Challenges and opportunities for implementing hypofractionated radiotherapy in Africa: lessons from the HypoAfrica clinical trial.

The rising cancer incidence and mortality in sub-Saharan Africa (SSA) warrants an increased focus on adopting or developing approaches that can significantly increase access to treatment in the region. One such approach recommended by the recent Lancet Oncology Commission for sub-Saharan Africa is hypofractionated radiotherapy (HFRT), which can substantially increase access to radiotherapy by reducing the overall duration of time (in days) each person spends being treated. Here we highlight challenges in adopting such an approach identified during the implementation of the HypoAfrica clinical trial. The HypoAfrica clinical trial is a longitudinal, multicentre study exploring the feasibility of applying HFRT for prostate cancer in SSA. This study has presented an opportunity for a pragmatic assessment of potential barriers and facilitators to adopting HFRT. Our results highlight three key challenges: quality assurance, study harmonisation and machine maintenance. We describe solutions employed to resolve these challenges and opportunities for longer term solutions that can facilitate scaling-up use of HFRT in SSA in clinical care and multicentre clinical trials. This report provides a valuable reference for the utilisation of radiotherapy approaches that increase access to treatment and the conduct of high-quality large-scale/multi-centre clinical trials involving radiotherapy. Trial registration: Not available yet.

Evaluation of Respiratory Sounds Using Image-Based Approaches for Health Measurement Applications.

Goal: The evaluation of respiratory events using audio sensing in an at-home setting can be indicative of worsening health conditions. This paper investigates the use of image-based transfer learning applied to five audio visualizations to evaluate three classification tasks (C1: wet vs. dry vs. whooping cough vs. restricted breathing; C2: wet vs. dry cough; C3: cough vs. restricted breathing). Methods: The five visualizations (linear spectrogram, logarithmic spectrogram, Mel-spectrogram, wavelet scalograms, and aggregate images) are applied to a pre-trained AlexNet image classifier for all tasks. Results: The aggregate image-based classifier achieved the highest overall performance across all tasks with C1, C2, and C3 having testing accuracies of 0.88, 0.88, and 0.91 respectively. However, the Mel-spectrogram method had the highest testing accuracy (0.94) for C2. Conclusions: The classification of respiratory events using aggregate image inputs to transfer learning approaches may help healthcare professionals by providing information that would otherwise be unavailable to them.

Fuzzy analytic hierarchy process-based risk priority number for risk assessments of commissioning process of a ring gantry LINAC.

PURPOSE: We propose a fuzzy analytic hierarchy process (AHP)-based risk priority number (RPN) method in failure modes and effects analysis (FMEA) to overcome the shortcomings of traditional RPN-based FMEA. Our research group has previously published the FMEA to mitigate the failure modes (FMs) for the commissioning process of a ring gantry LINAC. However, inter-relationships among FMs were observed in high ranked FMs due to a heavy reliance on imaging system. METHODS: Fuzzy AHP was applied to determine relative weights of risk impacts based on inter-relationships among FMs. Since the time sequence dependency is a major factor for risk factors, a hierarchical structure of AHP was used to reflect the directional impacts such as causal influence and feedback loop. Two fuzzy weighted RPNs, called (RPNW and FRPNW , were calculated depending on the input values of severity (S), occurrence (O), and probability of not being detected (D) from the evaluators. The RPNW used numerical values, whereas the fuzzy values were used for FRPNW . Both RPNs were calculated by multiplying the weighted O, S, and D using the fuzzy AHP method. RESULTS: The differences between the two fuzzy RPN rankings are due to inherent fuzzy uncertainty and deviations in O, S, and D values submitted by the evaluators. Considering all results of traditional and fuzzy-based FMEA, the two most highly ranked FMs were identified: errors in determining the non-isocentric SSD and SSD from MV images because of the unique features of the ring gantry LINAC. CONCLUSION: This study has demonstrated the feasibility of the use of a fuzzy AHP-based RPN to perform comprehensive analysis and prioritization of FMs. The risk analysis using fuzzy AHP can be improved and/or refined based on the department's specific workflow and clinical preferences taking various priority weighting approaches into account.

A Topical Mitochondria-Targeted Redox-Cycling Nitroxide Mitigates Oxidative Stress-Induced Skin Damage.

Skin is the largest human organ, and it provides a first line of defense that includes physical, chemical, and immune mechanisms to combat environmental stress. Radiation is a prevalent environmental stressor. Radiation-induced skin damage ranges from photoaging and cutaneous carcinogenesis caused by UV exposure, to treatment-limiting radiation dermatitis associated with radiotherapy, to cutaneous radiation syndrome, a frequently fatal consequence of exposures from nuclear accidents. The major mechanism of skin injury common to these exposures is radiation-induced oxidative stress. Efforts to prevent or mitigate radiation damage have included development of antioxidants capable of reducing reactive oxygen species. Mitochondria are particularly susceptible to oxidative stress, and mitochondrial-dependent apoptosis plays a major role in radiation-induced tissue damage. We reasoned that targeting a redox cycling nitroxide to mitochondria could prevent reactive oxygen species accumulation, limiting downstream oxidative damage and preserving mitochondrial function. Here we show that in both mouse and human skin, topical application of a mitochondrially targeted antioxidant prevents and mitigates radiation-induced skin damage characterized by clinical dermatitis, loss of barrier function, inflammation, and fibrosis. Further, damage mitigation is associated with reduced apoptosis, preservation of the skin's antioxidant capacity, and reduction of irreversible DNA and protein oxidation associated with oxidative stress.

Flattening filter-free accelerators: a report from the AAPM Therapy Emerging Technology Assessment Work Group.

This report describes the current state of flattening filter-free (FFF) radiotherapy beams implemented on conventional linear accelerators, and is aimed primarily at practicing medical physicists. The Therapy Emerging Technology Assessment Work Group of the American Association of Physicists in Medicine (AAPM) formed a writing group to assess FFF technology. The published literature on FFF technology was reviewed, along with technical specifications provided by vendors. Based on this information, supplemented by the clinical experience of the group members, consensus guidelines and recommendations for implementation of FFF technology were developed. Areas in need of further investigation were identified. Removing the flattening filter increases beam intensity, especially near the central axis. Increased intensity reduces treatment time, especially for high-dose stereotactic radiotherapy/radiosurgery (SRT/SRS). Furthermore, removing the flattening filter reduces out-of-field dose and improves beam modeling accuracy. FFF beams are advantageous for small field (e.g., SRS) treatments and are appropriate for intensity-modulated radiotherapy (IMRT). For conventional 3D radiotherapy of large targets, FFF beams may be disadvantageous compared to flattened beams because of the heterogeneity of FFF beam across the target (unless modulation is employed). For any application, the nonflat beam characteristics and substantially higher dose rates require consideration during the commissioning and quality assurance processes relative to flattened beams, and the appropriate clinical use of the technology needs to be identified. Consideration also needs to be given to these unique characteristics when undertaking facility planning. Several areas still warrant further research and development. Recommendations pertinent to FFF technology, including acceptance testing, commissioning, quality assurance, radiation safety, and facility planning, are presented. Examples of clinical applications are provided. Several of the areas in which future research and development are needed are also indicated.

Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs.

Intervertebral disc degeneration (IDD) is the leading cause of debilitating spinal disorders such as chronic lower back pain. Aging is the greatest risk factor for IDD. Previously, we demonstrated IDD in a murine model of a progeroid syndrome caused by reduced expression of a key DNA repair enzyme. This led us to hypothesize that DNA damage promotes IDD. To test our hypothesis, we chronically exposed adult wild-type (Wt) and DNA repair-deficient Ercc1(-/Δ) mice to the cancer therapeutic agent mechlorethamine (MEC) or ionization radiation (IR) to induce DNA damage and measured the impact on disc structure. Proteoglycan, a major structural matrix constituent of the disc, was reduced 3-5× in the discs of MEC- and IR-exposed animals compared to untreated controls. Expression of the protease ADAMTS4 and aggrecan proteolytic fragments was significantly increased. Additionally, new PG synthesis was reduced 2-3× in MEC- and IR-treated discs compared to untreated controls. Both cellular senescence and apoptosis were increased in discs of treated animals. The effects were more severe in the DNA repair-deficient Ercc1(-/Δ) mice than in Wt littermates. Local irradiation of the vertebra in Wt mice elicited a similar reduction in PG. These data demonstrate that genotoxic stress drives degenerative changes associated with IDD.

Acoustic breath-phase detection using tracheal breath sounds.

Current breathing flow estimation methods use tracheal breath sounds, but one step of the process, 'breath phase (inspiration/expiration) detection', is done by either assuming alternating breath phases or using a second acoustic channel of lung sounds. The alternating assumption is unreliable for long recordings, non-breathing events, such as apnea, swallow or cough change the alternating nature of the phases. Using lung sounds intensity requires the addition of a secondary channel and the associated labor. Hence, an automatic and accurate method for breath-phase detection using only tracheal sounds would be of great benefit. We present a method using several breath sound parameters to differentiate between the two respiratory phases. The proposed method is novel and independent of flow level; it requires only one prior- and one post-breath sound segment to identify the phase. The proposed method was tested on data from 93 healthy individuals, without any history of pulmonary diseases breathing at 4 different flow levels. The most prominent features were from the duration, volume and shape of the sound envelope. This method has shown an accuracy of 95.6% with 95.5% sensitivity and 95.6% specificity for breath-phase identification without assuming breath-phase-alteration and/or using any other information.

Automatic breath phase detection using only tracheal sounds.

While automatic distinction between the two breath phases (inspiration/expiration) can be done easily using lung sounds' intensity, it is challenging to do the same using only tracheal breath sounds. The current acoustic flow estimation methods use tracheal breath sounds to estimate the amount of flow and the onset of breath but also use lung sounds for respiratory phase identification. It would be advantageous to have an automatic and accurate method to identify breath phases from the tracheal signal. One may argue that given the alternation of respiratory phases, breath phase identification from tracheal sounds would be an easy task if one knows the first phase. However, during breathing, an event such as apnea, swallowing, or coughing may change the alternating nature of breath phases. In this study we have investigated several parameters derived from the phase duration, the shape of the sound envelope within each phase, and the sound's intensity in each phase, to develop a reliable method to differentiate between the two respiratory phases using only tracheal breath sounds. We used data from 6 healthy individuals, without any history of pulmonary diseases at 4 different flow levels (shallow, tidal, medium and very high). The most prominent features were found to be those derived from the duration, area and shape of the sound envelope in each phase. With a voting equation using the three most prominent features, our proposed method has shown an accuracy of 93.1% with sensitivity of 93.4% and specificity of 92.8% for breath phase identification without the need for assuming breath phase alteration.

Synchrony--cyberknife respiratory compensation technology.

Studies of organs in the thorax and abdomen have shown that these organs can move as much as 40 mm due to respiratory motion. Without compensation for this motion during the course of external beam radiation therapy, the dose coverage to target may be compromised. On the other hand, if compensation of this motion is by expansion of the margin around the target, a significant volume of normal tissue may be unnecessarily irradiated. In hypofractionated regimens, the issue of respiratory compensation becomes an important factor and is critical in single-fraction extracranial radiosurgery applications. CyberKnife is an image-guided radiosurgery system that consists of a 6-MV LINAC mounted to a robotic arm coupled through a control loop to a digital diagnostic x-ray imaging system. The robotic arm can point the beam anywhere in space with 6 degrees of freedom, without being constrained to a conventional isocenter. The CyberKnife has been recently upgraded with a real-time respiratory tracking and compensation system called Synchrony. Using external markers in conjunction with diagnostic x-ray images, Synchrony helps guide the robotic arm to move the radiation beam in real time such that the beam always remains aligned with the target. With the aid of Synchrony, the tumor motion can be tracked in three-dimensional space, and the motion-induced dosimetric change to target can be minimized with a limited margin. The working principles, advantages, limitations, and our clinical experience with this new technology will be discussed.

Should Younger Siblings of Peanut-Allergic Children Be Assessed by an Allergist before Being Fed Peanut?

: The objective of this study was to determine the risk of peanut allergy in siblings of peanut-allergic children. In 2005-2006, 560 households of children born in 1995 in the province of Manitoba, Canada, were surveyed. The index children (8-to 10-year-olds) were assessed by a pediatric allergist and had skin-prick testing and/or capRAST for peanut allergy. Surveys were completed by parents for siblings to determine the presence of peanut allergy. Of 560 surveys, 514 (92%) were completed. Twenty-nine (5.6%) index children were peanut allergic. Fifteen of 900 (1.7%) siblings had peanut allergy. Four of 47 (8.5%) were siblings of peanut-allergic children and 11 of 853 (1.3%) were siblings of non-peanut-allergic children. The risk of peanut allergy was markedly increased in siblings of a peanut-allergic child (odds ratio 6.72, 95% confidence interval 2.04-22.12). Siblings of peanut-allergic children are much more likely to be allergic to peanut. An allergy assessment by a qualified allergist should be routinely recommended before feeding peanut to these children.

Clinical implementation of tangential field intensity modulated radiation therapy (IMRT) using sliding window technique and dosimetric comparison with 3D conformal therapy (3DCRT) in breast cancer.

The purpose of this study was to evaluate the clinical implementation of tangential field IMRT using sliding window technique and to compare dosimetric parameters with 3-dimensional conformal radiation therapy (3DCRT). Twenty breast cancer patients were randomly selected for comparison of intensity modulated radiation therapy (IMRT)-based treatment plan with 3DCRT. Inverse treatment was performed using the sliding window technique, employing the Eclipse Planning System (version 7.1.59, Varian, Palo Alto, CA). The dosimetric parameters compared were V(95) (the percentage of target volume getting > or =95% of prescribed dose), V(105), V(110), and dose homogeneity index, DHI (percentage of target volume getting between 95% and 110% of prescribed dose). The mean V(95), DHI, V(105), and V(110) for target volume for IMRT vs. 3D were 90.6% (standard deviation [SD]: 3.2) vs. 91% (SD: 3.0), 87.7 (SD: 6.0) vs. 82.6 (SD: 7.8), 27.3% (SD: 20.3) vs. 49.4% (SD: 14.3), and 2.8 (SD: 5.6) vs. 8.4% (SD: 7.4), respectively. DHI was increased by 6.3% with IMRT compared to 3DCRT (p < 0.05). The reductions of V(105) and V(110) for the IMRT compared to 3DCRT were 44.7% and 66.3%, respectively (p < 0.01). The mean dose and V(30) for heart with IMRT were 2.3 (SD: 1.1) and 1.05 (SD: 1.5) respectively, which was a reduction by 6.8% and 7.9%, respectively, in comparison with 3D. Similarly, the mean dose and V(20) for the ipsilateral lung and the percentage of volume of contralateral volume lung receiving > 5% of prescribed dose with IMRT were reduced by 9.9%, 2.2%, and 35%, respectively. The mean of total monitor units used for IMRT and 3DCRT was about the same (397 vs. 387). The tangential field IMRT for intact breast using sliding window technique was successfully implemented in the clinic. We have now treated more than 1000 breast cancer patients with this technique. The dosimetric data suggest improved dose homogeneity in the breast and reduction in the dose to lung and heart for IMRT treatments, which may be of clinical value in potentially contributing to improved cosmetic results and reduced late treatment-related toxicity.

Performance characteristics and quality assurance aspects of kilovoltage cone-beam CT on medical linear accelerator.

A medical linear accelerator equipped with optical position tracking, ultrasound imaging, portal imaging, and radiographic imaging systems was installed at University of Pittsburgh Cancer Institute for the purpose of performing image-guided radiation therapy (IGRT) and image-guided radiosurgery (IGRS) in October 2005. We report the performance characteristics and quality assurance aspects of the kilovoltage cone-beam computed tomography (kV-CBCT) technique. This radiographic imaging system consists of a kilovoltage source and a large-area flat panel amorphous silicon detector mounted on the gantry of the medical linear accelerator via controlled arms. The performance characteristics and quality assurance aspects of this kV-CBCT technique involves alignment of the kilovoltage imaging system to the isocenter of the medical linear accelerator and assessment of (a) image contrast, (b) spatial accuracy of the images, (c) image uniformity, and (d) computed tomography (CT)-to-electron density conversion relationship were investigated. Using the image-guided tools, the alignment of the radiographic imaging system was assessed to be within a millimeter. The low-contrast resolution was found to be a 6-mm diameter hole at 1% contrast level and high-contrast resolution at 9 line pairs per centimeter. The spatial accuracy (50 mm +/- 1%), slice thickness (2.5 mm and 5.0 mm +/- 5%), and image uniformity (+/- 20 HU) were found to be within the manufacturer's specifications. The CT-to-electron density relationship was also determined. By using well-designed procedures and phantom, the number of parameter checks for quality assurance of the IGRT system can be carried out in a relatively short time.

Determination of CT-to-density conversion relationship for image-based treatment planning systems.

The implementation of tissue inhomogeneity correction in image-based treatment planning will improve the accuracy of radiation dose calculations for patients undergoing external-beam radiotherapy. Before the tissue inhomogeneity correction can be applied, the relationship between the computed tomography (CT) value and density must be established. This tissue characterization relationship allows the conversion of CT value in each voxel of the CT images into density for use in the dose calculations. This paper describes the proper procedure of establishing the CT value to density conversion relationship. A tissue characterization phantom with 17 inserts made of different materials was scanned using a GE Lightspeed Plus CT scanner (120 kVp). These images were then downloaded into the Eclipse and Pinnacle treatment planning systems. At the treatment planning workstation, the axial images were retrieved to determine the CT value of the inserts. A region of interest was drawn on the central portion of the insert and the mean CT value and its standard deviation were determined. The mean CT value was plotted against the density of the tissue inserts and fitted with bilinear equations. A new set of CT values vs. densities was generated from the bilinear equations and then entered into the treatment planning systems. The need to obtain CT values through the treatment planning system is very clear. The 2 treatment planning systems use different CT value ranges, one from -1024 to 3071 and the other from 0 to 4096. If the range is correct, it would result in inappropriate use of the conversion curve. In addition to the difference in the range of CT values, one treatment planning system uses physical density, while the other uses relative electron density.

Ionization chamber volume averaging effects in dynamic intensity modulated radiation therapy beams.

The commercial cylindrical ionization chamber ionization integration accuracy of dynamically moving fields was evaluated. The ionization chambers were exposed to long (14 cm), narrow (0.6, 1.0, 2.0, and 4.0 cm) 6 MV and 18 MV fields. Rather than rely on the linear accelerator to reproducibly scan across the chamber, the chambers were scanned beneath fixed portals. A water-equivalent phantom was constructed with cavities that matched the chambers and placed on a computer-controlled one-dimensional table. Computer-controlled electrometers were utilized in continuous charge integrate mode, with 10 samples of the charge, along with time stamps, acquired for each chamber location. A reference chamber was placed just beneath the linear accelerator jaws to adjust for variations in linear accelerator dose rate. The scan spatial resolution was selected to adequately sample regions of steep dose gradient and second spatial derivative (curvature). A fixed measurement in a 10 x 10 cm2 field was used to normalize the profiles to absolute chamber response. Three ionization chambers were tested, a microchamber (0.009 cm3), a Farmer chamber (0.6 cm3) and a waterproof scanning chamber (0.125 cm3). The larger chambers exhibited severe under-response at the small field's centers, but all of the chambers, independent of orientation, accurately integrated the ionization across the scanned portal. This indicates that the tested ionization chambers provide accurate integrated charges in regions of homogeneous dose regions. Partial integration (less than the field width plus the chamber length plus 2 cm), yielded integration errors of greater than 1% and 2% for 6 MV and 18 MV, respectively, with errors for the Farmer chamber of greater than 10% even for the 4 cm wide field.