Work-Related Issues and Physical and Psychological Burden in Canadian Patients With Axial Spondyloarthritis: Results From the International Map of Axial Spondyloarthritis.

OBJECTIVE: To identify factors associated with work-related issues in Canadian patients with axial spondyloarthritis. METHODS: Data from 542 Canadian patients who participated in the International Map of Axial Spondyloarthritis online survey were analyzed. Participants who were employed, unemployed, or on short-term disability were included in this analysis. Regression analysis was used to study the association between work-related issues, disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]), and psychological distress (12-item General Health Questionnaire [GHQ-12]). RESULTS: The mean age of surveyed participants was 44.3 (SD 13.9) years, 81% were university educated, and 52.6% employed. A substantial proportion had high disease activity (BASDAI ≥ 4, 72.1%) and psychological distress (GHQ-12 ≥ 3, 53.1%); 81% had work-related issues. This study analyzed responses from a subset of participants who were either employed, unemployed, or on short-term disability (n = 339). Ninety percent of this subset reported at least 1 work-related issue in the year before questionnaire completion, with the most frequent being absenteeism (49.3%) and missing work for healthcare provider visits (42.5%). Factoring in disability benefits eliminated the association between work-related issues and disease activity for all variables except fatigue (r = 0.217; P = 0.03) and discomfort (r = 0.196; P = 0.047). Difficulty fulfilling working hours (ß 2.342, 95% CI 1.413-3.272) and effect on professional advancement (ß 1.426, 95% CI 0.355-2.497) were associated with psychological distress. In the presence of disability benefits, only the effect on professional advancement remained (ß 2.304, 95% CI 0.082-4.527). CONCLUSION: Work-related issues are associated with worse patient-reported outcomes, both physical and psychological.

Medical cannabis use by rheumatology patients in routine clinical care: results from The Ontario Best Practices Research Initiative.

OBJECTIVES: Medical cannabis is often used to alleviate common symptoms in patients with chronic conditions. With cannabis legalisation in Canada and easier access, it is important that rheumatologists understand its potential impact on their practice. Among patients attending rheumatology clinics in Ontario we assessed: the prevalence of medical cannabis use; symptoms treated; rheumatologists' perceptions. METHODS: Eight rheumatology clinics recruited consecutive adult patients in a 3-part medical cannabis survey: the first completed by rheumatologists; the second by all patients; the third by medical cannabis users. Student's t-test and Chi-square test were used to compare medical cannabis users to never users. RESULTS: 799 patients participated, 163 (20.4%) currently using medical cannabis or within <2 years and 636 never users; most had rheumatoid arthritis (37.8%) or osteoarthritis (34.0%). Compared to never users, current/past-users were younger; more likely to be taking opioids/anti-depressants, have psychiatric/gastrointestinal disorders, and have used recreational cannabis (p<0.05); had higher physician (2.9 vs. 2.1) and patient (6.0 vs. 4.2) global scores, and pain (6.2 vs. 4.7) (p<0.0001). Pain (95.5%), sleeping (82.3%) and anxiety (58.9%) were the most commonly treated symptoms; 78.2% of current/past-users reported medical cannabis was at least somewhat effective. Most rheumatologists reported being uncomfortable to authorise medical cannabis, primarily due to lack of evidence, knowledge, and product standardisation. CONCLUSIONS: Medical cannabis use among rheumatology patients in Ontario was two-fold higher than that reported for the general population of similar age. Use was associated with more severe disease, pain, and prior recreational use. Reported lack of research, knowledge, and product standardisation were barriers for rheumatologist use authorisation.

Conjoint analysis of OPRPN and SMR3A protein expression as potential predictive biomarkers for head and neck squamous cell carcinoma after radiotherapy.

Increased submaxillary gland androgen­regulated protein 3A (SMR3A) expression was previously shown to serve as an independent risk factor for oropharyngeal squamous cell carcinoma (OPSCC) and as a surrogate biomarker for active estrogen receptor 2 signaling in radioresistant tumor cells. In the present study, it was aimed to unravel the expression and clinical significance of another member of the opiorphin family, opiorphin prepropeptide (OPRPN), in the radiotherapy for head and neck squamous cell carcinoma (HNSCC). Expression of SMR3A and OPRPN were analyzed for the prior and post fractionated irradiation (4x2 Gy) by double immunofluorescence staining in established HNSCC cell lines as well as by immunohistochemical (IHC) staining in ex vivo tumor tissues. Next, in a retrospective experimental cohort study, primary tumor samples from OPSCC patients (n=96), who received definitive surgery and adjuvant radiotherapy were reviewed, and expression levels of OPRPN protein were detected by IHC. Immunoreactivity scores (IRS) were associated with pathological and clinical risk factors by Chi­square analysis. Survival analysis was performed by using the Kaplan­Meier plot, log­rank test and Cox regression analysis. The expression levels of OPRPN and SMR3A protein were both induced by fractionated irradiation in vitro and ex vivo. In primary tumor samples, IRS of OPRPN was significantly higher than scores of SMR3A expression and positively correlated with expression patterns of SMR3A. SMR3A was confirmed to serve as an unfavorable factor, while OPRPN protein had no significant association with the clinical outcome of patients with OPSCC. A combinational analysis revealed that the subgroup with SMR3AhighOPRPNlow staining pattern had the worst clinical outcome among the various subgroups. Multivariate Cox regression analyses indicated that high expression of SMR3A serves as an independent unfavorable biomarker, while increased expression of OPRPN appears to exert protective function. In summary, the present study indicated that SMR3A and OPRPN serve as potential prognostic markers for HNSCC after radiotherapy.

Adaptive ERK signalling activation in response to therapy and in silico prognostic evaluation of EGFR-MAPK in HNSCC.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) patients frequently develop treatment resistance to cetuximab, a monoclonal antibody against EGFR, as well as radiotherapy. Here we addressed extracellular signal-regulated kinase 1/2 (ERK1/2) regulation by cetuximab or fractionated irradiation (IR) and conducted in silico prognostic evaluation of the EGFR-MAPK axis in HNSCC. METHODS: Expression of ERK1/2 phosphorylation (pERK1/2) was determined in HNSCC cell lines, which were treated with cetuximab or fractionated-IR. Furthermore, the effect of fractionated IR on pERK1/2 was confirmed in an ex vivo HNSCC tissue culture model. Expression and prognostic significance of EGFR-ERK axis was evaluated in a cohort of radiotherapy plus cetuximab-treated HNSCC. Correlations among EGFR-MAPK signalling components and association between transcript and protein expression profiles and patient survival in HNSCC were analysed using publicly available databases. RESULTS: ERK1/2 phosphorylation was rebounded by prolonged cetuximab administration and was induced by fractionated IR, which could be suppressed by a MEK inhibitor as a radiosensitiser. In silico assessments suggested that EGFR-MAPK cascade genes and proteins could predict HNSCC patients' survival as a prognostic signature. CONCLUSIONS: Activation of ERK1/2 signalling contributes to the cellular defence of HNSCC against cetuximab and fractionated IR treatment. EGFR-MAPK axis has a prognostic significance in HNSCC.

First prospective clinical evaluation of feasibility and patient acceptance of magnetic resonance-guided radiotherapy in Germany.

PURPOSE: Magnetic resonance-guided radiotherapy (MRgRT) has recently been introduced in our institution. As MRgRT requires high patient compliance compared to conventional techniques and can be associated with prolonged treatment times, feasibility and patient tolerance were prospectively assessed using patient-reported outcome questionnaires (PRO-Q). MATERIALS AND METHODS: Forty-three patients were enrolled in a prospective observational study and treated with MRgRT on a low-field hybrid Magnetic Resonance Linear Accelerator system (MR-Linac) between April 2018 and April 2019. For assistance in gated breath-hold delivery using cine-MRI, a video feedback system was installed. PRO-Qs consisted of questions on MR-related complaints and also assessed aspects of active patient participation. RESULTS: The most commonly treated anatomic sites were nodal metastases and liver lesions. The mean treatment time was 34 min with a mean beam-on time of 2:17 min. Gated stereotactic body radiotherapy (SBRT) was applied in 47% of all patients. Overall, patients scored MRgRT as positive or at least tolerable in the PRO­Q. Almost two thirds of patients (65%) complained about at least one item of the PRO­Q (score ≥4), mainly concerning coldness, paresthesia, and uncomfortable positioning. All patients reported high levels of satisfaction with their active role using the video feedback system in breath-hold delivery. CONCLUSION: MRgRT was successfully implemented in our clinic and well tolerated by all patients, despite MR-related complaints and complaints about uncomfortable immobilization. Prospective clinical studies are in development for further evaluation of MRgRT and for quantification of the benefit of MR-guided on-table adaptive radiotherapy.

Acute Toxicity and Early Oncological Outcomes After Intraoperative Electron Radiotherapy (IOERT) as Boost Followed by Whole Breast Irradiation in 157 Early Stage Breast Cancer Patients-First Clinical Results From a Single Center.

Introduction: Breast conserving surgery (BCS) followed by postoperative whole breast irradiation (WBI) is the current standard of care for early stage breast cancer patients. Boost to the tumor bed is recommended for patients with a higher risk of local recurrence and may be applied with different techniques. Intraoperative electron radiotherapy (IOERT) offers several advantages compared to other techniques, like direct visualization of the tumor bed, better skin sparing, less inter- and intrafractional motion, but also radiobiological effects may be beneficial. Objective of this retrospective analysis of IOERT as boost in breast cancer patients was to assess acute toxicity and early oncological outcomes. Material and Methods: All patients, who have been irradiated between 11/2014 and 01/2018 with IOERT during BCS were analyzed. IOERT was applied using the mobile linear accelerator Mobetron with a total dose of 10 Gy, prescribed to the 90% isodose. After ensured woundhealing, WBI followed with normofractionated or hypofractionated regimens. Patient reports, including diagnostic examinations and toxicity were analyzed after surgery and 6-8 weeks after WBI. Overall survival, distant progression-free survival, in-breast and contralateral breast local progression-free survival were calculated using the Kaplan-Meier method. Furthermore, recurrence patterns were assessed. Results: In total, 157 patients with a median age of 57 years were evaluated. Postoperative adverse events were mild with seroma and hematoma grade 1-2 in 26% and grade 3 in 0.6% of the patients. Wound infections grade 2-3 occurred in 2.2% and wound dehiscence grade 1-2 in 1.9% of the patients. Six to eight weeks after WBI radiotherapy-dependent acute dermatitis grade 1-2 was most common in 90.9% of the patients. Only 4.6% of the patients suffered from dermatitis grade 3. No grade 4 toxicities were documented after surgery or WBI. 2- and 3-year overall survival and distant progression-free survival, were 97.5 and 93.6, and 0.7 and 2.8%, respectively. In-breast recurrence and contralateral breast cancer rates after 3 years were 1.9 and 2.8%, respectively. Conclusion: IOERT boost during BCS is a safe treatment option with low acute toxicity. Short-term recurrence rates are comparable to previously published data and emphasize, that IOERT as boost is an effective treatment.

Technical and dosimetric aspects of the total skin electron beam technique implemented at Heidelberg University Hospital.

AIM: To give a technical description and present the dosimetric proporties of the total skin electron beam technique implemented at Heidelberg University Hospital. BACKGROUND: Techniques used for total skin electron beam irradiation were developed as early as in the 1960s to 1980s and have, since then, hardly changed. However, new measurements of the established methods allow deeper insight into the dose distributions and reasons for possible deviations from uniform dose. MATERIALS AND METHODS: The TSEI technique applied at Heidelberg University Hospital since 1992 consists of irradiating the patient with a superposition of two beams of low energy electrons at gantry angles of 72° and 108° while he is rotating in a standing position on a turntable at 370 cm distance from the accelerator. The energy of the electron beam is degraded to 3.9 MeV by passing through an attenuator of 6 mm of Perspex. A recent re-measurement of the dose distribution is presented using modern dosimetry tools like a linear array of ionization chambers in combination with established methods like thermoluminescent detectors and film dosimetry. RESULTS: The measurements show a strong dependence of dose uniformity on details of the setup like gantry angles. CONCLUSIONS: Dose uniformity of -4/+8% to the majority of the patient's skin can be achieved, however, for the described rotational technique overdoses up to more than 20% in small regions seem unavoidable.

Biological in-vivo measurement of dose distribution in patients' lymphocytes by gamma-H2AX immunofluorescence staining: 3D conformal- vs. step-and-shoot IMRT of the prostate gland.

BACKGROUND: Different radiation-techniques in treating local staged prostate cancer differ in their dose- distribution. Physical phantom measurements indicate that for 3D, less healthy tissue is exposed to a relatively higher dose compared to SSIMRT. The purpose is to substantiate a dose distribution in lymphocytes in-vivo and to discuss the possibility of comparing it to the physical model of total body dose distribution. METHODS: For each technique (3D and SSIMRT), blood was taken from 20 patients before and 10 min after their first fraction of radiotherapy. The isolated leukocytes were fixed 2 hours after radiation. DNA double-strand breaks (DSB) in lymphocytes' nuclei were stained immunocytochemically using the gamma-H2AX protein. Gamma-H2AX foci inside each nucleus were counted in 300 irradiated as well as 50 non-irradiated lymphocytes per patient. In addition, lymphocytes of 5 volunteer subjects were irradiated externally at different doses and processed under same conditions as the patients' lymphocytes in order to generate a calibration-line. This calibration-line assigns dose-value to mean number of gamma-H2AX foci/ nucleus. So the dose distributions in patients' lymphocytes were determined regarding to the gamma-H2AX foci distribution. With this information a cumulative dose-lymphocyte-histogram (DLH) was generated. Visualized distribution of gamma-H2AX foci, correspondingly dose per nucleus, was compared to the technical dose-volume-histogram (DVH), related to the whole body-volume. RESULTS: Measured in-vivo (DLH) and according to the physical treatment-planning (DVH), more lymphocytes resulted with low-dose exposure (< 20% of the applied dose) and significantly fewer lymphocytes with middle-dose exposure (30%-60%) during Step-and-Shoot-IMRT, compared to conventional 3D conformal radiotherapy. The high-dose exposure (> 80%) was equal in both radiation techniques. The mean number of gamma-H2AX foci per lymphocyte was 0.49 (3D) and 0.47 (SSIMRT) without significant difference. CONCLUSIONS: In-vivo measurement of the dose distribution within patients' lymphocytes can be performed by detecting gamma-H2AX foci. In case of 3D and SSIMRT, the results of this method correlate with the physical calculated total body dose-distribution, but cannot be interpreted unrestrictedly due to the blood circulation. One possible application of the present method could be in radiation-protection for in-vivo dose estimation after accidental exposure to radiation.

Surface dose in the treatment of breast cancer with helical tomotherapy.

PURPOSE: Investigation of the effects of breathing motion- and misregistration-induced errors on the superficial dose in the treatment of breast cancer using helical tomotherapy (HT). MATERIAL AND METHODS: Surface dose measurements were performed with thermoluminescence dosimetry (TLD). Two treatment plans with different planning target volume (PTV) definitions of the left breast were used: PTVskin had its ventral border exactly on skin level, while PTVair included also a 10-mm extension ventral to the PTVskin. With a thoracic static phantom, misregistration errors in an HT were simulated. A dynamic phantom was used to simulate a breathing patient during HT. Surface doses of breast cancer patients were measured both for an HT (179 points) and a conventional three-dimensional conformal treatment (70 points). RESULTS: In the static phantom misregistration setup, dose deviations of -31.9% for PTVskin to +35.4% for PTVair could be observed. The dynamic phantom measurements resulted in surface dose deviations from those in a static position between 0.8% and 3.8% without a significant difference for the PTV definitions. The measured surface doses on patients averaged (mean +/- standard deviation) 1.65 +/- 0.13 Gy for the HT and 1.42 +/- 0.11 Gy for the three-dimensional conformal treatment. CONCLUSION: HT enables a homogeneous and reproducible surface dose with small dose deviations in the treatment of breast cancer. HT is a feasible method to treat breast cancer under free shallow breathing of the patient using a treatment plan with a ventral PTV border on the skin level.