Evaluating the Effectiveness of Deep Learning Contouring across Multiple Radiotherapy Centres.

Background and purpose: Deep learning contouring (DLC) has the potential to decrease contouring time and variability of organ contours. This work evaluates the effectiveness of DLC for prostate and head and neck across four radiotherapy centres using a commercial system. Materials and methods: Computed tomography scans of 123 prostate and 310 head and neck patients were evaluated. Besides one head and neck model, generic DLC models were used. Contouring time using centres' existing clinical methods and contour editing time after DLC were compared. Timing was evaluated using paired and non-paired studies. Commercial software or in-house scripts assessed dice similarity coefficient (DSC) and distance to agreement (DTA). One centre assessed head and neck inter-observer variability. Results: The mean contouring time saved for prostate structures using DLC compared to the existing clinical method was 5.9 ± 3.5 min. The best agreement was shown for the femoral heads (median DSC 0.92 ± 0.03, median DTA 1.5 ± 0.3 mm) and the worst for the rectum (median DSC 0.68 ± 0.04, median DTA 4.6 ± 0.6 mm). The mean contouring time saved for head and neck structures using DLC was 16.2 ± 8.6 min. For one centre there was no DLC time-saving compared to an atlas-based method. DLC contours reduced inter-observer variability compared to manual contours for the brainstem, left parotid gland and left submandibular gland. Conclusions: Generic prostate and head and neck DLC models can provide time-savings which can be assessed with paired or non-paired studies to integrate with clinical workload. Reducing inter-observer variability potential has been shown.

Cherenkov light emission in molecular radiation therapy of the thyroid and its application to dosimetry.

Numerical experiments based on Monte Carlo simulations and clinical CT data are performed to investigate the spatial and spectral characteristics of Cherenkov light emission and the relationship between Cherenkov light intensity and deposited dose in molecular radiotherapy of hyperthyroidism and papillary thyroid carcinoma. It is found that Cherenkov light is emitted mostly in the treatment volume, the spatial distribution of Cherenkov light at the surface of the patient presents high-value regions at locations that depend on the symmetry and location of the treatment volume, and the surface light in the near-infrared spectral region originates from the treatment site. The effect of inter-patient variability in the tissue optical parameters and radioisotope uptake on the linear relationship between the dose absorbed by the treatment volume and Cherenkov light intensity at the surface of the patient is investigated, and measurements of surface light intensity for which this effect is minimal are identified. The use of Cherenkov light measurements at the patient surface for molecular radiation therapy dosimetry is also addressed.

Using multi-centre data to train and validate a knowledge-based model for planning radiotherapy of the head and neck.

Background and purpose: Knowledge-based radiotherapy planning models have been shown to reduce healthy tissue dose and optimisation times, with larger training databases delivering greater robustness. We propose a method of combining knowledge-based models from multiple centres to create a 'super-model' using their collective patient libraries, thereby increasing the breadth of training knowledge. Materials and methods: A head and neck super-model containing 207 patient datasets was created by merging the data libraries of three centres. Validation was performed on 30 independent datasets during which optimiser parameters were tuned to deliver the optimal set of model template objectives. The super-model was tested on a further 40 unseen patients from four radiotherapy centres, including one centre external to the training process. The generated plans were assessed using established plan evaluation criteria. Results: The super-model generated plans that surpassed the dose objectives for all patients with single optimisations in an average time of 10 min. Healthy tissue sparing was significantly improved over manual planning, with dose reductions to parotid of 4.7 ± 2.1 Gy, spinal cord of 3.3 ± 0.9 Gy and brainstem of 2.9 ± 1.7 Gy. Target coverage met the established constraints but was marginally reduced compared with clinical plans. Conclusions: Three centres successfully merged patient libraries to create a super-model capable of generating plans that met plan evaluation criteria for head and neck patients with improvements in healthy tissue sparing. The findings indicate that the super-model could improve head and neck planning quality, efficiency and consistency across radiotherapy centres.

High-Volume Colonic Lavage Is a Safe and Preferred Colonoscopy Preparation for Patients With Inflammatory Bowel Disease.

Background: Colonoscopies provide a crucial diagnostic and surveillance tool for inflammatory bowel disease (IBD). Accordingly, IBD patients undergo repeated and frequent colonoscopies. The oral purgative bowel prep (BP) is often burdensome on patients, resulting in delayed or missed colonoscopies due to patient noncompliance. Additionally, oral BP has been noted to possibly induce colon mucosal inflammatory changes in some patients, which may be misleading when assessing actual disease activity. Methods: In this retrospective clinical study, we evaluated the use of an FDA cleared, defecation-inducing high-volume colon irrigation (>40 L) BP to prepare IBD patients for colonoscopy. Data were collected at 4 US Hygieacare centers from September 2016 to March 2021. The IBD patient population consisted of 314 patients that underwent 343 BPs. The BPs were prescribed by 65 physicians and performed by 16 nurses and technicians. Results: Patient ages were 20-85 years old, 76% females, 24% males, and 97% of the patients were adequately prepared for their colonoscopy (n = 309). Patient satisfaction with the BP was very high, as reflected in postprocedure surveys and open-ended responses text analyses, and there were no serious adverse events. Conclusions: We present data supporting that the defecation-inducing high-volume colon irrigation BP for colonoscopy is safe, effective, and preferred for IBD patients. Using this BP for IBD patients can allow earlier interventions, significantly impacting disease management and future outcomes.

Textural analysis and lung function study: Predicting lung fitness for radiotherapy from a CT scan.

OBJECTIVE: This study tested the hypothesis that shows advanced image analysis can differentiate fit and unfit patients for radical radiotherapy from standard radiotherapy planning imaging, when compared to formal lung function tests, FEV1 (forced expiratory volume in 1 s) and TLCO (transfer factor of carbon monoxide). METHODS: An apical region of interest (ROI) of lung parenchyma was extracted from a standard radiotherapy planning CT scan. Software using a grey level co-occurrence matrix (GLCM) assigned an entropy score to each voxel, based on its similarity to the voxels around it. RESULTS: Density and entropy scores were compared between a cohort of 29 fit patients (defined as FEV1 and TLCO above 50 % predicted value) and 32 unfit patients (FEV1 or TLCO below 50% predicted). Mean and median density and median entropy were significantly different between fit and unfit patients (p = 0.005, 0.0008 and 0.0418 respectively; two-sided Mann-Whitney test). CONCLUSION: Density and entropy assessment can differentiate between fit and unfit patients for radical radiotherapy, using standard CT imaging. ADVANCES IN KNOWLEDGE: This study shows that a novel assessment can generate further data from standard CT imaging. These data could be combined with existing studies to form a multiorgan patient fitness assessment from a single CT scan.

Clinical applications of textural analysis in non-small cell lung cancer.

Lung cancer is the leading cause of cancer mortality worldwide. Treatment pathways include regular cross-sectional imaging, generating large data sets which present intriguing possibilities for exploitation beyond standard visual interpretation. This additional data mining has been termed "radiomics" and includes semantic and agnostic approaches. Textural analysis (TA) is an example of the latter, and uses a range of mathematically derived features to describe an image or region of an image. Often TA is used to describe a suspected or known tumour. TA is an attractive tool as large existing image sets can be submitted to diverse techniques for data processing, presentation, interpretation and hypothesis testing with annotated clinical outcomes. There is a growing anthology of published data using different TA techniques to differentiate between benign and malignant lung nodules, differentiate tissue subtypes of lung cancer, prognosticate and predict outcome and treatment response, as well as predict treatment side effects and potentially aid radiotherapy planning. The aim of this systematic review is to summarize the current published data and understand the potential future role of TA in managing lung cancer.

Factors influencing the robustness of P-value measurements in CT texture prognosis studies.

Several studies have recently reported on the value of CT texture analysis in predicting survival, although the topic remains controversial, with further validation needed in order to consolidate the evidence base. The aim of this study was to investigate the effect of varying the input parameters in the Kaplan-Meier analysis, to determine whether the resulting P-value can be considered to be a robust indicator of the parameter's prognostic potential. A retrospective analysis of the CT-based normalised entropy of 51 patients with lung cancer was performed and overall survival data for these patients were collected. A normalised entropy cut-off was chosen to split the patient cohort into two groups and log-rank testing was performed to assess the survival difference of the two groups. This was repeated for varying normalised entropy cut-offs and varying follow-up periods. Our findings were also compared with previously published results to assess robustness of this parameter in a multi-centre patient cohort. The P-value was found to be highly sensitive to the choice of cut-off value, with small changes in cut-off producing substantial changes in P. The P-value was also sensitive to follow-up period, with particularly noisy results at short follow-up periods. Using matched conditions to previously published results, a P-value of 0.162 was obtained. Survival analysis results can be highly sensitive to the choice in texture cut-off value in dichotomising patients, which should be taken into account when performing such studies to avoid reporting false positive results. Short follow-up periods also produce unstable results and should therefore be avoided to ensure the results produced are reproducible. Previously published findings that indicated the prognostic value of normalised entropy were not replicated here, but further studies with larger patient numbers would be required to determine the cause of the different outcomes.

Clinical validation and benchmarking of knowledge-based IMRT and VMAT treatment planning in pelvic anatomy.

PURPOSE: The aim of this work was to determine whether a commercial knowledge-based treatment planning (KBP) module can efficiently produce IMRT and VMAT plans in the pelvic region (prostate & cervical cancer), and to assess sensitivity of plan quality to training data and model parameters. METHODS: Initial benchmarking of KBP was performed using prostate cancer cases. Structures and dose distributions from 40 patients previously treated using a 5-field IMRT technique were used for model training. Two types of model were created: one excluded statistical outliers (as identified by RapidPlan guidelines) and the other had no exclusions. A separate model for cervix uteri cancer cases was subsequently developed using 37 clinical patients treated for cervical cancer using RapidArc™ VMAT, with no exclusions. The resulting models were then used to generate plans for ten patients from each patient group who had not been included in the modelling process. Comparisons of generated RapidPlans with the corresponding clinical plans were carried out to indicate the required modifications to the models. Model parameters were then iteratively adjusted until plan quality converged with that obtained by experienced planners without KBP. RESULTS: Initial automated model generation settings led to poor conformity, coverage and efficiency compared to clinical plans. Therefore a number of changes to the initial KBP models were required. Before model optimisation, it was found that the PTV coverage was slightly reduced in the superior and inferior directions for RapidPlan compared with clinical plans and therefore PTV parameters were adjusted to improve coverage. OAR doses were similar for both RapidPlan and clinical plans (p>0.05). Excluding outliers had little effect on plan quality (p≫0.05). Manually fixing key optimisation objectives enabled production of clinically acceptable treatment plans without further planner intervention for 9 of 10 prostate test patients and all 10 cervix test patients. CONCLUSIONS: The Varian RapidPlan™ system was able to produce IMRT & VMAT treatment plans in the pelvis, in a single optimisation, that had comparable sparing and comparable or better conformity than the original clinically acceptable plans. The system allows for better consistency and efficiency in the treatment planning process and has therefore been adopted clinically within our institute with over 100 patients treated.

4-Component relativistic calculations of L3 ionization and excitations for the isoelectronic species UO2(2+), OUN(+) and UN2.

We present a 4-component relativistic study of uranium 2p3/2 ionization and excitation in the isoelectronic series UO2(2+), OUN(+) and UN2. We calculate ionization energies by ΔSCF at the Hartree-Fock (HF) and Kohn-Sham (KS) level of theory. At the ΔHF level we observe a perfectly linear chemical shift of ionization energies with respect to uranium atomic charges obtained from projection analysis. We have also developed a non-canonical 2nd-order Møller-Plesset code for wave function based correlation studies. We observe the well-known failure of Koopmans' theorem for core ionization due to the dominance of orbital relaxation over electron correlation effects. More unexpectedly, we find that the correlation contribution has the same sign as the relaxation contribution and show that this is due to a strong coupling of relaxation and correlation. We simulate uranium L3 XANES spectra, dominated by 2p3/2 → U6d transitions, by restricted excitation window time-dependent density functional theory (REW-TDDFT) and the complex polarization propagator (CPP) approach and demonstrate that they give identical spectra when the same Lorentz broadening is chosen. We also simulate XANES spectra by the Hartree-Fock based static exchange (STEX) method and show how STEX excitation energies can be reproduced by time-dependent Hartree-Fock calculations within the Tamm-Dancoff approximation. We furthermore show that Koopmans' theorem provide a correct approximation of ionization energies in the linear response regime and use this observation to align REW-TDDFT and CPP spectra with STEX ones. We point out that the STEX method affords the most detailed assignment of spectra since it employs virtual orbitals optimized for the selected core ionization. The calculated XANES spectra reflect the loss of bound virtual orbitals as the molecular charge is reduced along the isoelectronic series.

Magnitude of observer error using cone beam CT for prostate interfraction motion estimation: effect of reducing scan length or increasing exposure.

OBJECTIVE: Cone beam CT (CBCT) enables soft-tissue registration to planning CT for position verification in radiotherapy. The aim of this study was to determine the interobserver error (IOE) in prostate position verification using a standard CBCT protocol, and the effect of reducing CBCT scan length or increasing exposure, compared with standard imaging protocol. METHODS: CBCT images were acquired using a novel 7 cm length image with standard exposure (1644 mAs) at Fraction 1 (7), standard 12 cm length image (1644 mAs) at Fraction 2 (12) and a 7 cm length image with higher exposure (2632 mAs) at Fraction 3 (7H) on 31 patients receiving radiotherapy for prostate cancer. Eight observers (two clinicians and six radiographers) registered the images. Guidelines and training were provided. The means of the IOEs were compared using a Kruzkal-Wallis test. Levene's test was used to test for differences in the variances of the IOEs and the independent prostate position. RESULTS: No significant difference was found between the IOEs of each image protocol in any direction. Mean absolute IOE was the greatest in the anteroposterior direction. Standard deviation (SD) of the IOE was the least in the left-right direction for each of the three image protocols. The SD of the IOE was significantly less than the independent prostate motion in the anterior-posterior (AP) direction only (1.8 and 3.0 mm, respectively: p = 0.017). IOEs were within 1 SD of the independent prostate motion in 95%, 77% and 96% of the images in the RL, SI and AP direction. CONCLUSION: Reducing CBCT scan length and increasing exposure did not have a significant effect on IOEs. To reduce imaging dose, a reduction in CBCT scan length could be considered without increasing the uncertainty in prostate registration. Precision of CBCT verification of prostate radiotherapy is affected by IOE and should be quantified prior to implementation. ADVANCES IN KNOWLEDGE: This study shows the importance of quantifying the magnitude of IOEs prior to CBCT implementation.

Mathematical modelling of tumour volume dynamics in response to stereotactic ablative radiotherapy for non-small cell lung cancer.

This paper reports a modelling study of tumour volume dynamics in response to stereotactic ablative radiotherapy (SABR). The main objective was to develop a model that is adequate to describe tumour volume change measured during SABR, and at the same time is not excessively complex as lacking support from clinical data. To this end, various modelling options were explored, and a rigorous statistical method, the Akaike information criterion, was used to help determine a trade-off between model accuracy and complexity. The models were calibrated to the data from 11 non-small cell lung cancer patients treated with SABR. The results showed that it is feasible to model the tumour volume dynamics during SABR, opening up the potential for using such models in a clinical environment in the future.

A neoteric neodymium model: ground and excited electronic state analysis of NdF2+.

Neodymium monofluoride dication was studied as a model of the Nd-F bond in NdFx. Multiconfigurational self-consistent field (MCSCF) and second order multireference quasi-degenerate perturbation theory (MCQDPT2) methods were used with a variety of active spaces to elucidate the roles of the Nd 4f, 5d, and 6s orbitals. Spin-orbit coupling calculations were performed at the SO-MCQDPT2 level, and potential energy curves were obtained for the four lowest energy quartet states as well as for the four lowest doublet states and the lowest sextet state. Inclusion of spin-orbit coupling splits these states into 30 levels. Equilibrium bond lengths, dissociation energies, transition energies, and crossing points were determined.

Immunodepletion plasma proteomics by tripleTOF 5600 and Orbitrap elite/LTQ-Orbitrap Velos/Q exactive mass spectrometers.

Plasma proteomic experiments performed rapidly and economically using several of the latest high-resolution mass spectrometers were compared. Four quantitative hyperfractionated plasma proteomics experiments were analyzed in replicates by two AB SCIEX TripleTOF 5600 and three Thermo Scientific Orbitrap (Elite/LTQ-Orbitrap Velos/Q Exactive) instruments. Each experiment compared two iTRAQ isobaric-labeled immunodepleted plasma proteomes, provided as 30 labeled peptide fractions, and 480 LC-MS/MS runs delivered >250 GB of data in 2 months. Several analysis algorithms were compared. At 1% false discovery rate, the relative comparative findings concluded that the Thermo Scientific Q Exactive Mass Spectrometer resulted in the highest number of identified proteins and unique sequences with iTRAQ quantitation. The confidence of iTRAQ fold-change for each protein is dependent on the overall ion statistics (Mascot Protein Score) attainable by each instrument. The benchmarking also suggested how to further improve the mass spectrometry parameters and HPLC conditions. Our findings highlight the special challenges presented by the low abundance peptide ions of iTRAQ plasma proteome because the dynamic range of plasma protein abundance is uniquely high compared with cell lysates, necessitating high instrument sensitivity.

Immunohistochemistry staining for the mismatch repair proteins in the clinical care of patients with colorectal cancer.

PURPOSE: The Ohio State University was one of the first medical centers to begin routinely performing immunohistochemical staining for the four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) on all newly diagnosed patients with colorectal cancer. The results of implementing this testing on a clinical basis are critically assessed. METHODS: From March 1, 2006, to March 31, 2008, 270 newly diagnosed colorectal cancer tumors received immunohistochemical staining for MLH1, MSH2, MSH6, and PMS2. If any stain was absent, the cancer genetic counselors were alerted, so that they could contact the patient. A follow-up genetic consultation was recommended for all patients with any stain absent other than MLH1 and to patients with absence of MLH1 +/- PMS2 who were diagnosed younger than 60 years had a multiple Lynch syndrome-associated cancers or had a first-degree relative with colorectal cancer or endometrial cancer. Those attending the genetic consultation were offered appropriate follow-up testing. RESULTS: There were 57 (21.1%) cases with abnormal immunohistochemical results. Genetics was able to contact 54 (94.7%) of these patients. It was determined that 34 (62.9%) of these 54 patients should be referred for a cancer genetics consultation, however, only nine (26.5%) made an appointment. Seven of the nine underwent additional testing, which was informative in five of the patients. Two (0.7%) new cases of Lynch syndrome were diagnosed and three patients were found to have proven/probable MLH1 promoter methylation. CONCLUSIONS: Routine immunohistochemical of the mismatch repair proteins on all newly diagnosed patients with colorectal cancer can be implemented clinically, however, patient uptake of follow-up genetic consultation is lower than expected.

Evaluation of the Delta4 phantom for IMRT and VMAT verification.

The Delta(4) diode array phantom (Scandidos, Uppsala, Sweden) was evaluated for verification of segmental intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) on an Elekta linear accelerator (Crawley UK). The device was tested for angular sensitivity by irradiating it from 36 different gantry angles, and the responses of the device to various step-and-shoot segment doses and dose rates were evaluated using an ionization chamber as a comparison. The phantom was then compared with ionization chamber and film results for two prostate and pelvic nodes IMRT plans, two head and neck IMRT plans and two lung VMAT plans. These plans were calculated using Pinnacle(3) (Philips Radiation Oncology Systems, Madison, WI). The uniformity of angular response was better than 0.5% over the range of gantry angles. The uniformity of response of the Delta(4) to different segment monitor units and dose rates was better than 0.5%. The assessment of the IMRT and VMAT plans showed that the Delta(4) measured a dose within 2.5% of the ionization chamber, and compared to film recorded a slightly larger region (range -2% to +7%) agreeing with the planned dose to within 3% and 3 mm. The Delta(4) is a complex device and requires careful benchmarking, but following the successful completion of these measurements, the Delta(4) has been introduced into clinical use.

Yttrium-90 microsphere induced gastrointestinal tract ulceration.

BACKGROUND: Radiomicrosphere therapy (RT) utilizing yttrium-90 (90Y) microspheres has been shown to be an effective regional treatment for primary and secondary hepatic malignancies. We sought to determine a large academic institution's experience regarding the extent and frequency of gastrointestinal complications. METHODS: Between 2004 and 2007, 27 patients underwent RT for primary or secondary hepatic malignancies. Charts were subsequently reviewed to determine the incidence and severity of GI ulceration. RESULTS: Three patients presented with gastrointestinal bleeding and underwent upper endoscopy. Review of the pretreatment angiograms showed normal vascular anatomy in one patient, sclerosed hepatic vasculature in a patient who had undergone prior chemoembolization in a second, and an aberrant left hepatic artery in a third. None had undergone prophylactic gastroduodenal artery embolization. Endoscopic findings included erythema, mucosal erosions, and large gastric ulcers. Microspheres were visible on endoscopic biopsy. In two patients, gastric ulcers were persistent at the time of repeat endoscopy 1-4 months later despite proton pump inhibitor therapy. One elderly patient who refused surgical intervention died from recurrent hemorrhage. CONCLUSION: Gastrointestinal ulceration is a known yet rarely reported complication of 90Y microsphere embolization with potentially life-threatening consequences. Once diagnosed, refractory ulcers should be considered for aggressive surgical management.

The frequency of Muir-Torre syndrome among Lynch syndrome families.

Lynch syndrome is the predisposition to visceral malignancies that are associated with deleterious germline mutations in DNA mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2. Muir-Torre syndrome is a variant of Lynch syndrome that includes a predisposition to certain skin tumors. We determined the frequency of Muir-Torre syndrome among 50 Lynch syndrome families that were ascertained from a population-based series of cancer patients who were newly diagnosed with colorectal or endometrial carcinoma. Histories of Muir-Torre syndrome-associated skin tumors were documented during counseling of family members. Muir-Torre syndrome was observed in 14 (28%) of 50 families and in 14 (9.2%) of 152 individuals with Lynch syndrome. Four (44%) of nine families with MLH1 mutations had a member with Muir-Torre syndrome compared with 10 (42%) of 24 families with MSH2 mutations (P = .302). Families who carried the c.942+3A>T MSH2 gene mutation had a higher frequency of Muir-Torre syndrome than families who carried other mutations in the MSH2 gene (75% vs 25%; P = .026). Muir-Torre syndrome was not found in families with mutations in the MSH6 or PMS2 genes. Our results suggest that Muir-Torre syndrome is simply a variant of Lynch syndrome. Screening for Muir-Torre syndrome-associated skin lesions among patients with Lynch syndrome is recommended.