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We assessed the accuracy of a prototype radiation detector with a built in CMOS amplifier for use in dosimetry for high dose rate brachytherapy. The detectors were fabricated on two substrates of epitaxial high resistivity silicon. The radiation detection performance of prototypes has been tested by ion beam induced charge (IBIC) microscopy using a 5.5 MeV alpha particle microbeam. We also carried out the HDR Ir-192 radiation source tracking at different depths and angular dose dependence in a water equivalent phantom. The detectors show sensitivities spanning from (5.8 ± 0.021) × 10-8 to (3.6 ± 0.14) × 10-8 nC Gy-1 mCi-1 mm-2. The depth variation of the dose is within 5% with that calculated by TG-43. Higher discrepancies are recorded for 2 mm and 7 mm depths due to the scattering of secondary particles and the perturbation of the radiation field induced in the ceramic/golden package. Dwell positions and dwell time are reconstructed within ±1 mm and 20 ms, respectively. The prototype detectors provide an unprecedented sensitivity thanks to its monolithic amplification stage. Future investigation of this technology will include the optimisation of the packaging technique.
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We have previously demonstrated that CD44 variant 6 (CD44v6) is associated with prostate cancer (CaP) growth and therapeutic resistance in vitro, however, the role of CD44v6 in CaP in vivo is not fully understood. The purpose of this study is to investigate the effect of CD44v6 on CaP growth and chemo-/radiotherapy response in NOD/SCID mouse models in vivo and to validate its role as a therapeutic target for CaP therapy. CD44v6 was knocked down in PC-3M CaP cell line using short hairpin RNA. Subcutaneous (s.c.) and orthotopic CaP mouse xenografts were established. The effect of CD44v6 knockdown (KD) on tumour growth was evaluated in both s.c. and orthotopic models. Chemo-/radiotherapy response was evaluated in the s.c. model. Association of CD44v6 with PI3K/Akt pathway was validated using immunohistochemistry staining. We found that KD of CD44v6 significantly reduced tumour growth in both models, and enhanced the sensitivity of tumours to chemotherapy and radiotherapy in the s.c. model. In addition, we demonstrated that KD of CD44v6 is associated with downregulation of the PI3K/Akt/mTOR pathway. Our data confirm that CaP growth and chemo-/radiosensitivity in vivo is associated with CD44v6, which holds great promises as a therapeutic target in the treatment of CaP.
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Quimioradioterapia/métodos , Docetaxel/farmacología , Variación Genética , Receptores de Hialuranos/metabolismo , Neoplasias de la Próstata/patología , Tolerancia a Radiación/genética , Animales , Antineoplásicos/farmacología , Apoptosis , Proliferación Celular , Rayos gamma , Humanos , Receptores de Hialuranos/genética , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Stereotactic radiosurgery (SRS) can be delivered with a standard linear accelerator (linac). At institutions having more than one linac, beam matching is common practice. In the literature, there are indications that machine central axis (CAX) matching for broad fields does not guarantee matching of small fields with side ≤2 cm. There is no indication on how matching for broad fields on axis translates to matching small fields off axis. These are of interest to multitarget single-isocenter (MTSI) SRS planning and the present work addresses that gap in the literature. METHODS: We used 6 MV flattening filter free (FFF) beams from four Elekta VersaHD® linacs equipped with an Agility™ multileaf collimator (MLC). The linacs were strictly matched for broad fields on CAX. We compared output factors (OPFs) and effective field size, measured concurrently using a novel 2D solid-state dosimeter "Duo" with a spatial resolution of 0.2 mm, in square and rectangular static fields with sides from 0.5 to 2 cm, either on axis or away from it by 5 to 15 cm. RESULTS: Among the four linacs, OPF for fields ≥1 × 1 cm2 ranged 1.3% on CAX, whereas off axis a maximum range of 1.9% was observed at 15 cm. A larger variability in OPF was noted for the 0.5 × 0.5 cm2 field, with a range of 5.9% on CAX, which improved to a maximum of 2.3% moving off axis. Two linacs showed greater consistency with a range of 1.4% on CAX and 2.2% at 15 cm off axis. Between linacs, the effective field size varied by <0.04 cm in most cases, both on and off axis. Tighter matching was observed for linacs with a similar focal spot position. CONCLUSIONS: Verification of small-field consistency for matched linacs used for SRS is an important task for dosimetric validation. A significant benefit of concurrent measurement of field size and OPF allowed for a comprehensive assessment using a novel diode array. Our study showed the four linacs, strictly matched for broad fields on CAX, were still matched down to a field size of 1 x 1 cm2 on and off axis.
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Radiocirugia , Humanos , Aceleradores de Partículas , Radiometría , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por ComputadorRESUMEN
Prostate cancer (CaP) is the most commonly diagnosed cancer in males in western countries. Orthotopic implantation is considered as an ideal xenograft model for CaP study, and noninvasive measurement of tumor volume changes is important for monitoring responses to anticancer therapies. In this study, the T2-weighted fast spin echo sequence magnetic resonance imaging (MRI) was performed on a CaP orthotopic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse model weekly for 6 weeks post PC-3 CaP cell inoculation, and the fat signal was suppressed using a chemical shift-selective pulse. Subsequently, the MRI data were imported into the image processing software Avizo Standard and stacked into three-dimensional (3D) volumes. Our results demonstrate that MRI, combined with 3D reconstruction, is a feasible and sensitive method to assess tumor growth in a PC-3 orthotopic CaP mouse model and this established monitoring approach is promising for longitudinal observation of CaP xenograft development after anticancer therapy in vivo. Further investigation is needed to validate this protocol in a larger cohort of mice to generate enough statistical power.
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Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Mediciones Luminiscentes , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Células PC-3 , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Carga Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: To develop a low literacy talking book (written book with accompanying audio-recording) about radiation therapy and explore its acceptability with patients and caregivers. METHOD: The talking book was developed iteratively using low literacy design principles and a multidisciplinary committee comprising consumers and experts in radiation oncology, nursing, behavioural sciences, and linguistics. It contained illustrations, photos, and information on: treatment planning, daily treatment, side effects, psychosocial health, and a glossary of medical terms. Semi-structured interviews were conducted with patients who self-reported low functional health literacy and caregivers to explore their views on the resource. Thematic analysis using a framework approach informed the analysis. RESULTS: Participants were very satisfied with the content, illustrations, and language in the resource. Most were unfamiliar with the term 'talking book', but liked the option of different media (text and audio). The resource was seen as facilitating communication with the cancer care team by prompting question-asking and equipping patients and their families with knowledge to communicate confidently. CONCLUSIONS: The low literacy talking book was well accepted by patients and their caregivers. The next step is to examine the effect of the resource on patients' knowledge, anxiety, concerns, and communication with the cancer care team.
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Alfabetización en Salud/métodos , Neoplasias/radioterapia , Libros , Comunicación , Femenino , Humanos , Masculino , Neoplasias/patologíaRESUMEN
BACKGROUND: Development of chemo-/radioresistance is a major challenge for the current prostate cancer (CaP) therapy. We have previously demonstrated that epithelial cell adhesion molecule (EpCAM) is associated with CaP growth and therapeutic resistance in vitro, however, the role of EpCAM in CaP in vivo is not fully elucidated. Here, we aimed to investigate how expression of EpCAM is involved in CaP growth and chemo-/radiotherapy response in NOD/SCID mouse models in vivo and to validate its role as a therapeutic target for CaP therapy. METHODS: EpCAM was knocked down in PC-3 CaP cell line using short hairpin RNA (shRNA). The effect of EpCAM-knockdown (KD) on tumour growth, chemo-/radiotherapy response and animal survival was evaluated on subcutaneous (s.c) and orthotopic mouse models. RESULTS: We found that KD of EpCAM significantly inhibited tumour growth, increased xenograft sensitivity to chemotherapy/radiotherapy, and prolonged the survival of tumour-bearing mice. In addition, we demonstrated that KD of EpCAM is associated with downregulation of the PI3K/Akt/mTOR pathway. CONCLUSIONS: In conclusion, our data confirms that CaP growth and chemo-/radioresistance in vivo is associated with over-expression of EpCAM, which serves both a functional biomarker and promising therapeutic target.
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Molécula de Adhesión Celular Epitelial/genética , Neoplasias de la Próstata/genética , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Quimioterapia Adyuvante , Modelos Animales de Enfermedad , Molécula de Adhesión Celular Epitelial/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/genética , Radioterapia Adyuvante , Transducción de Señal , Serina-Treonina Quinasas TOR , Carga Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: High Dose Rate Brachytherapy (HDRB) boost is a well-established treatment for prostate cancer (PC). We describe the PROstate Multicentre External beam radioTHErapy Using Stereotactic boost (PROMETHEUS) study. Non-surgical stereotactic techniques are used to deliver similar doses to HDRB boost regimens with a dose escalation sub-study. METHODS: Eligible patients have intermediate or high risk PC. PROMETHEUS explores the safety, efficacy and feasibility of multiple Australian centres cooperating in the delivery of Prostate Stereotactic Body Radiotherapy (SBRT) technology. A SBRT boost component Target Dose (TD) of 19Gy in two fractions is to be delivered, followed by a subsequent EBRT component of 46Gy in 23 fractions. Once accrual triggers have been met, SBRT doses can be escalated in 1 Gy increments to a maximum of 22Gy in two fractions. Patient safety will also be measured with the rate of both acute and late moderate to severe Gastro-Intestinal (GI) and Genito-Urinary (GU) Common Terminology Criteria for Adverse Events (CTCAE) toxicities as well as patient reported quality of life. Efficacy will be assessed via biochemical control after 3 years. DISCUSSION: PROMETHEUS aims to generate evidence for a non-surgical possible future alternative to HDRB boost regimens, and introduce advanced radiotherapy techniques across multiple Australian cancer centres. TRIAL REGISTRATION: The study was retrospectively registered on the ANZCTR (Australian New Zealand Clinical Trials Registry) with trial ID: ACTRN12615000223538 .
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Adenocarcinoma/radioterapia , Neoplasias de la Próstata/radioterapia , Traumatismos por Radiación/epidemiología , Radiocirugia/métodos , Radioterapia de Intensidad Modulada/métodos , Adenocarcinoma/sangre , Adenocarcinoma/patología , Adulto , Australia , Fraccionamiento de la Dosis de Radiación , Estudios de Factibilidad , Humanos , Calicreínas/sangre , Masculino , Estudios Multicéntricos como Asunto , Estadificación de Neoplasias , Medición de Resultados Informados por el Paciente , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Calidad de Vida , Traumatismos por Radiación/etiología , Radiocirugia/efectos adversos , Planificación de la Radioterapia Asistida por Computador , Radioterapia de Intensidad Modulada/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: This study aims to assess the accuracy of source position verification during high-dose rate (HDR) prostate brachytherapy using a novel, in-house developed two-dimensional (2D) diode array (the Magic Plate), embedded exactly below the patient within a carbon fiber couch. The effect of tissue inhomogeneities on source localization accuracy is examined. METHOD: Monte Carlo (MC) simulations of 12 source positions from a HDR prostate brachytherapy treatment were performed using the Geant4 toolkit. An Ir-192 Flexisource (Isodose Control, Veenendaal, the Netherlands) was simulated inside a voxelized patient geometry, and the dose deposited in each detector of the Magic Plate evaluated. The dose deposited in each detector was then used to localize the source position using a proprietary reconstruction algorithm. RESULTS: The accuracy of source position verification using the Magic Plate embedded in the patient couch was found to be affected by the tissue inhomogeneities within the patient, with an average difference of 2.1 ± 0.8 mm (k = 1) between the Magic Plate predicted and known source positions. Recalculation of the simulations with all voxels assigned a density of water improved this verification accuracy to within 1 mm. CONCLUSION: Source position verification using the Magic Plate during a HDR prostate brachytherapy treatment was examined using MC simulations. In a homogenous geometry (water), the Magic Plate was able to localize the source to within 1 mm, however, the verification accuracy was negatively affected by inhomogeneities; this can be corrected for by using density information obtained from CT, making the proposed tool attractive for use as a real-time in vivo quality assurance (QA) device in HDR brachytherapy for prostate cancer.
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Braquiterapia , Humanos , Radioisótopos de Iridio , Masculino , Método de Montecarlo , Fantasmas de Imagen , Neoplasias de la Próstata , Dosificación RadioterapéuticaRESUMEN
Radiation therapy (RT) continues to be one of the most popular treatment options for localized prostate cancer (CaP). Local CaP recurrence after RT is a pattern of treatment failure attributable to radioresistance of cancer cells. One major obstacle to RT is that there is a limit to the amount of radiation that can be safely delivered to the target organ. Recent results indicate that phosphoinositide 3-kinase (PI3K)/Akt/phosphatase and tensin homolog (PTEN)/mammalian target of rapamycin (mTOR) signaling pathway, autophagy, epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are involved in CaP metastasis and radioresistance. Emerging evidence also suggests that combining a radiosensitizer with RT increases the efficacy of CaP treatment. Understanding the mechanisms of radioresistance will help to overcome recurrence after RT in CaP patients and prevent metastasis. In this review, we discuss the novel findings of PI3K/Akt/PTEN/mTOR signaling pathway, autophagy, EMT and CSCs in the regulation of CaP metastasis and radioresistance, and focus on combination of radiosensitizers with RT in the treatment of CaP in preclinical studies to explore novel approaches for future clinical trials.
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Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapia , Tolerancia a Radiación , Animales , Autofagia , Terapia Combinada , Transición Epitelial-Mesenquimal , Humanos , Masculino , Metástasis de la Neoplasia , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de la radiación , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapia , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
INTRODUCTION: Prostate cancer (CaP) is the second leading malignancy in older men in Western countries. The role of CD44 variant 6 (CD44v6) in CaP progression and therapeutic resistance is still uncertain. Here, we investigated the roles of CD44v6 in CaP metastasis and chemo/radioresistance. Expression of CD44v6 in metastatic CaP cell lines, human primary CaP tissues and lymph node metastases was assessed using immunofluorescence and immunohistochemistry, respectively. METHODS: Knock down (KD) of CD44v6 was performed in PC-3M, DU145, and LNCaP cells using small interfering RNA (siRNA), and confirmed by confocal microscope, Western blot and quantitative real time polymerase chain reaction (qRT-PCR). Cell growth was evaluated by proliferation and colony formation assays. The adhesive ability and invasive potential were assessed using a hyaluronic acid (HA) adhesion and a matrigel chamber assay, respectively. Tumorigenesis potential and chemo-/radiosensitivity were measured by a sphere formation assay and a colony assay, respectively. RESULTS: Over-expression of CD44v6 was found in primary CaP tissues and lymph node metastases including cancer cells and surrounding stromal cells. KD of CD44v6 suppressed CaP proliferative, invasive and adhesive abilities, reduced sphere formation, enhanced chemo-/radiosensitivity, and down-regulated epithelial-mesenchymal transition (EMT), PI3K/Akt/mTOR, and Wnt/ß-catenin signaling pathway proteins in vitro. CONCLUSIONS: Our findings demonstrate that CD44v6 is an important cancer stem cell-like marker associated with CaP proliferation, invasion, adhesion, metastasis, chemo-/radioresistance, and the induction of EMT as well as the activation PI3K/Akt/mTOR and Wnt signaling pathways, suggesting that CD44v6 is a novel therapeutic target to sensitize CaP cells to chemo/radiotherapy.
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Receptores de Hialuranos/metabolismo , Metástasis Linfática/genética , Neoplasias de la Próstata/metabolismo , Línea Celular Tumoral , Proliferación Celular , Humanos , Receptores de Hialuranos/genética , Metástasis Linfática/patología , Masculino , Fosforilación , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
BACKGROUND: There currently exists no widespread high dose-rate (HDR) brachytherapy afterloader quality assurance (QA) tool for simultaneously assessing the afterloader's positional, temporal, transit velocity and air kerma strength accuracy. PURPOSE: The purpose of this study was to develop a precise and rigorous technique for performing daily QA of HDR brachytherapy afterloaders, incorporating QA of: dwell position accuracy, dwell time accuracy, transit velocity consistency and relative air kerma strength (AKS) of an Ir-192 source. METHOD: A Sharp ProGuide 240 mm catheter (Elekta Brachytherapy, Veenendaal, The Netherlands) was fixed 5 mm above a 256 channel epitaxial diode array 'dose magnifying glass' (DMG256) (Centre for Medical and Radiation Physics, University of Wollongong). Three dwell positions, each of 5.0 s dwell times, were spaced 13.0 mm apart along the array with the Flexitron HDR afterloader (Elekta Brachytherapy, Veenendaal, The Netherlands). The DMG256 was connected to a data acquisition system (DAQ) and a computer via USB2.0 link for live readout and post-processing. The outputted data files were analyzed using a Python script to provide positional and temporal localization of the Ir-192 source by tracking the centroid of the detected response. Measurements were repeated on a weekly basis, for a period of 5 weeks to determine the consistency of the measured parameters over an extended period. RESULTS: Using the DMG256 for relative AKS measurements resulted in measured values within 0.6%-3.0% of the expected activity over a 7-week period. The sub-millisecond temporal accuracy of the device allowed for measurements of the transit velocity with an average of (10.88 ± 1.01) cm/s for 13 mm steps. The dwell position localization for 1, 2, 3, 5, and 10 mm steps had an accuracy between 0.1 and 0.3 mm (3σ), with a fixed temporal accuracy of 10 ms. CONCLUSION: The DMG256 silicon strip detector allows for clinics to perform rigorous daily QA of HDR afterloader dwell position and dwell time accuracy with greater precision than the current standard methodology using closed circuit television and a stopwatch. Additionally, DMG256 unlocks the ability to perform measurements of transit velocity/time and relative AKS, which are not possible using current standard techniques.
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Braquiterapia , Silicio , Braquiterapia/instrumentación , Garantía de la Calidad de Atención de Salud , Radiometría/instrumentación , Dosificación Radioterapéutica , Control de CalidadRESUMEN
Conventional diagnostic tools for prostate cancer (PCa), such as prostate-specific antigen (PSA), transrectal ultrasound (TRUS), digital rectal examination (DRE), and tissue biopsy face, limitations in individual risk stratification due to invasiveness or reliability issues. Liquid biopsy is a less invasive and more accurate alternative. Metabolomic analysis of extracellular vesicles (EVs) holds a promise for detecting non-genetic alterations and biomarkers in PCa diagnosis and risk assessment. The current research gap in PCa lies in the lack of accurate biomarkers for early diagnosis and real-time monitoring of cancer progression or metastasis. Establishing a suitable approach for observing dynamic EV metabolic alterations that often occur earlier than being detectable by other omics technologies makes metabolomics valuable for early diagnosis and monitoring of PCa. Using four distinct metabolite extraction approaches, the metabolite cargo of PC3-derived large extracellular vesicles (lEVs) was evaluated using a combination of methanol, cell shearing using microbeads, and size exclusion filtration, as well as two fractionation chemistries (pHILIC and C18 chromatography) that are also examined. The unfiltered methanol-microbeads approach (MB-UF), followed by pHILIC LC-MS/MS for EV metabolite extraction and analysis, is effective. Identified metabolites such as L-glutamic acid, pyruvic acid, lactic acid, and methylmalonic acid have important links to PCa and are discussed. Our study, for the first time, has comprehensively evaluated the extraction and separation methods with a view to downstream sample integrity across omics platforms, and it presents an optimised protocol for EV metabolomics in PCa biomarker discovery.
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Prostate cancer (PCa) is a global health concern, ranking as the most common cancer among men in Western countries. Traditional diagnostic methods are invasive with adverse effects on patients. Due to the heterogeneous nature of PCa and their multifocality, tissue biopsies often yield false-negative results. To address these challenges, researchers are exploring innovative approaches, particularly in the realms of proteomics and metabolomics, to identify more reliable biomarkers and improve PCa diagnosis. Liquid biopsy (LB) has emerged as a promising non-invasive strategy for PCa early detection, biopsy selection, active surveillance for low-risk cases, and post-treatment and progression monitoring. Extracellular vesicles (EVs) are lipid-bilayer nanovesicles released by all cell types and play an important role in intercellular communication. EVs have garnered attention as a valuable biomarker resource in LB for PCa-specific biomarkers, enhancing diagnosis, prognostication, and treatment guidance. Metabolomics provides insight into the body's metabolic response to both internal and external stimuli, offering quantitative measurements of biochemical alterations. It excels at detecting non-genetic influences, aiding in the discovery of more accurate cancer biomarkers for early detection and disease progression monitoring. This review delves into the potential of EVs as a resource for LB in PCa across various clinical applications. It also explores cancer-related metabolic biomarkers, both within and outside EVs in PCa, and summarises previous metabolomic findings in PCa diagnosis and risk assessment. Finally, the article addresses the challenges and future directions in the evolving field of EV-based metabolomic analysis, offering a comprehensive overview of its potential in advancing PCa management.
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Biomarcadores de Tumor , Vesículas Extracelulares , Metabolómica , Neoplasias de la Próstata , Humanos , Vesículas Extracelulares/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Biomarcadores de Tumor/metabolismo , Masculino , Pronóstico , Metabolómica/métodos , Animales , Biopsia Líquida/métodosRESUMEN
BACKGROUND: In-vivo source tracking has been an active topic of research in the field of high-dose rate brachytherapy in recent years to verify accuracy in treatment delivery. Although detection systems for source tracking are being developed, the allowable threshold of treatment error is still unknown and is likely patient-specific due to anatomy and planning variation. PURPOSE: The purpose of this study was to determine patient and catheter-specific shift error thresholds for in-vivo source tracking during high-dose-rate prostate brachytherapy (HDRPBT). METHODS: A module was developed in the previously described graphical processor unit multi-criteria optimization (gMCO) algorithm. The module generates systematic catheter shift errors retrospectively into HDRPBT treatment plans, performed on 50 patients. The catheter shift model iterates through the number of catheters shifted in the plan (from 1 to all catheters), the direction of shift (superior, inferior, medial, lateral, cranial, and caudal), and the magnitude of catheter shift (1-6 mm). For each combination of these parameters, 200 error plans were generated, randomly selecting the catheters in the plan to shift. After shifts were applied, dose volume histogram (DVH) parameters were re-calculated. Catheter shift thresholds were then derived based on plans where DVH parameters were clinically unacceptable (prostate V100 < 95%, urethra D0.1cc > 118%, and rectum Dmax > 80%). Catheter thresholds were also Pearson correlated to catheter robustness values. RESULTS: Patient-specific thresholds varied between 1 to 6 mm for all organs, in all shift directions. Overall, patient-specific thresholds typically decrease with an increasing number of catheters shifted. Anterior and inferior directions were less sensitive than other directions. Pearson's correlation test showed a strong correlation between catheter robustness and catheter thresholds for the rectum and urethra, with correlation values of -0.81 and -0.74, respectively (p < 0.01), but no correlation was found for the prostate. CONCLUSIONS: It was possible to determine thresholds for each patient, with thresholds showing dependence on shift direction, and number of catheters shifted. Not every catheter combination is explorable, however, this study shows the feasibility to determine patient-specific thresholds for clinical application. The correlation of patient-specific thresholds with the equivalent robustness value indicated the need for robustness consideration during plan optimization and treatment planning.
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Braquiterapia , Neoplasias de la Próstata , Masculino , Humanos , Próstata , Estudios Retrospectivos , Dosificación Radioterapéutica , Neoplasias de la Próstata/radioterapia , Catéteres , Planificación de la Radioterapia Asistida por ComputadorRESUMEN
BACKGROUND AND OBJECTIVE: Despite the high efficacy of high-dose-rate brachytherapy boost (HDRB) in the management of prostate cancer (PC), use of this approach is declining. Similar dosimetry can be achieved using stereotactic body radiotherapy or "virtual HDRB" (vHDRB). The aim of the multicentre, single-arm, phase 2 PROMETHEUS trial (ACTRN12615000223538) was to evaluate the safety and efficacy of vHDRB in patients with PC. METHODS: Patients with intermediate-risk PC or selected patients with high-risk PC were eligible for inclusion. vHDRB was given as 19-20 Gy in two fractions, delivered 1 wk apart, followed by conventionally fractionated external beam radiotherapy (EBRT) at 46 Gy in 23 fractions or 36 Gy in 12 fractions. The primary endpoint was the biochemical/clinical relapse-free rate (bcRFR). Toxicity was graded using Common Terminology Criteria for Adverse Events version 4 and quality of life (QoL) data were collected used the Expanded Prostate Cancer Index Composite-26 questionnaire. KEY FINDINGS AND LIMITATIONS: From March 2014 to December 2018, 151 patients (74% intermediate risk, 26% high risk) with a median age of 69 yr were treated across five centres. Median follow-up was 60 mo. The 5-yr bcRFR was 94.1% (95% confidence interval [CI] 90-98%) and the local control rate was 98.7%. Acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity occurred in 6.6% and 23.2% of patients, respectively, with no acute grade 3 toxicity. At 60 mo after treatment, the prevalence of late grade ≥2 GI toxicity was 1.7% (95% CI 0.3-6.5%) and the prevalence of late grade ≥2 GU toxicity was 3.3% (95% CI 1.1-8.8%). Between baseline and 60 mo, QoL improved for urinary obstructive and hormonal domains, was stable for the bowel domain, and deteriorated slightly for the sexual and urinary incontinence domains. CONCLUSIONS: Delivery of gantry-based vHDRB followed by conventionally fractionated EBRT is feasible in a multicentre setting, with high 5-yr bcRFR and low toxicity. This approach is being compared with prostate ultrahypofractionated radiotherapy in the TROG 18.01 NINJA randomised trial (ACTRN12618001806257). PATIENT SUMMARY: The PROMETHEUS trial investigated noninvasive high-dose precision radiotherapy combined with conventional radiotherapy in patients with prostate cancer. We found that this new technique was well tolerated and resulted in better cancer control outcomes than historically reported.
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Diagnosis and stratification of prostate cancer (PCa) patients using the prostate-specific antigen (PSA) test is challenging. Extracellular vesicles (EVs), as a new star of liquid biopsy, has attracted interest to complement inaccurate PSA screening and invasiveness of tissue biopsy. In this study, a panel of potential small EV (sEV) protein biomarkers is identified from PCa cell lines using label-free LC-MS/MS proteomics. These biomarkers underwent further validation with plasma and urine samples from different PCa stages through parallel reaction monitoring-based targeted proteomics, western blotting, and ELISA. Additionally, a tissue microarray containing cancerous and noncancerous tissues is screened to provide additional evidence of selected sEV proteins associated with cancer origin. Results indicate that sEV protein LAMB1 is highly expressed in human plasma of metastatic PCa patients compared with localised PCa patients and control subjects, while sEV protein Histone H4 is highly expressed in human urine of high-risk PCa patients compared to low-risk PCa patients and control subjects. These two sEV proteins demonstrate higher specificity and sensitivity than the PSA test and show promise for metastatic PCa diagnosis, progression monitoring, and risk stratification.
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Biomarcadores de Tumor , Vesículas Extracelulares , Histonas , Neoplasias de la Próstata , Proteómica , Humanos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Masculino , Proteómica/métodos , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/orina , Vesículas Extracelulares/metabolismo , Histonas/metabolismo , Medición de Riesgo/métodos , Persona de Mediana Edad , Anciano , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , LamininaRESUMEN
PURPOSE: This study aimed to determine the viability of focal dose escalation to prostate cancer intraprostatic lesions (IPLs) from multiparametric magnetic resonance (mpMRI) and prostate-specific membrane antigen positron emission tomography (PSMA-PET) images using high-dose-rate (HDR) prostate brachytherapy (pBT). METHODS AND MATERIALS: Retrospective data from 20 patients treated with HDR pBT was utilized. The interobserver contouring variability of 5 observers was quantified using the dice similarity coefficient (DSC) and mean distance to agreement (MDA). Uncertainty in propagating IPL contours to trans-rectal ultrasound (TRUS) was quantified using a tissue equivalent prostate phantom. Feasibility of incorporating IPLs into HDR pBT planning was tested on retrospective patient data. RESULTS: The average observer DSC was 0.65 (PSMA-PET) and 0.52 (mpMRI). The uncertainty in propagating IPL contours was 0.6 mm (PSMA-PET), and 0.4 mm (mpMRI). Uncertainties could be accounted for by expanding IPL contours by 2 mm to create IPL PTVs. The mean D98% achieved using HDR pBT was 166% and 135% for the IPL and IPL PTV contours, respectively. CONCLUSIONS: Focal dose escalation to IPLs identified on either PSMA-PET or mpMRI is viable using TRUS-based HDR pBT. Utilizing HDR pBT allows dose escalation of up to 166% of the prescribed dose to the prostate.
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Braquiterapia , Neoplasias de la Próstata , Masculino , Humanos , Próstata/diagnóstico por imagen , Próstata/patología , Braquiterapia/métodos , Estudios Retrospectivos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/patología , Imagen por Resonancia Magnética/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodosRESUMEN
PURPOSE: Although radiation dose escalation improves prostate cancer disease control, it can cause increased toxicity. Genitourinary (GU) symptoms after prostate radiation therapy affect patient health-related quality of life (QoL). We compared patient-reported GU QoL outcomes following 2 alternative urethral sparing stereotactic body radiation therapy regimens. METHODS AND MATERIALS: Expanded Prostate Cancer Index Composite (EPIC)-26 GU scores were compared between 2 urethral sparing stereotactic body radiation therapy trials. The SPARK trial prescribed a "Monotherapy" dose of 36.25 Gy in 5 fractions to the prostate. The PROMETHEUS trial prescribed 2 phases: a 19- to 21-Gy in 2 fractions "Boost" to the prostate, followed by 46 Gy in 23 fractions or 36 Gy in 12 fractions. The biological effective dose (BED) for urethral toxicity was 123.9 Gy for Monotherapy and 155.8 to 171.2 Gy for Boost. Mixed effects logistic regression models were utilized to estimate the difference in the odds of a minimal clinically important change from baseline EPIC-26 GU score between regimens at each follow-up. RESULTS: 46 Monotherapy and 149 Boost patients completed baseline EPIC-26 scoring. Mean EPIC-26 GU scores revealed statistically superior urinary incontinence outcomes for Monotherapy at 12 months (mean difference, 6.9; 95% confidence interval [CI], 1.6-12.1; P = .01) and 36 months (mean difference, 9.6; 95% CI, 4.1-15.1; P < .01). Monotherapy also revealed superior mean urinary irritative/obstructive outcomes at 12 months (mean difference, 6.9; 95% CI, 2.0-12.9; P < .01) and 36 months (mean difference, 6.3; 95% CI, 1.9-10.8; P < .01). For both domains and at all time points, the absolute differences were <10%. There were no significant differences in the odds of reporting a minimal clinically important change between regimens at any time point. CONCLUSIONS: Even in the presence of urethral sparing, the higher BED delivered in the Boost schedule may have a small adverse effect on GU QoL compared with Monotherapy. However, this did not translate to statistically significant differences in minimal clinically important changes. Whether the higher BED of the boost arm offers an efficacy advantage is being investigated in the Trans Tasman Radiation Oncology Group 18.01 NINJA randomized trial.
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Braquiterapia , Neoplasias de la Próstata , Humanos , Masculino , Braquiterapia/efectos adversos , Braquiterapia/métodos , Fraccionamiento de la Dosis de Radiación , Próstata , Neoplasias de la Próstata/radioterapia , Calidad de VidaRESUMEN
Introduction: Despite strong epidemiological evidence that dietary factors modulate cancer risk, cancer control through dietary intervention has been a largely intractable goal for over sixty years. The effect of tumour genotype on synergy is largely unexplored. Methods: The effect of seven dietary phytochemicals, quercetin (0-100 µM), curcumin (0-80 µM), genistein, indole-3-carbinol (I3C), equol, resveratrol and epigallocatechin gallate (EGCG) (each 0-200 µM), alone and in all paired combinations om cell viability of the androgen-responsive, pTEN-null (LNCaP), androgen-independent, pTEN-null (PC-3) or androgen-independent, pTEN-positive (DU145) prostate cancer (PCa) cell lines was determined using a high throughput alamarBlue® assay. Synergy, additivity and antagonism were modelled using Bliss additivism and highest single agent equations. Patterns of maximum synergy were identified by polygonogram analysis. Network pharmacology approaches were used to identify interactions with known PCa protein targets. Results: Synergy was observed with all combinations. In LNCaP and PC-3 cells, I3C mediated maximum synergy with five phytochemicals, while genistein was maximally synergistic with EGCG. In contrast, DU145 cells showed resveratrol-mediated maximum synergy with equol, EGCG and genistein, with I3C mediating maximum synergy with only quercetin and curcumin. Knockdown of pTEN expression in DU145 cells abrogated the synergistic effect of resveratrol without affecting the synergy profile of I3C and quercetin. Discussion: Our study identifies patterns of synergy that are dependent on tumour cell genotype and are independent of androgen signaling but are dependent on pTEN. Despite evident cell-type specificity in both maximally-synergistic combinations and the pathways that phytochemicals modulate, these combinations interact with similar prostate cancer protein targets. Here, we identify an approach that, when coupled with advanced data analysis methods, may suggest optimal dietary phytochemical combinations for individual consumption based on tumour molecular profile.Graphical abstract.
RESUMEN
PURPOSE: The purpose of this study was to determine the feasibility of online adaptive transrectal ultrasound (TRUS)-based high-dose-rate prostate brachytherapy (HDRPBT) through retrospective simulation of source positioning and catheter swap errors on patient treatment plans. METHOD: Source positioning errors (catheter shifts in 1 mm increments in the cranial/caudal, anterior/posterior, and medial/lateral directions up to ±6 mm) and catheter swap errors (between the most and least heavily weighted) were introduced retrospectively into DICOM treatment plans of 20 patients that previously received TRUS HDRPBT. Dose volume histogram (DVH) indices were monitored as errors were introduced sequentially into individual catheters, simulating potential errors throughout treatment. Whenever DVH indices were outside institution thresholds: prostate V100% <95%, urethra D0.1cc >118% and rectum Dmax >80%, the plan was adapted using remaining catheters (i.e., simulating previous catheters as previously delivered). The final DVH indices were recorded. RESULTS: Prostate coverage (V100% >95%) could be maintained for source position errors up to 6 mm through online plan adaptation. The source position error at which the urethra D0.1cc and rectum Dmax was able to return to clinically acceptable levels using online adaptation varied between 6 mm to 1 mm, depending on the direction of the source position error and patient anatomy. After introduction of catheter swap errors to patient plans, prostate V100% was recoverable using online adaptation to near original plan characteristics. Urethra D0.1cc and rectum Dmax showed less recoverability. CONCLUSION: Online adaptive HDRPBT maintains the prostate V100% to clinically acceptable values for majority of directional shifts. However, the current online adaptive method may not correct for source position errors near organs at risk.