A joint physics and radiobiology DREAM team vision - Towards better response prediction models to advance radiotherapy.

Radiotherapy developed empirically through experience balancing tumour control and normal tissue toxicities. Early simple mathematical models formalized this practical knowledge and enabled effective cancer treatment to date. Remarkable advances in technology, computing, and experimental biology now create opportunities to incorporate this knowledge into enhanced computational models. The ESTRO DREAM (Dose Response, Experiment, Analysis, Modelling) workshop brought together experts across disciplines to pursue the vision of personalized radiotherapy for optimal outcomes through advanced modelling. The ultimate vision is leveraging quantitative models dynamically during therapy to ultimately achieve truly adaptive and biologically guided radiotherapy at the population as well as individual patient-based levels. This requires the generation of models that inform response-based adaptations, individually optimized delivery and enable biological monitoring to provide decision support to clinicians. The goal is expanding to models that can drive the realization of personalized therapy for optimal outcomes. This position paper provides their propositions that describe how innovations in biology, physics, mathematics, and data science including AI could inform models and improve predictions. It consolidates the DREAM team's consensus on scientific priorities and organizational requirements. Scientifically, it stresses the need for rigorous, multifaceted model development, comprehensive validation and clinical applicability and significance. Organizationally, it reinforces the prerequisites of interdisciplinary research and collaboration between physicians, medical physicists, radiobiologists, and computational scientists throughout model development. Solely by a shared understanding of clinical needs, biological mechanisms, and computational methods, more informed models can be created. Future research environment and support must facilitate this integrative method of operation across multiple disciplines.

International Survey of Antiseizure Medication Use in Patients with Complicated Mild Traumatic Brain Injury: A New York Neurotrauma Consortium Study.

BACKGROUND: Seizures and epilepsy after traumatic brain injury (TBI) negatively affect quality of life and longevity. Antiseizure medication (ASM) prophylaxis after severe TBI is associated with improved outcomes; these medications are rarely used in mild TBI. However, a paucity of research is available to inform ASM use in complicated mild TBI (cmTBI) and no empirically based clinical care guidelines for ASM use in cmTBI exist. We aim to identify seizure prevention and management strategies used by clinicians experienced in treating patients with cmTBI to characterize standard care and inform a systematic approach to clinical decision making regarding ASM prophylaxis. METHODS: We recruited a multidisciplinary international cohort through professional organizational listservs and social media platforms. Our questionnaire assessed factors influencing ASM prophylaxis after cmTBI at the individual, institutional, and health system-wide levels. RESULTS: Ninety-two providers with experience managing cmTBI completed the survey. We found a striking diversity of ASM use in cmTBI, with 30% of respondents reporting no/infrequent use and 42% reporting frequent use; these tendencies did not differ by provider or institutional characteristics. Certain conditions universally increased or decreased the likelihood of ASM use and represent consensus. Based on survey results, ASMs are commonly used in patients with cmTBI who experience acute secondary seizure or select positive neuroimaging findings; we advise caution in elderly patients and those with concomitant neuropsychiatric illness. CONCLUSIONS: This study is the first to characterize factors influencing clinical decision making in ASM prophylaxis after cmTBI based on multidisciplinary multicenter provider practices. Prospective controlled studies are necessary to inform standardized guideline development.

Speeding up training of automated bird recognizers by data reduction of audio features.

Automated acoustic recognition of birds is considered an important technology in support of biodiversity monitoring and biodiversity conservation activities. These activities require processing large amounts of soundscape recordings. Typically, recordings are transformed to a number of acoustic features, and a machine learning method is used to build models and recognize the sound events of interest. The main problem is the scalability of data processing, either for developing models or for processing recordings made over long time periods. In those cases, the processing time and resources required might become prohibitive for the average user. To address this problem, we evaluated the applicability of three data reduction methods. These methods were applied to a series of acoustic feature vectors as an additional postprocessing step, which aims to reduce the computational demand during training. The experimental results obtained using Mel-frequency cepstral coefficients (MFCCs) and hidden Markov models (HMMs) support the finding that a reduction in training data by a factor of 10 does not significantly affect the recognition performance.

Automated Sound Recognition Provides Insights into the Behavioral Ecology of a Tropical Bird.

Computer-assisted species recognition facilitates the analysis of relevant biological information in continuous audio recordings. In the present study, we assess the suitability of this approach for determining distinct life-cycle phases of the Southern Lapwing Vanellus chilensis lampronotus based on adult vocal activity. For this purpose we use passive 14-min and 30-min soundscape recordings (n = 33 201) collected in 24/7 mode between November 2012 and October 2013 in Brazil's Pantanal wetlands. Time-stamped detections of V. chilensis call events (n = 62 292) were obtained with a species-specific sound recognizer. We demonstrate that the breeding season fell in a three-month period from mid-May to early August 2013, between the end of the flood cycle and the height of the dry season. Several phases of the lapwing's life history were identified with presumed error margins of a few days: pre-breeding, territory establishment and egg-laying, incubation, hatching, parental defense of chicks, and post-breeding. Diurnal time budgets confirm high acoustic activity levels during midday hours in June and July, indicative of adults defending young. By August, activity patterns had reverted to nonbreeding mode, with peaks around dawn and dusk and low call frequency during midday heat. We assess the current technological limitations of the V. chilensis recognizer through a comprehensive performance assessment and scrutinize the usefulness of automated acoustic recognizers in studies on the distribution pattern, ecology, life history, and conservation status of sound-producing animal species.

Lerneca inalata beripocone subsp. nov. (Orthoptera: Phalangopsidae; Luzarinae): a new taxon for the northern Pantanal of Brazil.

The first record of the Orthoptera species Lerneca inalata for Brazil is presented here. The taxon is represented by a new subspecies Lerneca inalata beripocone subsp. nov. (Phalangopsidae, Luzarinae), collected in the Pantanal of Poconé, Mato Grosso, Brazil. This work includes morphological and morphometric data as well as descriptions of female genitalia and calling song. The new subspecies has as diagnostic features the male genitalia with six ventral spines on the B sclerite, the first spine having a subtle bifurcation; the mid-region of the strongly sclerotized pseudepiphallus; inclination of C sclerite with slightly concave curvature; tegmina-length ratio and the speculum (syn. mirror) width approximately three times the length of the apical area. The description of the female genitalia and the calling song is presented for the first time for the species Lerneca inalata. A distribution map covers the local occurrence of its subspecies.

Dysfunctional Effects of a Conflict in a Healthcare Organization.

UNLABELLED: Conflicts in healthcare settings are quite common events because of the continuous changes and transformations today's healthcare organizations are undergoing and the vigorous interaction between the medical professionals working in them. AIM: To survey the opinions of medical professionals about the possible destructive effects of conflicts on them in the workplace. MATERIALS AND METHODS: We conducted a direct individual survey of 279 medical employees at four general hospitals. We used a set of questions that reflect the negative effects and consequences of conflict on healthcare professionals as direct or indirect participants. All data were analysed using the descriptive statistics and non-parametric analysis at a significance level for the null hypothesis of p < 0.05. RESULTS: Workplace conflicts contribute a lot to the stress, psychological tension and emotional exhaustion medical professionals are exposed to. The confrontation the conflict brings the participants into acts as a catalyst of the conflict and enhances the manifestation of hostile actions. A conflict generates a situation which has an impact on the behaviour of all participants involved in it giving rise to emotional states such as anger, aggression and reproaches. The destructive consequences resulting from a conflict are seen in the reduced work satisfaction and demotivation to perform the work activity. The contradictions that arise as a result affect negatively the team cooperation and obstruct the collaborative efforts in solving the problems in the healthcare setting. CONCLUSION: A conflict in a healthcare setting exerts a considerable destructive effect on an employee, therefore it requires prompt identification and effective intervention to minimise its unfavourable outcomes.

A comparison of HDR brachytherapy and IMRT techniques for dose escalation in prostate cancer: a radiobiological modeling study.

A course of one to three large fractions of high dose rate (HDR) interstitial brachytherapy is an attractive alternative to intensity modulated radiation therapy (IMRT) for delivering boost doses to the prostate in combination with additional external beam irradiation for intermediate risk disease. The purpose of this work is to quantitatively compare single-fraction HDR boosts to biologically equivalent fractionated IMRT boosts, assuming idealized image guided delivery (igIMRT) and conventional delivery (cIMRT). For nine prostate patients, both seven-field IMRT and HDR boosts were planned. The linear-quadratic model was used to compute biologically equivalent dose prescriptions. The cIMRT plan was evaluated as a static plan and with simulated random and setup errors. The authors conclude that HDR delivery produces a therapeutic ratio which is significantly better than the conventional IMRT and comparable to or better than the igIMRT delivery. For the HDR, the rectal gBEUD analysis is strongly influenced by high dose DVH tails. A saturation BED, beyond which no further injury can occur, must be assumed. Modeling of organ motion uncertainties yields mean outcomes similar to static plan outcomes.

Developments in megavoltage cone beam CT with an amorphous silicon EPID: reduction of exposure and synchronization with respiratory gating.

We have studied the feasibility of a low-dose megavoltage cone beam computed tomography (MV CBCT) system for visualizing the gross tumor volume in respiratory gated radiation treatments of nonsmall-cell lung cancer. The system consists of a commercially available linear accelerator (LINAC), an amorphous silicon electronic portal imaging device, and a respiratory gating system. The gantry movement and beam delivery are controlled using dynamic beam delivery toolbox, a commercial software package for executing scripts to control the LINAC. A specially designed interface box synchronizes the LINAC, image acquisition electronics, and the respiratory gating system. Images are preprocessed to remove artifacts due to detector sag and LINAC output fluctuations. We report on the output, flatness, and symmetry of the images acquired using different imaging parameters. We also examine the quality of three-dimensional (3D) tomographic reconstruction with projection images of anthropomorphic thorax, contrast detail, and motion phantoms. The results show that, with the proper choice of imaging parameters, the flatness and symmetry are reasonably good with as low as three beam pulses per projection image. Resolution of 5% electron density differences is possible in a contrast detail phantom using 100 projections and 30 MU. Synchronization of image acquisition with simulated respiration also eliminated motion artifacts in a moving phantom, demonstrating the system's capability for imaging patients undergoing gated radiation therapy. The acquisition time is limited by the patient's respiration (only one image per breathing cycle) and is under 10 min for a scan of 100 projections. In conclusion, we have developed a MV CBCT system using commercially available components to produce 3D reconstructions, with sufficient contrast resolution for localizing a simulated lung tumor, using a dose comparable to portal imaging.

Predicting respiratory motion for four-dimensional radiotherapy.

Adapting radiation delivery to respiratory motion is made possible through corrective action based on real-time feedback of target position during respiration. The advantage of this approach lies with its ability to allow tighter margins around the target while simultaneously following its motion. A significant hurdle to the successful implementation of real-time target-tracking-based radiation delivery is the existence of a finite time delay between the acquisition of target position and the mechanical response of the system to the change in position. Target motion during the time delay leads to a resultant lag in the system's response to a change in tumor position. Predicting target position in advance is one approach to ensure accurate delivery. The aim of this manuscript is to estimate the predictive ability of sinusoidal and adaptive filter-based prediction algorithms on multiple sessions of patient respiratory patterns. Respiratory motion information was obtained from recordings of diaphragm motion for five patients over 60 sessions. A prediction algorithm that employed both prediction models-the sinusoidal model and the adaptive filter model-was developed to estimate prediction accuracy over all the sessions. For each session, prediction error was computed for several time instants (response time) in the future (0-1.8 seconds at 0.2-second intervals), based on position data collected over several signal-history lengths (1-7 seconds at 1-second intervals). Based on patient data included in this study, the following observations are made. Qualitative comparison of predicted and actual position indicated a progressive increase in prediction error with an increase in response time. A signal-history length of 5 seconds was found to be the optimal signal history length for prediction using the sinusoidal model for all breathing training modalities. In terms of overall error in predicting respiratory motion, the adaptive filter model performed better than the sinusoidal model. With the adaptive filter, average prediction errors of less than 0.2 cm (1sigma) are possible for response times less than 0.4 seconds. In comparing prediction error with system latency error (no prediction), the adaptive filter model exhibited lesser prediction errors as compared to the sinusoidal model, especially for longer response time values (>0.4 seconds). At smaller response time values (<0.4 seconds), improvements in prediction error reduction are required for both predictive models in order to maximize gains in position accuracy due to prediction. Respiratory motion patterns are inherently complex in nature. While linear prediction-based prediction models perform satisfactorily for shorter response times, their prediction accuracy significantly deteriorates for longer response times. Successful implementation of real-time target-tracking-based radiotherapy requires response times less than 0.4 seconds or improved prediction algorithms.

Virtual planning of multicatheter brachytherapy implants for accelerated partial breast irradiation.

Over the last decade, increasing numbers of breast cancer patients are being treated using interstitial radioactive implants (brachytherapy). Multiple catheters are placed in the breast using a free-hand or template-guided approach. The configuration of the catheters and their relation to the tumor target volume are crucial to effective treatment. Catheter insertion requires a high level of experience to produce an implant of excellent quality. Construction of optimal catheter configuration prior to the procedure (virtual planning) would reduce the dependence of implant quality on the skill of the physician. Currently available commercial planning systems do not allow for virtual planning. We have developed software which inputs the target anatomy for a prospective patient and matches it to a previously-delivered catheter configuration from an institutional implant library. The archived catheter arrangement is then customized to fit the new target volume. The user can actually explore the implications of variations in catheter number and spatial arrangement. This may significantly improve the quality of implants that would otherwise be designed strictly based on a physician's prior experience. In an academic environment, this new resource could lead to better, faster results in the treatment of breast cancer.

Intraoperative dynamic dosimetry for prostate implants.

This paper describes analytic tools in support of a paradigm shift in brachytherapy treatment planning for prostate cancer--a shift from standard pre-planning to intraoperative planning using dosimetric feedback based on the actual deposited seed positions within the prostate. The method proposed is guided by several desiderata: (a) bringing both planning and evaluation in the operating room (i.e. make post-implant evaluation superfluous) therefore making rectifications--if necessary--still achievable; (b) making planning and implant evaluation consistent by using the same imaging system (ultrasound); and (c) using only equipment commonly found in a hospital operating room. The intraoperative dosimetric evaluation is based on the fusion between ultrasound images and 3D seed coordinates reconstructed from fluoroscopic projections. Automatic seed detection and registration of the fluoroscopic and ultrasound information, two of the three key ingredients needed for the intraoperative dynamic dosimetry optimization (IDDO), are explained in detail. The third one, the reconstruction of 3D coordinates from projections, was reported in a previous article. The algorithms were validated using a custom-designed phantom with non-radioactive (dummy) seeds. Also, fluoroscopic images were taken at the conclusion of an actual permanent prostate implant and compared with data on the same patient obtained from radiographic-based post-implant evaluation. To offset the effect of organ motion the comparison was performed in terms of the proximity function of the two seed distributions. The agreement between the intra- and post-operative seed distributions was excellent.

Operator-free, film-based 3D seed reconstruction in brachytherapy.

In brachytherapy implants, the accuracy of dose calculation depends on the ability to localize radioactive sources correctly. If performed manually using planar images, this is a time-consuming and often error-prone process-primarily because each seed must be identified on (at least) two films. In principle, three films should allow automatic seed identification and position reconstruction; however, practical implementation of the numerous algorithms proposed so far appears to have only limited reliability. The motivation behind this work is to create a fast and reliable system for real-time implant evaluation using digital planar images obtained from radiotherapy simulators, or mobile x-ray/fluoroscopy systems. We have developed algorithms and code for 3D seed coordinate reconstruction. The input consists of projections of seed positions in each of three isocentric images taken at arbitrary angles. The method proposed here consists of a set of heuristic rules (in a sense, a learning algorithm) that attempts to minimize seed misclassifications. In the clinic, this means that the system must be impervious to errors resulting from patient motion as well as from finite tolerances accepted in equipment settings. The software program was tested with simulated data, a pelvic phantom and patient data. One hundred and twenty permanent prostate implants were examined (105 125I and 15 103Pd) with the number of seeds ranging from 35 to 138 (average 79). The mean distance between actual and reconstructed seed positions is in the range 0.03-0.11 cm. On a Pentium III computer at 600 MHz the reconstruction process takes 10-30 s. The total number of seeds is independently validated. The process is robust and able to account for errors introduced in the clinic.

Cone-beam CT with megavoltage beams and an amorphous silicon electronic portal imaging device: potential for verification of radiotherapy of lung cancer.

We investigate the potential of megavoltage (MV) cone-beam CT with an amorphous silicon electronic portal imaging device (EPID) as a tool for patient position verification and tumor/organ motion studies in radiation treatment of lung tumors. We acquire 25 to 200 projection images using a 22 x 29 cm EPID. The acquisition is automatic and requires 7 minutes for 100 projections; it can be synchronized with respiratory gating. From these images, volumetric reconstruction is accomplished with a filtered backprojection in the cone-beam geometry. Several important prereconstruction image corrections, such as detector sag, must be applied. Tests with a contrast phantom indicate that differences in electron density of 2% can be detected with 100 projections, 200 cGy total dose. The contrast-to-noise ratio improves as the number of projections is increased. With 50 projections (100 cGy), high contrast objects are visible, and as few as 25 projections yield images with discernible features. We identify a technique of acquiring projection images with conformal beam apertures, shaped by a multileaf collimator, to reduce the dose to surrounding normal tissue. Tests of this technique on an anthropomorphic phantom demonstrate that a gross tumor volume in the lung can be accurately localized in three dimensions with scans using 88 monitor units. As such, conformal megavoltage cone-beam CT can provide three-dimensional imaging of lung tumors and may be used, for example, in verifying respiratory gated treatments.

Pain and syringomyelia: a review.

The pathophysiological basis of chronic pain syndromes remains poorly defined. Central and dysesthetic pain are probably the most disabling of sensory disturbances associated with syringomyelia, and, unfortunately, effective treatment remains elusive. In this paper, the authors review their institutional experience with both clinical and laboratory studies of patients with syringomyelia, and they review the relevant literature. To date, there is no consensus as to the best treatment for central cord pain syndromes, although there are many promising areas of current research involving the use of neurochemicals in the spinal cord.

Inflammation and intracranial aneurysms.

OBJECTIVE: An intracranial aneurysm is an important acquired cerebrovascular disease that can cause a catastrophic subarachnoid hemorrhage. Despite modern therapy, most patients die or are left disabled as a direct result of a severe initial hemorrhage. The development of more effective treatment strategies depends on understanding the fundamental biology of cerebral aneurysms. The purpose of the present study is to determine whether inflammation or immunological reaction occurs in cerebral aneurysms. METHODS: Aneurysm tissue was collected at the time of microsurgical repair from 23 unruptured and 2 ruptured aneurysms (25 patients) and compared with 11 control basilar arteries harvested at autopsy. Immunohistochemistry was used to localize complement (C3c, C9), immunoglobulins (IgG, IgM), vascular cell adhesion molecule-1, macrophages and monocytes (CD68), T lymphocytes (CD3), and B lymphocytes (CD20). RESULTS: Complement (C3c, P < 0.0001; C9, P = 0.0017), immunoglobulin (IgG, P = 0.0013; IgM, P = 0.031), vascular cell adhesion molecule-1 (P = 0.0022), macrophages (CD68, P = 0.004), and T lymphocytes (CD3, P = 0.0004) were all frequently present in the wall of aneurysm tissue but were rarely identified in control basilar arteries. A few B lymphocytes (CD20, P = 0.41) were found in aneurysm tissue, but none were found in the basilar arteries. CONCLUSION: Extensive inflammatory and immunological reactions are common in unruptured intracranial aneurysms and may be related to aneurysm formation and rupture.

Identification of a serum gelatinase associated with the occurrence of cerebral aneurysms as pro-matrix metalloproteinase-2.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage from intracranial aneurysm rupture produces a severe form of stroke. Extracellular matrix remodeling is associated with cerebral aneurysms and may play a role in the formation or rupture of these lesions. We previously reported a 3-fold increase in a 72-kDa serum gelatinase in a subgroup of aneurysm patients. The purpose of the present study was to further characterize and identify this gelatinase. METHODS: Serum samples were collected from surgical patients with intracranial aneurysms. The following series of experiments was designed to further characterize and identify the predominant serum gelatinase found in the subgroup of patients with increased gelatinase activity. Gelatin zymography was performed on native serum samples and compared with serum that had been pretreated with a known metalloproteinase activator (4-aminophenylmercuric acetate [APMA]). Gelatin zymography was repeated in the presence of a matrix metalloproteinase (MMP) inhibitor (EDTA) and a serine proteinase inhibitor (phenylmethylsulfonyl fluoride [PMSF]). Final identification was made by Western blotting with the use of monoclonal antibodies to MMP-2 and MMP-9. RESULTS: A consistent gelatinolytic band (72 kDa) was identified in all serum samples (n = 60). Pretreatment of the serum by APMA (n = 60) lowered the molecular weight of the band to 66 kDa. The band was inhibited by EDTA (n = 10) but not PMSF (n = 10), thus characterizing the circulating 72-kDa gelatinase as an inactive pro-MMP. Western blotting (n=20) identified the 72-kDa band as MMP-2. CONCLUSIONS: These findings confirm that the increased gelatinolytic activity observed in vitro in a subset of cerebral aneurysm patients is due to pro-MMP-2.