Objective. To validate a respiratory motion model that uses real-time electromagnetic (EM) surface tracking acquired concurrently with time-resolved multi-cycle 4D MRI (TRMC-MRI) to estimate respiration-induced changes within the entire irradiated volume.Approach. Four volunteer participants with no self-reported history of lung cancer or other pulmonary disease underwent TRMC-MRI using a golden-angle stack-of-stars 3D GRE sequence while breathing freely for 2 min. Concurrently, real-time thoracoabdominal surface motion was recorded using four MR-compatible electromagnetic (EM) sensors (EndoScout II). Each MR volume was temporally aligned with corresponding EM data, resulting in 2,000 paired samples per participant. Deformation vector fields (DVFs) were generated through deformable image registration between a selected reference volume and all subsequent volumes. To capture temporal anatomical changes, additional DVFs were computed via consecutive volume-to-volume registration (e.g., volume 2 to 1, 3 to 2, and so on). Two machine learning models were developed to map surface motion to internal DVFs using dimensionality reduction: one employing Principal Component Analysis (PCA), and the other using Independent Component Analysis (ICA). Estimated DVFs were applied to the reference volume to reconstruct dynamic MR images, which were evaluated against ground truth using mutual information (MI) and an image-derived diaphragm profile-based root mean squared error (RMSE).Main results. Our preliminary results demonstrated that both PCA- and ICA-based models achieved comparable MI scores (mean 62%; one-way ANOVA, p > 0.05). Adaptive median filtering significantly improved MI to approximately 66% on average (one-way ANOVA, p < 0.001), outperforming no filtering across all participants (Tukey's HSD, p < 0.05). Diaphragm profile analysis showed close agreement with ground truth, with mean RMSE of 3.77-4.71 mm (SD: 1.07-1.63 mm).Significance. This proof-of-concept study demonstrates the feasibility of a non-invasive respiratory motion model derived from EM-based surface tracking combined with TRMC-MRI, with potential applications in MR-guided and conventional radiotherapy.

BACKGROUND:Despite advances in image-guided radiation therapy (IGRT), real-time, soft-tissue-based, volumetric motion monitoring remains unsolved. Integrated MRI+Linac systems are a solution, but are costly and complex. X-ray and optical photogrammetry-based systems have their limitations. Surrogate-based motion models, which use external signals to estimate internal motion, offer an alternative. We explore the feasibility of an electromagnetic (EM) fiducial-based device integrated with a surrogate-based motion model for real-time in-room volumetric motion monitoring. PURPOSE:To assess the feasibility of an EM-tracking system in the linac room, with an eventual goal of integrating it into an MRI-compatible system for real-time volumetric motion monitoring. METHODS:We empirically assessed the impact of gantry rotation and the radiation beam on EM-tracking accuracy using a sinusoidal motion trajectory (2 cm peak-to-peak, 5 s per cycle) programmed into a 2D motion platform. Four EM-tracking sensors were affixed to the platform, and their recorded trajectories were compared to the programmed motion under various conditions, including static and dynamic gantry positions, with and without radiation beams, and during CBCT acquisition. RESULTS:The EM-tracking system faithfully reproduced the programmed sinusoidal motion during treatment beam (MV) and CBCT acquisition (kV + gantry rotation). With the beam off and static gantry and static motion platform at 0°, the average point-wise tracking difference was < 0.5 mm compared to gantry angles of 90°, 180°, and 270°. Similarly, with a moving platform, the sensors achieved a < 1 mm difference at the same angles. Additionally, the gantry's clockwise and anticlockwise rotations caused a < 0.5 mm difference on average at all angles during beam-off. CONCLUSION:Preliminary results show the EM-tracking system operates with sub-millimeter accuracy in the linac room, with minimal effects from the radiation beam, gantry motion, or CBCT acquisition, supporting its feasibility for real-time volumetric motion monitoring during IGRT.

BackgroundPancreatic cancer is the fourth-leading cause of cancer death in the United States, with a 5-year survival rate of only 13%. Most patients with locally advanced pancreatic cancer receive chemotherapy with or without radiation therapy (RT). However, current treatment approaches often result in limited clinical response, highlighting the need for novel therapeutic strategies tested in robust model systems. Pancreas tumor-derived organoids offer a promising representative preclinical model for assessing responses to chemotherapy drugs, RT, and combination treatments.MethodsPancreatic tumor organoids (PTOs) were derived from Panc02 mouse flank tumors. The PTO microenvironment was characterized and compared with the in vivo tumor using immunohistochemical and immunofluorescence staining for alpha-smooth muscle actin (α-SMA) and vimentin. The organoids were treated with fractionated x-ray radiation, gemcitabine, 5-fluorouracil (5-FU), and combinations of drugs with radiation. Treatment response was observed and quantified using brightfield imaging and immunofluorescence to detect reactive oxygen species (ROS) and γH2AX.ResultsThree-dimensional PTOs exhibited expression patterns of α-SMA and vimentin similar to in vivo tumors, underscoring their relevance as a translational preclinical model. Dose-dependent growth suppression was observed following treatment with individual chemotherapy agents and radiation. Combination treatments with low-dose chemotherapy and radiation resulted in significantly greater inhibition of organoid growth compared to single-modality treatments. This enhanced effect was validated by reduced vimentin expression, increased γH2AX expression, and elevated reactive oxygen species (ROS) production, indicating amplified DNA damage and cytotoxicity.ConclusionCombining low-dose chemotherapy with radiation is significantly more effective at inhibiting pancreatic tumor organoid growth than either treatment alone, likely by targeting distinct signaling pathways. Additionally, the tumor organoid model holds promise for examining drug and radiation treatment responses, with potential for translational impact.

Purpose/Objective(s) We investigated 3 patient-derived pancreatic tumor organoids (PTOs) (ID # 8510, 7800 and 11777) response to gemcitabine, FOLFIRINOX, 5 FU and radiation therapy (RT). The aim of this study was to demonstrate that each patient's tumor organoids responded differently to chemotherapy drugs and RT, and genetic mutations played a role in RT resistance. The combination of chemotherapy followed by RT and the role of cancer stem cells (CSCs) in radiation resistance was also investigated. Materials/Methods 3-D Culture of tumor organoids: PTOs were obtained from the NCI and 3D culture was initiated in Matrigel. The mixture (Matrigel and organoids) was then pipetted into the wells of 24-well plates that were pre-warmed overnight and 750 µl of Panc complete media was added to each well with a dome and incubated at 37 ºC with 5 % CO2. Chemotherapy and RT Dose Response: The cultured tumor organoids were allowed to grow for 24 hours. Then, treated with different doses of gemcitabine, 5-fluorouracil and FOLFIRINOX (0-100 µM) and RT (2-12 Gy). After treatment MTT assay was performed using CellTiter 96 Reagent (Promega) and percentage viability was calculated and the IC-50 doses were determined. Results Dose response of patients derived pancreatic tumor organoids to chemotherapy drugs and RT: PTOs were treated with different doses of gemcitabine, FOLFIRINOX, 5 FU and RT and allowed to grow for 7 days. The treatment response of the tumor organoid was determined by MTT assay which measures organoids proliferation. The data has shown significant variation in IC50 dose of chemotherapy drugs and RT required to kill 50 % of tumor organoids. The tumor organoid 8510 exhibited higher tolerance to 5-fluorouracil and FOLFIRINOX treatment as compared to 7800 and 11777. We also observed 11777 showed resistance to 12 Gy of RT and the genetic profile of this patients showed mutation in ARID1A & PIM1 genes which could be linked to RT resistance. We further examined effectiveness of chemotherapy and RT alone vs combination treatment of chemotherapy and RT. Interestingly, tumor organoids treated with combination of chemotherapy and RT exhibited significant higher killing as compared to chemotherapy or RT alone. Upregulation of OCT4 and SOX2 in pancreatic cancer stem cells exhibited resistance to radiation treatment: The data demonstrated significant upregulation of SOX2 and OCT4 pancreatic cancer stem cell markers in tumor organoids treated with radiation therapy (RT). The data have shown upregulation of OCT4 and SOX2 (CSC) markers in tumor organoids treated with 4 and 8 Gy of RT, suggesting their role in therapy resistance. The combination of chemotherapy with RT suppressed OCT4 and SOX2 expression. Conclusion The data unambiguously suggest that PTOs showed differential sensitivity toward chemotherapy drugs and RT. The combination treatment modality exhibited significant higher killing than individual modality. The upregulation of OCT4 and SOX2, CSC markers in pancreatic tumor could be playing a role in radiation and chemotherapy resistance.

Vesicles are self-assembled nanocontainers (size similar to 100 nm) in which solutes such as drugs can be encapsulated. There is great interest in triggering vesicle-micelle transitions (VMTs) because such transitions will result in the release of encapsulated solute. Here, we focus on reactive oxygen species (ROS) as a trigger for VMTs. ROS arise in our body within cells, and ROS levels are known to be high near a tumor. Thus, ROS-responsive vesicles are of interest. We make such vesicles by combining the cationic amphiphile (4-phenylthiophenyl)diphenyl-sulfonium triflate (PDST), and the anionic surfactant sodium dodecylbenzene sulfonate (SDBS). By simply mixing these two commercially available molecules in water, we prepare 'catanionic' vesicles in an easy, low-cost, and scalable way. When exposed to ROS such as hydrogen peroxide (H2O2), the thioether in the PDST tail gets oxidized to a hydrophilic sulfoxide. As a result, the vesicles are transformed into spherical or short, cylindrical micelles. Evidence for the VMT comes from turbidity, light scattering, and cryo-TEM measurements. The same vesicles are also sensitive to other stimuli, specifically light and temperature: i.e., a VMT can also be induced by irradiation with UV light or heating above a critical temperature. We explain the origin of the VMT in each case based on changes in the driving forces for amphiphile assembly. Two common amphiphiles, a cationic photoinitiator and an anionic surfactant, are combined to create 'smart' nanoscale vesicles. When exposed to reactive oxygen species (ROS), light (UV) or heat, the vesicles are converted into smaller micelles.

Pancreatic cancer has a five-year survival rate of only 10%, mostly due to late diagnosis and limited treatment options. In patients with unresectable disease, either FOLFIRINOX, a combination of 5-fluorouracil (5-FU), oxaliplatin and irinotecan, or gemcitabine plus nab-paclitaxel combined with radiation are frontline standard regimens. However, chemo-radiation therapy has shown limited success because patients develop resistance to chemotherapy and/or radiation. In this study, we evaluated the role of pancreatic cancer stem cells (CSC) using OCT4 and SOX2, CSC markers in mouse pancreatic tumor organoids. We treated pancreatic tumor organoids with 4 or 8 Gy of radiation, 10 μM of 5-FU (5-Fluorouracil), and 100 μM 3-Bromopyruvate (3BP), a promising anti-cancer drug, as a single treatment modalities, and in combination with RT. Our results showed significant upregulation of, OCT4, and SOX2 expression in pancreatic tumor organoids treated with 4 and 8 Gy of radiation, and downregulation following 5-FU treatment. The expression of CSC markers with increasing treatment dose exhibited elevated upregulation levels to radiation and downregulation to 5-FU chemotherapy drug. Conversely, when tumor organoids were treated with a combination of 5-FU and radiation, there was a significant inhibition in SOX2 and OCT4 expression, indicating CSC self-renewal inhibition. Noticeably, we also observed that human pancreatic tumor tissues exhibited heterogeneous and aberrant OCT4 and SOX2 expression as compared to normal pancreas, indicating their potential role in pancreatic cancer growth and therapy resistance. In addition, the combination of 5-FU and radiation treatment exhibited significant inhibition of the β-catenin pathway in pancreatic tumor organoids, resulting in sensitization to treatment and organoid death. In conclusion, our study emphasizes the crucial role of CSCs in therapeutic resistance in PC treatment. We recommend using tumor organoids as a model system to explore the impact of CSCs in PC and identify new therapeutic targets.

Purpose/Objective(s) Multi-catheter interstitial high-dose rate brachytherapy (IHDR) with interstitial hyperthermia (IHT) has been shown to improve oncologic outcomes with minimal added toxicity for newly diagnosed cervical cancer. However, similar data for other gynecologic (GYN) cancers is limited, and it is not clear which patients may benefit most from the addition of IHT. We present a single-institution experience of patients with GYN cancers treated using IHDR with or without concurrent IHT (IHDR-IHT). Materials/Methods We retrospectively analyzed 97 patients with GYN cancers treated with IHDR with or without IHT (IHDR: 36, IHDR-IHT: 61) from 2015-2023. Primary indications for IHT included more advanced or treatment resistant disease such as recurrent, residual (following EBRT), or bulky tumor, guided by tumor location and geometry of needle placements within the HRCTV. IHDR was delivered 5 times over a 3-day period with a total of 2 IHT treatments (target temperature 40-44 °C for 1 hour) between IHDR treatments using the same set of catheters. Oncologic and toxicity outcomes were compared for both arms. Results Median follow up was 19.4 months for IHDR-IHT and 17.7 months for IHDR. Chi-square analysis showed that IHDR-IHT was more likely to have 3+ high risk characteristics which included minority race, non-cervical GYN histology, stage III+, re-irradiation, or recurrent disease (IHDR-IHT: 16.4%, IHDR: 2.8%, p = 0.041). Addition of IHT was well tolerated with similar rates of grade 2 or higher late toxicity compared to IHDR alone (IHDR-IHT: 14.75%, IHDR: 25%, p = 0.155). On univariate analysis, IHDR-IHT had worse local failure free survival (IHDR-IHT: 75.4%, IHDR: 91.7%, p = 0.047), defined as the time interval between last day of IHDR treatment to date of local recurrence. Cox regression showed that non-cervical GYN histology (HR 9.5 [95% CI = 1.2-78.3] p = 0.036), recurrent disease (HR 6.6 [95% CI = 1.3-33.1] p = 0.023), re-irradiation (HR 9.8 [95% CI = 1.9-50.3] p = 0.006), and minority race (HR 4.3 [95% CI = 0.98-18.9] p = 0.055) were associated with higher cumulative incidence rates for local failure in the IHDR-IHT group. These risk factors did not predict local failure for IHDR alone. Conclusion In this retrospective analysis we were unable to demonstrate an improvement of local failure free survival with the addition of IHT to IHDR. These worse outcomes observed for the IHDR-IHT group are likely due to worse prognostic factors of minority race, non-cervical GYN histology, higher staging, re-irradiation, or recurrent disease. Despite this, long term local control was observed in an otherwise unfavorable patient population, and the addition of IHT showed a similar toxicity profile. Future prospective studies involving a more homogenous GYN cancer population are warranted to clarify which patients benefit most from the addition of IHT to IHDR.

Abstract Introduction: Pancreatic ductal adenocarcinoma remains one of the most lethal forms of cancer with a five-year survival rate of less than 15%. Regardless of surgery eligibility, most patients receive systemic chemo-radiation therapy, which includes FOLFIRINOX or gemcitabine and nab-paclitaxel, often followed by radiation therapy (RT) with or without 5-FU. Unfortunately, patients’ tumors frequently develop resistance to these therapies, and it’s often unclear as to why. One potential source of resistance and recurrence is cancer stem cell (CSC) perseverance following treatment. Purpose: The purpose of this study was to characterize and treat three patient-derived pancreatic tumor organoids (IDs: 8510, 7800, and 11777) with RT and LD50 doses of relevant chemotherapy drugs to evaluate the treatment response. Furthermore, we sought to examine the impact of individual and combination treatments (i.e., chemo-RT) on the population of CSCs in these organoids. Methods: Organoids were cultured in 3D BME gel domes and grown in an NCI-recommended media formulation. Genome sequencing of 505 relevant genes was performed using a PGDx kit. The dose responses of three organoids to radiation (2-12 Gy) and several chemotherapy approaches were determined via MTT assay. CSCs were identified as those cells staining positive for markers SOX2 and OCT4. The population of CSCs before and after chemotherapy, RT, and combined chemo-RT were evaluated with immunofluorescence, western blotting, and flow cytometry. Results: The data revealed a variation in the responses of tumor organoids to treatments, as demonstrated by different LD50 doses. For instance, tumor organoid 8510 exhibited higher tolerance to 5-FU and FOLFIRINOX treatments compared to organoid 7800. Interestingly, organoid 11777 showed resistance to RT, unlike organoids 8510 and 7800. Clinical genomic sequencing revealed that organoid 11777 showed unique variants of several genes known to be involved with DNA repair, including PIM1, RAD54L, and SLX4, as well as mutations in the ARID1b and TGFBR2 genes. The latter two genes may have implications for radiation resistance and could explain the unique resistance of organoid 11777 to RT. Further investigation is warranted. Regarding the population of CSCs, the immunofluorescence data has confirmed the presence of SOX2 and OCT4 in these organoids, and the immunoblot data showed an upregulation of SOX2 and OCT4 in tumor organoids treated with radiation alone. Flow cytometry analysis confirmed that the percentage of CSCs increased following radiation treatment; however, the CSC population was slightly decreased following treatment with FOLFIRINOX and significantly decreased after combination treatment with FOLFIRINOX and RT. Conclusions: Patient-derived pancreatic tumor organoids can be used as a surrogate to provide molecular insights and therapeutic sensitivity profiles in individual patients. Additionally, while the data suggests a link between CSCs and RT resistance, the combination approach results in a more pronounced inhibition of the CSC population. Citation Format: Zachery L Keepers, Sanjit Roy, William Ryan, Binny Bhandary, Narottam Lamichhane, France Carrier, Ramaswamy K Iyer, Jason K Molitoris, William F Regine, Hem D Shukla. Patient-derived pancreatic tumor organoids as a tool to evaluate cancer stem cell populations and their role in therapeutic resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B086.

Background and purposePancreatic cancer (PC) is the fourth leading cause of cancer death in both men and women. The standard of care for patients with locally advanced PC of chemotherapy, stereotactic radiotherapy (RT), or chemo-radiation-therapy has shown highly variable and limited success rates. However, three-dimensional (3D) Pancreatic tumor organoids (PTOs) have shown promise to study tumor response to drugs, and emerging treatments under in vitro conditions. We investigated the potential for using 3D organoids to evaluate the precise radiation and drug dose responses of in vivo PC tumors.MethodsPTOs were created from mouse pancreatic tumor tissues, and their microenvironment was compared to that of in vivo tumors using immunohistochemical and immunofluorescence staining. The organoids and in vivo PC tumors were treated with fractionated X-ray RT, 3-bromopyruvate (3BP) anti-tumor drug, and combination of 3BP + fractionated RT.ResultsPancreatic tumor organoids (PTOs) exhibited a similar fibrotic microenvironment and molecular response (as seen by apoptosis biomarker expression) as in vivo tumors. Untreated tumor organoids and in vivo tumor both exhibited proliferative growth of 6 folds the original size after 10 days, whereas no growth was seen for organoids and in vivo tumors treated with 8 (Gray) Gy of fractionated RT. Tumor organoids showed reduced growth rates of 3.2x and 1.8x when treated with 4 and 6 Gy fractionated RT, respectively. Interestingly, combination of 100 µM of 3BP + 4 Gy of RT showed pronounced growth inhibition as compared to 3-BP alone or 4 Gy of radiation alone. Further, positive identification of SOX2, SOX10 and TGFβ indicated presence of cancer stem cells in tumor organoids which might have some role in resistance to therapies in pancreatic cancer.ConclusionsPTOs produced a similar microenvironment and exhibited similar growth characteristics as in vivo tumors following treatment, indicating their potential for predicting in vivo tumor sensitivity and response to RT and combined chemo-RT treatments.

PTOs produced a similar microenvironment and exhibited similar growth characteristics as in vivo tumors following treatment, indicating their potential for predicting in vivo tumor sensitivity and response to RT and combined chemo-RT treatments. Cancer stem cells in pancreatic cancer could be playing a role in resistance to therapies and recurrence in pancreatic cancer.

Primary radiation therapy using interstitial brachytherapy (IBT) provides excellent local tumor control for early-stage squamous cell carcinoma of the lip. Technical aspects of treatment are important to optimize outcomes. In this report, we discuss patient selection criteria, procedural details, and dosimetric considerations for performing IBT for cancers of the lip. Catheters are inserted across the length of tumor entering and exiting approximately 5 mm beyond the palpable tumor extent. A custom mouthpiece is fabricated to facilitate normal tissue sparing. Patients undergo computed tomography imaging, the gross tumor volume is contoured based on physical examination and computed tomography findings, and an individualized brachytherapy plan is generated with the goals of achieving gross tumor volume D90% ≥ 90% and minimizing V150%. Ten patients with primary (n = 8) or recurrent (n = 2) cancers of the lip who received high-dose-rate lip IBT using 2.0- to 2.5-week treatment regimens are described (median prescription: 47.6 Gy in 14 fractions of 3.4 Gy). Local tumor control was 100%. There were no cases of acute grade ≥4 or late grade ≥2 toxicity, and cosmesis scores were graded as good to excellent in all patients. IBT represents an excellent treatment option for patients with lip squamous cell carcinoma. With careful attention to technical considerations furthered described in the present report, high rates of tumor control, low rates of toxicity, and favorable esthetic and functional outcomes can be achieved with IBT for lip cancer.

Purpose Optimal placement and correct reconstruction of needles are paramount in achieving high treatment efficacy in interstitial high dose rate (HDR) brachytherapy. Nonetheless, abutting needles are sometimes observed in challenging cases, posing a potential risk for false needle reconstruction and thus error-prone dose calculation. This study aims to investigate the dosimetric impact of false reconstruction of abutting needles. Materials and Methods Syed HDR cases (n=72) were investigated. Needle reconstruction as well as clinical plan optimization was done in Oncentra® Brachy. A Matlab-based script was generated to detect abutting needles if their closest distance was smaller than 1.5 times the pixel size in the axial plane. A simulated plan was created simulating false reconstruction of the abutting needle pair with the smallest distance, by switching the needle segments superior to the abutting point location after which the dwell points in the clinical plan were replaced based on the simulated needle tips. Dose calculation for the clinical and simulated plans were conducted using a validated Matlab-based dose engine. Changes in dose volume histogram (DVH) metrics, including the high-risk clinical target volume (HRCTV) D90%, V90%, D100%, V100%, V150%, as well as bladder and rectum D2cc, were compared. Results Abutting needles were detected in 19 out of the 72 (26.4%) investigated cases. Compared to the clinical plans, the simulated plans showed negligible (<±1%) dosimetric changes in 14 cases, whereas significant (>±5%) changes in at least one DVH metric in the other 5 cases. Among all 19 cases, a wide range of DVH changes (%) were observed in HRCTV: V100% (-1.7 [-23.1 1.3]), V90% (-1.5 [-17.6 0.3]), D100% (-3.6 [-40.1 0.7]), D90% (-1.2 [-17.5 13.4]), V150% (-1.1 [-30.9 19.9]). The D2cc of bladder (-1.7 [-23.1 1.3]) and rectum (0.5 [-6.8 10.1]) showed similar changes. Conclusions False reconstruction of abutting needles may lead to significant dose changes to targets and sensitive organs. In case of uncertainty in needle reconstruction, strategies such as light loading of the needle pair and avoiding distinct loading patterns between them may be employed to minimize potential dosimetric errors. Optimal placement and correct reconstruction of needles are paramount in achieving high treatment efficacy in interstitial high dose rate (HDR) brachytherapy. Nonetheless, abutting needles are sometimes observed in challenging cases, posing a potential risk for false needle reconstruction and thus error-prone dose calculation. This study aims to investigate the dosimetric impact of false reconstruction of abutting needles. Syed HDR cases (n=72) were investigated. Needle reconstruction as well as clinical plan optimization was done in Oncentra® Brachy. A Matlab-based script was generated to detect abutting needles if their closest distance was smaller than 1.5 times the pixel size in the axial plane. A simulated plan was created simulating false reconstruction of the abutting needle pair with the smallest distance, by switching the needle segments superior to the abutting point location after which the dwell points in the clinical plan were replaced based on the simulated needle tips. Dose calculation for the clinical and simulated plans were conducted using a validated Matlab-based dose engine. Changes in dose volume histogram (DVH) metrics, including the high-risk clinical target volume (HRCTV) D90%, V90%, D100%, V100%, V150%, as well as bladder and rectum D2cc, were compared. Abutting needles were detected in 19 out of the 72 (26.4%) investigated cases. Compared to the clinical plans, the simulated plans showed negligible (<±1%) dosimetric changes in 14 cases, whereas significant (>±5%) changes in at least one DVH metric in the other 5 cases. Among all 19 cases, a wide range of DVH changes (%) were observed in HRCTV: V100% (-1.7 [-23.1 1.3]), V90% (-1.5 [-17.6 0.3]), D100% (-3.6 [-40.1 0.7]), D90% (-1.2 [-17.5 13.4]), V150% (-1.1 [-30.9 19.9]). The D2cc of bladder (-1.7 [-23.1 1.3]) and rectum (0.5 [-6.8 10.1]) showed similar changes. False reconstruction of abutting needles may lead to significant dose changes to targets and sensitive organs. In case of uncertainty in needle reconstruction, strategies such as light loading of the needle pair and avoiding distinct loading patterns between them may be employed to minimize potential dosimetric errors.

Purpose The American Association of Physicists in Medicine Radiation Oncology Medical Physics Education Subcommittee (ROMPES) has updated the radiation oncology physics core curriculum for medical residents in the radiation oncology specialty. Methods and Materials Thirteen physicists from the United States and Canada involved in radiation oncology resident education were recruited to ROMPES. The group included doctorates and master's of physicists with a range of clinical or academic roles. Radiation oncology physician and resident representatives were also consulted in the development of this curriculum. In addition to modernizing the material to include new technology, the updated curriculum is consistent with the format of the American Board of Radiology Physics Study Guide Working Group to promote concordance between current resident educational guidelines and examination preparation guidelines. Results The revised core curriculum recommends 56 hours of didactic education like the 2015 curriculum but was restructured to provide resident education that facilitates best clinical practice and scientific advancement in radiation oncology. The reference list, glossary, and practical modules were reviewed and updated to include recent literature and clinical practice examples. Conclusions ROMPES has updated the core physics curriculum for radiation oncology residents. In addition to providing a comprehensive curriculum to promote best practice for radiation oncology practitioners, the updated curriculum aligns with recommendations from the American Board of Radiology Physics Study Guide Working Group. New technology has been integrated into the curriculum. The updated curriculum provides a framework to appropriately cover the educational topics for radiation oncology residents in preparation for their subsequent career development.

Abstract Pancreatic cancer has a five-year survival rate of only 10%, mostly due to late diagnosis and limited treatment options. One of the standard treatments is chemo-radiation therapy that involves gemcitabine or FOLFIRINOX, a combination of leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin, combined fractionated radiation therapy (RT). However, chemo-radiation therapy has shown limited success because patients develop resistance to chemotherapy and/or radiation. In this study, we evaluated the role of pancreatic cancer stem cells (CSC) markers OCT-4 and SOX2 in mouse pancreatic tumor organoids. We treated pancreatic tumor organoids with 4 or 8 Gy of radiation, 10 μM of 5-FU (5-Fluotrouracil), and 100 μM 3-Bromopyruvate (3BP), a promising anti-cancer drug, as single treatment modalities, and in combination with RT. Our results showed significant upregulation of, OCT-4, and SOX2 expression in pancreatic tumor organoids treated with 4 and 8 Gy of radiation, and 5-FU. The expression of these CSC markers with increasing treatment dose exhibited elevated upregulation levels to radiation and 5-FU chemotherapy drugs. Conversely, when tumor organoids were treated with a combination of 5-FU and radiation, there was a significant inhibition in SOX2 and OCT-4 expression, indicating inhibition in CSC self-renewal. Noticeably, we also observed that human pancreatic tumor tissues exhibited heterogeneous and aberrant expression of OCT-4 and SOX2 CSCs markers as compared to normal pancreas, indicating their aberrant regulation in PC and their role in pancreatic cancer. In addition, the combination of 5-FU and radiation treatment exhibited significant inhibition of the β-catenin pathway in pancreatic tumor organoids, resulting in sensitization to treatment and organoid death. In conclusion, our study highlights the essential role of CSCs in therapeutic resistance in PC treatment. We recommend using tumor organoids as a model system to further explore the impact of CSCs in PC and identify new therapeutic targets.

Purpose Radiosensitization with external hyperthermia (HT) has demonstrated improved oncologic outcomes for patients with gynecological (GYN) malignancies. However, similar data for multicatheter interstitial HT (IHT) with interstitial high-dose rate (IHDR) brachytherapy is limited. We present a single-institution experience of patients with GYN cancers treated using IHDR with and without concurrent IHT (IHDR-IHT). Materials and Methods We retrospectively analyzed 63 patients with locally advanced GYN malignancies treated with IHDR using a Syed-Neblett template (IHDR: 29 and IHDR-IHT: 34 patients). Primary indication for adding IHT was bulky, residual or recurrent disease guided by number, location and geometry of needle placement within HRCTV to allow placement of IHT antennae and thermistors. IHT (target temperature 40-44°C) was performed after IHDR treatment using the same set of interstitial catheters. The median age was 60 yrs (27- 89). Primary sites included cervical (n=40), endometrial (n=9), vaginal (n=10), vulvar (n=3), and non-GYN malignancy with vaginal invasion (n=1). Pelvic radiation therapy was performed prior to IHDR in all but one patient with median dose of 45 Gy (Range, 30.6-55.0 Gy) and 52 patients received concurrent chemotherapy. Median IHDR dose was 23.75 Gy (10-30.0) and number of fractions was 5 (2-5). IHDR and IHDR-IHT groups had similar proportion of reirradiation (p=0.55), stage ≥ III (p=0.11) and HRCTV volume (p=0.65) with marginally higher recurrent cases in the IHDR cohort (p=0.07). Median D90 HRCTV EQD2 was higher in IHDR-IHT (78.2 Gy; 14-105) vs IHDR group (75.9 Gy; range 61-86); p = 0.005. Respective median HRCTV volume were 61.3 cc (25-376) and 48.6 cc (12-175); p = 0.21. Chi -square and Mann-Whitney tests were done to compare variables between the two cohorts. The Kaplan-Meier method with Cox Regression was used to estimate overall survival (OS), local control (LC), locoregional control (LRC) and distant control (DC) and evaluate predictors of LC. Results IHDR-IHT and IHDR were well tolerated with no acute procedure-related adverse events. With a median follow up of 12.1 months (<1-59) in IHDR group and 11.0 months (1-76), 1 IHDR-HT patient developed acute CTCAE grade 3+ toxicity (grade 3 urinary obstruction in a patient with horseshoe kidney). Late Grade 3+ toxicity was seen in 9 patients (IHDR: 5, IHDR-IHT: 4 patients); ureteral stricture/incontinence (4), fistula (3) and radiation proctitis (2). Median OS was 31 versus 42 months (p=0.55) in the IHDR and IHDR-IHT groups, respectively. 1 yr LC for IHDR vs IHDR-IHT of 86.9% vs 77.8% (p=0.051). Corresponding, 1-yr LRC and DC were 82.5 vs 74.8% (p=0.056) and 81 vs 77.6% (p=0.84), respectively. On cox regression undergoing IHT (HR 4.7 [95% CI 1.3-16.9] p=0.02) was associated with worse local control. Conclusions To our knowledge, this is the largest report describing outcomes from the addition of IHT to IHDR in patients with locally advanced GYN malignancies. Use of IHT had excellent tolerance without any procedural complications. With possible group imbalances, trend to shorter LC and LRC was seen in IHT. Prospective controlled studies will be needed to evaluate clinical benefits.