PET/SPECT/Spectral-CT/CBCT imaging in a small-animal radiation therapy platform: A Monte Carlo study-Part II: Biologically guided radiotherapy.

BACKGROUND: This study addresses the technical gap between clinical radiation therapy (RT) and preclinical small-animal RT, hindering the comprehensive validation of innovative clinical RT approaches in small-animal models of cancer and the translation of preclinical RT studies into clinical practices. PURPOSE: The main aim was to explore the feasibility of biologically guided RT implemented within a small-animal radiation therapy (SART) platform, with integrated quad-modal on-board positron emission tomography (PET), single-photon emission computed tomography, photon-counting spectral CT, and cone-beam CT (CBCT) imaging, in a Monte Carlo model as a proof-of-concept. METHODS: We developed a SART workflow employing quad-modal imaging guidance, integrating multimodal image-guided RT and emission-guided RT (EGRT). The EGRT algorithm was outlined using positron signals from a PET radiotracer, enabling near real-time adjustments to radiation treatment beams for precise targeting in the presence of a 2-mm setup error. Molecular image-guided RT, incorporating a dose escalation/de-escalation scheme, was demonstrated using a simulated phantom with a dose painting plan. The plan involved delivering a low dose to the CBCT-delineated planning target volume (PTV) and a high dose boosted to the highly active biological target volume (hBTV) identified by the 18F-PET image. Additionally, the Bayesian eigentissue decomposition method illustrated the quantitative decomposition of radiotherapy-related parameters, specifically iodine uptake fraction and virtual noncontrast (VNC) electron density, using a simulated phantom with Kidney1 and Liver2 inserts mixed with an iodine contrast agent at electron fractions of 0.01-0.02. RESULTS: EGRT simulations generated over 4,000 beamlet responses in dose slice deliveries and illustrated superior dose coverage and distribution with significantly lower doses delivered to normal tissues, even with a 2-mm setup error introduced, demonstrating the robustness of the novel EGRT scheme compared to conventional image-guided RT. In the dose-painting plan, doubling the dose to the hBTV while maintaining a low dose for the PTV resulted in an organ-at-risk (OAR) dose comparable to the low-dose treatment for the PTV alone. Furthermore, the decomposition of radiotherapy-related parameters in Kidney1 and Liver2 inserts, including iodine uptake fractions and VNC electron densities, exhibited average relative errors of less than 1.0% and 2.5%, respectively. CONCLUSIONS: The results demonstrated the successful implementation of biologically guided RT within the proposed quad-model image-guided SART platform, with potential applications in preclinical RT and adaptive RT studies.

Visual analysis of image-guided radiation therapy based on bibliometrics: A review.

Radiation therapy plays an important role in tumor treatment. The development of image-guided radiation therapy (IGRT) technology provides a strong guarantee for precise radiation therapy of tumors. However, bibliometric studies on IGRT research have rarely been reported. This study uses literature collected from the Web of Science during 1987 to 2021 as a sample and uses the bibliometric method to reveal the current research status, hotspots, and development trends in IGRT. Based on 6407 papers published from the Web of Science during 1987 to 2021, we utilized Microsoft Excel 2007 and cite space software to perform statistical analysis and visualization of IGRT. A total of 6407 articles were included, this area of IGRT has gone through 4 stages: budding period, growth period, outbreak period, and stationary period. The research category is mainly distributed in Radiology Nuclear Medicine Medical Imaging, which intersects with the research categories of Materials, Physics, and Mathematics. Yin FF, Tanderup K, and Sonke JJ are highly productive scholars who are active in IGRT research, while Jaffray DA, van Herk M and Guckenberger M are authors with high impact in this field. The team of scholars has close cooperation within the team and weak cooperation among teams. The League of European Research Universities, University of Texas System, University of Toronto, and Princess Margaret Cancer are the main research institutions in this field. The United States has the most research literature, followed by China and Germany. Six thousand four hundred seven articles are distributed in 712 journals, and the top 3 journals are Med Phys, Int J Radiat Oncol, and Radiather Oncol. Precise registration, intelligence, magnetic resonance guidance, and deep learning are current research hotspots. These results demonstrate that the research in this field is relatively mature and fruitful in the past 35 years, providing a solid theoretical basis and practical experience for precision radiotherapy.

Degradable multifunctional gold-liposomes as an all-in-one theranostic platform for image-guided radiotherapy.

To improve tumor destruction and minimize adverse effects to healthy tissues, image-guided radiation therapy (IGRT) has been developed to allow for the accurate delivery of radiation energy to tumor sites facilitated by real-time imaging. Nevertheless, the current IGRT platform still suffers from the limitation of poor tissue contrast, resulting in the incidental irradiation of healthy tissue. Gold nanoparticles (GNPs) have been identified as promising candidates to simultaneously improve both radiotherapy and imaging, thereby improving both the accuracy and safety of IGRT. However, despite much preclinical study, little clinical progress has been made due to uncertainty over GNP toxicity. Herein, we demonstrate the great potential of using GNP-coated liposomes, i.e., Lipogold, which combine the advantages of both large and small nanoparticles into one multifunctional formulation, as an ideal platform for IGRT. When irradiated with low doses (<2 Gy) of therapeutic X-rays, Lipogold induced a significant radiosensitization effect for PC-3 prostate cancer cells, which are moderately radiation-resistant. When imaged with computed tomography (CT), Lipogold was also found to possess consistent X-ray contrast of âˆ¼ 18-23 HU/mg across tube X-ray voltages (70-140 kVp), which could be boosted via the encapsulation of a small-molecule contrast agent containing iodine.

Characterization of imaging performance of a novel helical kVCT for use in image-guided and adaptive radiotherapy.

ClearRT helical kVCT imaging for the Radixact helical tomotherapy system recently received FDA approval and is available for clinical use. The system is intended to enhance image fidelity in radiation therapy treatment planning and delivery compared to the prior MV-based onboard imaging approach. The purpose of this work was to characterize the imaging performance of this system and compare this performance with that of clinical systems used in image-guided and/or adaptive radiotherapy (ART) or computed tomography (CT) simulation, including Radixact MVCT, TomoTherapy MVCT, Varian TrueBeam kV OBI CBCT, and the Siemens SOMATOM Definition Edge kVCT. A CT image quality phantom was scanned across clinically relevant acquisition modes for each system to evaluate image quality metrics, including noise, uniformity, contrast, spatial resolution, and CT number linearity. Similar noise levels were observed for ClearRT and Siemens Edge, whereas noise for the other systems was ∼1.5-5 times higher. Uniformity was best for Siemens Edge, whereas most scans for ClearRT exhibited a slight "cupping" or "capping" artifact. The ClearRT and Siemens Edge performed best for contrast metrics, which included low-contrast visibility and contrast-to-noise ratio evaluations. Spatial resolution was best for TrueBeam and Siemens Edge, whereas the three kVCT systems exhibited similar CT number linearity. Overall, these results provide an initial indication that ClearRT image quality is adequate for image guidance in radiotherapy and sufficient for delineating anatomic structures, thus enabling its use for ART. ClearRT also showed significant improvement over MVCT, which was previously the only onboard imaging modality available on Radixact. Although the acquisition of these scans does come at the cost of additional patient dose, reported CTDI values indicate a similar or generally reduced machine output for ClearRT compared to the other systems while maintaining comparable or improved image quality overall.

Ultrasound guidance for cervical implantation.

Ultrasound can provide real-time imagery without the risk of radiation exposure, and it is widely available at a relatively low cost. It can provide updated three-dimensional information that can improve the physician's spatial awareness during a brachytherapy procedure for cervical cancer. There is mounting evidence demonstrating the numerous benefits of ultrasound-guided brachytherapy in the published literature. This evidence supports its routine use to improve the safety and the effectiveness of cervical brachytherapy. In this report we will review various methods in which ultrasound imaging has been used during cervical brachytherapy. We also include a description of our own institutional approach to ultrasound-guided cervical implementation that has been in use for all cervical brachytherapy procedures over the past two decades.

Dosimetry Effects Due to the Presence of Fe Nanoparticles for Potential Combination of Hyperthermic Cancer Treatment with MRI-Based Image-Guided Radiotherapy.

Nanoparticles have proven to be biocompatible and suitable for many biomedical applications. Currently, hyperthermia cancer treatments based on Fe nanoparticle infusion excited by alternating magnetic fields are commonly used. In addition to this, MRI-based image-guided radiotherapy represents, nowadays, one of the most promising accurate radiotherapy modalities. Hence, assessing the feasibility of combining both techniques requires preliminary characterization of the corresponding dosimetry effects. The present work reports on a theoretical and numerical simulation feasibility study aimed at pointing out preliminary dosimetry issues. Spatial dose distributions incorporating magnetic nanoparticles in MRI-based image-guided radiotherapy have been obtained by Monte Carlo simulation approaches accounting for all relevant radiation interaction properties as well as charged particles coupling with strong external magnetic fields, which are representative of typical MRI-LINAC devices. Two main effects have been evidenced: local dose enhancement (up to 60% at local level) within the infused volume, and non-negligible changes in the dose distribution at the interfaces between different tissues, developing to over 70% for low-density anatomical cavities. Moreover, cellular uptakes up to 10% have been modeled by means of considering different Fe nanoparticle concentrations. A theoretical temperature-dependent model for the thermal enhancement ratio (TER) has been used to account for radiosensitization due to hyperthermia. The outcomes demonstrated the reliability of the Monte Carlo approach in accounting for strong magnetic fields and mass distributions from patient-specific anatomy CT scans to assess dose distributions in MRI-based image-guided radiotherapy combined with magnetic nanoparticles, while the hyperthermic radiosensitization provides further and synergic contributions.

Long-term clinical outcomes of lipiodol marking using standard gastroscopy for image-guided radiotherapy of upper gastrointestinal cancers.

BACKGROUND: Image-guided radiotherapy (IGRT) has significantly improved the precision in which radiotherapy is delivered in cancer treatment. Typically, IGRT uses bony landmarks and key anatomical structures to locate the tumor. Recent studies have demonstrated the feasibility of peri-tumor fiducials in enabling even more accurate delineation of target and normal tissue. The use of gold coils as fiducials in gastrointestinal tumors has been extensively studied. However, placement requires expertise and specialized endoscopic ultrasound equipment. This article reports the long-term outcomes of using a standard gastroscopy to inject liquid fiducials for the treatment of oesophageal and gastric tumors with IGRT. AIM: To assess the long-term outcomes of liquid fiducial-guided IGRT in a cohort of oesophageal and gastric cancer patients. METHODS: A retrospective cohort study of consecutive adults with Oesophagogastric cancers referred for liquid fiducial placement before definitive/neo-adjuvant or palliative IGRT between 2013 and 2021 at a tertiary hospital in Melbourne, Australia was conducted. Up to four liquid fiducials were inserted per patient, each injection consisting of 0.2-0.5mL of a 1:1 mixture of iodized oil (Lipiodol; Aspen Pharmacare) and n-butyl 2-cyanoacrylate (Histoacryl®; B. Braun). A 23-gauge injector (Cook Medical) was used for the injection. All procedures were performed by or under the supervision of a gastroenterologist. Liquid fiducial-based IGRT (LF-IGRT) consisted of computer-assisted direct matching of the fiducial region on cone-beam computerised tomography at the time of radiotherapy. Patients received standard-IGRT (S-IGRT) if fiducial visibility was insufficient, consisting of bone match as a surrogate for tumor position. Radiotherapy was delivered to 54Gy in 30 fractions for curative patients and up to 45Gy in 15 fractions for palliative treatments. RESULTS: 52 patients were referred for liquid fiducial placement within the study period. A total of 51 patients underwent liquid fiducial implantation. Of these a total of 31 patients received radiotherapy. Among these, the median age was 77.4 years with a range between 57.5 and 88.8, and 64.5% were male. Twenty-seven out of the 31 patients were able to have LF-IGRT while four had S-IGRT. There were no complications after endoscopic implantation of liquid fiducials in our cohort. The cohort overall survival (OS) post-radiotherapy was 19 mo (range 0 to 87 mo). Whilst the progression-free survival (PFS) post-radiotherapy was 13 mo (range 0 to 74 mo). For those treated with curative intent, the median OS was 22.0 mo (range 0 to 87 mo) with a PFS median of 14.0 mo (range 0 to 74 mo). Grade 3 complication rate post-radiotherapy was 29%. CONCLUSION: LF-IGRT is feasible in 87.1% of patients undergoing liquid fiducial placement through standard gastroscopy injection technique. Our cohort has an overall survival of 19 mo and PFS of 13 mo. Further studies are warranted to determine the long-term outcomes of liquid-fiducial based IGRT.

Preloaded 22-gauge fine-needle system facilitates placement of a higher number of fiducials for image-guided radiation therapy compared with traditional backloaded 19-gauge approach.

BACKGROUND AND AIMS: Image-guided radiation therapy (IGRT) often relies on EUS-guided fiducial markers. Previously used manually backloaded fiducial needles have multiple potential limitations including safety and efficiency concerns. Our aim was to evaluate the efficacy, feasibility, and safety of EUS-guided placement of gold fiducials using a novel preloaded 22-gauge needle compared with a traditional, backloaded 19-gauge needle. METHODS: This was a single-center comparative cohort study. Patients with pancreatic and hepatobiliary malignancy who underwent EUS-guided fiducial placement (EUS-FP) between October 2014 and February 2018 were included. The main outcome was the technical success of fiducial placement. Secondary outcomes were mean procedure time, fiducial visibility during IGRT, technical success of IGRT delivery, and adverse events. RESULTS: One hundred fourteen patients underwent EUS-FP during the study period. Of these, 111 patients had successful placement of a minimum of 2 fiducials. Fifty-six patients underwent placement using a backloaded 19-gauge needle and 58 patients underwent placement using a 22-gauge preloaded needle. The mean number of fiducials placed successfully at the target site was significantly higher in the 22-gauge group compared with the 19-gauge group (3.53 ± .96 vs 3.11 ± .61, respectively; P = .006). In the 22-gauge group, the clinical goal of placing 4 fiducials was achieved in 78%, compared with 23% in the 19-gauge group (P < .001). In univariate analyses, gender, age, procedure time, tumor size, and location did not influence the number of successfully placed fiducials. Technical success of IGRT with fiducial tracking was high in both the 19-gauge (51/56, 91%) and the 22-gauge group (47/58, 81%; P = .12). CONCLUSIONS: EUS-FP using a preloaded 22-gauge needle is feasible, effective, and safe and allows for a higher number of fiducials placed when compared with the traditional backloaded 19-gauge needle.

How Much Daily Image-guided Volumetric Modulated Arc Therapy Is Useful for Proctitis Prevention With Respect to Static Intensity Modulated Radiotherapy Supported by Topical Medications Among Localized Prostate Cancer Patients?

BACKGROUND/AIM: To evaluate if topical support therapy during static-intensity modulated radiotherapy (sIMRT) course is able to equal the characteristic minimum risk for radiation proctitis of Image-guided volumetric modulated arc therapy (IG-VMAT) treatment among localized prostate cancer patients. PATIENTS AND METHODS: Rectal toxicity data of the above patients were retrospectively collected throughout three different clinical periods at our Radiotherapy Deparment: from October 2011 to December 2012, prostate cancer patients were treated with sIMRT and in advance supported by means of daily topical corticosteroids; from January 2013 to November 2016, topical corticosteroids were replaced by daily hyaluronic acid enemas; from December 2016 to May 2018 eligible patients were treated with newly introduced IG-VMAT supported by only on-demand topical corticosteroids. RESULTS: Among 359 eligible patients, IG-VMAT was proven generally more effective than sIMRT supported by topical medications in terms of proctitis reduction, although without clinical and practical relevance. CONCLUSION: Topical medications might have a role in radiation proctitis prevention.

Current Landscape and Future Directions on Bladder Sparing Approaches to Muscle-Invasive Bladder Cancer.

OPINION STATEMENT: Although radical cystectomy is considered the gold standard approach for patients with muscle-invasive bladder cancer, tri-modal therapy (TMT) is a well-tolerated and efficacious alternative to radical cystectomy that is underutilized in inoperable patients and rarely offered to cystectomy candidates in the USA. Retrospective data suggest similar outcomes between radical cystectomy and TMT after adjusting for patient selection and other confounding factors. Nearly 70-80% of patients can keep their native bladder with favorable post-treatment quality of life metrics. Current trials are investigating novel combination strategies including immune checkpoint inhibition along with chemoradiation or radiation. Emerging techniques for improved patient selection and risk stratification include incorporating MP-MRI, and novel biomarkers such as inflammatory, stromal, and DNA damage response gene signatures may guide patient selection and expand the landscape of bladder preservation options available to patients in the future.

Multifunctional Hf/Mn-TCPP Metal-Organic Framework Nanoparticles for Triple-Modality Imaging-Guided PTT/RT Synergistic Cancer Therapy.

BACKGROUND: Recent studies have validated and confirmed the great potential of nanoscale metal-organic framework (NMOF) in the biomedical field, especially in improving the efficiency of cancer diagnosis and therapy. However, most previous studies only utilized either the metal cluster or the organic ligand of the NMOF for cancer treatments and merely reported limited theranostic functions, which may not be optimized. As a highly designable and easily functionalized material, prospective rational design offers a powerful way to extract the maximum benefit from NMOF for cancer theranostic applications. MATERIALS AND METHODS: A NMOF based on hafnium (Hf) cluster and Mn(III)-porphyrin ligand was rational designed and synthesized as a high-performance multifunctional theranostic agent. The folic acid (FA) was modified on the NMOF surface to enhance the cancer targeting efficacy. The proposed "all-in-one" FA-Hf-Mn-NMOF (fHMNM) was characterized and identified using various analytical techniques. Then, in vitro and in vivo studies were performed to further explore the effects of fHMNM both as the magnetic resonance imaging (MRI)/computed tomography (CT)/photoacoustic imaging (PAI) contrast agent and as the photothermal therapy (PTT)/radiotherapy (RT) agent. RESULTS: A tumour targeting multifunctional fHMNM was successfully synthesized with high performance for MRI/CT/PAI enhancements and image-guided PTT/RT synergistic therapy properties. Compared with the current clinical CT and MR contrast agents, the X-ray attenuation and T1 relaxation rate of this integrated nanosystem increased 1.7-fold and 3-5-fold, respectively. More importantly, the catalase-like Mn(III)-porphyrin ligand can decompose H2O2 into O2 in tumour microenvironments to improve the synergistic treatment efficiency of PTT and RT. Significant tumour growth inhibition was achieved in mouse cancer models without obvious damage to the other organs. CONCLUSION: This work highlights the potential of fHMNM as an easily designable material for biomedical applications, could be an effective tool for in vivo detection and subsequent treatment of tumour.

The Pivotal Role of the Therapeutic Radiographer/Radiation Therapist in Image-guided Radiotherapy Research and Development.

The ability to personalise radiotherapy to fit the individual patient and their diagnosis has been realised through technological advancements. There is now more opportunity to utilise these technologies and deliver precision radiotherapy for more patients. Image-guided radiotherapy (IGRT) has enabled users to safely and accurately plan, treat and verify complex cases; and deliver a high dose to the target volume, while minimising dose to normal tissue. Rapid changes in IGRT have required a multidisciplinary team (MDT) approach, carefully deciding optimum protocols to achieve clinical benefit. Therapeutic radiographer/radiation therapists (RTTs) play a pivotal role in this MDT. There is already a great deal of evidence that illustrates the contribution of RTTs in IGRT development; implementation; quality assurance; and maintaining training and competency programmes. Often this has required the RTT to undertake additional roles and responsibilities. These publications show how the profession has evolved, expanding the scope of practice. There are now more opportunities for RTT-led IGRT research. This is not only undertaken in the more traditional aspects of practice, but in recent times, more RTTs are becoming involved in imaging biomarkers research and radiomic analysis. The aim of this overview is to describe the RTT contribution to the ongoing development of IGRT and to showcase some of the profession's involvement in IGRT research.

Gadolinium-Rose Bengal Coordination Polymer Nanodots for MR-/Fluorescence-Image-Guided Radiation and Photodynamic Therapy.

Combination therapy based on nanomedicine has gained momentum in oncology in recent years, offering superior safety and efficacy over monotherapies. It is critical to design theranostics that are composed of imaging and therapeutic agents already approved. Herein, gadolinium (Gd)-rose bengal coordination polymer nanodots (GRDs) are reported. The GRDs exhibit a unique absorption property and 7.7-fold luminescence enhancement, as well as a 1.9-fold increase in singlet oxygen generation efficiency over free rose bengal. Meanwhile, GRDs exhibit a twofold increase in r1 relaxivity over gadopentetic acid (Gd-DTPA) and have better X-ray absorption ability than rose bengal alone. These excellent properties of the GRDs are verified both in vitro and in vivo. The combination of photodynamic therapy (PDT) and radiation therapy (RT) more significantly inhibits tumor growth than monotherapies (i.e., PDT or RT). This work offers a new route to designing and synthesizing Gd-based nanotheranostics for image-guided cancer therapy.

MRI-Guided Ultrafocal Salvage High-Dose-Rate Brachytherapy for Localized Radiorecurrent Prostate Cancer: Updated Results of 50 Patients.

PURPOSE: Most patients with local prostate cancer recurrence after radiation therapy undergo palliative androgen deprivation therapy because whole-gland salvage treatments have a high risk of severe toxicity. Focal treatment reduces this risk while offering a second opportunity for cure. We report updated outcomes of ultrafocal salvage high-dose-rate brachytherapy (HDR-BT). METHODS AND MATERIALS: Prospectively collected data from the first 50 treated patients were analyzed. Disease status was assessed by 3T multiparametric magnetic resonance imaging (MRI), 18F-Choline or 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography, and systematic or tumor-targeted biopsies. Ultrafocal salvage HDR-BT (1 × 19 Gy) was performed by implanting the clinical target volume (CTV: gross tumor volume + 5 mm margin) under fused transrectal ultrasound/MRI guidance. Follow-up included toxicity grading (using Common Terminology Criteria for Adverse Events 4.0), quality of life assessment, and prostate-specific antigen (PSA) testing. RESULTS: Median follow-up was 31 months. Median CTV D95% was 18.8 Gy. We observed 2% grade 3 genitourinary toxicity, no grade 3 gastrointestinal toxicity, and 22% newly developed grade 3 erectile dysfunction. Five of 13 patients (38%) with self-reported pretreatment potency (International Index of Erectile Function >17) remained potent. Clinically relevant quality of life deterioration was reported for only 6 of 31 items and was not statistically significant. Biochemical failure (nadir + 2) occurred in 26 patients. Among intraprostatic recurrences, 73% were in field. After 2.5 years, biochemical disease-free survival was 51% (95% confidence interval, 37%-69%), metastases-free survival was 75% (64%-89%), androgen deprivation therapy-free survival was 90% (82%-99%), and overall survival was 98% (94%-100%). Presalvage PSA, CTV size, and stage ≥T3 were significantly associated with biochemical failure. Higher-risk patients (stage ≥T3, PSA ≥10, or PSA double time ≤9 months) had 25% biochemical disease-free survival at 2.5 years versus 71% for lower-risk patients. CONCLUSIONS: At this early stage, MRI-guided ultrafocal HDR-BT seems to be a safe salvage treatment option, with acceptable biochemical control in a well-selected group of patients and potential for effectively postponing androgen deprivation therapy.

Efficacy and safety of CT-guided 125I seed implantation as a salvage treatment for locally recurrent head and neck soft tissue sarcoma after surgery and external beam radiotherapy: A 12-year study at a single institution.

OBJECTIVES: The objective of this study was to evaluate the efficacy and safety of CT-guided radioactive 125I seed implantation as a salvage treatment for locally recurrent head and neck soft tissue sarcoma (HNSTS) after surgery and external beam radiotherapy. METHODS AND MATERIALS: From December 2006 to February 2018, 25 patients with locally recurrent HNSTS after surgery and external beam radiotherapy were enrolled. All the patients successfully underwent CT-guided 125I seed implantation. The primary end points included the objective response rate (ORR) and local progression-free survival (LPFS). The secondary end points were survival (OS) and safety profiles. RESULTS: After 125I seed implantation, the ORR was 76.0%. The 1-, 3-, and 5-year LPFS rates were 65.6%, 34.4%, and 22.9%, respectively, with the median LPFS of 16.0 months. The 1-, 3-, and 5-year OS rates were 70.8%, 46.6%, and 34.0%, respectively, with the median OS of 28.0 months. Furthermore, univariate analyses showed that the recurrent T stage and histological grade were prognostic factors of LPFS, whereas only the histological grade was a predictor of OS. The major adverse events were skin/mucosal toxicities, which were generally of lower grade (≤Grade 2) and were well tolerated. CONCLUSIONS: Radioactive 125I seed implantation could be an effective and safe alternative treatment for locally recurrent HNSTS after failure of surgery and radiotherapy. Recurrent T stage and histological grade were the main factors influencing the efficacy.

Standard and Hypofractionated Dose Escalation to Intraprostatic Tumor Nodules in Localized Prostate Cancer: Efficacy and Toxicity in the DELINEATE Trial.

PURPOSE: To report a planned analysis of the efficacy and toxicity of dose escalation to the intraprostatic dominant nodule identified on multiparametric magnetic resonance imaging using standard and hypofractionated external beam radiation therapy. METHODS AND MATERIALS: DELINEATE is a single centre prospective phase 2 multicohort study including standard (cohort A: 74 Gy in 37 fractions) and moderately hypofractionated (cohort B: 60 Gy in 20 fractions) prostate image guided intensity modulated radiation therapy in patients with National Comprehensive Cancer Network intermediate- and high-risk disease. Patients received an integrated boost of 82 Gy (cohort A) and 67 Gy (cohort B) to lesions visible on multiparametric magnetic resonance imaging. Fifty-five patients were treated in cohort A, and 158 patients were treated in cohort B; the first 50 sequentially treated patients in cohort B were included in this planned analysis. The primary endpoint was late Radiation Therapy Oncology Group rectal toxicity at 1 year. Secondary endpoints included acute and late toxicity measured with clinician- and patient-reported outcomes at other time points and biochemical relapse-free survival for cohort A. Median follow-up was 74.5 months for cohort A and 52.0 months for cohort B. RESULTS: In cohorts A and B, 27% and 40% of patients, respectively, were classified as having National Comprehensive Cancer Network high-risk disease. The cumulative 1-year incidence of Radiation Therapy Oncology Group grade 2 or worse rectal and urinary toxicity was 3.6% and 0% in cohort A and 8% and 10% in cohort B, respectively. There was no reported late grade 3 rectal toxicity in either cohort. Within cohort A, 4 of 55 (7%) patients had biochemical relapse. CONCLUSIONS: Delivery of a simultaneous integrated boost to intraprostatic dominant nodules is feasible in prostate radiation therapy using standard and moderately hypofractionated regimens, with rectal and genitourinary toxicity comparable to contemporary series without an intraprostatic boost.

Absolute dosimetry of a 1.5 T MR-guided accelerator-based high-energy photon beam in water and solid phantoms using Aerrow.

PURPOSE: In this work, the fabrication, operation, and evaluation of a probe-format graphite calorimeter - herein referred to as Aerrow - as an absolute clinical dosimeter of high-energy photon beams while in the presence of a B = 1.5 T magnetic field is described. Comparable to a cylindrical ionization chamber (IC) in terms of utility and usability, Aerrow has been developed for the purpose of accurately measuring absorbed dose to water in the clinic with a minimum disruption to the existing clinical workflow. To our knowledge, this is the first reported application of graphite calorimetry to magnetic resonance imaging (MRI)-guided radiotherapy. METHODS: Based on a previously numerically optimized and experimentally validated design, an Aerrow prototype capable of isothermal operation was constructed in-house. Graphite-to-water dose conversions as well as magnetic field perturbation factors were calculated using Monte Carlo, while heat transfer and mass impurity corrections and uncertainties were assessed analytically. Reference dose measurements were performed in the absence and presence of a B = 1.5 T magnetic field using Aerrow in the 7 MV FFF photon beam of an Elekta MRI-linac and were directly compared to the results obtained using two calibrated reference-class IC types. The feasibility of performing solid phantom-based dosimetry with Aerrow and the possible influence of clearance gaps is also investigated by performing reference-type dosimetry measurements for multiple rotational positions of the detector and comparing the results to those obtained in water. RESULTS: In the absence of the B-field, as well as in the parallel orientation while in the presence of the B-field, the absorbed dose to water measured using Aerrow was found to agree within combined uncertainties with those derived from TG-51 using calibrated reference-class ICs. Statistically significant differences on the order of (2-4)%, however, were observed when measuring absorbed dose to water using the ICs in the perpendicular orientation in the presence of the B-field. Aerrow had a peak-to-peak response of about 0.5% when rotated within the solid phantom regardless of whether the B-field was present or not. CONCLUSIONS: This work describes the successful use of Aerrow as a straightforward means of measuring absolute dose to water for large high-energy photon fields in the presence of a 1.5 T B-field to a greater accuracy than currently achievable with ICs. The detector-phantom air gap does not appear to significantly influence the response of Aerrow in absolute terms, nor does it contribute to its rotational dependence. This work suggests that the accurate use of solid phantoms for absolute point dose measurement is possible with Aerrow.

Technical assessment of a mobile CT scanner for image-guided brachytherapy.

PURPOSE: The imaging performance and dose of a mobile CT scanner (Brainlab Airo®, Munich, Germany) is evaluated, with particular consideration to assessment of technique protocols for image-guided brachytherapy. METHOD: Dose measurements were performed using a 100-mm-length pencil chamber at the center and periphery of 16- and 32-cm-diameter CTDI phantoms. Hounsfield unit (HU) accuracy and linearity were assessed using materials of specified electron density (Gammex RMI, Madison, WI), and image uniformity, noise, and noise-power spectrum (NPS) were evaluated in a 20-cm-diameter water phantom as well as an American College of Radiology (ACR) CT accreditation phantom (Model 464, Sun Nuclear, Melbourne, FL). Spatial resolution (modulation transfer function, MTF) was assessed with an edge-spread phantom and visually assessed with respect to line-pair patterns in the ACR phantom and in structures of interest in anthropomorphic phantoms. Images were also obtained on a diagnostic CT scanner (Big Bore CT simulator, Philips, Amsterdam, Netherlands) for qualitative and quantitative comparison. The manufacturer's metal artifact reduction (MAR) algorithm was assessed in an anthropomorphic body phantom containing surgical instrumentation. Performance in application to brachytherapy was assessed with a set of anthropomorphic brachytherapy phantoms - for example, a vaginal cylinder and interstitial ring and tandem. RESULT: Nominal dose for helical and axial modes, respectively, was 56.4 and 78.9 mGy for the head protocol and 17.8 and 24.9 mGy for the body protocol. A high degree of HU accuracy and linearity was observed for both axial and helical scan modes. Image nonuniformity (e.g., cupping artifact) in the transverse (x,y) plane was less than 5 HU, but stitching artifacts (~5 HU) in the longitudinal (z) direction were observed in axial scan mode. Helical and axial modes demonstrated comparable spatial resolution of ~5 lp/cm, with the MTF reduced to 10% at ~0.38 mm-1 . Contrast-to-noise ratio was suitable to soft-tissue visualization (e.g., fat and muscle), but windmill artifacts were observed in helical mode in relation to high-frequency bone and metal. The MAR algorithm provided modest improvement to image quality. Overall, image quality appeared suitable to relevant clinical tasks in intracavitary and interstitial (e.g., gynecological) brachytherapy, including visualization of soft-tissue structures in proximity to the applicators. CONCLUSION: The technical assessment highlighted key characteristics of dose and imaging performance pertinent to incorporation of the mobile CT scanner in clinical procedures, helping to inform clinical deployment and technique protocol selection in brachytherapy. For this and other possible applications, the work helps to identify protocols that could reduce radiation dose and/or improve image quality. The work also identified areas for future improvement, including reduction of stitching, windmill, and metal artifacts.

"Navigate-dock-activate" anti-tumor strategy: Tumor micromilieu charge-switchable, hierarchically activated nanoplatform with ultrarapid tumor-tropic accumulation for trackable photothermal/chemotherapy.

The delivery of therapeutics into tumors remains a challenge in nanoparticle-mediated drug delivery. However, effective therapies such as photothermal therapy (PTT) are limited by quick systemic clearance and non-specific biodistribution. Anti-tumor strategies tailored to accommodate both tumor accumulation/retention and cellular internalization under a single platform would be a promising strategy. This work demonstrates a hierarchical activating strategy that would exhibit enhanced circulation and rapid tumor-tropism as well as facilitate tumor penetration, followed by tumor-specific drug release to realize trackable photothermal/chemotherapy. Methods: We engineered a lithocholic acid-conjugated disulfide-linked polyethyleneimine micelle (LAPMi) loaded with paclitaxel (LAPMi-PTX, L), followed by the electrostatic adsorption of indocyanine green (ICG, I) on LAPMI-PTX and subsequently coated them with thermosensitive DPPC and DSPE-PEG-NH2 lipids (L), producing Lipid/ICG/LAPMi-PTX (LIL-PTX) nanoparticles (NPs). The characteristics of NPs, including physicochemical characterization, photothermal & pH responsiveness, cell uptake, tumor spheroid penetration, anti-tumor efficacy and hierarchical activation of LIL-PTX NPs were investigated in vitro and in vivo by using CT26 cell line. The anti-metastatic potential of LIL-PTX NPs were demonstrated using 4T1 orthotopic tumor model. Results: The NPs synthesized possessed charge switchability in the mildly acidic pH, and were laser- and pH-responsive. Dual stimuli-responsive nature of LIL-PTX NPs improved the disposition of therapeutics to the tumor, reflected by enhanced intracellular uptake, tumor spheroid penetration and in vitro cytotoxicity studies. LIL-PTX NPs readily switched its surface charge from neutral to positive upon reaching the tumor milieu, thus resulting in rapid tumor tropism and accumulation. Under near-infrared laser irradiation, the thermosensitive lipids on LIL-PTX NPs were deshielded, and the tumor-penetrating LAPMi-PTX was subsequently exposed to the tumor milieu, thus resulting in enhanced intracellular internalization. Next, LAPMi-PTX evaded the endo-lysosomes, thereby releasing the PTX through the degradation of LAPMi mediated by intracellular GSH in the tumor. LIL-PTX NPs significantly improved the therapy by eradicating primary tumors completely and suppressing their subsequent lung metastasis. Conclusion: The improved therapeutic index is due to enhanced passive targeting by rapid tumor-tropic accumulation and tumor penetration by laser-driven exposure of LAPMi, thereby improving the therapeutic delivery for image-guided photothermal/chemotherapy.

A 3D printed modular phantom for quality assurance of image-guided small animal irradiators: Design, imaging experiments, and Monte Carlo simulations.

PURPOSE: The goal of this work was to develop and test a cylindrical tissue-equivalent quality assurance (QA) phantom for micro computed tomography (microCT) image-guided small animal irradiators that overcomes deficiencies of existing phantoms due to its mouse-like dimensions and composition. METHODS: The 8.6-cm-long and 2.4-cm-diameter phantom was three-dimensionally (3D) printed out of Somos NeXt plastic on a stereolithography (SLA) printer. The modular phantom consisted of four sections: (a) CT number evaluation section, (b) spatial resolution with slanted edge (for the assessment of longitudinal resolution) and targeting section, (c) spatial resolution with hole pattern (for the assessment of radial direction) section, and (d) uniformity and geometry section. A Python-based graphical user interface (GUI) was developed for automated analysis of microCT images and evaluated CT number consistency, longitudinal and radial modulation transfer function (MTF), image uniformity, noise, and geometric accuracy. The phantom was placed at the imaging isocenter and scanned with the small animal radiation research platform (SARRP) in the pancake geometry (long axis of the phantom perpendicular to the axis of rotation) with a variety of imaging protocols. Tube voltage was set to 60 and 70 kV, tube current was set to 0.5 and 1.2 mA, voxel size was set to 200 and 275 µm, imaging times of 1, 2, and 4 min were used, and frame rates of 6 and 12 frames per second (fps) were used. The phantom was also scanned in the standard (long axis of the phantom parallel to the axis of rotation) orientation. The quality of microCT images was analyzed and compared to recommendations presented in our previous work that was derived from a multi-institutional study. Additionally, a targeting accuracy test with a film placed in the phantom was performed. MicroCT imaging of the phantom was also simulated in a modified version of the EGSnrc/DOSXYZnrc code. Images of the resolution section with the hole pattern were acquired experimentally as well as simulated in both the pancake and the standard imaging geometries. The radial spatial resolution of the experimental and simulated images was evaluated and compared to experimental data. RESULTS: For the centered phantom images acquired in the pancake geometry, all imaging protocols passed the spatial resolution criterion in the radial direction (>1.5 lp/mm @ 0.2 MTF), the geometric accuracy criterion (<200 µm), and the noise criterion (<55 HU). Only the imaging protocol with 200-µm voxel size passed the criterion for spatial resolution in the longitudinal direction (>1.5 lp/mm @ 0.2 MTF). The 70-kV tube voltage dataset failed the bone CT number consistency test (<55 HU). Due to cupping artifacts, none of the imaging protocols passed the uniformity test of <55 HU. When the phantom was scanned in the standard imaging geometry, image uniformity and longitudinal MTF were satisfactory; however, the CT number consistency failed the recommended limit. A targeting accuracy of 282 and 251 µm along the x- and z-direction was observed. Monte Carlo simulations confirmed that the radial spatial resolution for images acquired in the pancake geometry was higher than the one acquired in the standard geometry. CONCLUSIONS: The new 3D-printed phantom presents a useful tool for microCT image analysis as it closely mimics a mouse. In order to image mouse-sized animals with acceptable image quality, the standard protocol with a 200-µm voxel size should be chosen and cupping artifacts need to be resolved.