanced Prostate Cancer Consensus Conference (APAC APCCC 2023) was to discuss the application in the Asia-Pacific (APAC) region of consensus statements from the 4th Advanced Prostate Cancer Consensus Conference (APCCC 2022). METHODS: The one-day meeting in July 2023 brought together 27 experts from 14 APAC countries. The meeting covered five topics: (1) Intermediate- and high-risk and locally advanced prostate cancer; (2) Management of newly diagnosed metastatic hormone-sensitive prostate cancer; (3) Management of non-metastatic castration-resistant prostate cancer; (4) Homologous recombination repair mutation testing; (5) Management of metastatic castration-resistant prostate cancer. Pre- and post-symposium polling gathered APAC-specific responses to APCCC consensus questions and insights on current practices and challenges in the APAC region. RESULTS: APAC APCCC highlights APAC-specific considerations in an evolving landscape of diagnostic technologies and treatment innovations for advanced prostate cancer. While new technologies are available in the region, cost and reimbursement continue to influence practice significantly. Individual patient considerations, including the impact of chemophobia on Asian patients, also influence decision-making. CONCLUSION: The use of next-generation imaging, genetic testing, and new treatment combinations is increasing the complexity and duration of prostate cancer management. Familiarity with new diagnostic and treatment options is growing in the APAC region. Insights highlight the continued importance of a multidisciplinary approach that includes nuclear medicine, genetic counseling, and quality-of-life expertise. The APAC APCCC meeting provides an important opportunity to share practice and identify APAC-specific issues and considerations in areas of low evidence where clinical experience is growing.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/patología , Asia/epidemiología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
PURPOSE: Androgen deprivation therapy (ADT) is the mainstay approach for prostate cancer (PCa) management. However, the most commonly used ADT modality, gonadotropin-releasing hormone (GnRH) agonists, has been associated with an increased risk of cardiovascular disease (CVD). METHODS: The PCa Cardiovascular (PCCV) Expert Network, consisting of multinational urologists, cardiologists and oncologists with expertise in managing PCa, convened to discuss challenges to routine cardiovascular risk assessment in PCa management, as well as how to mitigate such risks in the current treatment landscape. RESULTS: The experts identified several barriers, including lack of awareness, time constraints, challenges in implementing risk assessment tools and difficulties in establishing multidisciplinary teams that include cardiologists. The experts subsequently provided practical recommendations to improve cardio-oncology care for patients with PCa receiving ADT, such as simplifying cardiovascular risk assessment, individualising treatment based on CVD risk categories, establishing multidisciplinary teams and referral networks and fostering active patient engagement. A streamlined cardiovascular risk-stratification tool and a referral/management guide were developed for seamless integration into urologists' practices and presented herein. The PCCV Expert Network agreed that currently available evidence indicates that GnRH antagonists are associated with a lower risk of CVD than that of GnRH agonists and that GnRH antagonists are preferred for patients with PCa and a high CVD risk. CONCLUSION: In summary, this article provides insights and guidance to improve management for patients with PCa undergoing ADT.
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Enfermedades Cardiovasculares , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/inducido químicamente , Antagonistas de Andrógenos/efectos adversos , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Medición de Riesgo , Hormona Liberadora de GonadotropinaRESUMEN
INTRODUCTION: Androgen receptor targeted agents (ARTA) have increasingly been incorporated into treatment regimens for various stages of prostate cancer. Patients are living longer with prostate cancer, and thus have a higher cumulative exposure to the treatment and its accompanying side effects, especially those of cardiovascular disease. We aim to assess the differences in the incidence of cardiac-related adverse events after treatment of prostate cancer with ARTA versus placebo. METHODS: Three databases were thoroughly searched for relevant articles. The PICOS model was used to frame our clinical question, with which 2 independent authors went through several rounds of screening to select the final included studies. Meta-analysis was done using the Cochran-Mantel-Haenszel Method. Quality assessment was carried out with the Cochrane Risk of Bias tool RoB 2. RESULTS: The use of ARTA in prostate cancer increases the incidence of cardiac-related adverse events (RR: 1.56, 95% CI: 1.29-1.90, p < 0.00001), such as hypertension (RR: 1.69, 95% CI: 1.46-1.97, p < 0.00001), ischaemic heart disease (RR: 1.84, 95% CI: 1.36-2.50, p < 0.0001), and arrhythmia (RR: 1.38, 95% CI: 1.11-1.71, p = 0.004), although this did not manifest in an increased incidence of cardiac arrests/deaths (RR: 1.28, 95% CI: 0.87-1.88, p = 0.21). DISCUSSION: ARTA increases the risk of cardiac-related adverse events, hypertension, ischaemic heart disease and arrhythmia. Armed with this knowledge, we will be better poised to manage cardiac risks accordingly and involve a cardiologist as required when starting patients on ARTA.
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Enfermedades Cardiovasculares , Neoplasias de la Próstata , Receptores Androgénicos , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/uso terapéutico , Antagonistas de Receptores Androgénicos/efectos adversos , Incidencia , Terapia Molecular Dirigida/efectos adversosRESUMEN
Background: Prostate cancer (PC) has a serious public health impact, and its incidence is rising due to the aging population. There is limited evidence and consensus to guide the management of PC in Southeast Asia (SEA). We present real-world data on clinical practice patterns in SEA for advanced PC care. Method: A paper-based survey was used to identify clinical practice patterns and obtain consensus among the panelists. The survey included the demographics of the panelists, the use of clinical guidelines, and clinical practice patterns in the management of advanced PC in SEA. Results: Most panelists (81%) voted prostate-specific antigen (PSA) as the most effective test for early PC diagnosis and risk stratification. Nearly 44% of panelists agreed that prostate-specific membrane antigen positron emission tomography-computed tomography imaging for PC diagnostic and staging information aids local and systemic therapy decisions. The majority of the panel preferred abiraterone acetate (67%) or docetaxel (44%) as first-line therapy for symptomatic mCRPC patients. Abiraterone acetate (50%) is preferred over docetaxel as a first-line treatment in metastatic castration-sensitive prostate cancer patients with high-volume disease. However, the panel did not support the use of abiraterone acetate in non-metastatic castration-resistant prostate cancer (nmCRPC) patients. Apalutamide (75%) is the preferred treatment option for patients with nmCRPC. The cost and availability of modern treatments and technologies are important factors influencing therapeutic decisions. All panelists supported the use of generic versions of approved therapies. Conclusion: The survey results reflect real-world management of advanced PC in a SEA country. These findings could be used to guide local clinical practices and highlight the financial challenges of modern healthcare.
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Objective: To design a device to increase the accuracy of the targeting process and reduce the radiation exposure to both the patients and the medical staff. Methods: We analyzed the inherent problem and designed the External Assist Targeting Device (EATD) to assist in the alignment of needle targeting on the desired renal calyx under fluoroscopic guidance. The EATD was designed to allow rapid and precise access to calyces at all angles, with a simple two-step puncture protocol developed for puncturing a target renal calyx. We then tested the device in a pilot human trial with four patients. Results: In experiments with phantom models, the time for successful targeting was reduced by 31% using the device. The mean fluoroscopic time was reduced by 40%. In initial human trial, the puncture time was shortened by 66% and the radiation dose was decreased by 65% compared to free-hand technique. No complication was observed during the trial. Conclusion: The EATD was found to be cost effective, portable, simple to set up, and safe to operate for assisting in the percutaneous nephrolithotomy procedures. Our preliminary tests showed high degree of accuracy in gaining precise access to a targeted renal calyx with much shorter time and lesser radiation dose. The EATD also has the potential to be used to access other organs with precision under fluoroscopic guidance.
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OBJECTIVE: To perform a systematic review and meta-analysis to evaluate the impact of body mass index (BMI) on oncological (primary) and surgical (secondary) outcomes of patients who underwent nephrectomy, as obesity or high BMI is a known risk factor for renal cell carcinoma (RCC) and predictor of poorer outcomes. METHODS: Studies were identified from four electronic databases from database inception to 2 June 2021, according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. The review protocol was registered in the International Prospective Register of Systematic Reviews with the identification number: CRD42021275124. RESULTS: A total of 18 studies containing 13 865 patients were identified for the final meta-analysis. Regarding oncological outcomes, higher BMI predicted higher overall survival (BMI >25 vs BMI <25 kg/m2 : hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.58-0.85), cancer-specific survival (BMI >25 vs BMI <25 kg/m2 : HR 0.60, 95% CI 0.50-0.73; BMI 25-30 vs BMI <25 kg/m2 : HR 0.46, 95% CI 0.23-0.95; BMI >30 vs BMI <25 kg/m2 : HR 0.50, 95% CI 0.36-0.69), and recurrence-free survival rates (BMI >25 vs BMI <25 kg/m2 : HR 0.72, 95% CI 0.63-0.82; BMI 25-30 vs BMI <25 kg/m2 : HR 0.59, 95% CI 0.42-0.82). Those with a lower BMI fared better in surgical outcomes, such as operation time and warm ischaemic time, although the absolute difference was minimal and unlikely to be clinically significant. There was no difference between groups for length of hospital stay, intraoperative or postoperative complications, blood transfusion requirements, and conversion to open surgery. CONCLUSION: Our study suggests that a higher BMI is associated with improved long-term oncological survival and similar perioperative outcomes as a lower BMI. More research into the underlying biological and physiological mechanisms will enable better understanding of the effect of BMI, beyond mere association, on post-nephrectomy outcomes.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Neoplasias Renales/patología , Índice de Masa Corporal , Resultado del Tratamiento , Nefrectomía/métodosRESUMEN
BACKGROUND: Magnetic resonance imaging (MRI) scans are increasingly first-line investigations for suspected prostate cancer, and essential in the decision for biopsy. 5-alpha reductase inhibitor (5-ARI) use has been shown to reduce prostate size and prostate cancer risk. However, insufficient data exists on how 5-ARI use affects MRI findings and yield of biopsy. This study explores the differences in imaging and prostate cancer diagnoses between patients receiving and not receiving 5-ARI therapy. METHODS: From 2015 to 2020, we collected retrospective data of consecutive patients undergoing prostate biopsy at one centre. We included patients who were biopsy-naïve, had prior negative biopsies, or on active surveillance for low-grade prostate cancer. Clinical and pathological data was collected, including 5-ARI use, Prostate Imaging Reporting and Data System (PIRADS) classification and biopsy results. RESULTS: 351 men underwent saturation biopsy with or without targeted biopsies. 54 (15.3%) had a history of 5-ARI use. On mpMRI, there was no significant difference between the 5ARI and non-5-ARI groups in PIRADS distribution, number of lesions, and lesion location. Significantly fewer cancers were detected in the 5-ARI group (46.3% vs. 68.0%; p < 0.01). There were no significant differences in PIRADS distribution in 5-ARI patients with positive and negative biopsy. CONCLUSION: Our study found significant differences in biochemical, imaging and biopsy characteristics between 5-ARI and non-5-ARI groups. While both groups had similar PIRADS distribution, 5-ARI patients had a lower rate of positive biopsies across all PIRADS categories, which may suggest that the use of 5ARI may confound MRI findings. Further studies on how 5-ARI therapy affects the imaging characteristics of prostate cancer should be performed.
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Próstata , Neoplasias de la Próstata , Masculino , Humanos , Próstata/diagnóstico por imagen , Próstata/patología , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Estudios Retrospectivos , Biopsia Guiada por Imagen/métodos , Neoplasias de la Próstata/patología , Imagen por Resonancia Magnética/métodosRESUMEN
PURPOSE: We compare Prostate Health Index, Prostate Health Index density, and PSA density in predicting clinically significant prostate cancer in MRI-guided prostate biopsy. MATERIALS AND METHODS: This is a multicenter evaluation of prospectively maintained prostate biopsy databases at 10 urology centers. Men with Prostate Health Index and MRI-guided targeted and systematic prostate biopsy performed and without prior prostate cancer diagnosis were included. The additional value of PSA density, Prostate Health Index, and Prostate Health Index density to MRI PI-RADS (Prostate Imaging Reporting & Data System) score was evaluated with multivariable analyses, area under the curve, and decision curve analyses. The proportion of unnecessary biopsies that can be avoided are estimated for clinically significant prostate cancer (International Society of Urological Pathology group ≥2 prostate cancer). RESULTS: A total of 1,215 men were analyzed. Prostate cancer and clinically significant prostate cancer were diagnosed in 51% (617/1,215) and 35% (422/1,215) of men, respectively. Clinically significant prostate cancer was diagnosed in 4.4% (3/68), 15% (72/470), 39% (176/446), and 74% (171/231) of highest PI-RADS score of 2, 3, 4, and 5 lesions, respectively. In multivariable analyses, independent predictors for clinically significant prostate cancer detection included Prostate Health Index (OR 1.04), prostate volume (OR 0.97), and PI-RADS score 4 (OR 2.81) and 5 (OR 8.34). Area under the curve for clinically significant prostate cancer of PI-RADS + Prostate Health Index density (0.85) was superior to PI-RADS + PSA density (0.81), Prostate Health Index density (0.81), Prostate Health Index (0.78), PI-RADS (0.76), PSA density (0.72), and PSA (0.60) in the whole cohort, and the superiority of Prostate Health Index density was also observed in PI-RADS 3 lesions. Decision curve analysis showed Prostate Health Index density achieving the best net clinical benefit in PI-RADS 3 or 4 cases. Among PI-RADS 3 lesions, using cutoffs of PSA density 0.15, Prostate Health Index 38.0, and Prostate Health Index density 0.83 could reduce 58%, 67%, and 72% of unnecessary biopsies, respectively. CONCLUSIONS: Prostate Health Index density outperformed Prostate Health Index or PSA density in clinically significant prostate cancer detection in men with multiparametric MRI performed, and further reduced unnecessary biopsies in PI-RADS 3 lesions.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Próstata/patología , Antígeno Prostático Específico/análisis , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Biopsia Guiada por Imagen/métodosRESUMEN
INTRODUCTION: The classification of prostate cancer (PCa) lesions using Prostate Imaging Reporting and Data System (PI-RADS) suffers from poor inter-reader agreement. This study compared quantitative parameters or radiomic features from multiparametric magnetic resonance imaging (mpMRI) or positron emission tomography (PET), as inputs into machine learning (ML) to predict the Gleason scores (GS) of detected lesions for improved PCa lesion classification. METHODS: 20 biopsy-confirmed PCa subjects underwent imaging before radical prostatectomy. A pathologist assigned GS from tumour tissue. Two radiologists and one nuclear medicine physician delineated the lesions on the mpMR and PET images, yielding 45 lesion inputs. Seven quantitative parameters were extracted from the lesions, namely T2-weighted (T2w) image intensity, apparent diffusion coefficient (ADC), transfer constant (KTRANS), efflux rate constant (Kep), and extracellular volume ratio (Ve) from mpMR images, and SUVmean and SUVmax from PET images. Eight radiomic features were selected out of 109 radiomic features from T2w, ADC and PET images. Quantitative parameters or radiomic features, with risk factors of age, prostate-specific antigen (PSA), PSA density and volume, of 45 different lesion inputs were input in different combinations into four ML models - Decision Tree (DT), Support Vector Machine (SVM), k-Nearest-Neighbour (kNN), Ensembles model (EM). RESULTS: SUVmax yielded the highest accuracy in discriminating detected lesions. Among the 4 ML models, kNN yielded the highest accuracies of 0.929 using either quantitative parameters or radiomic features with risk factors as input. CONCLUSIONS: ML models' performance is dependent on the input combinations and risk factors further improve ML classification accuracy.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/patología , Imagen por Resonancia Magnética/métodos , Antígeno Prostático Específico , Clasificación del Tumor , Aprendizaje Automático , Estudios RetrospectivosRESUMEN
OBJECTIVE: To assess the degree of psychological impact among surgical providers during the COVID-19 pandemic. SUMMARY OF BACKGROUND DATA: The COVID-19 pandemic has extensively impacted global healthcare systems. We hypothesized that the degree of psychological impact would be higher for surgical providers deployed for COVID-19 work, certain surgical specialties, and for those who knew of someone diagnosed with, or who died, of COVID-19. METHODS: We conducted a global web-based survey to investigate the psychological impact of COVID-19. The primary outcomes were the depression anxiety stress scale-21 and Impact of Event Scale-Revised scores. RESULTS: A total of 4283 participants from 101 countries responded. 32.8%, 30.8%, 25.9%, and 24.0% screened positive for depression, anxiety, stress, and PTSD respectively. Respondents who knew someone who died of COVID-19 were more likely to screen positive for depression, anxiety, stress, and PTSD (OR 1.3, 1.6, 1.4, 1.7 respectively, all P < 0.05). Respondents who knew of someone diagnosed with COVID-19 were more likely to screen positive for depression, stress, and PTSD (OR 1.2, 1.2, and 1.3 respectively, all P < 0.05). Surgical specialties that operated in the head and neck region had higher psychological distress among its surgeons. Deployment for COVID- 19-related work was not associated with increased psychological distress. CONCLUSIONS: The COVID-19 pandemic may have a mental health legacy outlasting its course. The long-term impact of this ongoing traumatic event underscores the importance of longitudinal mental health care for healthcare personnel, with particular attention to those who know of someone diagnosed with, or who died of COVID-19.
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COVID-19 , Cirujanos , Humanos , Salud Mental , SARS-CoV-2 , Pandemias , Depresión/psicología , Ansiedad/psicología , Personal de Salud/psicología , Encuestas y Cuestionarios , Estrés Psicológico/psicologíaRESUMEN
Introduction: There has been a rapid evolution in the treatment strategies for metastatic castration-resistant prostate cancer (mCRPC) following the identification of targetable mutations, making genetic testing essential for patient selection. Although several international guidelines recommend genetic testing for patients with mCRPC, there is a lack of locally endorsed clinical practice guidelines in Singapore. Method: A multidisciplinary specialist panel with representation from medical and radiation oncology, urology, pathology, interventional radiology, and medical genetics discussed the challenges associated with patient selection, genetic counselling and sample processing in mCRPC. Results: A clinical model for incorporating genetic testing into routine clinical practice in Singapore was formulated. Tumour testing with an assay that is able to detect both somatic and germline mutations should be utilised. The panel also recommended the "mainstreaming" approach for genetic counselling in which pre-test counselling is conducted by the managing clinician and post-test discussion with a genetic counsellor, to alleviate the bottlenecks at genetic counselling stage in Singapore. The need for training of clinicians to provide pre-test genetic counselling and educating the laboratory personnel for appropriate sample processing that facilitates downstream genetic testing was recognised. Molecular tumour boards and multidisciplinary discussions are recommended to guide therapeutic decisions in mCRPC. The panel also highlighted the issue of reimbursement for genetic testing to reduce patient-borne costs and increase the reach of genetic testing among this patient population. Conclusion: This article aims to provide strategic and implementable recommendations to overcome the challenges in genetic testing for patients with mCRPC in Singapore.
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Asesoramiento Genético , Pruebas Genéticas , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Singapur , Pruebas Genéticas/métodos , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Asesoramiento Genético/métodos , Selección de Paciente , Mutación , Metástasis de la NeoplasiaRESUMEN
Objectives: Several therapies are available for the treatment of advanced/metastatic prostate cancer (PC). However, the systematic assessment of evidence pertaining to the use of these therapies in Asian patients is lacking. Methods: A systematic literature review (SLR) was conducted using PubMed/Medline search in May 2021 to identify the randomized/nonrandomized controlled trials (RCTs/non-RCTs) and real-world observational studies (prospective/retrospective). Only studies published as full manuscripts in English were included if reporting the efficacy, effectiveness, and/or safety of treatments in Asian patients with advanced/metastatic PC. Results: Of the 1,898 retrieved publications, 24 studies were included. These studies had patients with nonmetastatic castration-resistant PC (n = 2), metastatic castration-sensitive PC (n = 4), and metastatic castration-resistant PC (n = 18). Study designs included RCTs (n = 7), non-RCTs (n = 2), and real-world studies (n = 15). Treatments used in included studies were abiraterone acetate plus prednisone (AAP; n = 6), enzalutamide, lutetium-177 prostate-specific membrane antigen (177Lu-PSMA; n = 4 each), docetaxel (n = 3), apalutamide, radium-223 (n = 2 each), darolutamide, cabazitaxel, and pembrolizumab (n = 1 each). The evidence from RCTs (i.e., ARAMIS, SPARTAN, ARCHES, TITAN, LATITUDE, PREVAIL) demonstrated the clinical benefits of apalutamide, darolutamide, enzalutamide, and AAP in terms of overall, disease-free, and metastasis-free survival in Asian patients. These treatments were reported to be well tolerated, with no new safety signals identified in Asian population. The efficacy and safety profiles in Asian patients were consistent with the overall trial population. Data from real-world studies supported the effectiveness and tolerability of AAP, enzalutamide, radium-223, docetaxel, cabazitaxel, 177Lu-PSMA, and pembrolizumab in patients with advanced/metastatic PC. Conclusions: This SLR of the Asian data on therapies for advanced PC from the pivotal and real-world studies confirms similar efficacy and safety outcomes, consistent with the results from the pivotal clinical trials. These findings will help clinicians make better treatment decisions in clinical practice for patients with advanced/metastatic PC.
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Current intravesical chemotherapy for non-muscle invasive bladder cancer (NMIBC) has limited efficacy due to loss of the instilled agent from urine voiding and the agent's lack of specificity for the tumors. We developed a nanocarrier (txCD47-HNP, â¼100 nm) based on human serum albumin conjugated with a peptide that targets the cluster of differentiation 47 receptor overexpressed on bladder cancer (BC) cells. The IC50 of gemcitabine elaidate (GEM) loaded in the txCD47-HNP was almost an order of magnitude lower than that of free GEM. In a mouse orthotopic BC model, GEM loaded in txCD47-HNP effectively reduced the tumor burden. Tumor cells in BC patients' urine can also be targeted by fluorescence-labeled txCD47-HNP resulting in >83 % of the cells exhibiting fluorescence. Thus, txCD47-HNP can potentially be a theranostic agent in NMIBC management by serving as a targeted drug delivery vehicle as well as an alternative to urine cytology.
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Nanopartículas , Neoplasias de la Vejiga Urinaria , Animales , Ratones , Humanos , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Desoxicitidina/uso terapéutico , Albúminas , Sistemas de Liberación de Medicamentos/métodosRESUMEN
PURPOSE: To review the role of serum biomarkers: prostate-specific antigen (PSA), PSA density (PSAD), free:total PSA ratio, prostate health index (PHI) and PHI density (PHID), along with magnetic resonance imaging (MRI) for identification of clinically significant prostate cancer (PCa), comparing their utility in patients with persistently raised PSA levels after a prior negative prostate biopsy (PNB). METHODS: In this single-centre prospective observational study conducted from September 2015 to October 2020, patients underwent a saturation biopsy via the transperineal route. If a Prostate Imaging Reporting and Data System version 2 (PIRADS) 3 and above lesion was seen on MRI, targeted biopsies were also obtained. Information on clinical history, lesion characteristics, PIRADS classification and follow-up was collected. The sensitivity, specificity and area under curve (AUC) for each of the biomarkers were calculated. RESULTS: 351 men underwent saturation biopsy with or without targeted biopsies. 103 patients had a PNB. Among this PNB cohort, 43 (41.7%) men had a benign outcome, while 60 (58.3%) men had histopathologically diagnosed PCa, of which 41 (39%) were clinically significant. All patients underwent multiparametric MRI scans prior to biopsy. Within this cohort, PHI and PHID had the best abilities to predict for clinically significant PCa with an AUC of 0.73 and 0.70 respectively, compared to 0.65 for PSAD, 0.34 for free:total PSA and 0.56 for PSA. CONCLUSION: A significant proportion of patients are diagnosed with PCa after a PNB. This study shows that PHI and PHI densities may be suitable adjuncts predicting for clinically significant PCa in patients with PNB.
Asunto(s)
Próstata , Neoplasias de la Próstata , Biopsia , Humanos , Biopsia Guiada por Imagen , Imagen por Resonancia Magnética , Masculino , Próstata/diagnóstico por imagen , Próstata/patología , Antígeno Prostático Específico , Neoplasias de la Próstata/patologíaRESUMEN
Within the heterogeneous population of patients with bacillus Calmette-Guérin failure, there are clear differences in prognosis and therapy with regard to the timeline when bacillus Calmette-Guérin failure occurred. There are a variety of classifications which include bacillus Calmette-Guérin refractory disease, relapsing, unresponsive, and intolerant. Further profiling of these patients may help to shed light on other forms of therapy that are less radical. We hereby summarize the different biomarkers that predicts for response to bacillus Calmette-Guérin immunotherapy and bacillus Calmette-Guérin failure for non-muscle invasive bladder cancer.