Comparison of Volumetric and 2D Measurements and Longitudinal Trajectories in the Response Assessment of BRAF V600E-Mutant Pediatric Gliomas in the Pacific Pediatric Neuro-Oncology Consortium Clinical Trial.

BACKGROUND AND PURPOSE: Response on imaging is widely used to evaluate treatment efficacy in clinical trials of pediatric gliomas. While conventional criteria rely on 2D measurements, volumetric analysis may provide a more comprehensive response assessment. There is sparse research on the role of volumetrics in pediatric gliomas. Our purpose was to compare 2D and volumetric analysis with the assessment of neuroradiologists using the Brain Tumor Reporting and Data System (BT-RADS) in BRAF V600E-mutant pediatric gliomas. MATERIALS AND METHODS: Manual volumetric segmentations of whole and solid tumors were compared with 2D measurements in 31 participants (292 follow-up studies) in the Pacific Pediatric Neuro-Oncology Consortium 002 trial (NCT01748149). Two neuroradiologists evaluated responses using BT-RADS. Receiver operating characteristic analysis compared classification performance of 2D and volumetrics for partial response. Agreement between volumetric and 2D mathematically modeled longitudinal trajectories for 25 participants was determined using the model-estimated time to best response. RESULTS: Of 31 participants, 20 had partial responses according to BT-RADS criteria. Receiver operating characteristic curves for the classification of partial responders at the time of first detection (median = 2 months) yielded an area under the curve of 0.84 (95% CI, 0.69-0.99) for 2D area, 0.91 (95% CI, 0.80-1.00) for whole-volume, and 0.92 (95% CI, 0.82-1.00) for solid volume change. There was no significant difference in the area under the curve between 2D and solid (P = .34) or whole volume (P = .39). There was no significant correlation in model-estimated time to best response (ρ = 0.39, P >.05) between 2D and whole-volume trajectories. Eight of the 25 participants had a difference of ≥90 days in transition from partial response to stable disease between their 2D and whole-volume modeled trajectories. CONCLUSIONS: Although there was no overall difference between volumetrics and 2D in classifying partial response assessment using BT-RADS, further prospective studies will be critical to elucidate how the observed differences in tumor 2D and volumetric trajectories affect clinical decision-making and outcomes in some individuals.

A review of mechanistic learning in mathematical oncology.

Mechanistic learning refers to the synergistic combination of mechanistic mathematical modeling and data-driven machine or deep learning. This emerging field finds increasing applications in (mathematical) oncology. This review aims to capture the current state of the field and provides a perspective on how mechanistic learning may progress in the oncology domain. We highlight the synergistic potential of mechanistic learning and point out similarities and differences between purely data-driven and mechanistic approaches concerning model complexity, data requirements, outputs generated, and interpretability of the algorithms and their results. Four categories of mechanistic learning (sequential, parallel, extrinsic, intrinsic) of mechanistic learning are presented with specific examples. We discuss a range of techniques including physics-informed neural networks, surrogate model learning, and digital twins. Example applications address complex problems predominantly from the domain of oncology research such as longitudinal tumor response predictions or time-to-event modeling. As the field of mechanistic learning advances, we aim for this review and proposed categorization framework to foster additional collaboration between the data- and knowledge-driven modeling fields. Further collaboration will help address difficult issues in oncology such as limited data availability, requirements of model transparency, and complex input data which are embraced in a mechanistic learning framework.

Persistent complement dysregulation with signs of thromboinflammation in active Long Covid.

Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome coronavirus 2 infection. Analysis of >6500 proteins in 268 longitudinal samples revealed dysregulated activation of the complement system, an innate immune protection and homeostasis mechanism, in individuals experiencing Long Covid. Thus, active Long Covid was characterized by terminal complement system dysregulation and ongoing activation of the alternative and classical complement pathways, the latter associated with increased antibody titers against several herpesviruses possibly stimulating this pathway. Moreover, markers of hemolysis, tissue injury, platelet activation, and monocyte-platelet aggregates were increased in Long Covid. Machine learning confirmed complement and thromboinflammatory proteins as top biomarkers, warranting diagnostic and therapeutic interrogation of these systems.

Studying missingness in spinal cord injury data: challenges and impact of data imputation.

BACKGROUND: In the last decades, medical research fields studying rare conditions such as spinal cord injury (SCI) have made extensive efforts to collect large-scale data. However, most analysis methods rely on complete data. This is particularly troublesome when studying clinical data as they are prone to missingness. Often, researchers mitigate this problem by removing patients with missing data from the analyses. Less commonly, imputation methods to infer likely values are applied. OBJECTIVE: Our objective was to study how handling missing data influences the results reported, taking the example of SCI registries. We aimed to raise awareness on the effects of missing data and provide guidelines to be applied for future research projects, in SCI research and beyond. METHODS: Using the Sygen clinical trial data (n = 797), we analyzed the impact of the type of variable in which data is missing, the pattern according to which data is missing, and the imputation strategy (e.g. mean imputation, last observation carried forward, multiple imputation). RESULTS: Our simulations show that mean imputation may lead to results strongly deviating from the underlying expected results. For repeated measures missing at late stages (> = 6 months after injury in this simulation study), carrying the last observation forward seems the preferable option for the imputation. This simulation study could show that a one-size-fit-all imputation strategy falls short in SCI data sets. CONCLUSIONS: Data-tailored imputation strategies are required (e.g., characterisation of the missingness pattern, last observation carried forward for repeated measures evolving to a plateau over time). Therefore, systematically reporting the extent, kind and decisions made regarding missing data will be essential to improve the interpretation, transparency, and reproducibility of the research presented.

Comparison of volumetric and 2D-based response methods in the PNOC-001 pediatric low-grade glioma clinical trial.

Background: Although response in pediatric low-grade glioma (pLGG) includes volumetric assessment, more simplified 2D-based methods are often used in clinical trials. The study's purpose was to compare volumetric to 2D methods. Methods: An expert neuroradiologist performed solid and whole tumor (including cyst and edema) volumetric measurements on MR images using a PACS-based manual segmentation tool in 43 pLGG participants (213 total follow-up images) from the Pacific Pediatric Neuro-Oncology Consortium (PNOC-001) trial. Classification based on changes in volumetric and 2D measurements of solid tumor were compared to neuroradiologist visual response assessment using the Brain Tumor Reporting and Data System (BT-RADS) criteria for a subset of 65 images using receiver operating characteristic (ROC) analysis. Longitudinal modeling of solid tumor volume was used to predict BT-RADS classification in 54 of the 65 images. Results: There was a significant difference in ROC area under the curve between 3D solid tumor volume and 2D area (0.96 vs 0.78, P = .005) and between 3D solid and 3D whole volume (0.96 vs 0.84, P = .006) when classifying BT-RADS progressive disease (PD). Thresholds of 15-25% increase in 3D solid tumor volume had an 80% sensitivity in classifying BT-RADS PD included in their 95% confidence intervals. The longitudinal model of solid volume response had a sensitivity of 82% and a positive predictive value of 67% for detecting BT-RADS PD. Conclusions: Volumetric analysis of solid tumor was significantly better than 2D measurements in classifying tumor progression as determined by BT-RADS criteria and will enable more comprehensive clinical management.

Gastrointestinal Toxicity Prediction Not Influenced by Rectal Contour or Dose-Volume Histogram Definition.

PURPOSE: Rectal dose delivered during prostate radiation therapy is associated with gastrointestinal toxicity. Treatment plans are commonly optimized using rectal dose-volume constraints, often whole-rectum relative-volumes (%). We investigated whether improved rectal contouring, use of absolute-volumes (cc), or rectal truncation might improve toxicity prediction. METHODS AND MATERIALS: Patients from the CHHiP trial (receiving 74 Gy/37 fractions [Fr] vs 60 Gy/20 Fr vs 57 Gy/19 Fr) were included if radiation therapy plans were available (2350/3216 patients), plus toxicity data for relevant analyses (2170/3216 patients). Whole solid rectum relative-volumes (%) dose-volume-histogram (DVH), as submitted by treating center (original contour), was assumed standard-of-care. Three investigational rectal DVHs were generated: (1) reviewed contour per CHHiP protocol; (2) original contour absolute volumes (cc); and (3) truncated original contour (2 versions; ±0 and ±2 cm from planning target volume [PTV]). Dose levels of interest (V30, 40, 50, 60, 70, 74 Gy) in 74 Gy arm were converted by equivalent-dose-in-2 Gy-Fr (EQD2α/ß= 3 Gy) for 60 Gy/57 Gy arms. Bootstrapped logistic models predicting late toxicities (frequency G1+/G2+, bleeding G1+/G2+, proctitis G1+/G2+, sphincter control G1+, stricture/ulcer G1+) were compared by area-undercurve (AUC) between standard of care and the 3 investigational rectal definitions. RESULTS: The alternative dose/volume parameters were compared with the original relative-volume (%) DVH of the whole rectal contour, itself fitted as a weak predictor of toxicity (AUC range, 0.57-0.65 across the 8 toxicity measures). There were no significant differences in toxicity prediction for: (1) original versus reviewed rectal contours (AUCs, 0.57-0.66; P = .21-.98); (2) relative- versus absolute-volumes (AUCs, 0.56-0.63; P = .07-.91); and (3) whole-rectum versus truncation at PTV ± 2 cm (AUCs, 0.57-0.65; P = .05-.99) or PTV ± 0 cm (AUCs, 0.57-0.66; P = .27-.98). CONCLUSIONS: We used whole-rectum relative-volume DVH, submitted by the treating center, as the standard-of-care dosimetric predictor for rectal toxicity. There were no statistically significant differences in prediction performance when using central rectal contour review, with the use of absolute-volume dosimetry, or with rectal truncation relative to PTV. Whole-rectum relative-volumes were not improved upon for toxicity prediction and should remain standard-of-care.

The Fraction Size Sensitivity of Late Genitourinary Toxicity: Analysis of Alpha/Beta (α/ß) Ratios in the CHHiP Trial.

PURPOSE: Moderately hypofractionated external beam intensity modulated radiation therapy (RT) for prostate cancer is now standard-of-care. Normal tissue toxicity responses to fraction size alteration are nonlinear: the linear-quadratic model is a widely used framework accounting for this, through the α/ß ratio. Few α/ß ratio estimates exist for human late genitourinary endpoints; here we provide estimates derived from a hypofractionation trial. METHODS AND MATERIALS: The CHHiP trial randomized 3216 men with localized prostate cancer 1:1:1 between conventionally fractionated intensity modulated RT (74 Gy/37 fractions (Fr)) and 2 moderately hypofractionated regimens (60 Gy/20 Fr and 57 Gy/19 Fr). RT plan and suitable follow-up assessment was available for 2206 men. Three prospectively assessed clinician-reported toxicity scales were amalgamated for common genitourinary endpoints: dysuria, hematuria, incontinence, reduced flow/stricture, and urine frequency. Per endpoint, only patients with baseline zero toxicity were included. Three models for endpoint grade ≥1 (G1+) and G2+ toxicity were fitted: Lyman Kutcher-Burman (LKB) without equivalent dose in 2 Gy/Fr (EQD2) correction [LKB-NoEQD2]; LKB with EQD2-correction [LKB-EQD2]; LKB-EQD2 with dose-modifying-factor (DMF) inclusion [LKB-EQD2-DMF]. DMFs were age, diabetes, hypertension, pelvic surgery, prior transurethral resection of prostate (TURP), overall treatment time and acute genitourinary toxicity (G2+). Bootstrapping generated 95% confidence intervals and unbiased performance estimates. Models were compared by likelihood ratio test. RESULTS: The LKB-EQD2 model significantly improved performance over LKB-NoEQD2 for just 3 endpoints: dysuria G1+ (α/ß = 2.0 Gy; 95% confidence interval [CI], 1.2-3.2 Gy), hematuria G1+ (α/ß = 0.9 Gy; 95% CI, 0.1-2.2 Gy) and hematuria G2+ (α/ß = 0.6 Gy; 95% CI, 0.1-1.7 Gy). For these 3 endpoints, further incorporation of 2 DMFs improved on LKB-EQD2: acute genitourinary toxicity and prior TURP (hematuria G1+ only), but α/ß ratio estimates remained stable. CONCLUSIONS: Inclusion of EQD2-correction significantly improved model fitting for dysuria and hematuria endpoints, where fitted α/ß ratio estimates were low: 0.6 to 2 Gy. This suggests therapeutic gain for clinician-reported GU toxicity, through hypofractionation, might be lower than expected by typical late α/ß ratio assumptions of 3 to 5 Gy.

Determinants of SARS-CoV-2 transmission to guide vaccination strategy in an urban area.

Transmission chains within small urban areas (accommodating ∼30 per cent of the European population) greatly contribute to case burden and economic impact during the ongoing coronavirus pandemic and should be a focus for preventive measures to achieve containment. Here, at very high spatio-temporal resolution, we analysed determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in a European urban area, Basel-City (Switzerland). We combined detailed epidemiological, intra-city mobility and socio-economic data sets with whole-genome sequencing during the first SARS-CoV-2 wave. For this, we succeeded in sequencing 44 per cent of all reported cases from Basel-City and performed phylogenetic clustering and compartmental modelling based on the dominating viral variant (B.1-C15324T; 60 per cent of cases) to identify drivers and patterns of transmission. Based on these results we simulated vaccination scenarios and corresponding healthcare system burden (intensive care unit (ICU) occupancy). Transmissions were driven by socio-economically weaker and highly mobile population groups with mostly cryptic transmissions which lacked genetic and identifiable epidemiological links. Amongst more senior population transmission was clustered. Simulated vaccination scenarios assuming 60-90 per cent transmission reduction and 70-90 per cent reduction of severe cases showed that prioritising mobile, socio-economically weaker populations for vaccination would effectively reduce case numbers. However, long-term ICU occupation would also be effectively reduced if senior population groups were prioritised, provided there were no changes in testing and prevention strategies. Reducing SARS-CoV-2 transmission through vaccination strongly depends on the efficacy of the deployed vaccine. A combined strategy of protecting risk groups by extensive testing coupled with vaccination of the drivers of transmission (i.e. highly mobile groups) would be most effective at reducing the spread of SARS-CoV-2 within an urban area.

Characterization of Acoustic, Cavitation, and Thermal Properties of Poly(vinyl alcohol) Hydrogels for Use as Therapeutic Ultrasound Tissue Mimics.

The thermal and mechanical effects induced in tissue by ultrasound can be exploited for therapeutic applications. Tissue-mimicking materials (TMMs), reflecting different soft tissue properties, are required for experimental evaluation of therapeutic potential. In the study described here, poly(vinyl alcohol) (PVA) hydrogels were characterized. Hydrogels prepared using different concentrations (5%-20% w/w) and molecular weights of PVA ± cellulose scatterers (2.5%-10% w/w) were characterized acoustically (sound speed, attenuation) as a function of temperature (25°C-45°C), thermally (thermal conductivity, specific heat capacity) and in terms of their cavitation thresholds. Results were compared with measurements in fresh sheep tissue (kidney, liver, spleen). Sound speed depended most strongly on PVA concentration, and attenuation, on cellulose content. For the range of formulations investigated, the PVA gel acoustic properties (sound speed: 1532 ± 17 to 1590 ± 9 m/s, attenuation coefficient: 0.08 ± 0.01 to 0.37 ± 0.02 dB/cm) fell within those measured in fresh tissue. Cavitation thresholds for 10% PVA hydrogels (50% occurrence: 4.1-5.4 MPa, 75% occurrence: 5.4-8.2 MPa) decreased with increasing cellulose content. In summary, PVA cellulose composite hydrogels may be suitable mimics of acoustic, cavitation and thermal properties of soft tissue for a number of therapeutic ultrasound applications.

A Century of Fractionated Radiotherapy: How Mathematical Oncology Can Break the Rules.

Radiotherapy is involved in 50% of all cancer treatments and 40% of cancer cures. Most of these treatments are delivered in fractions of equal doses of radiation (Fractional Equivalent Dosing (FED)) in days to weeks. This treatment paradigm has remained unchanged in the past century and does not account for the development of radioresistance during treatment. Even if under-optimized, deviating from a century of successful therapy delivered in FED can be difficult. One way of exploring the infinite space of fraction size and scheduling to identify optimal fractionation schedules is through mathematical oncology simulations that allow for in silico evaluation. This review article explores the evidence that current fractionation promotes the development of radioresistance, summarizes mathematical solutions to account for radioresistance, both in the curative and non-curative setting, and reviews current clinical data investigating non-FED fractionated radiotherapy.

reComBat: batch-effect removal in large-scale multi-source gene-expression data integration.

Motivation: With the steadily increasing abundance of omics data produced all over the world under vastly different experimental conditions residing in public databases, a crucial step in many data-driven bioinformatics applications is that of data integration. The challenge of batch-effect removal for entire databases lies in the large number of batches and biological variation, which can result in design matrix singularity. This problem can currently not be solved satisfactorily by any common batch-correction algorithm. Results: We present reComBat, a regularized version of the empirical Bayes method to overcome this limitation and benchmark it against popular approaches for the harmonization of public gene-expression data (both microarray and bulkRNAsq) of the human opportunistic pathogen Pseudomonas aeruginosa. Batch-effects are successfully mitigated while biologically meaningful gene-expression variation is retained. reComBat fills the gap in batch-correction approaches applicable to large-scale, public omics databases and opens up new avenues for data-driven analysis of complex biological processes beyond the scope of a single study. Availability and implementation: The code is available at https://github.com/BorgwardtLab/reComBat, all data and evaluation code can be found at https://github.com/BorgwardtLab/batchCorrectionPublicData. Supplementary information: Supplementary data are available at Bioinformatics Advances online.

Intermittent radiotherapy as alternative treatment for recurrent high grade glioma: a modeling study based on longitudinal tumor measurements.

Recurrent high grade glioma patients face a poor prognosis for which no curative treatment option currently exists. In contrast to prescribing high dose hypofractionated stereotactic radiotherapy (HFSRT, [Formula: see text] Gy [Formula: see text] 5 in daily fractions) with debulking intent, we suggest a personalized treatment strategy to improve tumor control by delivering high dose intermittent radiation treatment (iRT, [Formula: see text] Gy [Formula: see text] 1 every 6 weeks). We performed a simulation analysis to compare HFSRT, iRT and iRT plus boost ([Formula: see text] Gy [Formula: see text] 3 in daily fractions at time of progression) based on a mathematical model of tumor growth, radiation response and patient-specific evolution of resistance to additional treatments (pembrolizumab and bevacizumab). Model parameters were fitted from tumor growth curves of 16 patients enrolled in the phase 1 NCT02313272 trial that combined HFSRT with bevacizumab and pembrolizumab. Then, iRT +/- boost treatments were simulated and compared to HFSRT based on time to tumor regrowth. The modeling results demonstrated that iRT + boost(- boost) treatment was equal or superior to HFSRT in 15(11) out of 16 cases and that patients that remained responsive to pembrolizumab and bevacizumab would benefit most from iRT. Time to progression could be prolonged through the application of additional, intermittently delivered fractions. iRT hence provides a promising treatment option for recurrent high grade glioma patients for prospective clinical evaluation.

Quantification of Differential Response of Tumour and Normal Cells to Microbeam Radiation in the Absence of FLASH Effects.

Microbeam radiotherapy (MRT) is a preclinical method of delivering spatially-fractionated radiotherapy aiming to improve the therapeutic window between normal tissue complication and tumour control. Previously, MRT was limited to ultra-high dose rate synchrotron facilities. The aim of this study was to investigate in vitro effects of MRT on tumour and normal cells at conventional dose rates produced by a bench-top X-ray source. Two normal and two tumour cell lines were exposed to homogeneous broad beam (BB) radiation, MRT, or were separately irradiated with peak or valley doses before being mixed. Clonogenic survival was assessed and compared to BB-estimated surviving fractions calculated by the linear-quadratic (LQ)-model. All cell lines showed similar BB sensitivity. BB LQ-model predictions exceeded the survival of cell lines following MRT or mixed beam irradiation. This effect was stronger in tumour compared to normal cell lines. Dose mixing experiments could reproduce MRT survival. We observed a differential response of tumour and normal cells to spatially fractionated irradiations in vitro, indicating increased tumour cell sensitivity. Importantly, this was observed at dose rates precluding the presence of FLASH effects. The LQ-model did not predict cell survival when the cell population received split irradiation doses, indicating that factors other than local dose influenced survival after irradiation.

Estimates of Alpha/Beta (α/ß) Ratios for Individual Late Rectal Toxicity Endpoints: An Analysis of the CHHiP Trial.

PURPOSE: Changes in fraction size of external beam radiation therapy exert nonlinear effects on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/ß ratio. We sought to study individual α/ß ratios for different late rectal effects after prostate external beam radiation therapy. METHODS AND MATERIALS: The CHHiP trial (ISRCTN97182923) randomized men with nonmetastatic prostate cancer 1:1:1 to 74 Gy/37 fractions (Fr), 60 Gy/20 Fr, or 57 Gy/19 Fr. Patients in the study had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhea, pain, proctitis, sphincter control, and stricture. Lyman-Kutcher-Burman models with or without equivalent dose in 2 Gy/Fr correction were log-likelihood fitted by endpoint, estimating α/ß ratios. The α/ß ratio estimate sensitivity was assessed using sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and hemorrhoids. 95% confidence intervals (CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared the models. RESULTS: Late rectal α/ß ratio estimates (without DMF) ranged from bleeding (G1 + α/ß = 1.6 Gy; 95% CI, 0.9-2.5 Gy) to sphincter control (G1 + α/ß = 3.1 Gy; 95% CI, 1.4-9.1 Gy). Bowel pain modelled poorly (α/ß, 3.6 Gy; 95% CI, 0.0-840 Gy). Inclusion of IBD/diverticular disease as a DMF significantly improved fits for stool frequency G2+ (P = .00041) and proctitis G1+ (P = .00046). However, the α/ß ratios were similar in these no-DMF versus DMF models for both stool frequency G2+ (α/ß 2.7 Gy vs 2.5 Gy) and proctitis G1+ (α/ß 2.7 Gy vs 2.6 Gy). Frequency-weighted averaging of endpoint α/ß ratios produced: G1 + α/ß ratio = 2.4 Gy; G2 + α/ß ratio = 2.3 Gy. CONCLUSIONS: We estimated α/ß ratios for several common late adverse effects of rectal radiation therapy. When comparing dose-fractionation schedules, we suggest using late a rectal α/ß ratio ≤ 3 Gy.

3D tumour spheroids for the prediction of the effects of radiation and hyperthermia treatments.

For multimodality therapies such as the combination of hyperthermia and radiation, quantification of biological effects is key for dose prescription and response prediction. Tumour spheroids have a microenvironment that more closely resembles that of tumours in vivo and may thus be a superior in vitro cancer model than monolayer cultures. Here, the response of tumour spheroids formed from two established human cancer cell lines (HCT116 and CAL27) to single and combination treatments of radiation (0-20 Gy), and hyperthermia at 47 °C (0-780 CEM43) has been evaluated. Response was analysed in terms of spheroid growth, cell viability and the distribution of live/dead cells. Time-lapse imaging was used to evaluate mechanisms of cell death and cell detachment. It was found that sensitivity to heat in spheroids was significantly less than that seen in monolayer cultures. Spheroids showed different patterns of shrinkage and regrowth when exposed to heat or radiation: heated spheroids shed dead cells within four days of heating and displayed faster growth post-exposure than samples that received radiation or no treatment. Irradiated spheroids maintained a dense structure and exhibited a longer growth delay than spheroids receiving hyperthermia or combination treatment at (thermal) doses that yielded equivalent levels of clonogenic cell survival. We suggest that, unlike radiation, which kills dividing cells, hyperthermia-induced cell death affects cells independent of their proliferation status. This induces microenvironmental changes that promote spheroid growth. In conclusion, 3D tumour spheroid growth studies reveal differences in response to heat and/or radiation that were not apparent in 2D clonogenic assays but that may significantly influence treatment efficacy.

A cellular automaton model for spheroid response to radiation and hyperthermia treatments.

Thermo-radiosensitisation is a promising approach for treatment of radio-resistant tumours such as those containing hypoxic subregions. Response prediction and treatment planning should account for tumour response heterogeneity, e.g. due to microenvironmental factors, and quantification of the biological effects induced. 3D tumour spheroids provide a physiological in vitro model of tumour response and a systems oncology framework for simulating spheroid response to radiation and hyperthermia is presented. Using a cellular automaton model, 3D oxygen diffusion, delivery of radiation and/or hyperthermia were simulated for many ([Formula: see text]) individual cells forming a spheroid. The iterative oxygen diffusion model was compared to an analytical oxygenation model and simulations were calibrated and validated against experimental data for irradiated (0-10 Gy) and/or heated (0-240 CEM43) HCT116 spheroids. Despite comparable clonogenic survival, spheroid growth differed significantly following radiation or hyperthermia. This dynamic response was described well by the simulation ([Formula: see text] > 0.85). Heat-induced cell death was implemented as a fast, proliferation-independent process, allowing reoxygenation and repopulation, whereas radiation was modelled as proliferation-dependent mitotic catastrophe. This framework stands out both through its experimental validation and its novel ability to predict spheroid response to multimodality treatment. It provides a good description of response where biological dose-weighting based on clonogenic survival alone was insufficient.

Focused Ultrasound-Mediated Hyperthermia in Vitro: An Experimental Arrangement for Treating Cells under Tissue-Mimicking Conditions.

An experimental arrangement that allows in vitro exposure of cells to focused ultrasound-mediated hyperthermia (43°C-55°C) in a tissue-mimicking phantom with biological, acoustic and thermal properties comparable to those of human soft tissue is described. Cells were embedded in a compressed collagen gel, which was sandwiched between 6-mm-thick slices of biocompatible, acoustically absorbing and thermally tissue mimicking poly(vinyl alcohol) cryo-gel. To illustrate the system's potential, cells were exposed using a 1.66-MHz focused ultrasound beam (spatial-peak temporal-average intensities (ISPTA) = 900-1400 W/cm2) that traced out a circular trajectory (5-8 mm in diameter). Real-time temperature monitoring allowed cells to be exposed reproducibly to a pre-determined thermal dose. An experimental planning tool that estimates the thermal dose distribution throughout the sample and allows spatial correlation with cell position has been developed. Treatment response was evaluated qualitatively using microscopy and cell viability testing. This experimental arrangement has significant potential for future, biologically relevant, in vitro focused ultrasound-mediated hyperthermia studies.

EUD-based biological optimization for carbon ion therapy.

PURPOSE: Treatment planning for carbon ion therapy requires an accurate modeling of the biological response of each tissue to estimate the clinical outcome of a treatment. The relative biological effectiveness (RBE) accounts for this biological response on a cellular level but does not refer to the actual impact on the organ as a whole. For photon therapy, the concept of equivalent uniform dose (EUD) represents a simple model to take the organ response into account, yet so far no formulation of EUD has been reported that is suitable to carbon ion therapy. The authors introduce the concept of an equivalent uniform effect (EUE) that is directly applicable to both ion and photon therapies and exemplarily implemented it as a basis for biological treatment plan optimization for carbon ion therapy. METHODS: In addition to a classical EUD concept, which calculates a generalized mean over the RBE-weighted dose distribution, the authors propose the EUE to simplify the optimization process of carbon ion therapy plans. The EUE is defined as the biologically equivalent uniform effect that yields the same probability of injury as the inhomogeneous effect distribution in an organ. Its mathematical formulation is based on the generalized mean effect using an effect-volume parameter to account for different organ architectures and is thus independent of a reference radiation. For both EUD concepts, quadratic and logistic objective functions are implemented into a research treatment planning system. A flexible implementation allows choosing for each structure between biological effect constraints per voxel and EUD constraints per structure. Exemplary treatment plans are calculated for a head-and-neck patient for multiple combinations of objective functions and optimization parameters. RESULTS: Treatment plans optimized using an EUE-based objective function were comparable to those optimized with an RBE-weighted EUD-based approach. In agreement with previous results from photon therapy, the optimization by biological objective functions resulted in slightly superior treatment plans in terms of final EUD for the organs at risk (OARs) compared to voxel-based optimization approaches. This observation was made independent of the underlying objective function metric. An absolute gain in OAR sparing was observed for quadratic objective functions, whereas intersecting DVHs were found for logistic approaches. Even for considerable under- or overestimations of the used effect- or dose-volume parameters during the optimization, treatment plans were obtained that were of similar quality as the results of a voxel-based optimization. CONCLUSIONS: EUD-based optimization with either of the presented concepts can successfully be applied to treatment plan optimization. This makes EUE-based optimization for carbon ion therapy a useful tool to optimize more specifically in the sense of biological outcome while voxel-to-voxel variations of the biological effectiveness are still properly accounted for. This may be advantageous in terms of computational cost during treatment plan optimization but also enables a straight forward comparison of different fractionation schemes or treatment modalities.