Rational Design of a Circularly Permuted Flavin-Based Fluorescent Protein.

Flavin-based fluorescent proteins are oxygen-independent reporters that hold great promise for imaging anaerobic and hypoxic biological systems. In this study, we explored the feasibility of applying circular permutation, a valuable method for the creation of fluorescent sensors, to flavin-based fluorescent proteins. We used rational design and structural data to identify a suitable location for circular permutation in iLOV, a flavin-based reporter derived from A. thaliana. However, relocating the N- and C-termini to this position resulted in a significant reduction in fluorescence. This loss of fluorescence was reversible, however, by fusing dimerizing coiled coils at the new N- and C-termini to compensate for the increase in local chain entropy. Additionally, by inserting protease cleavage sites in circularly permuted iLOV, we developed two protease sensors and demonstrated their application in mammalian cells. In summary, our work establishes the first approach to engineer circularly permuted FbFPs optimized for high fluorescence and further showcases the utility of circularly permuted FbFPs to serve as a scaffold for sensor engineering.

Validation of large language models for detecting pathologic complete response in breast cancer using population-based pathology reports.

AIMS: The primary goal of this study is to evaluate the capabilities of Large Language Models (LLMs) in understanding and processing complex medical documentation. We chose to focus on the identification of pathologic complete response (pCR) in narrative pathology reports. This approach aims to contribute to the advancement of comprehensive reporting, health research, and public health surveillance, thereby enhancing patient care and breast cancer management strategies. METHODS: The study utilized two analytical pipelines, developed with open-source LLMs within the healthcare system's computing environment. First, we extracted embeddings from pathology reports using 15 different transformer-based models and then employed logistic regression on these embeddings to classify the presence or absence of pCR. Secondly, we fine-tuned the Generative Pre-trained Transformer-2 (GPT-2) model by attaching a simple feed-forward neural network (FFNN) layer to improve the detection performance of pCR from pathology reports. RESULTS: In a cohort of 351 female breast cancer patients who underwent neoadjuvant chemotherapy (NAC) and subsequent surgery between 2010 and 2017 in Calgary, the optimized method displayed a sensitivity of 95.3% (95%CI: 84.0-100.0%), a positive predictive value of 90.9% (95%CI: 76.5-100.0%), and an F1 score of 93.0% (95%CI: 83.7-100.0%). The results, achieved through diverse LLM integration, surpassed traditional machine learning models, underscoring the potential of LLMs in clinical pathology information extraction. CONCLUSIONS: The study successfully demonstrates the efficacy of LLMs in interpreting and processing digital pathology data, particularly for determining pCR in breast cancer patients post-NAC. The superior performance of LLM-based pipelines over traditional models highlights their significant potential in extracting and analyzing key clinical data from narrative reports. While promising, these findings highlight the need for future external validation to confirm the reliability and broader applicability of these methods.

Association of Apparent Diffusion Coefficient with Disease Recurrence in Patients with Locally Advanced Cervical Cancer Treated with Radical Chemotherapy and Radiation Therapy.

PURPOSE: To investigate whether volumetrically derived apparent diffusion coefficient (ADC) from pretreatment diffusion-weighted (DW) magnetic resonance (MR) imaging is associated with disease recurrence in women with locally advanced cervical cancer treated with chemotherapy and radiation therapy. MATERIALS AND METHODS: An ethics board-approved, retrospective study was conducted in 85 women with stage IB-IVA cervical cancer treated with chemo- and radiation therapy in 2009-2013. All patients underwent MR imaging for staging, including T2-weighted and DW MR imaging series, by using a 1.5- or 3.0-T imager. The mean, median, 75th, 90th, and 95th percentile ADCs (ADCmean, ADC50, ADC75, ADC90, and ADC95, respectively) of all voxels that comprised each tumor were extracted and normalized to the mean urine ADC (nADCmean, nADC50, nADC75, nADC90, and nADC95, respectively) to reduce variability. The primary outcome was disease-free survival (DFS). Uni- and multivariable Cox regression analyses were used to evaluate the association of ADC parameters and relevant clinical variables with DFS. RESULTS: Of the 85 women included, 62 were free of disease at last follow-up. Median follow-up was 37 months (range, 5-68 months). Significant variables at univariable analysis included T2-weighted derived tumor diameter, para-aortic nodal involvement, advanced stage, ADC90 and ADC95, nADC75, nADC90, and nADC95. Normalized parameters were more highly associated (hazard ratio per 0.01 increase in normalized ADC, 0.91-0.94; P < .04). Because nADC75, nADC90, and nADC95 were highly correlated, only nADC95 (which had the lowest P value) was included in multivariable analysis. At multivariable analysis, absolute and normalized ADC95 remained associated with DFS (hazard ratio, 0.90-0.98; P < .05). CONCLUSION: The volumetric ADC95 may be a useful imaging metric to predict treatment failure in patients with locally advanced cervical cancer treated with chemo- and radiation therapy.

Comparing dosimetry of locally advanced cervical cancer patients treated with 3 versus 4 fractions of MRI-guided brachytherapy.

PURPOSE: To demonstrate the feasibility of treating cervical cancer patients with MRI-guided brachytherapy (MRgBT) using 24 Gy in 3 fractions (F) versus a standard, more resource-intensive regimen of 28 Gy in 4F, and its ability to meet EMBRACE II planning aims. METHODS AND MATERIALS: A retrospective review of 224 patients with FIGO Stage IB-IVA cervical cancer treated with 28 Gy/4F (n = 91) and 24 Gy/3F (n = 133) MRgBT between 2016-2021 was conducted. Multivariable linear regression models were fitted to compare dosimetric parameters between the two groups, adjusting for CTVHR and T stage. RESULTS: Most patients had squamous cell carcinoma, T2b disease, and were treated with intracavitary applicator plus interstitial needles (96%). The 28 Gy/4F group had higher CTVHR (median 28 vs. 26 cm3, p = 0.04), CTVIR D98% (mean 65.5 vs. 64.5 Gy, p = 0.03), rectum D2cm3 (mean 61.7 vs. 59.2 Gy, p = 0.04) and bladder D2cm3 (81.3 vs. 77.9 Gy, p = 0.03). There were no significant differences in the proportion of patients meeting the EMBRACE II OAR dose constraints and planning aims, except fewer patients treated with 28 Gy/4F met rectum D2cm3 < 65 Gy (73 vs. 85%, p = 0.027) and ICRU rectovaginal point < 65 Gy (65 vs. 84%, p = 0.005). CONCLUSIONS: Cervical cancer patients treated with 24 Gy/3F MRgBT had comparable target doses and lower OAR doses compared to those treated with 28 Gy/4F. A less-resource intense fractionation schedule of 24 Gy/3F is an alternative to 28 Gy/4F in cervix MRgBT.

Auto-segmentation of normal and target structures in head and neck CT images: a feature-driven model-based approach.

PURPOSE: Intensity modulated radiation therapy (IMRT) allows greater control over dose distribution, which leads to a decrease in radiation related toxicity. IMRT, however, requires precise and accurate delineation of the organs at risk and target volumes. Manual delineation is tedious and suffers from both interobserver and intraobserver variability. State of the art auto-segmentation methods are either atlas-based, model-based or hybrid however, robust fully automated segmentation is often difficult due to the insufficient discriminative information provided by standard medical imaging modalities for certain tissue types. In this paper, the authors present a fully automated hybrid approach which combines deformable registration with the model-based approach to accurately segment normal and target tissues from head and neck CT images. METHODS: The segmentation process starts by using an average atlas to reliably identify salient landmarks in the patient image. The relationship between these landmarks and the reference dataset serves to guide a deformable registration algorithm, which allows for a close initialization of a set of organ-specific deformable models in the patient image, ensuring their robust adaptation to the boundaries of the structures. Finally, the models are automatically fine adjusted by our boundary refinement approach which attempts to model the uncertainty in model adaptation using a probabilistic mask. This uncertainty is subsequently resolved by voxel classification based on local low-level organ-specific features. RESULTS: To quantitatively evaluate the method, they auto-segment several organs at risk and target tissues from 10 head and neck CT images. They compare the segmentations to the manual delineations outlined by the expert. The evaluation is carried out by estimating two common quantitative measures on 10 datasets: volume overlap fraction or the Dice similarity coefficient (DSC), and a geometrical metric, the median symmetric Hausdorff distance (HD), which is evaluated slice-wise. They achieve an average overlap of 93% for the mandible, 91% for the brainstem, 83% for the parotids, 83% for the submandibular glands, and 74% for the lymph node levels. CONCLUSIONS: Our automated segmentation framework is able to segment anatomy in the head and neck region with high accuracy within a clinically-acceptable segmentation time.

Virtual Reality for Evaluating Prosthetic Hand Control Strategies: A Preliminary Report.

Improving prosthetic hand functionality is critical in reducing abandonment rates and improving the amputee's quality of life. Techniques such as joint force estimation and gesture recognition using myoelectric signals could enable more realistic control of the prosthetic hand. To accelerate the translation of these advanced control strategies from lab to clinic, We created a virtual prosthetic control environment that enables rich user interactions and dexterity evaluation. The virtual environment is made of two parts, namely the Unity scene for rendering and user interaction, and a Python back-end to support accurate physics simulation and communication with control algorithms. By utilizing the built-in tracking capabilities of a virtual reality headset, the user can visualize and manipulate a virtual hand without additional motion tracking setups. In the virtual environment, we demonstrate actuation of the prosthetic hand through decoded EMG signal streaming, hand tracking, and the use of a VR controller. By providing a flexible platform to investigate different control modalities, we believe that our virtual environment will allow for faster experimentation and further progress in clinical translation.

Repeatability and reproducibility of MRI-based radiomic features in cervical cancer.

PURPOSE: The aims of this study are to evaluate the stability of radiomic features from T2-weighted MRI of cervical cancer in three ways: (1) repeatability via test-retest; (2) reproducibility between diagnostic MRI and simulation MRI; (3) reproducibility in inter-observer setting. MATERIALS AND METHODS: This retrospective cohort study included FIGO stage IB-IVA cervical cancer patients treated with chemoradiation between 2005 and 2014. There were three cohorts of women corresponding to each aim of the study: (1) 8 women who underwent test-retest MRI; (2) 20 women who underwent MRI on different scanners (diagnostic and simulation MRI); (3) 34 women whose diagnostic MRIs were contoured by three observers. Radiomic features based on first-order statistics, shape features and texture features were extracted from the original, Laplacian of Gaussian (LoG)-filtered and wavelet-filtered images, for a total of 1761 features. Stability of radiomic features was assessed using intraclass correlation coefficient (ICC). RESULTS: The inter-observer cohort had the most reproducible features (95.2% with ICC ≥0.75) whereas the diagnostic-simulation cohort had the fewest (14.1% with ICC ≥0.75). Overall, 229 features had ICC ≥0.75 in all three tests. Shape features emerged as the most stable features in all cohorts. CONCLUSION: The diagnostic-simulation test resulted in the fewest reproducible features. Further research in MRI-based radiomics is required to validate the use of reproducible features in prognostic models.

Patient-reported sexual adjustment after definitive chemoradiation and MR-guided brachytherapy for cervical cancer.

PURPOSE: The treatment of locally advanced cervical cancer with definitive chemoradiation (CRT) is associated with vaginal toxicity and altered sexual satisfaction. This prospective study assessed patient-reported sexual adjustment, vaginal dosimetry, and physician-reported vaginal toxicity in patients with cervical cancer treated with CRT and MR-guided brachytherapy (BT). MATERIALS AND METHODS: Between 2008 and 2010, International Federation of Gynecologists and Obstetricians stage IB-IVA patients with cervical cancer receiving definitive CRT were enrolled in a feasibility study assessing MR-guided BT. Patients completed the validated sexual adjustment questionnaire (SAQ) before BT (baseline) and during followup. Physician-reported vaginal toxicity was recorded. The International Commission on Radiation Units and Measurements rectovaginal point, mean vaginal dose, and D2cm3 were calculated. Mean SAQ scores at baseline and followup assessments were calculated. Mean time effects were estimated using a linear mixed-effects model. A multivariable linear mixed-effects model was used to examine the association between total and individual scores (repeated measures) and covariates. RESULTS: Sixty patients were approached to participate: 29 consented and 27 completed the SAQ at baseline and followup. The diagnosis of cervical cancer and treatment negatively impacted sexual relationships in 61% and 39%, respectively. There were no significant changes in sexual adjustment over time (p = 0.599). There were no associations between sexual adjustment and the International Commission on Radiation Units and Measurements rectovaginal point dose or clinical vaginal involvement. Patients with higher International Federation of Gynecologists and Obstetricians stages (≥IIB) had significantly worse sexual adjustment (p = 0.005). CONCLUSION: CRT and MR-guided BT negatively impacted sexual relationships in patients with cervix cancer; however, there were no significant longitudinal changes in patient-reported sexual adjustment. Worse sexual adjustment may be associated with more advanced disease presentations.

Measurement of Tumor Hypoxia in Patients With Locally Advanced Cervical Cancer Using Positron Emission Tomography with 18F-Fluoroazomyin Arabinoside.

PURPOSE: To assess cervical tumor hypoxia using the hypoxia tracer 18F-fluoroazomycin arabinoside (18F-FAZA) and compare different reference tissues and thresholds for quantifying tumor hypoxia. METHODS AND MATERIALS: Twenty-seven patients with cervical cancer were studied prospectively by positron emission tomography (PET) imaging with 18F-FAZA before starting standard chemoradiation. The hypoxic volume was defined as all voxels within a tumor (T) with standardized uptake values (SUVs) greater than 3 standard deviations from the mean gluteus maximus muscle SUV value (M) or SUVs greater than 1 to 1.4 times the mean SUV value of the left ventricle, a blood (B) surrogate. The hypoxic fraction was defined as the ratio of the number of hypoxic voxels to the total number of tumor voxels. RESULTS: A 18F-FAZA-PET hypoxic volume could be identified in the majority of cervical tumors (89% when using T/M or T/B > 1.2 as threshold) on the 2-hour static scan. The hypoxic fraction ranged from 0% to 99% (median 31%) when defined using the T/M threshold and from 0% to 78% (median 32%) with the T/B > 1.2 threshold. Hypoxic volumes derived from the different thresholds were highly correlated (Spearman's correlation coefficient ρ between T/M and T/B > 1-1.4 were 0.82-0.91), as were hypoxic fractions (0.75-0.85). Compartmental analysis of the dynamic scans showed k3, the FAZA accumulation constant, to be strongly correlated with hypoxic fraction defined using the T/M (Spearman's ρ=0.72) and T/B > 1.2 thresholds (0.76). CONCLUSIONS: Hypoxia was detected in the majority of cervical tumors on 18F-FAZA-PET imaging. The extent of hypoxia varied markedly between tumors but not significantly with different reference tissues/thresholds.

Comparison of dosimetric parameters derived from whole organ and wall contours for bladder and rectum in cervical cancer patients treated with intracavitary and interstitial brachytherapy.

For volumes up to 2 cm3 of the bladder and possibly up to 5 cm3 of the rectum, doses computed from the whole organ were good estimates of the doses in the wall in cervix brachytherapy, and there were no significant differences between patients treated with or without interstitial needles.

Technique adaptation, strategic replanning, and team learning during implementation of MR-guided brachytherapy for cervical cancer.

PURPOSE: MR-guided brachytherapy (MRgBT) with interstitial needles is associated with improved outcomes in cervical cancer patients. However, there are implementation barriers, including magnetic resonance (MR) access, practitioner familiarity/comfort, and efficiency. This study explores a graded MRgBT implementation strategy that included the adaptive use of needles, strategic use of MR imaging/planning, and team learning. METHODS AND MATERIALS: Twenty patients with cervical cancer were treated with high-dose-rate MRgBT (28 Gy in four fractions, two insertions, daily MR imaging/planning). A tandem/ring applicator alone was used for the first insertion in most patients. Needles were added for the second insertion based on evaluation of the initial dosimetry. An interdisciplinary expert team reviewed and discussed the MR images and treatment plans. RESULTS: Dosimetry-trigger technique adaptation with the addition of needles for the second insertion improved target coverage in all patients with suboptimal dosimetry initially without compromising organ-at-risk (OAR) sparing. Target and OAR planning objectives were achieved in most patients. There were small or no systematic differences in tumor or OAR dosimetry between imaging/planning once per insertion vs. daily and only small random variations. Peer review and discussion of images, contours, and plans promoted learning and process development. CONCLUSIONS: Technique adaptation based on the initial dosimetry is an efficient approach to implementing MRgBT while gaining comfort with the use of needles. MR imaging and planning once per insertion is safe in most patients as long as applicator shifts, and large anatomical changes are excluded. Team learning is essential to building individual and programmatic competencies.

Intermediate dose-volume parameters and the development of late rectal toxicity after MRI-guided brachytherapy for locally advanced cervix cancer.

PURPOSE: The dose delivered to the most exposed 2 cm3 [Formula: see text] of the rectum and bladder is predictive of late rectal and bladder toxicity in cervix cancer patients. We investigated the predictive value of intermediate doses to the rectum and bladder for late rectal/bladder toxicity after MRI-guided brachytherapy for patients with locally advanced cervix cancer. METHODS AND MATERIALS: Toxicity was prospectively graded using Common Toxicity Criteria for Adverse Events v4.0 and retrospectively verified for women with Stage IB-IVA cervix cancer treated consecutively with MRI-guided brachytherapy between 2008 and 2013. The minimum equivalent dose in 2 Gy fractions delivered to 0.1, 1, 2, 5, and 10 cm3 of the rectum and bladder and the absolute volume of the rectum receiving 55, 60, 65, 70, and 75 Gy3 (V55-75) were collected. The association between dose-volume parameters and Grade 2+ rectal/bladder toxicity was examined using logistic regression. RESULTS: With a median followup of 44 months, cumulative incidences of Grade 2+ rectal and bladder toxicity among the 106 patients were 29% and 15% at 3 years, respectively. All the dose-volume parameters were significantly associated with late Grade 2+ rectal and bladder toxicity (p < 0.05), except for bladder [Formula: see text] . On multivariable logistic regression, both [Formula: see text]  > 70 Gy3 and V55 > 11 cm3 (p < 0.05) were predictive of late Grade 2+ rectal toxicity, with improved model fitting and higher area under the curve compared with the model with [Formula: see text]  > 70 Gy3 alone. CONCLUSIONS: In this study, V55 was predictive of late Grade 2+ rectal toxicity. Adding V55 to  [Formula: see text] improved prediction accuracy.

Automated Delineation of the Normal Urinary Bladder on Planning CT and Cone Beam CT.

PURPOSE: To quantify the volumetric effect of delineation variability when using manual versus semiautomated tools to contour the normal bladder on planning computed tomography (CT) and cone beam CT. METHODS: Following research ethics board approval, 10 prostate cancer patients were selected. For each patient, one pretreatment cone beam CT (CBCT) was randomly selected from the first treatment week and registered to the planning CT (planCT). Model-based auto adaptation was used to delineate the outer bladder (OB) surface for the planCT. That contour was then propagated and manually adapted onto the CBCT. A second observer delineated OB for the planCT and CBCT using typical manual methods. These delineation procedures were repeated four times on each image set, with observers blinded to the previous contours. Metrics of volumetric, geometric, and overlap concordance were used to compare the manual and automated OB contours. RESULTS: The mean pairwise difference between the manual and model-based planCT volumes was 4 cm3 (2%), and the model-based contours exhibited approximately half the observer variation of the manual ones (3 cm3, 2%). The mean of pairwise differences between the manual and propagated CBCT volumes was 13 cm3 (8%), but the propagated contours exhibited approximately half the observer related volume variation (11 cm3, 6%). Small CBCT bladder volumes displayed larger observer variation with manual methods (r2, -0.640). Variability between the automated contours was significantly smaller than for the corresponding manual observations (P = .004 and .002, respectively). Metrics of three-dimensional overlap concordance indicated excellent agreement within and between the delineation methods. Automated CBCT contours were significantly smoother than the manual ones (surface sphericity index, 1.29 vs. 1.35; P = .03). CONCLUSIONS: Volumetric, geometric, and overlap metrics all indicated that planCT and CBCT automated OB contours fell within the range of manually delineated contours. The CBCT propagated contours were significantly smoother and associated with smaller intraobserver variability, compared with manual contours. Importantly, the findings from this research suggest that contour propagation may be more robust than manual delineation, especially in the presence of poor image quality.

A prospective study of DWI, DCE-MRI and FDG PET imaging for target delineation in brachytherapy for cervical cancer.

BACKGROUND AND PURPOSE: We examined the utility of dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted MRI (DWI), and FDG-PET imaging for brachytherapy target delineation in patients with locally advanced cervical cancer. MATERIALS AND METHODS: Twenty-two patients had DWI, DCE-MRI, and FDG-PET/CT scans after brachytherapy applicator insertion, in addition to standard T2-weighted (T2w) 3T MRI. Gross tumor volume (GTVB) and high-risk clinical target volume (HRCTV) were contoured first on T2w images, and then modified if indicated upon review of DWI/DCE-MRI/FDG-PET images by two observers. The primary endpoint was utility, determined by the number of patients whose volumes were modified, and interobserver variability. RESULTS: Eleven patients' T2w-GTVB were modified based on DWI/DCE-MRI/FDG-PET by observer 1, due to clearer demarcation (7) and residual disease not well visualized on T2w MRI (4). GTVB was modified in 17 patients by observer 2 (11 and 6, respectively). Incorporation of functional imaging improved the conformity index (CI) for GTVB from 0.54 (T2w alone) to 0.65 (P=0.003). HRCTV was modified in 3 and 8 patients by observers 1 and 2, respectively, with a trend toward higher CI using functional imaging (0.71 to 0.76, P=0.06). CONCLUSIONS: DWI/DCE-MRI/FDG-PET imaging as a supplement to T2w MRI decreased interobserver variability in GTVB delineation.

Hybrid adaptive radiotherapy with on-line MRI in cervix cancer IMRT.

PURPOSE: Substantial organ motion and tumor shrinkage occur during radiotherapy for cervix cancer. IMRT planning studies have shown that the quality of radiation delivery is influenced by these anatomical changes, therefore the adaptation of treatment plans may be warranted. Image guidance with off-line replanning, i.e. hybrid-adaptation, is recognized as one of the most practical adaptation strategies. In this study, we investigated the effects of soft tissue image guidance using on-line MR while varying the frequency of off-line replanning on the adaptation of cervix IMRT. MATERIALS AND METHOD: 33 cervical cancer patients underwent planning and weekly pelvic MRI scans during radiotherapy. 5 patients of 33 were identified in a previous retrospective adaptive planning study, in which the coverage of gross tumor volume/clinical target volume (GTV/CTV) was not acceptable given single off-line IMRT replan using a 3mm PTV margin with bone matching. These 5 patients and a randomly selected 10 patients from the remaining 28 patients, a total of 15 patients of 33, were considered in this study. Two matching methods for image guidance (bone to bone and soft tissue to dose matrix) and three frequencies of off-line replanning (none, single, and weekly) were simulated and compared with respect to target coverage (cervix, GTV, lower uterus, parametrium, upper vagina, tumor related CTV and elective lymph node CTV) and OAR sparing (bladder, bowel, rectum, and sigmoid). Cost (total process time) and benefit (target coverage) were analyzed for comparison. RESULTS: Hybrid adaptation (image guidance with off-line replanning) significantly enhanced target coverage for both 5 difficult and 10 standard cases. Concerning image guidance, bone matching was short of delivering enough doses for 5 difficult cases even with a weekly off-line replan. Soft tissue image guidance proved successful for all cases except one when single or more frequent replans were utilized in the difficult cases. Cost and benefit analysis preferred (soft tissue) image guidance over (frequent) off-line replanning. CONCLUSIONS: On-line MRI based image guidance (with combination of dose distribution) is a crucial element for a successful hybrid adaptive radiotherapy. Frequent off-line replanning adjuvantly enhances adaptation quality.

Dosimetrically triggered adaptive intensity modulated radiation therapy for cervical cancer.

PURPOSE: The widespread use of intensity modulated radiation therapy (IMRT) for cervical cancer has been limited by internal target and normal tissue motion. Such motion increases the risk of underdosing the target, especially as planning margins are reduced in an effort to reduce toxicity. This study explored 2 adaptive strategies to mitigate this risk and proposes a new, automated method that minimizes replanning workload. METHODS AND MATERIALS: Thirty patients with cervical cancer participated in a prospective clinical study and underwent pretreatment and weekly magnetic resonance (MR) scans over a 5-week course of daily external beam radiation therapy. Target volumes and organs at risk (OARs) were contoured on each of the scans. Deformable image registration was used to model the accumulated dose (the real dose delivered to the target and OARs) for 2 adaptive replanning scenarios that assumed a very small PTV margin of only 3 mm to account for setup and internal interfractional motion: (1) a preprogrammed, anatomy-driven midtreatment replan (A-IMRT); and (2) a dosimetry-triggered replan driven by target dose accumulation over time (D-IMRT). RESULTS: Across all 30 patients, clinically relevant target dose thresholds failed for 8 patients (27%) if 3-mm margins were used without replanning. A-IMRT failed in only 3 patients and also yielded an additional small reduction in OAR doses at the cost of 30 replans. D-IMRT assured adequate target coverage in all patients, with only 23 replans in 16 patients. CONCLUSIONS: A novel, dosimetry-triggered adaptive IMRT strategy for patients with cervical cancer can minimize the risk of target underdosing in the setting of very small margins and substantial interfractional motion while minimizing programmatic workload and cost.

Tumor and normal tissue dosimetry changes during MR-guided pulsed-dose-rate (PDR) brachytherapy for cervical cancer.

BACKGROUND AND PURPOSE: To analyze systematic changes in tumor and normal tissue anatomy and dosimetry using serial MR imaging during pulsed dose rate brachytherapy (PDR BT) for cervical cancer. MATERIAL AND METHODS: Forty-three patients with cervical cancer underwent MR-guided PDR BT using an intrauterine applicator alone after external beam radiotherapy. MR imaging was repeated on days 2 and 3 of treatment and the day 1 plan was applied to the re-contoured volumes. RESULTS: The mean uterine volume and mean HR CTV increased during treatment. This resulted in a decrease in the mean HR CTV D90 relative to the day 1 planned dose. There was no change in the mean bladder volume during treatment but the mean rectal volume increased. This correlated with an increase in the mean rectal dose. There were four local recurrences. There was no apparent relationship between either the planned or the delivered HR CTV D90 and local recurrence. There was only one case of late bladder toxicity but nine patients developed late rectal toxicity. The cumulative rectal dose during treatment was a better predictor of late rectal toxicity than the planned dose. CONCLUSIONS: Significant changes in tumor and normal tissue anatomy and dosimetry can occur during PDR BT and should be tracked and corrected using serial imaging and plan adaptation, especially when the day 1 tumor or normal tissue doses are close to the planning constraints.

The effect of delineation method and observer variability on bladder dose-volume histograms for prostate intensity modulated radiotherapy.

PURPOSE: To quantify the effect of delineation method on bladder DVH, observer variability (OV) and contouring time for prostate IMRT plans. MATERIALS AND METHODS: Planning CT scans and IMRT plans of 30 prostate cancer patients were anonymized. For 20 patients, 1 observer delineated the bladder using 9 methods. The effect of delineation method on the DVH curve, discrete dose levels and delineation time was quantified. For the 10 remaining CTs, 6 observers delineated bladder wall using 4 methods. Observer-based volume variation and intraclass correlation coefficient (ICC) were used to describe the dosimetric effects of OV. RESULTS: Manual delineation of the bladder wall (BW_m) was significantly slower than any other method (mean: 20 min vs. ≤ 13 min) and the dosimetric effect of OV was significantly larger (V70 Gy ICC: 0.78 vs. 0.98). Only volumes created using a 2.5mm contraction from the outer surface, and a method providing a consistent wall volume, showed no notable dosimetric differences from BW_m in both absolute and relative volume. CONCLUSIONS: Automatic contractions from the outer surface provide quicker, more reproducible and reasonably accurate substitutes for BW_m. The widespread use of automatic contractions to create a bladder wall volume would assist in the consistent application of IMRT dose constraints and the interpretation of reported dose.

Automated weekly replanning for intensity-modulated radiotherapy of cervix cancer.

PURPOSE: The adoption of intensity-modulated radiotherapy (IMRT) to treat cervical malignancies has been limited in part by complex organ and tumor motion during treatment. This study explores the limits of a highly adaptive, small-margin treatment scenario to accommodate this motion. In addition, the dosimetric consequences of organ and tumor motion are modeled using a combination of deformable registration and fractional dose accumulation techniques. METHODS AND MATERIALS: Thirty-three cervix cancer patients had target volumes and organs-at-risk contoured on fused, pretreatment magnetic resonance-computed tomography images and weekly magnetic resonance scans taken during treatment. The dosimetric impact of interfraction organ and target motion was compared for two hypothetical treatment scenarios: a 3-mm margin plan with no replanning, and a 3-mm margin plan with an automated replan performed on the updated weekly patient geometry. RESULTS: Of the 33 patients, 24 (73%) met clinically acceptable target coverage (98% of the clinical target volume receiving at least 95% of the prescription dose) using the 3-mm margin plan without replanning. The range in dose to 98% of the clinical target volume across all patients was 7.9% of the prescription dose if no replanning was performed. After weekly replanning, this range was tightened to 2.6% of the prescription dose and all patients met clinically acceptable target coverage while maintaining organ-at-risk dose sparing. CONCLUSIONS: The dosimetric impact of anatomical motion underscores the challenges of applying IMRT to treat cervix cancer. An appropriate adaptive strategy can ensure target coverage for small-margin IMRT treatments and maintain favorable organ-at-risk dose sparing.

The development of EERA: software for assessing rheumatic joint erosions.

OBJECTIVE: The principal aim of this study was to create a segmentation program, to be used by nonmusculoskeletal or junior fellows, that defines the bones in the metacarpophalangeal joint in a dynamic 3-dimensional image that will lead to higher inter-reader agreement of bone erosion scores. METHODS: The second to fifth metacarpal head and phalangeal bases of 15 participants were rated according to the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system by one trained and one untrained reader. Two comparisons were made. The first comparison was between the 2 readers using only the traditional 2-dimensional magnetic resonance image set. The second comparison was between the 2 readers, with the untrained reader using a custom segmentation program with traditional 2-dimensional magnetic resonance image set. RESULTS: The software marginally increased inter-reader reliability with the exception of the second metacarpal head, for which reliability was increased substantially. Future work will concentrate on improving image acquisition, better delineate erosions from surrounding bone oedema, and address methods to directly determine erosion volumes. CONCLUSIONS: Software designed to display dynamic 3-dimensional images enables a relatively untrained user to score the metacarpophalangeal joints in the hand for erosions equivalent to that produced by an expert using the manual methods.