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1.
BMC Health Serv Res ; 21(1): 909, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479565

RESUMO

BACKGROUND: To evaluate the cost-effectiveness of six diagnostic strategies involving magnetic resonance imaging (MRI) targeted biopsy for diagnosing prostate cancer in initial and repeat biopsy settings from the Singapore healthcare system perspective. METHODS: A combined decision tree and Markov model was developed. The starting model population was men with mean age of 65 years referred for a first prostate biopsy due to clinical suspicion of prostate cancer. The six diagnostic strategies were selected for their relevance to local clinical practice. They comprised MRI targeted biopsy following a positive pre-biopsy multiparametric MRI (mpMRI) [Prostate Imaging - Reporting and Data System (PI-RADS) score ≥ 3], systematic biopsy, or saturation biopsy employed in different testing combinations and sequences. Deterministic base case analyses with sensitivity analyses were performed using costs from the healthcare system perspective and quality-adjusted life years (QALY) gained as the outcome measure to yield incremental cost-effectiveness ratios (ICERs). RESULTS: Deterministic base case analyses showed that Strategy 1 (MRI targeted biopsy alone), Strategy 2 (MRI targeted biopsy ➔ systematic biopsy), and Strategy 4 (MRI targeted biopsy ➔ systematic biopsy ➔ saturation biopsy) were cost-effective options at a willingness-to-pay (WTP) threshold of US$20,000, with ICERs ranging from US$18,975 to US$19,458. Strategies involving MRI targeted biopsy in the repeat biopsy setting were dominated. Sensitivity analyses found the ICERs were affected mostly by changes to the annual discounting rate and prevalence of prostate cancer in men referred for first biopsy, ranging between US$15,755 to US$23,022. Probabilistic sensitivity analyses confirmed Strategy 1 to be the least costly, and Strategies 2 and 4 being the preferred strategies when WTP thresholds were US$20,000 and US$30,000, respectively. LIMITATIONS AND CONCLUSIONS: This study found MRI targeted biopsy to be cost-effective in diagnosing prostate cancer in the biopsy-naïve setting in Singapore.


Assuntos
Imageamento por Ressonância Magnética , Neoplasias da Próstata , Idoso , Biópsia , Análise Custo-Benefício , Humanos , Masculino , Neoplasias da Próstata/diagnóstico por imagem , Singapura/epidemiologia
2.
Lancet ; 398(10305): 1075-1090, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34370973

RESUMO

The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer.

3.
Comput Biol Med ; 134: 104497, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34022486

RESUMO

Nine previously proposed segmentation evaluation metrics, targeting medical relevance, accounting for holes, and added regions or differentiating over- and under-segmentation, were compared with 24 traditional metrics to identify those which better capture the requirements for clinical segmentation evaluation. Evaluation was first performed using 2D synthetic shapes to highlight features and pitfalls of the metrics with known ground truths (GTs) and machine segmentations (MSs). Clinical evaluation was then performed using publicly-available prostate images of 20 subjects with MSs generated by 3 different deep learning networks (DenseVNet, HighRes3DNet, and ScaleNet) and GTs drawn by 2 readers. The same readers also performed the 2D visual assessment of the MSs using a dual negative-positive grading of -5 to 5 to reflect over- and under-estimation. Nine metrics that correlated well with visual assessment were selected for further evaluation using 3 different network ranking methods - based on a single metric, normalizing the metric using 2 GTs, and ranking the network based on a metric then averaging, including leave-one-out evaluation. These metrics yielded consistent ranking with HighRes3DNet ranked first then DenseVNet and ScaleNet using all ranking methods. Relative volume difference yielded the best positivity-agreement and correlation with dual visual assessment, and thus is better for providing over- and under-estimation. Interclass Correlation yielded the strongest correlation with the absolute visual assessment (0-5). Symmetric-boundary dice consistently yielded good discrimination of the networks for all three ranking methods with relatively small variations within network. Good rank discrimination may be an additional metric feature required for better network performance evaluation.


Assuntos
Benchmarking , Próstata , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Próstata/diagnóstico por imagem
4.
Updates Surg ; 73(3): 1189-1196, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33891279

RESUMO

Proctoring may facilitate a safe transition to robotic-assisted partial nephrectomy (RAPN) for centres performing open (OPN) and laparoscopic partial nephrectomies (LPN). This study compared the 5-year outcomes of RAPN, initiated with a team-based proctorship, with OPN and LPN. Following an observation course at the proctor's institution and a 3-surgeon performance of proctored RAPN in August 2014, a review of 90 RAPN, 29 LPN and 43 OPN consecutively performed by the same team from 2013 to 2019 at National University Hospital, Singapore was conducted. Peri-operative data, functional and oncological outcomes were compared amongst the three groups. Most cases were performed robotically after 2015 with comparable baseline characteristics in all groups. Median RENAL Nephrometry Score was not significantly different between RAPN (8 [IQR 6, 9]) and OPN (9 [IQR 7, 10]) (P = 0.12) but was significantly lower for LPN (7 [IQR 5, 8]) compared to RAPN (P = 0.002). RAPN achieved the lowest blood loss (226 ml vs.348 ml and 263 ml for OPN and LPN respectively, P = 0.02), transfusion rate (3% vs.21% and 17% respectively, P = 0.003) and median length of stay after surgery (4 vs.6 and 5 days respectively, P = 0.001). Complication rates, warm ischemic times were similar between the three approaches with no differences in 1-year and long-term renal function. The rate of positive surgical margin was 8%, 8% and 3% for RAPN, LPN and OPN, respectively (P = 0.76), with a single recurrence in each arm. Despite modest hospital volume, a team-based proctorship facilitated the transition to the Da Vinci robotic platform to perform partial nephrectomies of equivalent complexities as open surgery, achieving improved perioperative outcomes, while maintaining oncological and kidney functional results.

5.
Ann Surg ; 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33491983

RESUMO

OBJECTIVE: To assess the degree of psychological impact among surgical providers during the COVID-19 pandemic. SUMMARY 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 (DASS-21) and Impact of Event Scale-Revised (IES-R) scores. RESULTS: 4283 participants from 101 countries responded. 32.8%, 30.8%, 25.9% and 24.0% screened positive for depression, anxiety, stress and Post-Traumatic Stress Disorder (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 specialities 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.

6.
BJU Int ; 127(4): 445-453, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32794357

RESUMO

OBJECTIVES: To investigate plasma and urinary kynurenine (KYN)-tryptophan (TRP) ratios in bladder cancer, expression of indoleamine 2,3-dioxygenase 1 (IDO1) in relation to tryptophan 2,3-dioxygenase (TDO2) in bladder tumour, and the correlation of KYN-TRP ratio with bladder tumour burden. METHODS: Metabotyping of the TRP-KYN metabolic axis was performed via a clinical case-control study. Expression of IDO1 and TDO2 was measured in human biopsied tissues. Correlational experiments between KYN-TRP ratio and bladder tumour were performed using a murine orthotopic prostate-specific antigen (PSA)-secreting MB49 bladder cancer model. RESULTS: We established for the first time that plasma TRP level was significantly decreased, while both plasma and urinary KYN-TRP ratios were significantly higher in bladder cancer patients, and expression level of IDO1 but not TDO2 was increased in human bladder tumour. We reported the positive correlation between IDO1 expression, KYN-TRP ratio, normalized PSA to creatinine, and bladder tumour burden in the murine model. CONCLUSION: Kynurenine-tryptophan ratio is a promising surveillance biomarker for bladder cancer, but would require further validation before clinical translation.

7.
Urol Oncol ; 39(4): 238.e1-238.e7, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33250346

RESUMO

OBJECTIVES: Optimal patient stratification is critical in the era of personalized medicine. Germline polymorphisms play an important role in the treatment response of various human diseases, including bladder cancer. Intravesical BCG therapy is widely-used for bladder cancer. However, tumor recurrence and progression are very common. Stratification based on germline polymorphisms may contribute to circumvent this clinical challenge. Autophagy pathway plays an important role in the nonspecific protective effects of BCG. Patients that carry C allele of rs3759601 in autophagy gene ATG2B showed increased risk of recurrence and progression in European population. We thus sought to analyze rs3759601 and its relevance in BCG response in Asian NMIBC patients. METHOD: Functional impact of rs3759601 ATG2B (p.Gln1383Glu) was analyzed by bioinformatics programs including NCBI Conserved Domain Search, Clustal Omega, Polyphen and SIFT. NMIBC patients who received intravesical BCG at multiple hospitals in Singapore from 1995 to 2016 were included. These patients were genotyped for rs3759601 using high resolution melt analysis. The rs3759601 polymorphism was studied in correlation with the bladder cancer recurrence rate and disease progression rate in our cohort. Statistical analysis was conducted using Kaplan-Meier plots and the Chi-squared analysis. RESULTS: In total, 307 individules were included in the study including 161 NMIBC patients and 146 healthy controls, predominately Chinese. The rs3759601 genotype distributions in our NMIBC patients were (GG 72.1%; GC 27.9%; CC 0%), which were distinct from the Dutch report (GG 32.8%; GC 47.4% and CC 19.8%, Buffen K et al, 2014). Consistently, the C allele frequencies of rs3759601 are 0.171 in our controls and 0.177 in East Asians from 1,000 Genome, but 0.406 in Europeans from 1,000 Genome. In silico analysis suggested rs3759601 ATG2B (p.Gln1383Glu) alteration is unlikely to be functionally deleterious. Statistical analysis revealed no significant association between ATG2B rs3759601 C allele and risk of bladder cancer recurrence (P= 0.353, GC vs. GG: hazard ratio [HR]= 1.324), or cancer progression (P= 0.454, GC vs. GG: HR = 0.658). CONCLUSION: In contrast to European NMIBC patients, ATG2B rs3759601 C allele is much less common in Asians and it not associated with BCG response in Asian NMIBC patients.

9.
Comput Math Methods Med ; 2020: 8861035, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33144873

RESUMO

Prostate segmentation in multiparametric magnetic resonance imaging (mpMRI) can help to support prostate cancer diagnosis and therapy treatment. However, manual segmentation of the prostate is subjective and time-consuming. Many deep learning monomodal networks have been developed for automatic whole prostate segmentation from T2-weighted MR images. We aimed to investigate the added value of multimodal networks in segmenting the prostate into the peripheral zone (PZ) and central gland (CG). We optimized and evaluated monomodal DenseVNet, multimodal ScaleNet, and monomodal and multimodal HighRes3DNet, which yielded dice score coefficients (DSC) of 0.875, 0.848, 0.858, and 0.890 in WG, respectively. Multimodal HighRes3DNet and ScaleNet yielded higher DSC with statistical differences in PZ and CG only compared to monomodal DenseVNet, indicating that multimodal networks added value by generating better segmentation between PZ and CG regions but did not improve the WG segmentation. No significant difference was observed in the apex and base of WG segmentation between monomodal and multimodal networks, indicating that the segmentations at the apex and base were more affected by the general network architecture. The number of training data was also varied for DenseVNet and HighRes3DNet, from 20 to 120 in steps of 20. DenseVNet was able to yield DSC of higher than 0.65 even for special cases, such as TURP or abnormal prostate, whereas HighRes3DNet's performance fluctuated with no trend despite being the best network overall. Multimodal networks did not add value in segmenting special cases but generally reduced variations in segmentation compared to the same matched monomodal network.

11.
Singapore Med J ; 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32798360

RESUMO

INTRODUCTION: Usage of metformin is associated with improved survival in lung, breast and prostate cancer, and metformin has been shown to inhibit cancer cell growth and proliferation in in vitro studies. Given the lack of clinical data on metformin use in patients with bladder cancer, we aimed to evaluate the role of metformin in their oncological outcomes. METHODS: Medication use from a prospectively maintained database of 122 patients with non-muscle invasive bladder cancer treated with intravesical Bacille Calmette-Guerin (BCG), who were recruited under a randomised, double-blinded, controlled clinical trial, was collected and analysed. Kaplan-Meier curves were used to assess overall survival (OS) and disease-specific survival (DSS). RESULTS: At a median follow-up duration of 102 (range 3-357) months, 53 (43.4%) patients experienced disease recurrence and 21 (17.2%) experienced disease progression. There was no significant difference in mortality between patients with diabetes mellitus and those without. There was significant difference in OS among patients without diabetes mellitus, patients with diabetes mellitus on metformin and patients with diabetes mellitus not on metformin (p = 0.033); patients with diabetes mellitus on metformin had the best prognosis. Metformin use was associated with significantly lower DSS (p = 0.042). Other oral hypoglycaemic agents, insulin or statins were not associated with disease recurrences or progression. CONCLUSION: Metformin use was associated with improved oncological outcomes in patients with non-muscle invasive bladder cancer treated with intravesical BCG. Prospective studies with larger patient populations are needed to validate the role of metformin as potential therapy for bladder cancer.

15.
Medicine (Baltimore) ; 99(22): e20336, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481410

RESUMO

INTRODUCTION: Synchronous colorectal and prostate malignancies are uncommon, with standard treatment guidelines not yet established. Chemoradiation therapy is involved in both colorectal and prostate cancers. However, differing dosage regimens and effects of irradiation field on anatomical planes for surgery makes management of the synchronous cancers challenging. We report the first case of synchronous prostate and rectal cancer being treated with a combination of treatment modalities with a unique addition of high dose rate prostate brachytherapy boost. PATIENT CONCERNS: The patient, a 69-year-old Chinese gentleman, presented with per-rectal bleeding with alternating bowel habits and a hemoglobin drop. He also had a history of urinary urge incontinence. DIAGNOSIS: Following diagnostic workup, he was diagnosed with synchronous rectal adenocarcinoma (T3N1M0) and prostate malignancy (T2bN0M0). INTERVENTIONS: The management consisted of neoadjuvant androgen deprivation therapy (ADT) and pelvic chemoradiation, followed by high dose rate prostate brachytherapy boost and subsequently anterior resection. OUTCOMES: Following therapy, the patient has no evidence of local recurrence or distant metastasis. CONCLUSION: We suggest a new feasible treatment strategy for the management of synchronous colorectal and prostate cancers.


Assuntos
Neoplasias da Próstata/complicações , Neoplasias da Próstata/terapia , Neoplasias Retais/complicações , Neoplasias Retais/terapia , Idoso , Antagonistas de Androgênios/uso terapêutico , Quimiorradioterapia/métodos , Humanos , Masculino
17.
J Pharmacol Exp Ther ; 374(3): 438-451, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32554434

RESUMO

Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex. The in vitro inhibition constant of the final high-affinity CYP17A1-abiraterone complex ( ( K i * = 0.39 nM )yielded a binding free energy of -12.8 kcal/mol that was quantitatively consistent with the in silico prediction of -14.5 kcal/mol. Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells after abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced-fit model. Given the extended residence time (42 hours) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even when most abiraterone has been eliminated systemically. Subsequent pharmacokinetic-pharmacodynamic (PK-PD) modeling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulfate at both 1000- and 500-mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, in which equipotent reduction of downstream plasma DHEA-sulfate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for re-evaluating the current dosing paradigm of abiraterone with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden. SIGNIFICANCE STATEMENT: With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions, and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow-, tight-binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes.


Assuntos
Androstenos/farmacologia , Inibidores Enzimáticos/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Linhagem Celular Tumoral , Desidroepiandrosterona/farmacologia , Humanos , Cinética , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Esteroides/farmacologia
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