Browsing by Subject "Prostate cancer"
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Item Open Access A 3-D Multiparametric Ultrasound Elasticity Imaging System for Targeted Prostate Biopsy Guidance(2023) Chan, Derek Yu XuanProstate cancer is the most common cancer and second-leading cause of cancer death among men in the United States. Early and accurate diagnosis of prostate cancer remains challenging; following an abnormal rectal exam or elevated levels of prostate-specific antigen in serum, clinical guidelines recommend transrectal ultrasound-guided biopsy. However, lesions are often indistinguishable from noncancerous prostate tissue in conventional B-mode ultrasound images, which have a diagnostic sensitivity of about 30%, so the biopsy is not typically targeted to suspicious regions. Instead, the biopsy systematically samples 12 pre-specified regions of the gland. Systematic sampling often fails to detect cancer during the first biopsy, and while multiparametric MRI (mpMRI) techniques have been developed to guide a targeted biopsy, fused with live ultrasound, this approach remains susceptible to registration errors, and is expensive and less accessible.
The goal of this work is to leverage ultrasound elasticity imaging methods, including acoustic radiation force impulse (ARFI) imaging and shear wave elasticity imaging (SWEI), to develop and optimize a robust 3-D elasticity imaging system for ultrasound-guided prostate biopsies and to quantify its performance in prostate cancer detection. Towards that goal, in this dissertation advanced techniques for generating ARFI and SWEI images are developed and evaluated, and a deep learning framework is explored for multiparametric ultrasound (mpUS) imaging, which combines data from different ultrasound-based modalities.
In Chapter 3, an algorithm is implemented that permits the simultaneous imaging of prostate cancer and zonal anatomy using both ARFI and SWEI. This combined sequence involves using closely spaced push beams across the lateral field of view, which enables the collection of higher signal-to-noise (SNR) shear wave data to reconstruct the SWEI volume than is typically acquired. Data from different push locations are combined using an estimated shear wave propagation time between push excitations to align arrival times, resulting in SWEI imaging of prostate cancer with high contrast-to-noise ratio (CNR), enhanced spatial resolution, and reduced reflection artifacts.
In Chapter 4, a fully convolutional neural network (CNN) is used for ARFI displacement estimation in the prostate. A novel method for generating ultrasound training data is described, in which synthetic 3-D displacement volumes with a combination of randomly seeded ellipsoids are used to displace scatterers, from which simulated ultrasonic imaging is performed. The trained network enables the visualization of in vivo prostate cancer and prostate anatomy, providing comparable performance with respect to both accuracy and speed compared to standard time delay estimation approaches.
Chapter 5 explores the application of deep learning for mpUS prostate cancer imaging by evaluating the use of a deep neural network (DNN) to generate an mpUS image volume from four ultrasound-based modalities for the detection of prostate cancer: ARFI, SWEI, quantitative ultrasound, and B-mode. The DNN, which was trained to maximize lesion CNR, outperforms the previous method of using a linear support vector machine to combine the input modalities, and generates mpUS image volumes that provide clear visualization of prostate cancer.
Chapter 6 presents the results of the first in vivo clinical trial that assesses the use of ARFI imaging for targeted prostate biopsy guidance in a single patient visit, comparing its performance with mpMRI-targeted biopsy and systematic sampling. The process of data acquisition, processing, and biopsy targeting is described. The study demonstrates the feasibility of using 3-D ARFI for guiding a targeted biopsy of the prostate, where it is most sensitive to higher-grade cancers. The findings also indicate the potential for using 2-D ARFI imaging to confirm target location during live B-mode imaging, which could improve existing ultrasonic fusion biopsy workflows.
Chapter 7 summarizes the research findings and considers potential directions for future research. By developing advanced ARFI and SWEI imaging techniques for imaging the prostate gland, and combining information from different ultrasound modalities, prostate cancer and zonal anatomy can be imaged with high contrast and resolution. The findings from this work suggest that ultrasound elasticity imaging holds great promise for facilitating image-guided targeted biopsies of clinically significant prostate cancer.
Item Open Access Dietary Carbohydrate Restriction Slows Prostate Tumor Growth(2008) Mavropoulos, John ChristakisGlucose metabolism remains an intensely explored topic of cancer biology since the initial discoveries of Otto Warburg nearly 80 years ago. Many solid tumors metabolize glucose primarily to lactate despite the availability of oxygen, revealing a dependence on glycolysis that may serve as a basis for targeted therapy. In particular, a diet devoid of carbohydrate may minimize the growth capabilities of glucose-dependent cancers. As our interests lie in prostate cancer, we examined whether a ketogenic diet devoid of carbohydrate (NCKD) would reduce the growth rate of tumors derived from human prostate cancer cell lines in a murine xenograft model.
Our initial experiments utilized the LAPC-4 cell line, a human androgen-sensitive prostate cancer cell line, in a SCID-mouse xenograft model to determine the effects of an NCKD on tumor growth and animal survival relative to two other diets: (1.) a Western-type diet (WD) reflecting consumptions patterns of men diagnosed with prostate-cancer in the Western world and (2.) a low-fat diet (LFD) representing the present standard of care. Following this study, we conducted a second study utilizing a different human prostate cancer cell line (LNCaP) in order to assess whether our initial observations were robust across multiple prostate cancer tumor models and to also further explore the molecular underpinnings of our observations. Both studies revealed the NCKD leads to a reduction in tumor growth rate and greater overall mouse survival relative to the WD. In addition, the NCKD was equivalent in these parameters to the LFD. We also observed key associations between survival and extent of urinary ketosis as well as favorable changes in insulin and insulin-like growth factor-1 (IGF-1) and gene expression that would be predictive of prolonged survival in mice consuming the NCKD.
We believe these data provide compelling evidence to consider a potential therapeutic role for dietary carbohydrate restriction in prostate cancer. We hope these results ultimately serve as a basis to conduct future clinical trials assessing whether dietary carbohydrate restriction, either alone or in combination with more conventional therapies, provides clinicians with an additional weapon against prostate cancer.
Item Open Access Efficacy of ELP as an Intratumoral Depot for Radionuclide Therapy of PC-3 Prostate Cancer in an Orthotopic, Nude Mouse Model(2012) Schaal, Jeffrey LaurenceBrachytherapy has emerged as one of the pre-eminent radiotherapy modalities for the treatment of prostate cancer. Current clinical methods utilize titanium encased radioactive seeds that are fixated within the prostate and permanently implanted. A novel brachytherapy alternative that has been developed to improve the delivery of radionuclide intratumorally is the synthetically designed elastin-like polypeptide (ELP). ELP can be injected in fluid form and undergoes an inverse phase transition to a biocompatible coascervate capable of serving as a biocompatible, intratumoral depot. Utilizing a previously developed ELP with a 7 tyrosine C-terminus tail, the therapeutic efficacy of ELP as a radioactive depot for treating prostate cancer was examined in a preclinical, orthotopic model. The orthotopic prostate model was first established by xenografting Bioware® PC-3M-luc-C6 cells into immunoincompetent, Balb/c nude mice. A non-invasive method for tracking tumor progression in vivo was developed using a correlation model comparing quantitative luminescent flux emitted from the cell line against the actual tumor size. The correlation between flux and tumor volume was determined to as Volume = 7.234x10-9x - 18.54, (±21.7%), where x is the supine photon flux measured from a 10 second exposure taken 18 minutes after D-luciferin injection. Radionuclide conjugation of 131I to ELP was conducted using the established IODO-GEN reaction methodology and mice were administered a therapeutic dose of 2mCi / 40µl ELP / 150 mm3 prostate tumor. Intratumoral deposition resulted in tumor regression in 90.9% of treated mice (n=11); 63.6% of which achieved tumor size reduction by over 60%. Radioactivity measurements demonstrate an 89.9% ELP depot retention over 2 weeks. Survival rates of the test group (64%) compared with controls (100%, n=14) indicate further testing is required to optimize radionuclide dosimetry.
Item Open Access Empowering Patients as Decision Makers in the Context of Early Stage Prostate Cancer(2018) Scherr, Karen A.Patients with early stage prostate cancer face a difficult preference-sensitive decision. There are multiple treatment options, each of which is associated with a unique set of benefits and risks. For example, surgery may cure the cancer but also come with the risk of serious side effects, such as impotence and incontinence. Alternatively, active surveillance avoids those side effects but requires patients to live with an untreated cancer inside their body. The optimal treatment for each patient will thus depend not only on his medical characteristics but also on how he personally values those risks and benefits. Ideally, patients and their physicians would partner together in a process of shared decision making (SDM) to ensure that patients receive treatments that reflect their personal preferences (i.e., preference-concordant treatments). In this dissertation, I use both qualitative and quantitative methods to examine patients’ decision-making processes in the context of early stage prostate cancer, focusing on if and how patients and physicians work together in the decision-making process to incorporate patients’ preferences into their treatment choices.
Essay 1 examines patients’ decision making processes within the context of a larger trial that was designed to assess the impact of a novel patient-centered (vs. standard) decision aid (DA) on patients’ decision making processes. The patient-centered DA increased patients’ desire to participate in the decision-making process and interest in active surveillance (Fagerlin et al., unpublished). However, regardless of which DA patients received, their treatment choices were primarily driven by physicians’ recommendation which, in turn, were driven by patients’ medical characteristics (e.g., cancer severity) and not their personal preferences (e.g., interest in sexual activity). Qualitative analyses of clinical appointments revealed relatively passive patients regardless of condition, suggesting that patients may not have known how to participate in clinical appointments and would benefit from pre-appointment communication skills training.
Essay 2 examines the effect of a novel patient communication skills intervention plus a patient-centered DA (vs. a patient-centered DA only) on several measures of patient empowerment using a randomized controlled trial. The intervention was a video (DVD) that modeled specific communication skills patients could use to participate in their upcoming appointments. The intervention increased patients’ intentions to use four process skills (e.g., taking notes) and sense of self-efficacy regarding their ability to ask for referrals and express personal concerns during their upcoming clinical appointments. It did not increase patients’ sense of self-efficacy regarding their ability to seek information or make assertive utterances.
Essay 3 examines focuses on a specific moment in clinical appointments: patients’ requests for treatment recommendations (data from Essay 1). Patient requests for recommendations are a pivotal and powerful moment in clinical appointments, yet no existing studies have examined how patients actually request recommendations nor what patient characteristics are associated with requests for recommendations. Patients or their companions requested recommendations in approximately 20% of appointments. Patients who requested recommendations had higher prostate cancer anxiety, placed increased importance on sex in their lives, preferred shared (vs. patient-led) decision making, and were more likely to prefer active treatment prior to appointments. When requesting recommendations, patients discussed physicians’ expertise and the role of their recommendations, asked physicians to engage in self-disclosure (e.g., “What would you do?”) and repeated their requests.
Truly empowering patients as decision makers in the context of early stage prostate cancer is difficult, and both patients and physicians may be uncertain how to behave in this new paradigm of patient empowerment. Patient communication skills interventions show promise, but continued research is needed to truly transform clinical medicine into a domain in which patients are empowered to fully participate in the medical decision-making process.
Item Open Access Functional Analysis of Trefoil Factors 1 and 3 in Tumorigenesis(2009) Radiloff, Daniel RayAbstract
The trefoil factor family of secreted proteins contains three members; trefoil factor 1 or TFF1, trefoil factor 2 or TFF2, and trefoil factor 3 or TFF3. These three proteins share a conserved 42-43 amino acid domain containing 6 cysteine residues resulting in three disulfide bonds that holds the protein in a characteristic three-loop or "trefoil structure" known as the P domain. TFF1 is primarily localized to the stomach and secreted by the gastric mucosa while TFF2 and TFF3 are primarily localized to the colon and duodenum and secreted by the goblet cells. All three of these proteins play a protective role in the gastrointestinal tract where they are normally localized and have been identified as possible tumor suppressors, however, these proteins are also upregulated in cancer within tissues where they are not normally expressed including the breast, pancreas, prostate, and liver. The mechanisms by which two of these factors, TFF1 and TFF3, promote tumorigenesis remain largely undefined. In this dissertation we will attempt to elucidate these mechanisms as well as the regulation of these two proteins in both pancreatic and prostate cancer. Many of the underlying genetic and molecular mechanisms involved in the development of both pancreatic and prostate cancer remain largely unknown and as a result, therapeutic and diagnostic tools for treating these diseases are not as effective as they could be. By deciphering the role of TFF1 and TFF3 in these cancers, they could potentially serve as new therapeutic targets or biomarkers for treating both diseases.
Chapter 2 of this dissertation will examine the functional role of TFF1 promoting tumorigenesis in pancreatic and prostate cancer. We will show that TFF1 expression is critical for the viability of both pancreatic and prostate cancer cells and that reduction of TFF1 expression in these cells results in decreased tumorigenicity when implanted in immunocompromised mice. It will also be demonstrated that TFF1's function in promoting tumorigenicity is its ability to assist tumor cells overcome the tumor suppressive barrier of senescence. Thirdly, we show that the form of senescence that TFF1 assists in allowing the cells overcome is oncogene-induced senescence (OIS). Lastly, a cell cycle array identifies the potential downstream target p21CIP, a cyclin-dependent kinase inhibitor and OIS marker, whose expression is induced by loss of TFF1 expression.
In Chapter 3 of this work, we examine the role of another trefoil factor family member, TFF3, and its role in promoting prostate tumorigenesis. Just as with TFF1, it appears that TFF3 3 expression is critical for prostate cancer cell viability and tumorigenicity using the same experimental techniques used in Chapter 2. Using a genetically defined model of prostate cancer, a PI3-kinase-dependent regulatory mechanism of TFF3 emerges in this prostate cancer context. Using this system we begin to see a divergence in both regulation and function of TFF1 and TFF3 in prostate cancer. Finally, a mouse model expressing TFF3 was developed to monitor the histopthological changes associated with expression of this protein. Initial characterization of this model suggests a hyperplastic phenotype coinciding with TFF3 expression in the prostate.
The two studies in this dissertation establish a role of TFF1 and TFF3 in both prostate and pancreatic tumorigenesis and demonstrate that ablation of expression of both proteins is a potent inhibitor of tumorigenesis. With this knowledge, it is possible that TFF1 and TFF3 may become a potential therapeutic target or diagnostic marker for better treatment of prostate and pancreatic cancer.
Item Open Access Health Disparities and Prostate Cancer: Can Educational Status, Race and Geographical Distance to Care Facilities Impact Risk and Severity on Initial Biopsy?(2013) Gaines, Alexis RuthIntroduction: Prostate Cancer (PC) screening has become a controversial topic both in the United States and abroad, stimulating debates surrounding who should and should not be screened. United States (USA) population-based studies have established a link between race and PC risk, but whether race predicts PC after adjusting for clinical characteristics is unclear. In Brazil, where cancer registries are limited, underprivileged men have limited access to both education and health care due to geographic barriers. Thus, we investigated the association between, educational status, geographic distance from screening site to follow-up care facility and non-compliance with having cancer, and, risk of low and high-grade PC in men undergoing initial prostate biopsy in equal access medical centers in the USA and Brazil.
Materials & Methods: In our first analysis, we conducted a retrospective record review of 887 men (49.1% black, 50.9% white) from the Durham Veterans Affairs Medical Center (DVAMC) who underwent initial prostate biopsy between 2001 and 2009. Multivariable logistic regression analysis of race and biopsy outcome was conducted adjusting for age, body mass index (BMI), number of cores taken, prostate specific antigen (PSA), and digital rectal exam (DRE) findings. Multinomial logistic regression was used to test the association between black race and PC grade (Gleason <7 vs. >7). Our second analysis used data from the Barretos Cancer Hospital (BCH) screening study, another retrospective record review of 1,561 men who were recommended to prostate biopsy after obtaining an initial screen on the medical mobile units between 2004 and 2007. Multivariable logistic regression analysis of geographic distance from screening site to BCH (km), maximum level of education achieved, and risk of non-compliance was performed adjusting for age and calendar year of biopsy. Among those who complied with biopsy recommendations and received a biopsy (n=850), multivariable logistic regression analyses were conducted to test the association between geographic distance, educational achievement and having PC. Of those men with PC, a multinomial logistic regression test was used to evaluate the association between geographic distance, educational attainment and risk of low and high-grade PC (Gleason <7 vs. >7).
Results: In the DVAMC study, Black men were younger at biopsy (median: 61 vs. 65 years, p<0.001), and had a higher pre-biopsy total PSA (tPSA, median: 6.6 vs. 5.8ng/ml, p=0.001) than white men. A total of 499 (56.3%) men had PC on biopsy (245 low-grade; 254 high-grade). In multivariable analyses, black race was significantly predictive of PC overall (odds ratio, [OR]: 1.50, 1.12 - 2.00, p=0.006), and high-grade PC (relative risk ratio [RRR]: 1.84, 1.28 - 2.66, p=0.001), but was not significantly associated with low-grade PC (RRR: 1.29, 0.92 - 1.80, p=0.139). In the BCH studies, non-compliant men were older at initial screen (median: 68 vs. 66 years, p<0.001), had a higher tPSA (median: 4.90 vs. 4.2 ng/mL, 0<0.001), were less likely to have an abnormal DRE (19.5% vs. 33.4%, p<0.001), had less education (low education: illiterate or incomplete primary, vs. high education: complete primary, high school or college, 1,402 vs. 159, p=0.14, data not shown) and were more likely to live more than 500km from BCH (66.3% vs. 19.6%, p<0.001) when compared to men who complied with biopsy recommendations. On crude and multivariable analyses, non-compliance was significantly associated with increased distance from screening site to BCH relative to traveling less than 250km for care (250-500km: OR: 2.00, 500-1000km: OR: 5.88, >1000 km: OR: 15.98, p<0.001). On crude and multivariable analysis, increased educational attainment relative to being illiterate had a protective association with non-compliance (incomplete primary: OR: 0.53, complete primary: OR: 0.33, p<0.001, high school + college: OR: 0.87, p=0.64). Of the screened men who were recommended to and had an initial biopsy, 320 men had cancer (207 low-grade, 113 high-grade). Stratified by educational status, illiterate men were older at biopsy (median: 69 vs. 65 vs. 64 vs. 58 years, p<0.001), and had a higher tPSA at screening (median: 6.04 vs. 4.47 vs. 4.73 vs. 4.16, p=0.001). There were no differences, based on education, distance from screen site to Barretos (p=0.43), year of screening (p=0.08), number of abnormal DREs (p=0.42) or family history of cancer, especially PC (p=0.07). Before biopsy, confirmatory median tPSA was 7 (IQR: 4 - 16 ng/mL). With respect to PC on initial biopsy, there was no association between distance from screening site to BCH (relative to < 250km) and increased education achievement. On multinomial analysis, educational achievement showed an association with neither low nor high-grade cancer relative to no cancer. There was no association between increased distance and low-grade PC. There was no association between traveling 500-1000km (p=0.96) or >1000km (p=0.15) and high-grade cancer; however, there was a significant association between traveling 250-500km relative to <250km and high-grade PC risk (RRR: 2.44, 95% p=0.04).
Conclusion: In a USA-based equal access health care facility, black race was associated with greater risk of PC detection on initial biopsy and of high-grade cancer after adjusting for clinical characteristics. In Brazil, where cancer data are limited, education and geographic distance from point of screening to care facility are not associated with having PC on biopsy or biopsy grade. Distance was, however, significantly associated with risk of non-compliance after primary screen. Thus, additional investigation of mechanisms linking black race and PC risk and PC aggressiveness is needed.
Item Open Access Identification of Endocrine Therapy Induced Targetable Vulnerabilities in Cancer(2021) Krebs, Taylor KaleiProstate and breast cancers are major health concerns, being amongst the most common forms of cancers in both men and women. The majority of prostate and breast cancers are driven by the hormone receptors androgen receptor (AR) and estrogen receptor (ESR1), respectively, and as such, endocrine therapies targeting the actions of these receptors has been a cornerstone of treatment for these patients. While these endocrine therapies are generally initially efficacious, resistance inevitably emerges. Resistance can emerge through various mechanisms, such as amplification of the receptor, generation of activating point mutations, alternative splicing of the receptor resulting in constitutively active forms of the receptor, and activating cross-talk from growth factor signaling pathways. A salient feature of these diseases is that the nuclear receptor (AR or ER) often remains engaged upon the emergence of resistance, and thus targeting of the receptor still provides therapeutic benefit. Therefore, much work in these fields has been performed to design better forms of endocrine therapy to help patients upon tumor progression. As cells are altering their signaling to deal with these pressures, this thesis work investigated the global genomic changes which arise in prostate and breast cancer cells after endocrine therapy to understand the effects of utilizing different forms of endocrine therapy, and whether these alterations in the cells induce novel vulnerabilities which can be therapeutically exploited. In the first set of studies, the differences between utilizing a competitive antagonist (enzalutamide-Enz) vs an AR degrader (AR-targeting proteolysis targeting chimera-PROTAC) were evaluated in prostate cancer. PROTACs are a new form of therapy for prostate cancer which have encouraging results in early clinical trials, so we wanted to better understand the genomic architecture and gene expression landscape after this new treatment modality compared to the current standard of care with an aim to use this knowledge to understand endocrine therapy resistance and identify therapeutically targetable pathways emerging from treatment. A factor agnostic approach was taken utilizing ATACseq and RNAseq to compare the genomic landscape after Enz or PROTAC treatment. It was found that the different AR inhibitors create distinct genomic landscapes which appear to be driven by unique sets of transcription factors. Further, it was discovered that AR inhibition, especially through degradation creates a novel liability which can be therapeutically exploited. AR was found to mediate these effects through regulating expression of a key transcription factor, and we propose a model in which the two proteins interact to regulate this axis. As AR is expressed in many other malignancies, it is feasible this strategy of degrading AR to induce this therapeutic vulnerability could have efficacy beyond prostate cancer. In the second set of studies, we investigated the genomic changes which are manifest after the emergence of endocrine therapy resistance in breast cancer and identified a novel signaling pathway that, when targeted, impairs tumor progression. Utilizing, DNAse hypersensitivity analysis, ChIP-seq, and RNAseq, it was found that GRHL2 cooperates with FOXA1 to drive a novel cistrome in endocrine therapy resistant breast cancer cells. The protein LYPD3 was found to be a downstream effector of GRHL2 and targeting LYPD3, or its ligand AGR2, with monoclonal antibodies significantly impaired primary tumor growth. Further studies into the functional role of LYPD3 were then undertaken, and it was discovered that LYPD3 knockdown significantly alters metastatic outgrowth of breast cancer cells in the lung. Investigation into the signaling of LYPD3 revealed a novel function of this protein. This work and future mechanistic studies will elucidate the signaling of LYPD3, and as LYPD3 is expressed in numerous subtypes of advanced cancers, understanding its signaling could provide a new biomarker for cancers which would be amenable to the targeted therapies identified in these studies in combination with LYPD3 targeted therapies.
Item Open Access Imaging and Characterizing Human Prostates Using Acoustic Radiation Force(2009) Zhai, LiangProstate cancer (PCa) is the most common non-cutaneous cancer in men in the United States. Early detection of PCa is essential for improving treatment outcomes and survival rates. However, diagnosis of PCa at an early stage is challenged by the lack of an imaging method that can accurately visualize PCas. Because pathological processes change the mechanical properties of the tissue, elasticity imaging methods have the potential to differentiate PCas from other prostatic tissues. Acoustic radiation force impulse (ARFI) imaging is a relatively new elasticity imaging method that visualizes the local stiffness variations inside soft tissue.
The work presented in this dissertation investigates the feasibility of prostate ARFI imaging. Volumetric ARFI data acquisition and display methods were developed to visualize anatomic structures and pathologies in ex vivo human prostates. The characteristic appearances of various prostatic tissues in ARFI images were identified by correlating ARFI images with McNeal's zonal anatomy and the correlated histological slides, in which prostatic pathologies were delineated by a pathologist blinded to the ARFI images. The results suggest ARFI imaging is able to differentiate anatomic structures and identify suspicious PCa regions in the prostate.
To investigate the correlation between ARFI displacement amplitudes and the underlying tissue stiffness in the prostate ARFI images, the mechanical properties of prostatic tissues were characterized using a quantitative method, based upon shear wave elasticity imaging (SWEI). Co-registered ARFI and SWEI datasets were acquired in excised prostate specimens to reconstruct the shear moduli of prostatic tissues. The results demonstrated that variations in ARFI displacement amplitudes were inversely related to the underlying tissue stiffness; and the reconstructed shear moduli of prostatic tissues had good agreements with those reported in literature. The study suggests the matched ARFI and SWEI datasets provide complementary
information about tissue's elasticity.
To increase the efficiency of the data acquisition, a novel imaging sequence was developed to acquired matched ARFI-SWEI datasets without increasing the number of excitations compared to a conventional ARFI imaging sequence. Imaging parameters were analyzed both theoretically and experimentally. An analytical model was derived to quantify the fundamental accuracy limit in the reconstructed shear modulus, and demonstrated good agreement with the experimental data. The novel sequence was demonstrated in tissue-mimicking phantoms.
Finally, ARFI imaging sequences were developed in a transrectal probe, and ARFI images were presented from in vivo data acquired in patients under radical prostatectomy. The in vivo ARFI images demonstrated decreased contrast and resolution as compared to the matched ex vivo ARFI data. However, prostate anatomy and some PCa were successfully visualized in the in vivo ARFI images. Thus, we conclude that ARFI imaging has the potential to provide image guidance for locating cancerous regions during PCa diagnosis and treatment.
Item Open Access Improving Prostate Cancer Detection using Multiparametric Ultrasound(2021) Morris, Daniel CodyProstate cancer (PCa) is the second most common cancer diagnosis, behind skin cancer, and the second most common cause of cancer-related death, behind lung cancer, for men in the United States. The prevalence of PCa increases with age and ranges from 1.8% of men being diagnosed with PCa before age 59 to 11.6% of men being diagnosed with PCa over the course of their entire lives. PCa is typically diagnosed using transrectal ultrasound (TRUS) guided biopsy which commonly consists of 10-12 systematically sampled biopsy cores taken from specified regions within the prostate. In TRUS guided biopsy, the TRUS B-mode imaging is used by the clinician to ensure the biopsy needles remain within the prostate but is not sensitive nor specific enough to identify and target PCa-suspicious regions. Multiparametric magnetic resonance imaging (mpMRI) fusion biopsy is the current gold standard for targeted PCa biopsy, though this approach comes at added cost and is not widely available. mpMRI fusion biopsy also requires the registration of the pre-biopsy mpMRI with real-time TRUS B-mode imaging which can result in an incorrectly targeted lesion due to registration error.This thesis explores advanced ultrasound techniques, such as acoustic radiation force impulse (ARFI) imaging, shear wave elasticity imaging (SWEI), quantitative ultrasound’s (QUS) midband fit parameter (MF), and multiparametric ultrasound (mpUS), for PCa identification and targeting during biopsy. The goals of this thesis are to (1) establish a shear wave speed (SWS) threshold for identifying PCa using SWEI, (2) create an mpUS approach which combines ARFI, SWEI, MF, and B-mode imaging and assess the improvement in PCa visibility when using mpUS and (3) assess the performance of ARFI, SWEI, MF, and mpUS when locating suspicious regions which align with mpMRI-identified PCa to provide registration validation during fusion biopsy. Combined, this thesis provides preliminary data and motivation for future work developing and assessing advanced ultrasound imaging methods for image-guided targeted prostate biopsy. The data included throughout this thesis was acquired using a custom ultrasound setup capable of acquiring both elasticity (ARFI and SWEI) and acoustic backscatter (B-mode and MF) data in a single imaging session. Additionally, the ultrasound system was paired with a rotation stage allowing for 3D data acquisition which yielded co-registered image volumes for each of the four ultrasound modalities. This data was acquired in patients immediately preceding radical prostatectomy. Histopathology analysis of the excised prostates was used to determine the ground truth locations of PCa for each patient, allowing for the labeling of the ultrasound data as PCa or healthy tissue. In Chapter 3, the SWEI data volumes were used to identify a shear wave speed (SWS) value threshold to separate PCa from healthy prostate tissue. This SWS threshold yielded sensitivities and specificities akin to mpMRI fusion biopsy. Additionally, a SWS ratio was assessed to normalize for tissue compression and patient variability. This threshold was accompanied by a substantial increase in specificity, positive predictive value (PPV), and area under the receiver operating characteristic curve (AUC). This section demonstrates the feasibility of using 3D SWEI data to detect and localize PCa and demonstrates the benefits of normalizing for applied compression during data acquisition for use in biopsy targeting studies. In Chapter 4, a linear support vector machine (SVM) was used to combine B-mode imaging, ARFI, SWEI, and MF into a synthesized mpUS volume to enhance lesion visibility. mpUS led to improvements in lesion visibility metrics compared to each individual ultrasound modality. The individual advanced ultrasound modalities (ARFI, MF, and SWEI) also all outperformed B-mode in contrast. The improved performance of mpUS demonstrates the benefit of combining ultrasound techniques based on different contrast mechanisms, supporting its utility for ultrasound-based targeted prostate biopsy. In Chapter 5, the histologically determined PCa locations were identified in mpMRI’s T2 and apparent diffusion coefficient (ADC) images and compared to the corresponding regions in B-mode, ARFI, SWEI, MF, and mpUS images. SWEI only failed to identify one PCa lesion in the posterior of the prostate and B-mode, MF, and ARFI all successfully identified 100% of the anterior lesions, indicating that, when combined, advanced ultrasound techniques facilitate the visualization of the majority of mpMRI-identified regions of interest throughout the entire prostate. Additionally, the mpUS combination developed in Chapter 4 was applied to a subset of 10 patients and resulted in correct localization of 88% (14/16) of the mpMRI-identified lesions. This work demonstrates the feasibility of using advanced ultrasound techniques to locate mpMRI-identified lesions, which would enable improved registration validation during fusion biopsy. Finally, Chapter 6 includes further insights into this work and the implications it may have on the diagnosis of PCa. Advanced ultrasound is a promising approach for both targeted PCa biopsy and for screening. Additionally, combining information from multiple advanced ultrasound techniques (ARFI, SWEI, and MF) yields improved performance over any single method indicating that the future of prostate ultrasound is multiparametric.
Item Open Access Patterns of inpatient care for prostate cancer in men with spina bifida.(Disability and health journal, 2020-04) Johnston, Ashley W; Wolf, Steven; Alkazemi, Muhammad H; Pomann, Gina-Maria; Wood, Hadley; Wiener, John S; Routh, Jonathan CBACKGROUND:Advances in medical care have increased the long-term survival of patients with spina bifida. Despite this growing population, limited knowledge is available on age-related illnesses in adults with spina bifida, particularly prostate cancer for which there is no published data. OBJECTIVE:Our aim was to describe inpatient care for prostate cancer in men with spina bifida in the United States. METHODS:We performed a descriptive, retrospective study utilizing the 1998 to 2014 National Inpatient Sample from the Healthcare Cost and Utilization Project. Weights were applied to the sample to make national level inferences. We identified all adult encounters (≥18 years old) with prostate cancer and spina bifida. RESULTS:We identified 253 encounters (mean age 64.9 years). Most were Caucasian (67.5%) and had public insurance (61.6%). 44% of encounters included a major urologic procedure. 38.4% of encounters included prostatectomies, 28.3% included lymph node dissections, and 7.8% included cystectomies. Robotic surgery was performed in 9.4%. Mean length of stay was 5.6 days (95% CI: 3.7, 7.5). The average total cost was $14,074 (95% CI: $8990.3, $19,158.6). CONCLUSIONS:In this first-ever exploration of inpatient care for prostate cancer in men with spina bifida, we found that length of stay and total costs were higher in men with spina bifida. Almost half of encounters included a prostatectomy, cystectomy, and/or lymph node dissection. More detailed investigations are necessary to assess comparative treatment outcomes and complications, including prevalence and mortality rates of prostate cancer among adult men with SB.Item Open Access RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis.(The Journal of clinical investigation, 2023-03) Wang, Mu-En; Chen, Jiaqi; Lu, Yi; Bawcom, Alyssa R; Wu, Jinjin; Ou, Jianhong; Asara, John M; Armstrong, Andrew J; Wang, Qianben; Li, Lei; Wang, Yuzhuo; Huang, Jiaoti; Chen, MingInactivation of the RB1 tumor suppressor gene is common in several types of therapy-resistant cancers, including metastatic castration-resistant prostate cancer, and predicts poor clinical outcomes. Effective therapeutic strategies against RB1-deficient cancers, however, remain elusive. Here we showed that RB1-loss/E2F activation sensitized cancer cells to ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, by upregulating expression of ACSL4 and enriching ACSL4-dependent arachidonic acid-containing phospholipids, which are key components of ferroptosis execution. ACSL4 appeared to be a direct E2F target gene and was critical to RB1 loss-induced sensitization to ferroptosis. Importantly, using cell line-derived xenografts and genetically engineered tumor models, we demonstrated that induction of ferroptosis in vivo by JKE-1674, a highly selective and stable GPX4 inhibitor, blocked RB1-deficient prostate tumor growth and metastasis and led to improved survival of the mice. Thus, our findings uncover an RB/E2F/ACSL4 molecular axis that governs ferroptosis, and also suggest a promising approach for the treatment of RB1-deficient malignancies.Item Open Access Shared Inherited Genetics of Benign Prostatic Hyperplasia and Prostate Cancer.(European urology open science, 2022-09) Glaser, Alexander; Shi, Zhuqing; Wei, Jun; Lanman, Nadia A; Ladson-Gary, Skylar; Vickman, Renee E; Franco, Omar E; Crawford, Susan E; Lilly Zheng, S; Hayward, Simon W; Isaacs, William B; Helfand, Brian T; Xu, JianfengBackground
The association between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remains controversial, largely due to a detection bias in traditional observational studies.Objective
To assess the association between BPH and PCa using inherited single nucleotide polymorphisms (SNPs).Design setting and participants
The participants were White men from the population-based UK Biobank (UKB).Outcome measurements and statistical analysis
The association between BPH and PCa was tested for (1) phenotypic correlation using chi-square, (2) genetic correlation (r g) based on genome-wide SNPs using linkage disequilibrium score regression, and (3) cross-disease genetic associations based on known risk-associated SNPs (15 for BPH and 239 for PCa), individually and cumulatively using genetic risk score (GRS).Results and limitations
Among 214 717 White men in the UKB, 24 623 (11%) and 14 311 (6.7%) had a diagnosis of BPH and PCa, respectively. Diagnoses of these two diseases were significantly correlated (χ2 = 1862.80, p < 0.001). A significant genetic correlation was found (r g = 0.16; 95% confidence interval 0.03-0.28, p = 0.01). In addition, significant cross-disease genetic associations for established risk-associated SNPs were also found. Among the 250 established genome-wide association study-significant SNPs of PCa or BPH, 49 were significantly associated with the risk of the other disease at p < 0.05, significantly more than expected by chance (N = 12, p < 0.001; χ2 test). Furthermore, significant cross-disease GRS associations were also found; GRSBPH was significantly associated with PCa risk (odds ratio [OR] = 1.26 [1.18-1.36], p < 0.001), and GRSPCa was significantly associated with BPH risk (OR = 1.03 [1.02-1.04], p < 0.001). Moreover, GRSBPH was significantly and inversely associated with lethal PCa risk in a PCa case-case analysis (OR = 0.58 [0.41-0.81], p = 0.002). Only White men were studied.Conclusions
BPH and PCa share common inherited genetics, which suggests that the phenotypic association of these two diseases in observational studies is not entirely caused by the detection bias.Patient summary
For the first time, we found that benign prostatic hyperplasia and prostate cancer are genetically related. This finding may have implications in disease etiology and risk stratification.Item Open Access Structure-Function Relationships of Long Non-coding RNA in Prostate Cancer(2020) McFadden, Emily JosephineThe noncoding RNA (ncRNA) revolution has revealed myriad RNA species that play critical roles at all stages of life, including embryogenesis and disease progression. For example, three long ncRNA (lncRNA), Hox Transcript Antisense Intergenic RNA (HOTAIR; ~2.5 kb), Metastasis Associated Lung Adenocarcinoma Transcript-1 (MALAT1; ~6.7 kb) and Second Chromosome Locus Associated with Prostate-1 (SChLAP1; ~1.5 kb), are basally expressed in normal prostate tissue but are dysregulated in prostate cancer. HOTAIR scaffolds the PRC2 and LSD1 protein complexes to selectively methylate and demethylate, respectively, histone proteins, thereby regulating downstream gene expression. MALAT1 acts in trans at nuclear speckles during mRNA post-transcriptional processing while SChLAP1 acts in cis to influence oncogenic gene expression. Initial work on HOTAIR developed technical skills that were then applied to the lncRNAs MALAT and SChLAP1 to learn more about their role in prostate cancer. There is compelling evidence that the 3′–end of MALAT1 is a triple helix structure that acts as a molecular knot, driving transcript accumulation in cancer cells and furthering their metastatic potential, but we currently lack any biophysical data detailing the relationship between SChLAP1 structure and function. In general, the relationship among lncRNA structure, dynamics, and function is not well understood; for example, even with high-resolution structures of the MALAT1 triple helix, questions remain regarding the role of intrinsic dynamics in transcript stability or protein binding. As lncRNA represent an underexplored therapeutic avenue, this work aims to investigate the role of lncRNA structure and dynamics in driving prostate cancer metastasis. This work uses biophysical and biochemical methods including chemical probing, NMR, SAXS, and native gels to study the two lncRNA MALAT1 and SChLAP1 and learn more about their respective structure-function relationships. From this work, we have found a discrete structure within the lncRNA SChLAP1 that is highly structured and implicated in driving metastasis via protein recognition. Additionally, our preliminary studies regarding MALAT1 support the presence of non-triplex states that require further characterization. Overall, this work supports a deeper understanding of lncRNA structure as it relates to their function in cancer and provides examples for the biophysical analysis of large and/or structurally complex RNA.
Item Open Access Targeting androgen receptor-independent pathways in therapy-resistant prostate cancer.(Asian journal of urology, 2019-01) Xu, Lingfan; Chen, Junyi; Liu, Weipeng; Liang, Chaozhao; Hu, Hailiang; Huang, JiaotiSince androgen receptor (AR) signaling is critically required for the development of prostate cancer (PCa), targeting AR axis has been the standard treatment of choice for advanced and metastatic PCa. Unfortunately, although the tumor initially responds to the therapy, treatment resistance eventually develops and the disease will progress. It is therefore imperative to identify the mechanisms of therapeutic resistance and novel molecular targets that are independent of AR signaling. Recent advances in pathology, molecular biology, genetics and genomics research have revealed novel AR-independent pathways that contribute to PCa carcinogenesis and progression. They include neuroendocrine differentiation, cell metabolism, DNA damage repair pathways and immune-mediated mechanisms. The development of novel agents targeting the non-AR mechanisms holds great promise to treat PCa that does not respond to AR-targeted therapies.Item Open Access Targeting Histone Deacetylases in Advanced Prostate Cancer(2015) Brunner, Abigail MariaThe androgen receptor (AR) signaling axis is a well-established therapeutic target in prostate cancer, due to its central role in tumor maintenance and progression. Although patients respond initially to androgen deprivation therapies and AR antagonists, they invariably progress to a castration-resistant state. Consequently, there is an unmet need for agents that target the AR signaling axis in a unique manner.
Histone deacetylase (HDAC) inhibitors repress AR signaling and prostate cancer growth in cellular and xenograft models. However, HDAC inhibitors also induce epithelial to mesenchymal (EMT) and neuroendocrine differentiation, both of which are associated with prostate cancer progression and aggressiveness. Given that 18 different HDAC isoforms have been identified in humans, and non-selective or Class I (HDAC1, 2, 3, and 8) HDAC inhibitors have been used in most of these studies, the relative contribution of individual HDAC isoforms to AR transcriptional activity and prostate cancer pathophysiology remains to be elucidated. The overarching goals of this study were to (1) determine the role of individual Class I HDACs in AR transcriptional activity and prostate cancer growth, (2) identify selective HDAC inhibitors that have reduced adverse profiles to the treatment of prostate cancer, and (3) identify potential HDAC-interacting proteins that regulate AR target gene transcription and prostate cancer growth.
Using genetic knockdown studies and pharmacological inhibitors with isoform selectivity, we identified that HDAC3 was required for AR transcriptional activity and proliferation in cellular models of androgen-sensitive and castration-resistant prostate cancer (CRPC). Additionally, we found that RGFP966, an HDAC3-selective inhibitor, attenuated the growth of a xenograft model of CRPC. Furthermore, non-selective HDAC inhibitors induced EMT and neuroendocrine markers in prostate cancer cells, but RGFP966 treatment did not. These studies provide rationale for selective inhibition of HDAC3 for the treatment of CRPC, and could provide an explanation for the lack of success using non-selective HDAC inhibitors in clinical trials for prostate cancer.
We also assessed the role of REV-ERB alpha, an HDAC3-interacting protein, in the regulation of AR transcriptional activity and prostate cancer growth. Using siRNA knockdown studies, REV-ERB inhibitors, and overexpression studies, we concluded that REV-ERB alpha; was required for AR target gene induction and prostate cancer growth, including models of CRPC. These studies also provide rational for targeting REV-ERB alpha; for the treatment of CRPC.
Taken together, these studies identify two novel targets in the HDAC signaling axis for the treatment of prostate cancer: HDAC3 and REV-ERB alpha. Our studies provide greater insight into AR transcriptional regulation and prostate cancer pathophysiology.
Item Open Access The Role of Autophagy and Translation Initiation Factors in Overcoming Resistance to mTOR Inhibitors in Prostate Cancer.(2013) Herbert, James TaylorCastration resistant prostate cancer (CRPC) causes significant morbidity and mortality around the world and improving treatment options for patients with CRPC is a major concern for biomedical research. Because of the importance of activating mutations in the PI3K/AKT/mTOR pathway in prostate cancer, several mTOR inhibitors have been tested for efficacy in CRPC but despite promising preclinical findings, the results of clinical trials have been disappointing. The findings of several groups, including a clinical trial of RAD001 conducted at Duke, suggest that feedback upregulation of PI3K and autophagy may be potential mechanisms for resistance of CRPC to mTOR inhibitor therapy.
The main goal of this dissertation was to explore these mechanisms in vitro and to determine if combinations of PI3K inhibitors and different classes of mTOR inhibitors can overcome resistance to mTOR inhibitor monotherapy. In particular, we used immunoblotting, reverse phase protein microarrays, polysome profile analysis, cell cycle analysis, and several techniques for determining cell survival and proliferation to explore the differences in survival, proliferation, autophagy, and activity of the AKT, translation initiation, and autophagy cell signaling networks between prostate cancer cell lines treated with different combinations of mTOR and PI3K inhibitors. Our findings revealed that the combination of PI3K and mTOR inhibition leads to a synergistic inhibition of prostate cancer cell survival and cytostasis that is correlated decreased translation rates, hypophosphorylation of 4E-BP1, autophagy, and an uncoupling of normal signaling between AKT and mTOR. We were able produce an effect on cell survival similar to treatment with high doses of mTOR/PI3K inhibitor combinations by inhibiting cap-dependent translation using a non-phosphorylatable mutant of 4E-BP1. In contrast, knocking down two major autophagy genes had little to no effect on the survival of prostate cancer cells treated with PI3K/mTOR inhibitors but did protect from cell death caused by the UPR activator tunicamycin.
We conclude that treatment strategies that target PI3K, mTORC1 and mTORC2 simultaneously have the potential to be clinically useful in CRPC, probably due to the increased inhibition of eIF4E activity and cap-dependent translation when compared to monotherapy with allosteric mTORC1 inhibitors. Although autophagic cell death can be induced in prostate cancer cells, the autophagy observed after inhibition of PI3K and mTOR does not appear to contribute to cell death and is not a major resistance mechanism under these conditions. Nevertheless, we did observe different roles for autophagy in the survival of cells exposed to different types of stressors, and further elucidation of autophagy signaling networks may yet provide useful clinical targets.
Item Open Access The Roles of Rap1 in Cancer Metastasis and Pancreatic Islet Beta Cell Function(2009) Bailey, Candice LeeSignaling from the G protein, Rap1 is involved in several fundamental biological processes. Yet the mechanism or even consequence of Rap1 signaling in several biologies and diseases is still unclear. Rap1 has been implicated in cancer tumorigenesis, but its role in cancer invasion and metastasis is less understood. Rap1 signals to pathways involved in cell adhesion, migration, and survival, suggesting that Rap1 may promote several processes associated with metastasis. Recent studies in another biological system have demonstrated that the Rap activator proteins, Epac, are important regulators of pancreatic β-cell insulin secretion. However, the role of Rap1 in β-cell biology has not yet been defined. Here we established roles for Rap1 in distinct signaling events and begin to answer some of the key questions about Rap1 function in two diverse biologies: cancer metastasis and pancreatic islet β-cell function.
Elucidating the mechanisms of prostate and breast cancer survival and metastasis are critical to the discovery of novel therapeutic targets. Examination of prostate cancer cell lines revealed cells with a high metastatic ability exhibited increased Rap1 activity and reduced expression of the negative regulator, Rap1GAP. Activation of Rap1 increased prostate and breast cancer cell migration and invasion, and inhibition of Rap1A activity via RNAi-mediated knockdown or ectopic expression of Rap1GAP markedly impaired cancer cell migration and invasion. Additional studies implicated integrins α4, β3, and αvβ3 in the mechanism of Rap1-mediated prostate and breast cancer migration. Furthermore, these same integrins and matrix metalloproteinases were shown to be involved in Rap1-induced prostate cancer invasion. Introduction of activated Rap1 into prostate cancer cells dramatically enhanced the rate and incidence of CaP metastasis in a mouse metastasis model. In another mouse xenograft model, blockade of Rap1 signaling by expression of Rap1GAP abrogated breast cancer metastastasis. These studies support a role for aberrant Rap1 activation in prostate and breast cancer metastatic progression, and suggest that targeting Rap1 signaling could provide a means to control metastatisis of these cancers.
In a seperate biological system, the effects of Rap1 signaling on pancreatic β-cells was directly examined. Activation of Rap1 was demonstrated to promote ribosomal protein S6 phosphorylation through the mTOR and p70 S6 kinase (S6K1) pathway, a known growth-regulatory pathway. This newly defined β-cell axis acts downstream of cAMP, in parallel with the stimulation of both Epac and PKA. Like previous studies on Epac, activation of Rap1 indeed increased glucose stimulated insulin secretion (GSIS) from rat islet β-cells; however, Rap1-mediated GSIS did not appear to signal through this new S6 pathway. Interestingly, Rap1 was show to significantly increase islet cell proliferation and this indeed occured through signaling to mTOR and S6. In summary, these findings represent a new link between cAMP signaling and the pathways controlling β-cell proliferation, and suggest that directly targeting this pathway may have beneficial therapeutic effects for patients with Type 2 diabetes. Furthermore, an additional benefit to targeting Rap1 signaling is the potentiation of insulin secretion, which could possibly prevent or reverse β-cell dysfunction (i.e., defects in both β-cell mass and insulin secretory capacity) in diabetes.
Item Open Access Thermally-Responsive Biopolymer Depots for the Delivery of High-Dose, β-Radionuclide Brachytherapy in the Treatment of Prostate and Pancreatic Cancer(2018) Schaal, Jeffrey LaurenceIntratumoral radiation therapy – ‘brachytherapy’ – is a highly effective treatment for solid tumors, particularly prostate cancer. Current titanium seed implants, however, are permanent and are limited in clinical application to indolent malignancies of low- to intermediate-risk. Attempts to develop polymeric alternatives, however, have been plagued by poor retention and off-target toxicity due to degradation.
Herein, we report on a new approach whereby thermally sensitive micelles composed of an elastin-like polypeptide (ELP) are labeled with the radionuclide 131-Iodine to form an in situ hydrogel that is stabilized by two independent mechanisms: first, body heat triggers the radioactive ELP micelles to rapidly phase transition into an insoluble, viscous coacervate in under 2 minutes; second, the high energy β-emissions of 131-Iodine further stabilize the depot by introducing crosslinks within the ELP depot over 24 hours. These injectable brachytherapy hydrogels were used to treat two aggressive orthotopic tumor models in athymic nude mice: a human PC-3M-luc-C6 prostate tumor and a human BxPc3-luc2 pancreatic tumor model. The ELP depots retained greater than 52% and 70% of their radioactivity through 60 days in the prostate and pancreatic tumors with no appreciable radioactive accumulation (≤ 0.1% ID) in off-target tissues after 72 hours. The 131I-ELP depots achieved >95% tumor regression in the prostate tumors (n=8); with a median survival of more than 60 days compared to 12 days for control mice. For the pancreatic tumors, ELP brachytherapy (n=6) induced significant growth inhibition (p = 0.001, ANOVA) and enhanced median survival to 27 days over controls.
We then demonstrated that 131I-ELP brachytherapy can work synergistically with paclitaxel chemotherapy to overcome the intrinsic resistance found in pancreatic tumors. Treating tumors with an optimized radioactivity dose of 10.0 µCi/mg and systemically administered paclitaxel nanoparticles achieved complete regression in BxPc3-luc2, MIA PaCa-2, and AsPc-1 tumor models. Moreover, responses occurred irrespective of the paclitaxel dose (between 12.5-50 mg/kg) or the formulation (Abraxane or micelle formulation). A comparative study utilizing an aggressive 5x 5Gy hypofractionated X-ray radiation produced only minor growth inhibition, with or without paclitaxel.
The mechanistic underpinnings of this effect were explored in an orthotopic model to reveal the fundamental differences between 131I-ELP therapy and conventional radiotherapy. Continuous dose exposure was found to coordinate much more effectively with the temporal sensitization mechanisms of paclitaxel, as evidenced by TUNEL immunohistochemistry. Stromal collagen and cellular junctional proteins regulating interstitial permeability (Claudin-4, CD31, and VE-Cadherin) were dysregulated after 131I-ELP treatment. Fluorescent analysis of paclitaxel nanoparticles revealed significantly higher paclitaxel accumulation in brachytherapy tumors after treatment (p<0.01). These results show that 131I-ELP biopolymer brachytherapy offers a highly attractive alternative to current radiotherapy techniques and demonstrated negligible toxicity.
Item Open Access Towards the Clinical Implementation of Online Adaptive Radiation Therapy for Prostate Cancer(2013) Li, TaoranThe online adaptive radiation therapy for prostate cancer based on re-optimization has been shown to provide better daily target coverage through the treatment course, especially in treatment sessions with large anatomical deformation. However, the clinical implementation of such technique is still limited primarily due to two major challenges: the low efficiency of re-optimization and the lack of online quality assurance technique to verify delivery accuracy. This project aims at developing new techniques and understandings to address these two challenges.
The study was based on retrospective study on patient data following IRB-approved protocol, including both planning Computer Tomography (CT) and daily Cone-Beam Computer Tomography (CBCT) images. The project is divided in to three parts. The first two parts address primarily the efficiency challenge; and the third part of this project aims at validating the deliverability of the online re-optimized plans and developing an online delivery monitoring system.
I. Overall implementation scheme. In this part, an evidence-based scheme, named Adaptive Image-Guided Radiation Therapy (AIGRT), was developed to integrate the re-optimization technique with the current IGRT technique. The AIGRT process first searches for a best plan for the daily target from a plan pool, which consists the original CT plan and all previous re-optimized plans. If successful, the selected plan is used for the daily treatment with translational shifts. Otherwise, the AIGRT invokes re-optimization process of the CT plan for the anatomy-of-the-day, which is added to the plan pool afterwards as a candidate plan for future fractions. The AIGRT scheme is evaluated by comparisons with daily re-optimization and online repositioning techniques based on daily target coverage, Organ-at-Risk (OAR) sparing and implementation efficiency. Simulated treatment courses for 18 patients with re-optimization alone, re-positioning alone and AIGRT shows that AIGRT offers reliable daily target coverage that is highly comparable to re-optimization everyday and significantly improves compared to re-positioning. AIGRT is also seen to provide improved organs-at-risk (OARs) sparing compared to re-positioning. Apart from dosimetric benefits, AIGRT in addition offers an efficient scheme to integrate re-optimization to current re-positioning-based IGRT workflow.
II. Strategies for automatic re-optimization. This part aims at improving the efficiency of re-optimization through automation and strategic selections of optimization parameters. It investigates the strategies for performing fast (~2 min) automatic online re-optimization with a clinical treatment planning system; and explores the performance with different input parameters settings: the DVH objective settings, starting stage and iteration number (in the context of real time planning). Simulated treatments of 10 patients were re-optimized daily for the first week of treatment (5 fractions) using 12 different combinations of optimization strategies. Options for objective settings included guideline-based RTOG objectives, patient-specific objectives based on anatomy on the planning CT, and daily-CBCT anatomy-based objectives adapted from planning CT objectives. Options for starting stages involved starting re-optimization with and without the original plan's fluence map. Options for iteration numbers were 50 and 100. The adapted plans were then analysed by statistical modelling, and compared both in terms of dosimetry and delivery efficiency. The results show that all fast online re-optimized plans provide consistent coverage and conformity to the daily target. For OAR sparing however, different planning parameters led to different optimization results. The 3 input parameters, i.e. DVH objectives, starting stages and iteration numbers, contributed to the outcome of optimization nearly independently. Patient-specific objectives generally provided better OAR sparing compared to guideline-based objectives. The benefit in high-dose sparing from incorporating daily anatomy into objective settings was positively correlated with the relative change in OAR volumes from planning CT to daily CBCT. The use of the original plan fluence map as the starting stage reduced OAR dose at the mid-dose region, but increased 17% more monitor units. Only < 2cc differences in OAR V50% / V70Gy / V76Gy were observed between 100 and 50 iterations. Based on these results, it is feasible to perform automatic online re-optimization in ~2 min using a clinical treatment planning system. Selecting optimal sets of input parameters is the key to achieving high quality re-optimized plans, and should be based on the individual patient's daily anatomy, delivery efficiency and time allowed for plan adaptation.
III. Delivery accuracy evaluation and monitoring. This part of the project aims at validating the deliverability of the online re-optimized plans and developing an online delivery monitoring system. This system is based on input from Dynamic Machine Information (DMI), which continuously reports actual multi-leaf collimator (MLC) positions and machine monitor units (MUs) at 50ms intervals. Based on these DMI inputs, the QA system performed three levels of monitoring/verification on the plan delivery process: (1) Following each input, actual and expected fluence maps delivered up to the current MLC position were dynamically updated using corresponding MLC positions in the DMI. The difference between actual and expected fluence maps creates a fluence error map (FEM), which is used to assess the delivery accuracy. (2) At each control point, actual MLC positions were verified against the treatment plan for potential errors in data transfer between the treatment planning system (TPS) and the MLC controller. (3) After treatment, delivered dose was reconstructed in the treatment planning system based on DMI data during delivery, and compared to planned dose. FEMs from 210 prostate IMRT beams were evaluated for error magnitude and patterns. In addition, systematic MLC errors of ±0.5 and ±1 mm for both banks were simulated to understand error patterns in resulted FEMs. Applying clinical IMRT QA standard to the online re-optimized plans suggests the deliverability of online re-optimized plans are similar to regular IMRT plans. Applying the proposed QA system to online re-optimized plans also reveals excellent delivery accuracy: over 99% leaf position differences are < 0.5 mm, and the majority of pixels in FEMs are < 0.5 MU with errors exceeding 0.5 MU primarily located on the edge of the fields. All clinical FEMs observed in this study have positive errors on the left edges, and negative errors on the right. Analysis on a typical FEM reveals positive correlation between the magnitude of fluence errors and the corresponding leaf speed. FEMs of simulated erroneous delivery exhibit distinct patterns for different MLC error magnitudes and directions, indicating the proposed QA system is highly specific in detecting the source of errors. Based on these results, it can be concluded that the proposed online delivery monitoring system is very sensitive to leaf position errors, highly specific of the error types, and therefore meets the purpose for online delivery accuracy verification. Post-treatment dosimetric verification shows minimal difference between planned and actual delivered DVH, further confirming that the online re-optimized plans can be accurately delivered.
In summary, this project addressed two most important challenges for clinical implementation of online ART, efficiency and quality assurance, through innovative system design, technique development and validation with clinical data. The efficiencies of the overall treatment scheme and the re-optimization process have been improved significantly; and the proposed online quality assurance system is found to be effective in catching and differentiating leaf motion errors.