An international survey of imaging practices in radiotherapy.

Improvements in delivery of radiation dose to target tissues in radiotherapy have increased the need for better image quality and led to a higher frequency of imaging patients. Imaging for treatment planning extends to function and motion assessment and devices are incorporated into medical linear accelerators (linacs) so that regions of tissue can be imaged at time of treatment delivery to ensure dose distributions are delivered as accurately as possible. A survey of imaging in 97 radiotherapy centres in nine countries on six continents has been undertaken with an on-line questionnaire administered through the International Commission on Radiological Protection mentorship programme to provide a snapshot of imaging practices. Responses show that all centres use CT for planning treatments and many utilise additional information from magnetic resonance imaging and positron emission tomography scans. Most centres have kV cone beam CT attached to at least some linacs and use this for the majority of treatment fractions. The imaging options available declined with the human development index (HDI) of the country, and the frequency of imaging during treatment depended more on country than treatment site with countries having lower HDIs imaging less frequently. The country with the lowest HDI had few kV imaging facilities and relied on MV planar imaging intermittently during treatment. Imaging protocols supplied by vendors are used in most centres and under half adapt exposure conditions to individual patients. Recording of patient doses, a knowledge of which is important in optimisation of imaging protocols, was limited primarily to European countries.

Constitutive Model of Radiation Aging Effects in Filled Silicone Elastomers under Strain.

Filled silicone elastomers, an essential component in many technological applications, are often subjected to controlled or unintended radiation for a variety of reasons. Radiation exposure can lead to permanent mechanical and structural changes in the material, which is manifested as altered mechanical response, and in some cases, a permanent set. For unfilled elastomers, network theories developed and refined over decades can explain these effects in terms of chain-scission and cross-link formation and a hypothesis involving independent networks formed at different strain levels of the material. Here, we expose a filled silicone rubber to gamma radiation while being under finite elongational strain and show that the observed mechanical and structural changes can be quantitatively modeled within the same theoretical framework developed for unfilled elastomers as long as nuances associated with the Mullins effect are accounted for in a consistent manner. In this work, we employ Ogden's incompressible hyperelastic model within the framework of Tobolsky's two-network scheme to describe the observed permanent set and mechanical modulus changes as a function of radiation dosage. In the process, we conclude that gamma radiation induces both direct cross-linking at chain crossings (H-links) and main-chain-scission followed by cross-linking (Y-links). We provide an estimate of the ratio of chain-scission to cross-linking rates, which is in reasonable agreement with previous experimental estimate from Charlesby-Pinner analysis. We use density functional theory (DFT)-based quantum mechanical calculations to explore the stability of -Si and -SiO radicals that form upon a radiation-induced chain-scission event, which sheds light on the relative rates of Y-linking and H-linking processes.

Age-aware constitutive materials model for a 3D printed polymeric foam.

Traditional open or closed-cell stochastic elastomeric foams have wide-ranging applications in numerous industries: from thermal insulation, shock absorbing/gap-filling support cushions, packaging, to light-weight structural and positional components. Recent developments in 3D printing technologies by direct ink-write have opened the possibility of replacing stochastic foam parts by more controlled printed micro-structures with superior stress-distribution and longer functional life. For successful deployment as mechanical support or structural components, it is crucial to characterize the response of such printed materials to long-term external loads in terms of stress-strain behavior evolution and in terms of irreversible structural and load-bearing capacity changes over time. To this end, here we report a thermal-age-aware constitutive model for a 3D printed close-packed foam structure under compression. The model is based on the Ogden hyperfoam strain-energy functional within the framework of Tobolsky two-network scheme. It accurately describes experimentally measured stress-strain response, compression set, and load retention for various aging times and temperatures. Through the technique of time-temperature-superposition the model enables the prediction of long-term changes along with the quantification of uncertainty stemming from sample-to-sample variation and measurement noise. All aging parameters appear to possess the same Arrhenius activation barrier, which suggests a single dominant aging mechanism at the molecular/network level.

Barriers and facilitators to implementing addiction medicine fellowships: a qualitative study with fellows, medical students, residents and preceptors.

BACKGROUND: Although progress in science has driven advances in addiction medicine, this subject has not been adequately taught to medical trainees and physicians. As a result, there has been poor integration of evidence-based practices in addiction medicine into physician training which has impeded addiction treatment and care. Recently, a number of training initiatives have emerged internationally, including the addiction medicine fellowships in Vancouver, Canada. This study was undertaken to examine barriers and facilitators of implementing addiction medicine fellowships. METHODS: We interviewed trainees and faculty from clinical and research training programmes in addiction medicine at St Paul's Hospital in Vancouver, Canada (N = 26) about barriers and facilitators to implementation of physician training in addiction medicine. We included medical students, residents, fellows and supervising physicians from a variety of specialities. We analysed interview transcripts thematically by using NVivo software. RESULTS: We identified six domains relating to training implementation: (1) organisational, (2) structural, (3) teacher, (4) learner, (5) patient and (6) community related variables either hindered or fostered addiction medicine education, depending on context. Human resources, variety of rotations, peer support and mentoring fostered implementation of addiction training. Money, time and space limitations hindered implementation. Participant accounts underscored how faculty and staff facilitated the implementation of both the clinical and the research training. CONCLUSIONS: Implementation of addiction medicine fellowships appears feasible, although a number of barriers exist. Research into factors within the local/practice environment that shape delivery of education to ensure consistent and quality education scale-up is a priority.

A multi-institutional analysis of intraoperative radiotherapy for early breast cancer: Does age matter?

BACKGROUND: Single-session intraoperative radiation therapy (IORT) minimizes treatment demands associated with traditional whole breast radiation therapy (WBRT) but outcomes on local disease control and morbidity among the elderly is limited. METHODS: A multi-institutional retrospective registry was established from 19 centers utilizing IORT from 2007 to 2013. Patient, tumor, and treatment variables were analyzed for ages <70 and ≥70. RESULTS: We evaluated 686 patients (<70 = 424; ≥70 = 262) who were margin and lymph node negative. Patients <70 were more likely to have longer operative time, oncoplastic closure, higher rates of IORT used as planned boost, and receive chemotherapy and post-operative WBRT. Wound complication rates were low and not significantly different between age groups. Median follow-up was 1.06 (range 0.51-1.9) years for < 70 and 1.01 (range 0.5-1.68) years for ≥ 70. There were 5 (0.73%) breast recurrences (4 in <70 and 1 ≥ 70, p = 0.65) and no axillary recurrences during follow-up. CONCLUSIONS: IORT was associated with a low rate of wound complication and local recurrence on short-term follow-up in this cohort.

Two birds with one stone: experiences of combining clinical and research training in addiction medicine.

BACKGROUND: Despite a large evidence-base upon which to base clinical practice, most health systems have not combined the training of healthcare providers in addiction medicine and research. As such, addiction care is often lacking, or not based on evidence or best practices. We undertook a qualitative study to assess the experiences of physicians who completed a clinician-scientist training programme in addiction medicine within a hospital setting. METHODS: We interviewed physicians from the St. Paul's Hospital Goldcorp Addiction Medicine Fellowship and learners from the hospital's academic Addiction Medicine Consult Team in Vancouver, Canada (N = 26). They included psychiatrists, internal medicine and family medicine physicians, faculty, mentors, medical students and residents. All received both addiction medicine and research training. Drawing on Kirkpatrick's model of evaluating training programmes, we analysed the interviews thematically using qualitative data analysis software (Nvivo 10). RESULTS: We identified five themes relating to learning experience that were influential: (i) attitude, (ii) knowledge, (iii) skill, (iv) behaviour and (v) patient outcome. The presence of a supportive learning environment, flexibility in time lines, highly structured rotations, and clear guidance regarding development of research products facilitated clinician-scientist training. Competing priorities, including clinical and family responsibilities, hindered training. CONCLUSIONS: Combined training in addiction medicine and research is feasible and acceptable for current doctors and physicians in training. However, there are important barriers to overcome and improved understanding of the experience of addiction physicians in the clinician-scientist track is required to improve curricula and research productivity.

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG): clinical trial design for rare ovarian tumours.

This manuscript reports the consensus statements on designing clinical trials in rare ovarian tumours reached at the fifth Ovarian Cancer Consensus Conference (OCCC) held in Tokyo, November 2015. Three important questions were identified concerning rare ovarian tumours (rare epithelial ovarian cancers (eOC), sex-cord stromal tumours (SCST) and germ cell tumours (GCT)): (i) What are the research and trial issues that are unique to rare ovarian tumours? There is a lack of randomised phase III data defining standards of care which makes it difficult to define control arms, but identifies unmet needs that merit investigation. Internationally agreed upon diagnostic criteria, expert pathological review and translational research are crucial. (ii) What should be investigated in rare eOC, GCT and SCST? Trials dedicated to each rare ovarian tumour should be encouraged. Nonetheless, where the question is relevant, rare eOC can be included in eOC trials but with rigorous stratification. Although there is emerging evidence suggesting that rare eOC have different molecular profiles, trials are needed to define new type-specific standards for each rare eOC (clear cell, low grade serous and mucinous). For GCTs, a priority is reducing toxicities from treatment while maintaining cure rates. Both a robust prognostic scoring system and more effective treatments for de novo poor prognosis and relapsed GCTs are needed. For SCSTs, validated prognostic markers as well as alternatives to the current standard of bleomycin/etoposide/cisplatin (BEP) should be identified. (iii) Are randomised trials feasible? Randomised controlled trials (RCT) should be feasible in any of the rare tumours through international collaboration. Ongoing trials have already demonstrated the feasibility of RCT in rare eOC and SCST. Mucinous OC may be considered for inclusion, stratified, into RCTs of non-gynaecological mucinous tumours, while RCTs in high risk or relapsed GCT may be carried out as a subset of male and/or paediatric germ cell studies.

3D printed cellular solid outperforms traditional stochastic foam in long-term mechanical response.

3D printing of polymeric foams by direct-ink-write is a recent technological breakthrough that enables the creation of versatile compressible solids with programmable microstructure, customizable shapes, and tunable mechanical response including negative elastic modulus. However, in many applications the success of these 3D printed materials as a viable replacement for traditional stochastic foams critically depends on their mechanical performance and micro-architectural stability while deployed under long-term mechanical strain. To predict the long-term performance of the two types of foams we employed multi-year-long accelerated aging studies under compressive strain followed by a time-temperature-superposition analysis using a minimum-arc-length-based algorithm. The resulting master curves predict superior long-term performance of the 3D printed foam in terms of two different metrics, i.e., compression set and load retention. To gain deeper understanding, we imaged the microstructure of both foams using X-ray computed tomography, and performed finite-element analysis of the mechanical response within these microstructures. This indicates a wider stress variation in the stochastic foam with points of more extreme local stress as compared to the 3D printed material, which might explain the latter's improved long-term stability and mechanical performance.

Mullins effect in a filled elastomer under uniaxial tension.

Modulus softening and permanent set in filled polymeric materials due to cyclic loading and unloading, commonly known as the Mullins effect, can have a significant impact on their use as support cushions. A quantitative analysis of such behavior is essential to ensure the effectiveness of such materials in long-term deployment. In this work we combine existing ideas of filler-induced modulus enhancement, strain amplification, and irreversible deformation within a simple non-Gaussian constitutive model to quantitatively interpret recent measurements on a relevant PDMS-based elastomeric cushion. We find that the experimental stress-strain data is consistent with the picture that during stretching (loading) two effects take place simultaneously: (1) the physical constraints (entanglements) initially present in the polymer network get disentangled, thus leading to a gradual decrease in the effective cross-link density, and (2) the effective filler volume fraction gradually decreases with increasing strain due to the irreversible pulling out of an initially occluded volume of the soft polymer domain.

Clinical outcomes in international federation of gynecology and obstetrics stage IA endometrial cancer with myometrial invasion treated with or without postoperative vaginal brachytherapy.

PURPOSE: To assess the clinical outcomes of patients with Stage IA endometrial cancer with myometrial invasion treated with postoperative vaginal brachytherapy (VBT) with those who received no adjuvant therapy (NAT). METHODS AND MATERIALS: All patients treated with hysterectomy for endometrial cancer at Northwestern Memorial Hospital between 1978 and 2005 were identified. Those patients with Stage IA disease with myometrial invasion who were treated with VBT alone or NAT were identified and included in the present analysis. RESULTS: Of 252 patients with Stage IA endometrial cancer with superficial (<50%) myometrial invasion who met the inclusion criteria, 169 underwent VBT and 83 received NAT. The median follow-up in the VBT and NAT groups was 103 and 61 months, respectively. In the VBT group, 56.8% had Grade 1, 37.9% had Grade 2, and 5.3% had Grade 3 tumors. In the NAT group, 75.9%, 20.5%, and 3.6% had Grade 1, 2, and 3 tumors, respectively. Lymphatic or vascular space invasion was noted in 12.4% of the VBT patients and 5.6% of the NAT patients. The 5-year overall survival rate was 95.5%. The 5-year recurrence-free survival rate was 92.4% for all patients, 94.4% for the VBT group, and 87.4% for the NAT group (p = NS). Of the 169 VBT patients and 83 NAT patients, 8 (4.7%) and 6 (7.2%) developed recurrent disease. One vaginal recurrence occurred in the VBT group (0.6%) and three in the NAT group (3.8%). Recurrences developed 2-102 months after surgical treatment. Two of the four vaginal recurrences were salvaged. No Grade 3 or higher acute or late radiation toxicity was noted. CONCLUSIONS: The use of postoperative VBT in patients with Stage I endometrial cancer with <50% myometrial invasion yielded excellent vaginal disease control and disease-free survival, with minimal toxicity.

Radiation-induced mechanical property changes in filled rubber.

In a recent paper we exposed a filled elastomer to controlled radiation dosages and explored changes in its cross-link density and molecular weight distribution between network junctions [A. Maiti et al., Phys. Rev. E 83, 031802 (2011)]. Here we report mechanical response measurements when the material is exposed to radiation while being under finite nonzero strain. We observe interesting hysteretic behavior and material softening representative of the Mullins effect, and materials hardening due to radiation. The net magnitude of the elastic modulus depends upon the radiation dosage, strain level, and strain-cycling history of the material. Using the framework of Tobolsky's two-stage independent network theory we develop a model that can quantitatively interpret the observed elastic modulus and its radiation and strain dependence.

The effects of bevacizumab on postoperative complications in patients undergoing colorectal and pancreatic cancer resection.

Bevacizumab (Avastin™; rhuMab VEGF), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has seen increased use in the perioperative treatment of colorectal and pancreatic cancer. Little is known, however, regarding its impact on surgical outcomes in patients undergoing resection. The objective of this review was to examine if the addition of bevacizumab to existing neoadjuvant regimens increases morbidity after cancer resection.

Public injecting among a cohort of injecting drug users in Vancouver, Canada.

BACKGROUND: Despite the implementation of policy interventions to address open drug consumption, public injecting continues to occur in many urban settings. This study sought to examine public injecting among a community-recruited cohort of injecting drug users (IDUs) in Vancouver. METHODS: The prevalence and correlates of recent public injecting among participants enrolled in the Vancouver Injection Drug User Study during the period of 1 December 2003 to 30 November 2005 were examined prospectively using generalised estimating equations (GEEs). RESULTS: Among the sample of 620 active IDUs, at some point during the study period, 142 (22.9%) individuals reported "usually" or "always" injecting in public in the 6 months prior to their study visit. Factors that were significant and positively associated with recent frequent public injecting in multivariate GEE analysis include homelessness (adjusted OR (AOR) 6.70); frequent crack use (AOR 1.48); and frequent heroin injection (AOR 1.56). Recent frequent public injecting was found to be negatively associated with cooking and filtering drugs prior to injecting (AOR 0.50) and older age (AOR 0.95). CONCLUSION: The findings indicate that a substantial proportion of local IDUs frequently inject in public, and those who report recently injecting in public spaces appear to be a vulnerable population facing significant health hazards. The provision of secure housing may have the potential to protect the health of IDUs in this setting and significantly decrease the prevalence of public injecting. In addition, the findings support previous work suggesting that removing barriers to the use of Vancouver's existing supervised injection site may serve to further reduce public drug use.

Low-dose nonenhanced head CT protocol for follow-up evaluation of children with ventriculoperitoneal shunt: reduction of radiation and effect on image quality.

BACKGROUND AND PURPOSE: Children with a shunt for hydrocephalus often undergo multiple follow-up head CT scans, increasing the risk for long-term effects of ionizing radiation. The purpose of our study was to evaluate if an unenhanced low-dose head CT could consistently provide acceptable image quality and diagnostic information. MATERIALS AND METHODS: Ninety-two children (mean age, 9 years; range, 8 months to 21 years; 45 boys and 47 girls) with a shunt for hydrocephalus and no clinical evidence of shunt malfunction who were referred for a follow-up nonenhanced head CT were included in the study. All studies were performed on a 4-section multidetector CT. Two CT studies were selected retrospectively for each patient, 1 performed at standard dose (220 mA) and 1 at low dose (80 mAs). Two radiologists independently evaluated and graded both standard-dose and low-dose studies for various image quality parameters. Attenuation and noise levels were measured, and gray-white differentiation and contrast-to-noise ratio (CNR) were calculated. RESULTS: Low-dose CT resulted in 63% mean dose reduction. All low-dose CT scans were diagnostically acceptable. Image quality parameters were significantly lower at low dose (P = .0001) except for the parameters for streak artifacts (P = .46) and need for further imaging (P = .47), which were higher. Mean noise levels were significantly higher (P = .001) in low-dose studies, whereas CNR was significantly higher in standard dose CT (P = .001). A moderate to perfect agreement was noted between the 2 readers with regard to image quality assessment (65%-99%). CONCLUSION: Low-dose nonenhanced head CT consistently provides diagnostically acceptable images with relevant diagnostic information in children with VP shunts resulting in substantial dose savings.

Embolectomy in a rabbit acute arterial occlusion model using a novel electromechanical extraction device.

A prototype endovascular electromechanical clot-extraction device was fabricated using a combination of shape memory polymer and shape memory nickel-titanium alloy (nitinol). Five embolic vascular occlusions were created in 4 rabbits by injecting thermally coagulated blood through a 4F catheter in the common carotid artery. Angiography immediately after clot injection showed complete or partial occlusion of the common carotid artery. Posttreatment angiography showed complete (2/5), partial (2/5), or no (1/5) restoration of blood flow.

Immune response and serum immunoglobulin G concentrations in beef calves suckling cows of differing body condition score at parturition and supplemented with high-linoleate or high-oleate safflower seeds.

Two experiments were conducted to determine the effect of maternal lipid supplementation on the immune response to antigenic challenge in suckling calves. In Exp. 1, beginning 1 d postpartum, 18 primiparous crossbred beef cows were fed Foxtail millet hay and a low-fat (control) supplement or a supplement containing cracked, high-linoleate safflower seed in individual feeding stanchions until d 40 of lactation. The diets were formulated to provide similar quantities of N and TDN, and the linoleate diet was formulated to contain 5% of DMI as fat. Calves were injected s.c. with 15 mg of antigen (ovalbumin) at d 21 and again at d 35 of age. To measure the total serum antibody production in response to the antigen, blood samples were collected from the calves every 7 d via jugular venipuncture from d 14 to 42. Calves from linoleate-supplemented cows had a decrease (P = 0.04) in total antibody production in response to ovalbumin and appeared to have a delayed response to antigen challenge. Total antibody production increased (P < 0.001) after secondary exposure to ovalbumin. In Exp. 2, 36 Angus x Gelbvieh beef cows that were nutritionally managed to achieve a BCS of 4 or 6 at parturition were used to determine the effects of prepartum energy balance and postpartum lipid supplementation on the passive transfer of immunoglobulins and the immune response to antigenic challenge in their calves. Beginning at 3 d postpartum and continuing until d 60 of lactation, cows were fed hay and a low-fat control supplement or supplements consisting of either cracked, high-linoleate or high-oleate safflower seeds. Safflower seed supplements were formulated to provide 5% of DMI as fat. Calves were injected s.c. with 15 mg of ovalbumin at 21 d of age and again at 48 d of age. The antibody responses were determined in serum; cell-mediated immunity was assessed by intradermal antigen injection at 60 d of age. A trend was noted (P = 0.10) for calves suckling control-supplemented cows to have a greater response to antigen compared with calves from linoleate- and oleate-supplemented cows; however, no difference was observed among treatments (P = 0.86) in cell-mediated immune response. Postpartum oilseed supplementation in beef cows appears to decrease antibody production in response to antigenic challenge in suckling calves. However, BCS at parturition did not influence passive transfer of immunoglobulins in neonatal calves.

Photodynamic therapy with PhotoPoint photosensitiser MV6401, indium chloride methyl pyropheophorbide, achieves selective closure of rat corneal neovascularisation and rabbit choriocapillaris.

AIM: The new photosensitiser PhotoPoint MV6401, indium chloride methyl pyropheophorbide, was assessed as a possible ocular photodynamic therapy agent in a rat model of experimentally induced corneal neovascularisation and in choriocapillaris closure in the rabbit. Optimal drug and light activation parameters were determined. METHODS: MV6401 (Miravant Pharmaceuticals, Inc, Santa Barbara, CA, USA) was activated at 664 nm using a DD3-0665 (Miravant Systems Inc) 0.5 W diode laser. Corneal neovascularisation in rats was induced using an N-heptanol technique. The evaluated drug dosages, light dosages, and post-injection activation times ranged from 0.01-0.1 micromol/kg, 5-25 J/cm(2), and 10-60 minutes, respectively. The efficacy of MV6401 on normal choriocapillaris and choroidal vessels was evaluated in rabbits with indirect ophthalmoscopy, fundus photography, fluorescein angiography, and histology. In rabbits, the evaluated drug dosages, light dosages, and post-injection activation times ranged from 0.025-0.25 micromol/kg, 3.3-20 J/cm(2), and 10 minutes, respectively. RESULTS: In the rat corneal neovascularisation model, an optimal intravenous drug dosage of 0.075 micromol/kg was activated by a 20 J/cm(2) light dose at 10 minutes after drug administration, the results of which demonstrated early evidence of efficacy in ocular neovascularisation. In rabbits, closure of the normal choriocapillaris was selectively achieved at a drug dosage of 0.15 micromol/kg using light doses from 3.3 to 20 J/cm(2). CONCLUSION: PhotoPoint MV6401 is a potent photosensitiser that demonstrates both efficacy and selectivity in experimental ocular models.

Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12.

Unresectable cancer of the pancreas was treated with the combination of weekly paclitaxel and external beam irradiation in an effort to improve palliation and extend life expectancy. One hundred twenty-two patients were entered in a multicentered protocol. Thirteen patients were either ineligible, cancelled, or had delinquent data, thus providing 109 for analysis. Unresectable cancer was based on imaging studies (computed tomography or magnetic resonance imaging), all had histologic proof of adenocarcinoma, and none had evidence of metastatic disease or peritoneal seeding. Image-guided radiotherapy treatment consisted of 50.4 Gy in 28 fractions over 5.5 weeks with coplanar anterior/posterior and lateral ports. An initial dose of 45 Gy was given to fields covering the primary tumor plus the regional peripancreatic, celiac, and porta hepatis lymph nodes. A cone down field was used for the last three fractions to encompass the gross tumor volume with a 1- to 1.5-cm margin. Paclitaxel was administered weekly with irradiation in a dosage of 50 mg/m2 as a 3-hour infusion. The median age was 63 and 53% were female. The Karnofsky performance status was greater than or equal to 80 in 81%. Eighty percent were classified T3 or 4; 20% had N1 disease. The primary tumor was located in the pancreatic head in 65%. Eighty-five percent received all six cycles of paclitaxel per protocol, whereas 93% received irradiation with acceptable protocol variation. Field placement, total dose, fractionation, and overall treatment time were given per protocol in greater than or equal to 90%. Acute toxicity (worst per patient) occurred in 39% with grade III (35% of these were asymptomatic neutropenia), 5% with grade IV, and one patient died of infection during the fourth cycle of chemotherapy (grade V). The median follow-up time for alive patients is 20.6 months (range 5-30). The median survival is 11.2 months (95% CI 10.1, 12.3) with estimated 1- and 2-year survivals of 43% and 13%, respectively. External irradiation plus concurrent weekly paclitaxel is well tolerated when given with large-field radiotherapy. The median survival is better than historical results achieved with irradiation and fluoropyrimidines. These data provide the basis for a new Radiation Therapy Oncology Group trial using paclitaxel and irradiation combined with a second radiation sensitizer, gemcitabine, now under way.