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1.
Cell Genom ; 4(3): 100511, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38428419

RESUMEN

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.


Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/genética , Próstata/metabolismo , Mutación , Genómica , Evolución Molecular
3.
BMJ Open ; 13(10): e075888, 2023 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-37890967

RESUMEN

INTRODUCTION: Epilepsy is one of the most common neurological conditions worldwide. Despite many antiseizure medications (ASMs) being available, up to one-third of patients do not achieve seizure control. Preclinical studies have shown treatment with sodium selenate to have a disease-modifying effect in a rat model of chronic temporal lobe epilepsy (TLE). AIM: This randomised placebo-controlled trial aims to evaluate the antiseizure and disease-modifying effects of sodium selenate in people with drug-resistant TLE. METHODS: This will be a randomised placebo-controlled trial of sodium selenate. One hundred and twenty-four adults with drug-resistant TLE and ≥4 countable seizures/month will be recruited. Outcomes of interest will be measured at baseline, week 26 and week 52 and include an 8-week seizure diary, 24-hour electroencephalogram and cognitive, neuropsychiatric and quality of life measures. Participants will then be randomised to receive a sustained release formulation of sodium selenate (initially 10 mg three times a day, increasing to 15 mg three times a day at week 4 if tolerated) or a matching placebo for 26 weeks. OUTCOMES: The primary outcome will be a consumer codesigned epilepsy-Desirability of Outcome Rank (DOOR), combining change in seizure frequency, adverse events, quality of life and ASM burden measures into a single outcome measure, compared between treatment arms over the whole 52-week period. Secondary outcomes will compare baseline measures to week 26 (antiseizure) and week 52 (disease modification). Exploratory measures will include biomarkers of treatment response. ETHICS AND DISSEMINATION: The study has been approved by the lead site, Alfred Hospital Ethics Committee (594/20). Each participant will provide written informed consent prior to any trial procedures. The results of the study will be presented at national and international conferences, published in peer-reviewed journals and disseminated through consumer organisations. CONCLUSION: This study will be the first disease-modification randomised controlled trial in patients with drug-resistant TLE. TRIAL REGISTRATION NUMBER: ANZCTR; ACTRN12623000446662.


Asunto(s)
Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Adulto , Humanos , Animales , Ratas , Ácido Selénico , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Calidad de Vida , Resultado del Tratamiento , Epilepsia Refractaria/tratamiento farmacológico , Convulsiones , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase II como Asunto
4.
J Natl Cancer Inst ; 115(4): 468-472, 2023 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-36610996

RESUMEN

Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.


Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Factores de Riesgo , Pronóstico , Predisposición Genética a la Enfermedad
5.
Cancers (Basel) ; 16(1)2023 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-38201549

RESUMEN

Lymphovascular invasion, whereby tumour cells or cell clusters are identified in the lumen of lymphatic or blood vessels, is thought to be an essential step in disease dissemination. It has been established as an independent negative prognostic indicator in a range of cancers. We therefore aimed to assess the impact of lymphovascular invasion at the time of prostatectomy on oncological outcomes. We performed a multicentre, retrospective cohort study of 3495 men who underwent radical prostatectomy for localised prostate cancer. Only men with negative preoperative staging were included. We assessed the relationship between lymphovascular invasion and adverse pathological features using multivariable logistic regression models. Kaplan-Meier curves and Cox proportional hazard models were created to evaluate the impact of lymphovascular invasion on oncological outcomes. Lymphovascular invasion was identified in 19% (n = 653) of men undergoing prostatectomy. There was an increased incidence of lymphovascular invasion-positive disease in men with high International Society of Urological Pathology (ISUP) grade and non-organ-confined disease (p < 0.01). The presence of lymphovascular invasion significantly increased the likelihood of pathological node-positive disease on multivariable logistic regression analysis (OR 15, 95%CI 9.7-23.6). The presence of lymphovascular invasion at radical prostatectomy significantly increased the risk of biochemical recurrence (HR 2.0, 95%CI 1.6-2.4). Furthermore, lymphovascular invasion significantly increased the risk of metastasis in the whole cohort (HR 2.2, 95%CI 1.6-3.0). The same relationship was seen across D'Amico risk groups. The presence of lymphovascular invasion at the time of radical prostatectomy is associated with aggressive prostate cancer disease features and is an indicator of poor oncological prognosis.

7.
Cancers (Basel) ; 14(19)2022 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-36230886

RESUMEN

Targeted therapies for cancers have improved primary tumor response rates, but concomitantly, brain metastases (BM) have become the most common brain tumors in adults and are associated with a dismal prognosis of generally less than 6 months, irrespective of the primary cancer type. They most commonly occur in patients with primary breast, lung, or melanoma histologies; however, they also appear in patients with other primary cancers including, but not limited to, prostate cancer, colorectal cancer, and renal cell carcinoma. Historically, molecular biomarkers have normally been identified from primary tumor resections. However, clinically informative genomic alterations can occur during BM development and these potentially actionable alterations are not always detected in the primary tumor leading to missed opportunities for effective targeted therapy. The molecular mechanisms that facilitate and drive metastasis to the brain are poorly understood. Identifying the differences between the brain and other extracranial sties of metastasis, and between primary tumors and BM, is essential to improving our understanding of BM development and ultimately patient management and survival. In this review, we present the current data on the genomic landscape of BM from various primary cancers which metastasize to the brain and outline potential mechanisms which may play a role in promoting the formation of the distant metastases in the brain.

8.
PLoS One ; 17(9): e0273783, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36103484

RESUMEN

The question of whether it is appropriate to attribute authorship to deceased individuals of original studies in the biomedical literature is contentious. Authorship guidelines utilized by journals do not provide a clear consensus framework that is binding on those in the field. To guide and inform the implementation of authorship frameworks it would be useful to understand the extent of the practice in the scientific literature, but studies that have systematically quantified the prevalence of this phenomenon in the biomedical literature have not been performed to date. To address this issue, we quantified the prevalence of publications by deceased authors in the biomedical literature from the period 1990-2020. We screened 2,601,457 peer-reviewed papers from the full text Europe PubMed Central database. We applied natural language processing, stringent filtering and manual curation to identify a final set of 1,439 deceased authors. We then determined these authors published a total of 38,907 papers over their careers with 5,477 published after death. The number of deceased publications has been growing rapidly, a 146-fold increase since the year 2000. This rate of increase was still significant when accounting for the growing total number of publications and pool of authors. We found that more than 50% of deceased author papers were first submitted after the death of the author and that over 60% of these papers failed to acknowledge the deceased authors status. Most deceased authors published less than 10 papers after death but a small pool of 30 authors published significantly more. A pool of 266 authors published more than 90% of their total publications after death. Our analysis indicates that the attribution of deceased authorship in the literature is not an occasional occurrence but a burgeoning trend. A consensus framework to address authorship by deceased scientists is warranted.


Asunto(s)
Autoria , Edición , Europa (Continente) , Humanos , Revisión por Pares , PubMed
9.
Methods Cell Biol ; 170: 21-30, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35811101

RESUMEN

Cancer stem cells are defined as low-abundance, quiescent cells and are considered a major cellular source of tumor recurrence following therapy, which identifies these cells as important therapeutic targets for difficult-to-treat cancers, including high-grade gliomas. By contrast to the highly proliferative bulk tumor cells, glioma stem cells (GSC) are slow-cycling, and therefore less sensitive to DNA damaging cytotoxic drugs. GSC are also less reliant on aerobic glycolytic metabolism, leading to inadequate clearing of GSC by chemotherapy and radiotherapy. The definition of GSC is based on the expression of specific stem cell protein markers. This method of GSC isolation is successful in isolating cell populations that can reliably recapitulate the tumor. However, cell populations that lack stem marker expression may also be capable of tumor recapitulation. Therefore, robust, reproducible methods for isolating GSC are required to identify and isolate cells with stem cell characteristics. Here, we provide a comprehensive and reproducible protocol for the isolation of slow-cycling GSC. Using this method, GSC isolated retain key characteristics of the cells in situ, including expression of genes associated with cell quiescence and invasive potential, compared to non-quiescent cell populations. Thus, isolation of GSC gated on cell proliferation offers a reliable alternative method for in vitro GSC identification, that adequately mirrors the physiological properties of GSC seen in vivo.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Glioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Glioblastoma/patología , Glioma/genética , Glioma/metabolismo , Glioma/patología , Humanos , Células Madre Neoplásicas/patología
10.
Clin Genitourin Cancer ; 20(5): 452-458, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35688680

RESUMEN

BACKGROUND: Disease recurrence is common following prostatectomy in patients with localised prostate cancer with high-risk features. Although androgen deprivation therapy increases the rates of organ-confined disease and negative surgical margins, there is no significant benefit on disease recurrence. Multiple lines of evidence suggest that (Fibroblast Growth Factor/Fibroblast Growth Factor Receptor) FGF/FGFR-signalling is important in supporting prostate epithelial cell survival in hostile conditions, including acute androgen deprivation. Given the recent availability of oral FGFR inhibitors, we investigated whether combination therapy could improve tumour response in the neo-adjuvant setting. METHODS: We conducted an open label phase II study of the combination of erdafitinib (3 months) and androgen deprivation therapy (4 months) in men with localised prostate cancer with high-risk features prior to prostatectomy using a Simon's 2 stage design. The co-primary endpoints were safety and tolerability and pathological response in the prostatectomy specimen. The effect of treatment on residual tumours was explored by global transcriptional profiling with RNA-sequencing. RESULTS: Nine patients were enrolled in the first stage of the trial. The treatment combination was poorly tolerated. Erdafitinib treatment was discontinued early in six patients, three of whom also required dose interruptions/reductions. Androgen deprivation therapy for 4 months was completed in all patients. The most common adverse events were hyperphosphataemia, taste disturbance, dry mouth and nail changes. No patients achieved a complete pathological response, although patients who tolerated erdafitinib for longer had smaller residual tumours, associated with reduced transcriptional signatures of epithelial cell proliferation. CONCLUSIONS: Although there was a possible enhanced anti-tumour effect of androgen deprivation therapy in combination with erdafitnib in treatment naïve prostate cancer, the poor tolerability in this patient population prohibits the use of this combination in this setting.


Asunto(s)
Antagonistas de Andrógenos , Neoplasias de la Próstata , Antagonistas de Andrógenos/uso terapéutico , Andrógenos , Factores de Crecimiento de Fibroblastos/uso terapéutico , Humanos , Masculino , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/cirugía , Neoplasia Residual , Antígeno Prostático Específico , Prostatectomía , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , ARN/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/uso terapéutico
11.
Alzheimers Dement (N Y) ; 8(1): e12299, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35574563

RESUMEN

Introduction: Sodium selenate increases tau dephosphorylation through protein phosphatase 2 activation. Here we report an open-label Phase 1b study of sodium selenate as a disease-modifying treatment for behavioral variant frontotemporal dementia (bvFTD). Methods: Twelve participants with bvFTD received sodium selenate (15 mg, three times a day) for 52 weeks. Safety assessments were carried out throughout the trial. Primary outcomes were frequency of adverse events (AEs), serious adverse events (SAEs), and discontinuations. Secondary outcomes of potential efficacy included cognitive and behavioral assessments, magnetic resonance imaging (MRI) whole brain volume, and cerebrospinal fluid (CSF) and blood total tau (t-tau), phosphorylated tau (p-tau), and neurofilament light (NfL) levels, which were measured at baseline and at week 52. Results: Sodium selenate was safe and well tolerated. All participants completed the study, and the majority (64.7%) of reported AEs were mild. One SAE occurred, which was not treatment related. Small declines in MRI and cognitive and behavioral measures were observed over the treatment period. There was no evidence for change in CSF protein levels (t-tau, p-tau, or NfL). Further analysis showed two distinct groups when measuring disease progression markers over the course of the study-one (n = 4) with substantial brain atrophy (2.5% to 6.5% reduction) and cognitive and behavioral decline over the 12-month treatment period, and the second group (n = 7) with no detectable change in cognitive and behavioral measures and less brain atrophy (0.3% to 1.7% reduction). Conclusion: Sodium selenate is safe and well tolerated in patients with bvFTD. Randomized-controlled trials are warranted to investigate potential efficacy.

12.
BMJ Open ; 11(12): e055019, 2021 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-34916328

RESUMEN

INTRODUCTION: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder for which there are currently no disease-modifying therapies. The neuropathology of PSP is associated with the accumulation of hyperphosphorylated tau in the brain. We have previously shown that protein phosphatase 2 activity in the brain is upregulated by sodium selenate, which enhances dephosphorylation. Therefore, the objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying therapy for PSP. METHODS AND ANALYSIS: This will be a multi-site, phase 2b, double-blind, placebo-controlled trial of sodium selenate. 70 patients will be recruited at six Australian academic hospitals and research institutes. Following the confirmation of eligibility at screening, participants will be randomised (1:1) to receive 52 weeks of active treatment (sodium selenate; 15 mg three times a day) or matching placebo. Regular safety and efficacy visits will be completed throughout the study period. The primary study outcome is change in an MRI volume composite (frontal lobe+midbrain-3rd ventricle) over the treatment period. Analysis will be with a general linear model (GLM) with the MRI composite at 52 weeks as the dependent variable, treatment group as an independent variable and baseline MRI composite as a covariate. Secondary outcomes are change in PSP rating scale, clinical global impression of change (clinician) and change in midbrain mean diffusivity. These outcomes will also be analysed with a GLM as above, with the corresponding baseline measure entered as a covariate. Secondary safety and tolerability outcomes are frequency of serious adverse events, frequency of down-titration occurrences and frequency of study discontinuation. Additional, as yet unplanned, exploratory outcomes will include analyses of other imaging, cognitive and biospecimen measures. ETHICS AND DISSEMINATION: The study was approved by the Alfred Health Ethics Committee (594/20). Each participant or their legally authorised representative and their study partner will provide written informed consent at trial commencement. The results of the study will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620001254987).


Asunto(s)
Parálisis Supranuclear Progresiva , Australia , Ensayos Clínicos Fase II como Asunto , Método Doble Ciego , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Ácido Selénico/uso terapéutico , Parálisis Supranuclear Progresiva/tratamiento farmacológico , Resultado del Tratamiento
13.
JCO Precis Oncol ; 52021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34322653

RESUMEN

PURPOSE: Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. METHODS: We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. RESULTS: We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2, a key regulator of EMT reprogramming. CONCLUSION: We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2, a key transcriptional regulator of EMT, correlates with clinical response.


Asunto(s)
Antagonistas de Andrógenos/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Transición Epitelial-Mesenquimal/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Factores de Transcripción de la Familia Snail/genética , Anciano , Antagonistas de Andrógenos/efectos adversos , Androstenos , Anilidas , Antineoplásicos Hormonales/efectos adversos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Nitrilos , Oligopéptidos , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Transducción de Señal , Factores de Transcripción de la Familia Snail/deficiencia , Compuestos de Tosilo
14.
BMC Cancer ; 21(1): 846, 2021 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-34294073

RESUMEN

BACKGROUND: Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. RESULTS: In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. CONCLUSIONS: This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.


Asunto(s)
Perfilación de la Expresión Génica , Monocitos/metabolismo , Monocitos/patología , Neoplasias de la Próstata/genética , Transcriptoma , Microambiente Tumoral/genética , Biología Computacional/métodos , Progresión de la Enfermedad , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Inmunofenotipificación , Estimación de Kaplan-Meier , Masculino , Anotación de Secuencia Molecular , Pronóstico , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/mortalidad
15.
BJU Int ; 128 Suppl 3: 45-51, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34310033

RESUMEN

OBJECTIVES: To assess the concordance between biopsy and radical prostatectomy (RP) specimens using the 2005 Gleason score (GS) and the International Society of Urological Pathology (ISUP) 2014/World Health Organization 2016 modified system, accounting for the introduction of transperineal biopsy and pre-biopsy multiparametric magnetic resonance imaging (mpMRI). PATIENTS AND METHODS: Between 2002 and 2019, we identified 2431 patients with paired biopsy and RP histopathology from a prospectively recorded and maintained prostate cancer database. Biopsy specimens were graded according to the 2005 GS or ISUP 2014 modified system, according to the year of diagnosis. Multivariable logistic regression analysis was conducted to retrospectively assess the impact of prostate-specific antigen (PSA), PSA density, age, pre-biopsy mpMRI, and biopsy method, on the rate of upgraded disease. The kappa coefficient was used to establish the degree of change in concordance between groups. RESULTS: Overall, 24% of patients had upgraded disease and 8% of patients had downgraded disease when using the modified ISUP 2014 criteria. Agreement in the updated ISUP 2014 cohort was 68%, compared with 55% in the 2005 GS group, which was validated by a kappa coefficient that was good (k = 0.5 ± 0.4) and poor (k = 0.3 ± 0.1), respectively. In multivariable models, a change in grading system independently improved overall disease concordance (P = 0.02), and there were no other co-segregated patient or pathological factors such as PSA, total number of cores, maximum cancer length, biopsy route or the use of mpMRI that impacted this finding. CONCLUSION: The 2014 ISUP modifed system improves overall concordance between biopsy and surgical specimens, and thus allows more accurate prognostication and management in high-grade disease, independent of more extensive prostate sampling and the use of mpMRI.


Asunto(s)
Adenocarcinoma/patología , Adenocarcinoma/cirugía , Clasificación del Tumor , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Adenocarcinoma/sangre , Adenocarcinoma/diagnóstico por imagen , Biopsia , Humanos , Masculino , Imágenes de Resonancia Magnética Multiparamétrica , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/diagnóstico por imagen , Estudios Retrospectivos
16.
Prostate Cancer Prostatic Dis ; 24(4): 1167-1180, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34108644

RESUMEN

BACKGROUND: Recent publications have shown patients with defects in the DNA mismatch repair (MMR) pathway driven by either MSH2 or MSH6 loss experience a significant increase in the incidence of prostate cancer. Moreover, this increased incidence of prostate cancer is accompanied by rapid disease progression and poor clinical outcomes. METHODS AND RESULTS: We show that androgen-receptor activation, a key driver of prostate carcinogenesis, can disrupt the MSH2 gene in prostate cancer. We screened tumours from two cohorts (recurrent/non-recurrent) of prostate cancer patients to confirm the loss of MSH2 protein expression and identified decreased MSH2 expression in recurrent cases. Stratifying the independent TCGA prostate cancer cohort for MSH2/6 expression revealed that patients with lower levels of MSH2/6 had significant worse outcomes, in contrast, endometrial and colorectal cancer patients with lower MSH2/6 levels. MMRd endometrial and colorectal tumours showed the expected increase in mutational burden, microsatellite instability and enhanced immune cell mobilisation but this was not evident in prostate tumours. CONCLUSIONS: We have shown that loss or reduced levels of MSH2/MSH6 protein in prostate cancer is associated with poor outcome. However, our data indicate that this is not associated with a statistically significant increase in mutational burden, microsatellite instability or immune cell mobilisation in a cohort of primary prostate cancers.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Endometriales/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias de la Próstata/genética , Neoplasias Colorrectales/inmunología , Reparación de la Incompatibilidad de ADN , Neoplasias Endometriales/inmunología , Femenino , Reordenamiento Génico , Mutación de Línea Germinal , Humanos , Masculino , Inestabilidad de Microsatélites , Neoplasias de la Próstata/inmunología , Transcriptoma , Células Tumorales Cultivadas , Secuenciación Completa del Genoma
17.
Eur J Cancer ; 148: 440-450, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33678516

RESUMEN

BACKGROUND: Ductal adenocarcinoma is an uncommon prostate cancer variant. Previous studies suggest that ductal variant histology may be associated with worse clinical outcomes, but these are difficult to interpret. To address this, we performed an international, multi-institutional study to describe the characteristics of ductal adenocarcinoma, particularly focussing on the effect of presence of ductal variant cancer on metastasis-free survival. METHODS: Patients with ductal variant histology from two institutional databases who underwent radical prostatectomies were identified and compared with an independent acinar adenocarcinoma cohort. After propensity score matching, the effect of the presence of ductal adenocarcinoma on time to biochemical recurrence, initiation of salvage therapy and the development of metastatic disease was determined. Deep whole-exome sequencing was performed for selected cases (n = 8). RESULTS: A total of 202 ductal adenocarcinoma and 2037 acinar adenocarcinoma cases were analysed. Survival analysis after matching demonstrated that patients with ductal variant histology had shorter salvage-free survival (8.1 versus 22.0 months, p = 0.03) and metastasis-free survival (6.7 versus 78.6 months, p < 0.0001). Ductal variant histology was consistently associated with RB1 loss, as well as copy number gains in TAP1, SLC4A2 and EHHADH. CONCLUSIONS: The presence of any ductal variant adenocarcinoma at the time of prostatectomy portends a worse clinical outcome than pure acinar cancers, with significantly shorter times to initiation of salvage therapies and the onset of metastatic disease. These features appear to be driven by uncoupling of chromosomal duplication from cell division, resulting in widespread copy number aberration with specific gain of genes implicated in treatment resistance.


Asunto(s)
Adenocarcinoma/mortalidad , Carcinoma Ductal/mortalidad , Prostatectomía/mortalidad , Neoplasias de la Próstata/mortalidad , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Anciano , Carcinoma Ductal/secundario , Carcinoma Ductal/cirugía , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Estudios Retrospectivos , Tasa de Supervivencia
18.
Cancer Immunol Immunother ; 70(7): 1811-1820, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33389014

RESUMEN

Recent developments in cancer immunotherapy promise better outcomes for cancer patients, although clinical trials for difficult to treat cancers such as malignant brain cancer present special challenges, showing little response to first generation immunotherapies. Reasons for differences in immunotherapy response in some cancer types are likely due to the nature of tumor microenvironment, which harbors multiple cell types which interact with tumor cells to establish immunosuppression. The cell types which appear to hold the key in regulating tumor immunosuppression are the tumor-infiltrating immune cells. The current standard treatment for difficult to treat cancer, including the most malignant brain cancer, glioblastoma, continues to offer a bleak outlook for patients. Immune-profiling and correlation with pathological and clinical data will lead to a deeper understanding of the tumor immune microenvironment and contribute toward the selection, optimization and development of novel precision immunotherapies. Here, we review the current understanding of the tumor microenvironmental landscape in glioblastoma with a focus on next-generation technologies including multiplex immunofluorescence and computational approaches to map the brain tumor microenvironment to decipher the role of the immune system in this lethal malignancy.


Asunto(s)
Biomarcadores de Tumor/inmunología , Neoplasias Encefálicas/tratamiento farmacológico , Simulación por Computador , Tolerancia Inmunológica/inmunología , Inmunohistoquímica/métodos , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Animales , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Humanos , Terapia Molecular Dirigida , Medicina de Precisión
19.
BMJ Neurol Open ; 3(2): e000223, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34988458

RESUMEN

INTRODUCTION: Sodium selenate is a potential disease-modifying treatment for Alzheimer's disease (AD) which reduces hyperphosphorylated tau through activation of the protein phosphatase 2A enzyme. We have shown sodium selenate to be safe and well tolerated in a 24-week, phase 2a double-blind placebo-controlled randomised controlled trial (RCT), also reporting sodium selenate reduced neurodegeneration on diffusion-weighted MRI. This study assessed the safety and tolerability of chronic sodium selenate treatment (up to 23 months) in patients with AD who had been enrolled in the RCT. Cognitive measures served as secondary outcomes of potential disease-modification. METHODS: An open-label extension study of sodium selenate (10 mg three times a day) in patients with AD who had completed the previous RCT. Twenty-eight patients were enrolled. Patients were regularly monitored for safety, adverse events (AEs) and protocol compliance. Cognitive tests were administered for measures of disease progression. RESULTS: Sixteen patients were discontinued by the sponsor, and 12 discontinued for other reasons. Treatment duration ranged from 6 to 23 months. The majority of AEs were mild (83%), and 33% were treatment-related. Common treatment-related AEs were alopecia (21%) and nail disorder (32%), which both resolved either prior to or following cessation of treatment. Two serious AEs occurred, which were not treatment-related. Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 score increased 1.8 points over 12 months. DISCUSSION: Chronic sodium selenate treatment is safe and well tolerated in patients with AD. Cognitive measures suggest a slowing of disease progression though this could not be confirmed as the study was not controlled. Further research into sodium selenate as a treatment for AD is warranted.

20.
Cancers (Basel) ; 14(1)2021 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-35008330

RESUMEN

Prostate cancer (PCa) is a hormone driven cancer, characterised by defects in androgen receptor signalling which drive the disease process. As such, androgen targeted therapies have been the mainstay for PCa treatment for over 70 years. High-risk PCa presents unique therapeutic challenges, namely in minimising the primary tumour, and eliminating any undetected micro metastases. Trials of neoadjuvant androgen deprivation therapy aim to address these challenges. Patients typically respond well to neoadjuvant treatment, showing regression of the primary tumour and negative surgical margins at the time of resection, however the majority of patients relapse and progress to metastatic disease. The mechanisms affording this resistance are largely unknown. This commentary attempts to explore theories of resistance more broadly, namely, clonal evolution, cancer stem cells, cell persistence, and drug tolerance. Moreover, it aims to explore the application of these theories in the PCa setting. This commentary also highlights the distinction between castration resistant PCa, and neoadjuvant resistant disease, and identifies the markers and characteristics of neoadjuvant resistant disease presented by current literature.

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