Robust treatment planning in whole pelvis pencil beam scanning proton therapy for prostate cancer.

Whole-pelvis pencil beam scanning (PBS) proton therapy is utilized in both the intact and post-operative settings in patients with prostate cancer. As whole pelvis prostate radiotherapy has traditionally been delivered with standard photon beams, limited evidence and technical descriptions have been reported regarding the use of proton therapy. Here we present two robust three-field treatment planning approaches utilized to maximize target coverage in the presence of anatomic and delivery uncertainties. Both techniques, conventional optimization (CO) and robust optimization (RO), create treatment plans with acceptable target coverage and sparing of organs at risk (OAR). While the RO method is less time intensive and may theoretically allow for superior OAR sparing and improved robustness, the CO method can be implemented by institutions who do not have RO capabilities.

Twists, turns and trade: A new look at the Indian Screw tree (Helicteres isora).

ETHNOPHARMACOLOGICAL RELEVANCE: This is the first study of global trade in fruits of the widely used traditional medicine, Helicteres isora L. It is used in Ayurvedic, Siddha, Unani medical systems and/or local folk traditional medicines in Bangladesh, India and Pakistan. The roots are used in Traditional Chinese Medicines in China and the fruits in jamu products in Indonesia, Malaysia and Thailand. In addition, H. isora fruits are also used in "traditional" medical systems far beyond the natural distribution of this species, for example in Zulu herbal medicine (South Africa) and Kurdish herbal medicines (Iraq). AIMS OF THE STUDY: This study had three aims: (i) to assess the global trade in H. isora fruits; (ii) to study the H. isora trade from West Timor to Java in terms of actors and prices along the value chain and (iii) to get a better understanding of the potential of this species to improve household income in eastern Indonesia. MATERIALS AND METHODS: This study uses historical records, a contemporary analysis of global trade data (2014-2016) and field assessments of value chains and the biological factors influencing H. isora fruit production. RESULTS: Globally, the major exporter of H. isora fruits is India, which exports H. isora fruits to 19 countries, far beyond the natural geographical distribution of this species. Over a 36-month period (January 2014-December 2016), India exported 392 t of H. isora fruits, with a Free-On-Board (FOB) value of Indian rupiah (INR) 18,337,000 (US$ 274,055). This represents an average annual export quantity of about 130,526 kg/year. Over this three year period, most of these exports (85.5%) were to Indonesia (346.58 t), followed by Thailand (6.85%). Indian H. isora exports are also used in many other medical systems, including Kurdish and Zulu "traditional" medicines in Iraq and South Africa. Formation of an Indian diaspora in Bahrain, Mauritius, South Africa, Tanzania and Trinidad and Tobago over the past 130 years is one of the drivers of H. isora fruit trade outside the natural geographic distribution of the species. In Indonesia, demand for H. isora fruits is supplemented by an intra-island trade in Java and an inter-island trade from East Nusa Tenggara. West Timor, for example, exports around 31-37 t of air-dried H. isora fruits per year to Java. At the farm gate, local harvesters in West Timor get 4000 IDR (c. 0.3 US$) per kg, with businesses in Java paying 25,000 IDR (c.US$2) per kg for H. isora fruits. This is similar to the price paid for H. isora fruits imported from India to Java. CONCLUSIONS: India is the major exporter of whole dried H. isora fruits, including to countries where this species has never been in traditional use. In Indonesia, H. isora fruit extracts are used in the cosmetic industry as well as in jamu herbal medicines, including "Tolak Angin", the country's most popular commercial "jamu" preparation. Indonesia also is the major importer of H. isora fruits from India. In eastern Indonesia, improved income to local villagers from the H. isora fruit trade could come from improved H. isora fruit quality due to better drying techniques. This would also reduce health risks along the supply chain from to mycotoxins that have been recorded on poorly dried H. isora fruits. There also is an opportunity for cultivation of H. isora in small-holder teak plantations in Indonesia, with harvest of H. isora fruits as well as the medicinal bark.

Cost-effective immobilization for whole brain radiation therapy.

To investigate the inter- and intra-fraction motion associated with the use of a low-cost tape immobilization technique as an alternative to thermoplastic immobilization masks for whole-brain treatments. The results of this study may be of interest to clinical staff with severely limited resources (e.g., in low-income countries) and also when treating patients who cannot tolerate standard immobilization masks. Setup reproducibility of eight healthy volunteers was assessed for two different immobilization techniques. (a) One strip of tape was placed across the volunteer's forehead and attached to the sides of the treatment table. (b) A second strip was added to the first, under the chin, and secured to the table above the volunteer's head. After initial positioning, anterior and lateral photographs were acquired. Volunteers were positioned five times with each technique to allow calculation of inter-fraction reproducibility measurements. To estimate intra-fraction reproducibility, 5-minute anterior and lateral videos were taken for each technique per volunteer. An in-house software was used to analyze the photos and videos to assess setup reproducibility. The maximum intra-fraction displacement for all volunteers was 2.8 mm. Intra-fraction motion increased with time on table. The maximum inter-fraction range of positions for all volunteers was 5.4 mm. The magnitude of inter-fraction and intra-fraction motion found using the "1-strip" and "2-strip" tape immobilization techniques was comparable to motion restrictions provided by a thermoplastic mask for whole-brain radiotherapy. The results suggest that tape-based immobilization techniques represent an economical and useful alternative to the thermoplastic mask.

The influence of non-rigid anatomy and patient positioning on endoscopy-CT image registration in the head and neck.

PURPOSE: To assess the influence of non-rigid anatomy and differences in patient positioning between CT acquisition and endoscopic examination on endoscopy-CT image registration in the head and neck. METHODS: Radiotherapy planning CTs and 31-35 daily treatment-room CTs were acquired for nineteen patients. Diagnostic CTs were acquired for thirteen of the patients. The surfaces of the airways were segmented on all scans and triangular meshes were created to render virtual endoscopic images with a calibrated pinhole model of an endoscope. The virtual images were used to take projective measurements throughout the meshes, with reference measurements defined as those taken on the planning CTs and test measurements defined as those taken on the daily or diagnostic CTs. The influence of non-rigid anatomy was quantified by 3D distance errors between reference and test measurements on the daily CTs, and the influence of patient positioning was quantified by 3D distance errors between reference and test measurements on the diagnostic CTs. The daily CT measurements were also used to investigate the influences of camera-to-surface distance, surface angle, and the interval of time between scans. RESULTS: Average errors in the daily CTs were 0.36 ± 0.61 cm in the nasal cavity, 0.58 ± 0.83 cm in the naso- and oropharynx, and 0.47 ± 0.73 cm in the hypopharynx and larynx. Average errors in the diagnostic CTs in those regions were 0.52 ± 0.69 cm, 0.65 ± 0.84 cm, and 0.69 ± 0.90 cm, respectively. All CTs had errors heavily skewed towards 0, albeit with large outliers. Large camera-to-surface distances were found to increase the errors, but the angle at which the camera viewed the surface had no effect. The errors in the Day 1 and Day 15 CTs were found to be significantly smaller than those in the Day 30 CTs (P < 0.05). CONCLUSIONS: Inconsistencies of patient positioning have a larger influence than non-rigid anatomy on projective measurement errors. In general, these errors are largest when the camera is in the superior pharynx, where it sees large distances and a lot of muscle motion. The errors are larger when the interval of time between CT acquisitions is longer, which suggests that the interval of time between the CT acquisition and the endoscopic examination should be kept short. The median errors found in this study are comparable to acceptable levels of uncertainty in deformable CT registration. Large errors are possible even when image alignment is very good, indicating that projective measurements must be made carefully to avoid these outliers.

The feasibility of endoscopy-CT image registration in the head and neck without prospective endoscope tracking.

PURPOSE: Endoscopic examinations are frequently-used procedures for patients with head and neck cancer undergoing radiotherapy, but radiation treatment plans are created on computed tomography (CT) scans. Image registration between endoscopic video and CT could be used to improve treatment planning and analysis of radiation-related normal tissue toxicity. The purpose of this study was to explore the feasibility of endoscopy-CT image registration without prospective physical tracking of the endoscope during the examination. METHODS: A novel registration technique called Location Search was developed. This technique uses physical constraints on the endoscope's view direction to search for the virtual endoscope coordinates that maximize the similarity between the endoscopic video frame and the virtual endoscopic image. Its performance was tested on phantom and patient images and compared to an established registration technique, Frame-To-Frame Tracking. RESULTS: In phantoms, Location Search had average registration errors of 0.55 ± 0.60 cm for point measurements and 0.29 ± 0.15 cm for object surface measurements. Frame-To-Frame Tracking achieved similar results on some frames, but it failed on others due to the virtual endoscope becoming lost. This weakness was more pronounced in patients, where Frame-To-Frame tracking could not make it through the nasal cavity. On successful patient video frames, Location Search was able to find endoscope positions with an average distance of 0.98 ± 0.53 cm away from the ground truth positions. However, it failed on many frames due to false similarity matches caused by anatomical structural differences between the endoscopic video and the virtual endoscopic images. CONCLUSIONS: Endoscopy-CT image registration without prospective physical tracking of the endoscope is possible, but more development is required to achieve an accuracy suitable for clinical translation.

Calculations and measurements of the scintillator-to-water stopping power ratio of liquid scintillators for use in proton radiotherapy.

Liquid scintillators are a promising detector for high-resolution three-dimensional proton therapy dosimetry. Because the scintillator comprises both the active volume of the detector and the phantom material, an ideal scintillator will exhibit water equivalence in its radiological properties. One of the most fundamental of these is the scintillator's stopping power. The objective of this study was to compare calculations and measurements of scintillator-to-water stopping power ratios to evaluate the suitability of the liquid scintillators BC-531 and OptiPhase HiSafe 3 for proton dosimetry. We also measured the relative scintillation output of the two scintillators. Both calculations and measurements show that the linear stopping power of OptiPhase is significantly closer to water than that of BC-531. BC-531 has a somewhat higher scintillation output. OptiPhase can be mixed with water at high concentrations, which further improves its scintillator-to-water stopping power ratio. However, this causes the solution to become cloudy, which has a negative impact on the scintillation output and spatial resolution of the detector. OptiPhase is preferred over BC-531 for proton dosimetry because its density and scintillator-to-water stopping power ratio are more water equivalent.

SU-E-T-116: The Water Equivalence of Organic Liquid Scintillators for Proton Dosimetry.

PURPOSE: Organic liquid scintillators are currently under investigation for use in proton dosimetry. The purpose of this work is to evaluate the water equivalence of these materials as a preliminary step to identify scintillators that are well-suited to this purpose. METHODS: Stopping powers were calculated for 0.001-1000 MeV protons in water, polystyrene, and two organic liquid scintillators: BC-531 and OptiPhase 'Hi-Safe' 3 at 0%, 25%, and 50% concentrations of water. Angular scatter was quantified by theta0, a characteristic multiple Coulomb scattering angle analogous to the standard deviation of a Gaussian distribution of proton angles relative to the incident beam axis. Theta0 was calculated as a function of depth over the range of 200 MeV protons in these materials. RESULTS: Collisional stopping power in BC-531 ranged from +44% to +1% ofthat in water. It remained within 6% from 2-600 MeV. OptiPhase ranged from +24% to -2%, with smaller deviations at increased water concentrations. At all concentrations, OptiPhase showed smaller deviations than polystyrene and BC-531 and remained within 1% of water from 2-600 MeV.Theta0 was very similar for all materials, with deviations from water of 5 milliradians or less over the majority of the proton range. BC-531 showed deviations of 10 milliradians or more in the last few millimeters of the range. OptiPhase showed smaller deviations than BC-531 or polystyrene, and these deviations decreased with increasing water concentration. CONCLUSIONS: OptiPhase was found to be more water equivalent than BC-531 or polystyrene in stopping power and angular scatter, and increased water concentration improved both quantities. Large deviations in stopping power were only found below 2 MeV for any material, where proton range is less than 0.1 millimeter. The deviations from water found in angular scatter were less significant, and probably too small to affect measurement.

Impact of pretransplant comorbidities on alemtuzumab-based reduced-intensity conditioning allogeneic hematopoietic SCT for patients with high-risk myelodysplastic syndrome and AML.

We report a retrospective analysis of 128 consecutive patients with high-risk myelodysplastic syndrome (MDS) and AML who received an alemtuzumab-based reduced-intensity conditioning hematopoietic SCT (RIC HSCT). The median recipient age was 53 years (range 21-72 years). A total of 49 (38%) recipients had a sibling donor and 79 (62%) had a volunteer-unrelated donor. The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was assigned to all patients with a score of 0 in 40 (31%), of 1-2 in 45 (35%) and >or=3 in 43 (34%) patients. The 3-year non-relapse mortality (NRM) was 31%, disease-free survival (DFS) was 41% and overall survival (OS) was 46%. The 3-year NRM for patients with a HCT-CI score of 0, 1-2 or >or=3 was 16, 24 and 42%, respectively. The 3-year DFS and OS by HCT-CI was 58 and 69% (score 0), 39 and 39% (score 1-2) and 24 and 32% (score >or=3), respectively. On multivariate analysis, HCT-CI was an independent variable affecting 3-year NRM, DFS and OS (P-value=0.04, 0.01 and <0.01, respectively). Although the disease stage at the time of transplant was an additional independent predictive variable on transplant outcomes, recipient age (>or<50 years) did not have a significant predictive impact. In MDS or AML patients with advanced disease receiving alemtuzumab-based RIC HSCT, the HCT-CI provides an important means of stratifying patients with a high risk of inferior transplant outcomes.

Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling.

Aberrant regulation of signalling mechanisms that normally orchestrate embryonic development, such as the Hedgehog, Wnt and Notch pathways, is a common feature of tumorigenesis. In order to better understand the neoplastic events mediated by Hedgehog signalling, we identified over 200 genes regulated by Sonic Hedgehog in multipotent mesodermal cells. Widespread crosstalk with other developmental signalling pathways is evident, suggesting a complex network of interactions that challenges the often over-simplistic representation of these pathways as simple linear entities. Hes1, a principal effector of the Notch pathway, was found to be a target of Sonic Hedgehog in both C3H/10T1/2 mesodermal and MNS70 neural cells. Desert Hedgehog also elicited a strong Hes1 response. While Smoothened function was found necessary for upregulation of Hes1 in response to Sonic Hedgehog, the mechanism does not require gamma-secretase-mediated cleavage of Notch receptors, and appears to involve transcription factors other than RBP-Jkappa. Thus, we have defined a novel mechanism for Hes1 regulation in stem-like cells that is independent of canonical Notch signalling.

Clonal gammopathies following alemtuzumab-based reduced intensity conditioning haematopoietic stem cell transplantation: association with chronic graft-versus-host disease and improved overall survival.

The presence of clonal gammopathies (CG) has been reported following both conventional myeloablative and autologous haematopoietic stem cell transplantation (HSCT). We monitored the occurrence of CG in a cohort of patients with myeloid malignancies receiving FBC (fludarabine-busulphan-alemtuzumab)-based reduced intensity conditioned (RIC) HSCT, and assessed its correlation with infections, graft-versus-host disease (GvHD) and survival. Serial serum protein electrophoresis was analysed in a total of 138 patients and CG were detected in 49 patients (36%). The predominant Ig isotype was IgG (82%). There was no difference in the incidence of viral infections between patient groups. However, patients with gammopathies were more likely to have had prior chronic GvHD (OR 2.7, 95% CI 1.3-5.5, P<0.001). On multivariate analysis, the only factors that were found to influence overall survival (OS) were presence of gammopathies, which was associated with an improved OS (OR 0.35 95% CI 0.14-0.86, P=0.02) as well as disease stage, patients with advanced disease having a higher risk of death (OR 2.20 95% CI 1.18-4.11, P=0.02). Disease stage was the only variable that influenced relapse incidence on multivariate analysis (OR 4.22 95% CI 1.82-9.78, P<0.01). Clonal gammopathies are a frequent but benign occurrence following alemtuzumab-based RIC HSCT, and their appearance may define a group of patients with a favourable overall outcome.

Respiratory epithelial adenomatoid hamartoma: a case report.

Respiratory epithelial adenomatoid (READ) hamartoma is a recently described entity characterized by abnormal glandular formations arising from the epithelium of the nasal cavity. The etiology of the lesion is unclear and may be secondary to either sinonasal inflammation or developmental error. We present a case of a 54-year-old man with a unilateral nasal mass found to be consistent with READ hamartoma upon pathologic review. Although READ hamartomas are thought to be rare, awareness of the lesion is important since it may be confused with sinonasal adenocarcinoma, leading to overly aggressive treatment. Therefore, READ hamartoma should be included in the differential diagnosis of a unilateral nasal mass.

Getting the measure of spasticity in multiple sclerosis: the Multiple Sclerosis Spasticity Scale (MSSS-88).

Spasticity is most commonly defined as an inappropriate, velocity dependent, increase in muscle tonic stretch reflexes, due to the amplified reactivity of motor segments to sensory input. It forms one component of the upper motor neuron syndrome and often leads to muscle stiffness and disability. Spasticity can, therefore, be measured through electrophysiological, biomechanical and clinical evaluation, the last most commonly using the Ashworth scale. None of these techniques incorporate the patient experience of spasticity, nor how it affects people's daily lives. Consequently, we set out to construct a rating scale to quantify the perspectives of the impact of spasticity on people with multiple sclerosis. Qualitative methods (in-depth patient interviews and focus groups, expert opinion and literature review) were used to develop a conceptual framework of spasticity impact, and to generate a pool of items with the potential to convert this framework into a rating scale with multiple dimensions. This item pool was administered, in the form of a questionnaire, to a sample of people with multiple sclerosis and spasticity. Guided by Rasch analysis, we constructed and validated a rating scale for each component of the conceptual framework. Decisions regarding item selection were based on the integration and assimilation of seven specific analyses including clinical meaning, ordering of thresholds, fit statistics and differential item functioning. The qualitative phase (17 patient interviews, 3 focus groups) generated 144 potential scale items and a conceptual model with eight components addressing symptoms (muscle stiffness, pain and discomfort and muscle spasms,), physical impact (activities of daily living, walking and body movements) and psychosocial impact (emotional health, social functioning). The first postal survey was sent to 272 people with multiple sclerosis and had a response rate of 88%. Findings supported the development of scales for each component but demonstrated that five item response options were too many. The 144-item questionnaire, reformatted with four-item response options, was administered with four validating instruments to an independent sample of 259 people with multiple sclerosis (response rate 78%). From the responses, an 88-item instrument with eight subscales was developed that satisfied criteria for reliable and valid measurement. Correlations with other measures were consistent with predictions. The 88-item Multiple Sclerosis Spasticity Scale (MSSS-88) is a reliable and valid, patient-based, interval-level measure of the impact of spasticity in multiple sclerosis. It has the potential to advance outcomes measurement in clinical trials and clinical practice, and provides a new perspective in the clinical evaluation of spasticity.

Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up.

OBJECTIVE: To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. METHODS: In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to 12 months in the follow up study reported here. RESULTS: Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (Delta(9)-THC mean reduction 1.82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI -0.99 to 1.19), placebo -0.23 (n = 176, 95% CI -1.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of Delta(9)-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. CONCLUSIONS: These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

Results with abdominal vascular trauma in the modern era.

This is a report of a 10-year experience (1989-1998) with 300 consecutive patients found to have an injury to a named abdominal vessel at the time of an exploratory laparotomy for trauma. An abdominal gunshot wound was the mechanism of injury in 78 per cent of patients, and injury to more than one named abdominal vessel was present in 42 per cent. The abdominal aorta, inferior vena cava, and external iliac artery and vein were the most commonly injured vessels. When management for the five most commonly injured arteries was grouped, exsanguination before attempts at repair occurred in 11 to 15 per cent of patients and the mean survival in the remainder was 46 per cent. When management for the five most commonly injured veins was grouped, exsanguination before attempts at repair occurred in 5 per cent of patients and the mean survival in the remainder was 64 per cent. A number of administrative and medical changes in the management of patients with abdominal trauma occurred from 1992 through 1994. Despite significantly increased Injury Severity Scores for patients treated from 1993 through 1998 as compared with those treated from 1989 through 1992 survival rates for patients with injuries to the abdominal aorta and inferior vena cava were unchanged. Survival rates for injuries to the external iliac artery and vein increased significantly. The local changes in management should be considered for prospective studies in other urban trauma centers.

Skin only or silo closure in the critically ill patient with an open abdomen.

BACKGROUND: The morbidity and mortality of various open abdominal techniques remains unclear. METHODS: A retrospective review was made of all trauma or general surgery patients who underwent an open abdominal closure from January 1997 to December 2000, at a large urban acute care hospital. Data are mean +/- SD. RESULTS: From 1997 to 2000, 181 patients (aged 39.8 +/- 16.5 years) had an open abdomen for abdominal infection, planned reexploration, abdominal compartment syndrome, inability to reapproximate fascia, or as part of a "damage control" procedure. Twenty-three patients went on to develop an abdominal compartment syndrome. Gastrointestinal fistulas occurred in 26 patients, and 9 patients had a dehiscence. The overall mortality was 44.7%. Of the survivors, 52% went on to fascial closure, requiring 1 to 7 additional abdominal operations. CONCLUSIONS: The morbidity of the open abdomen varies with the particular indication. Gastrointestinal fistulas are the most common acute complication and an abdominal wall hernia, the most common chronic complication.

Pregnancy as a tissue expander in the repair of a massive ventral hernia.

The use of tissue expanders has been described in numerous applications, including the closure of massive abdominal wall defects. The advantages of tissue expansion include providing adequate soft tissue for stable coverage of prosthetic material. In a subfascial plane, expanders can also expand muscle and fascia to allow total autologous repair of massive ventral hernias. These techniques for abdominal wall reconstruction are well established to cover viscera, to repair hernias, and to restore acceptable contour. The authors present the novel case of a woman with unstable skin graft coverage of a massive ventral hernia whose pregnancy was used as a surrogate intra-abdominal tissue expander to facilitate abdominal wall reconstruction.