Early radiologic and metabolic tumour response assessment during combined chemo-radiotherapy for locally advanced NSCLC.

Background: The role of early treatment response for patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with concurrent chemo-radiotherapy (cCRT) is unclear. The study aims to investigate the predictive value of response to induction chemotherapy (iCX) and the correlation with pattern of failure (PoF). Materials and methods: Patients with LA-NSCLC treated with cCRT were included for analyses (n = 276). Target delineations were registered from radiotherapy planning PET/CT to diagnostic PET/CT, in between which patients received iCX. Volume, sphericity, and SUVpeak were extracted from each scan. First site of failure was categorised as loco-regional (LR), distant (DM), or simultaneous LR+M (LR+M). Fine and Gray models for PoF were performed: a baseline model (including performance status (PS), stage, and histology), an image model for squamous cell carcinoma (SCC), and an image model for non-SCC. Parameters included PS, volume (VOL) of tumour, VOL of lymph nodes, ΔVOL, sphericity, SUVpeak, ΔSUVpeak, and oligometastatic disease. Results: Median follow-up was 7.6 years. SCC had higher sub-distribution hazard ratio (sHR) for LRF (sHR = 2.771 [1.577:4.87], p < 0.01) and decreased sHR for DM (sHR = 0.247 [0.125:0.485], p  <  0.01). For both image models, high diagnostic SUVpeak increased risk of LRF (sHR = 1.059 [1.05:1.106], p < 0.01 for SCC, sHR = 1.12 [1.03:1.21], p < 0.01 for non-SCC). Patients with SCC and less decrease in VOL had higher sHR for DM (sHR = 1.025[1.001:1.048] pr. % increase, p = 0.038). Conclusion: Poor response in disease volume was correlated with higher sHR of DM for SCC, no other clear correlation of response and PoF was observed. Histology significantly correlated with PoF with SCC prone to LRF and non-SCC prone to DM as first site of failure. High SUVpeak at diagnosis increased the risk of LRF for both histologies.

The odd one out - Orthographic oddball processing in children with poor versus typical reading skills in a fast periodic visual stimulation EEG paradigm.

The specialization of left ventral occipitotemporal brain regions to automatically process word forms develops with reading acquisition and is diminished in children with poor reading skills (PR). Using a fast periodic visual oddball stimulation (FPVS) design during electroencephalography (EEG), we examined the level of sensitivity and familiarity to word form processing in ninety-two children in 2nd and 3rd grade with varying reading skills (n = 35 for PR, n = 40 for typical reading skills; TR). To test children's level of "sensitivity", false font (FF) and consonant string (CS) oddballs were embedded in base presentations of word (W) stimuli. "Familiarity" was examined by presenting letter string oddballs with increasing familiarity (CS, pseudoword - PW, W) in FF base stimuli. Overall, our results revealed stronger left-hemispheric coarse sensitivity effects ("FF in W" > "CS in W") in TR than in PR in both topographic and oddball frequency analyses. Further, children distinguished between orthographically legal and illegal ("W/PW in FF" > "CS in FF") but not yet between lexical and non-lexical ("W in FF" vs "PW in FF") word forms. Although both TR and PR exhibit visual sensitivity and can distinguish between orthographically legal and illegal letter strings, they still struggle with nuanced lexical distinctions. Moreover, the strength of sensitivity is linked to reading proficiency. Our work adds to established knowledge in the field to characterize the relationship between print tuning and reading skills and suggests differences in the developmental progress to automatically process word forms.

Different benefits of adaptive radiotherapy for different histologies of NSCLC.

BACKGROUND: Adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the most frequent histological subtypes of non-small cell lung cancer (NSCLC). The aim of this study was to investigate how patients with AC and SCC benefit from image-guided adaptive radiotherapy (ART) with tumour match. MATERIAL AND METHODS: Consecutive patients diagnosed with AC or SCC of the lung treated with definitive chemo-radiotherapy before and after the implementation of ART and tumour match were retrospectively included for analyses. Data collection included baseline patient and treatment characteristics in addition to clinical data on radiation pneumonitis (RP), failure, and survival. Patients were divided into four categories based on their histology and treatment before (n = 173 [89 AC and 84 SCC]) and after implementation of ART (n = 240 [141 AC and 99 SCC]). RESULTS: Median follow-up was 5.7 years for AC and 6.3 years for SCC. Mean lung dose decreased for both histologies with ART, whereas mean heart dose only decreased for patients with AC. Incidences of grade 3 and 5 RP decreased for both histologies with ART. Loco-regional failure (LRF) rates decreased significantly for patients with SCC after ART (p = .04), no significant difference was observed for AC. Overall survival (OS) increased significantly for SCC after ART (p < .01): the 2-year OS increased from 31.0% (95% confidence interval [CI] [22.5-42.6]) to 54.5% (95% CI [45.6-65.3]). No significant effect on OS was observed for patients with AC. CONCLUSION: ART and tumour match in the radiotherapeutic treatment of patients with locally advanced NSCLC primarily led to decreased LRF and improved OS for patients with SCC.

Difference between planned and delivered radiotherapy dose to the internal mammary nodes in high-risk breast cancer patients.

Background and purpose: Chest wall movement during radiotherapy can impact the delivered dose to the internal mammary nodes (IMN) in high-risk breast cancer patients. Using portal imaging and dose reconstruction we aimed to examine the delivered IMN dose coverage. Material and methods: Cine MV images were recorded for 39 breast cancer patients treated with daily image-guided radiotherapy (IGRT) in deep-inspiration breath-hold (DIBH). On the final frame of each cine MV recording the chest wall was matched with the Digitally Reconstructed Radiograph (DRR) from the treatment plan. The geometrical chest wall error was determined in the imager-plane perpendicular to the cranio-caudal direction, rounded to integer millimeters, and binned. For each 1 mm bin, an isocenter-shifted treatment plan was recalculated assuming that the projected error observed in the cine MV image was caused by anterior-posterior chest wall movement in the IMN region. A weighted plan sum yielded the IMN clinical target volume receiving at least 90% dose (V90_CTVn_IMN). Results: The mean number of cine MV observations per patient was 36 (range 26-55). Most patients (67%) had on average a posterior chest wall position at treatment compared to planned. This translated into a change in the delivered median V90_CTVn_IMN of -0.7% (range, -11.9-2.9%; p < 0.001). The V90_CTVn_IMN reduction was greater than 9% in three patients. No clinically relevant differences were found for the mean lung dose or mean heart dose. Conclusion: Using cine MV images, we found that the delivered V90_CTVn_IMN was significantly lower than planned. In 8% of the patients, the V90_CTVn_IMN reduction exceeded 9%.

Estimated dose to site of loco-regional recurrence after radiotherapy in anal cancer using point of origin methods.

Background and purpose: Loco-regional recurrence (LRR) dominates the failure pattern after curative radiotherapy in anal cancer. The aim of this study was to estimate dose of LRRs in anal cancer using a point of origin-based method. Method and materials: Of 321 patients with squamous cell carcinoma of the anus, 31 patients with LRR (29 local recurrences and 5 regional lymph node recurrences) were available for analysis. The recurrence volumes were delineated on recurrence magnetic resonance imaging (rMRI). Rigid and subsequent deformable co-registration of planning computerised tomography scans and rMRI were performed. Point of origin was estimated as the centre of mass (COM) and an observer-based point of origin (obs-PO). Doses to COM and obs-PO, as well as the full recurrence volume, were estimated and the relation to target volumes was extracted. Results: The median minimum dose to COM was 63.8 Gy (range 32.5-65.1 Gy) and 63.7 Gy (range 35.5-65.2 Gy) to obs-PO of local recurrences. COM was included in the high dose volume (64 Gy) in 86 % of cases, and obs-PO was included in 75 % of cases. There was no difference in minimum dose to COM and obs-PO, and the median distance between the two points was 3.3 mm (range 0.6-19.8 mm). No recurrences occurred in primarily boosted lymph nodes. Conclusion: The majority of LLRs were located within the high dose volume indicating radioresistance as the primary cause of recurrence in anal cancer. No difference between the use of COM and obs-PO was evident.

Disentangling influences of dyslexia, development, and reading experience on effective brain connectivity in children.

Altered brain connectivity between regions of the reading network has been associated with reading difficulties. However, it remains unclear whether connectivity differences between children with dyslexia (DYS) and those with typical reading skills (TR) are specific to reading impairments or to reading experience. In this functional MRI study, 132 children (M = 10.06 y, SD = 1.46) performed a phonological lexical decision task. We aimed to disentangle (1) disorder-specific from (2) experience-related differences in effective connectivity and to (3) characterize the development of DYS and TR. We applied dynamic causal modeling to age-matched (ndys = 25, nTR = 35) and reading-level-matched (ndys = 25, nTR = 22) groups. Developmental effects were assessed in beginning and advanced readers (TR: nbeg = 48, nadv = 35, DYS: nbeg = 24, nadv = 25). We show that altered feedback connectivity between the inferior parietal lobule and the visual word form area (VWFA) during print processing can be specifically attributed to reading impairments, because these alterations were found in DYS compared to both the age-matched and reading-level-matched TR. In contrast, feedforward connectivity from the VWFA to parietal and frontal regions characterized experience in TR and increased with age and reading skill. These directed connectivity findings pinpoint disorder-specific and experience-dependent alterations in the brain's reading network.

Survival benefits for non-small cell lung cancer patients treated with adaptive radiotherapy.

INTRODUCTION: Tumor match and adaptive radiotherapy based on on-treatment imaging increases the precision of RT. This allows a reduction of treatment volume and, consequently, of the dose to organs at risk. We investigate the clinical benefits of tumor match and adaptive radiotherapy for a cohort of non-small cell lung cancer patients (NSCLC). METHODS: In 2013, tumor match and adaptive radiotherapy based on daily cone-beam CT scans was introduced to ensure adaption of the radiotherapy treatment plan for all patients with significant anatomical changes during radiotherapy. Before 2013, the daily cone-beam CT scans were matched on the vertebra and anatomical changes were not evaluated systematically. To estimate the effect of tumor match and adaptive radiotherapy, 439 consecutive NSCLC patients treated with definitive chemo-radiotherapy (50-66 Gy/25-33 fractions, 2010-2018) were investigated retrospectively. They were split in two groups, pre-ART (before tumor match and adaptive radiotherapy, 184 patients), and ART (after tumor match and adaptive radiotherapy, 255 patients) and compared with respect to clinical, treatment-specific and dosimetric variables (χ2 tests, Mann Whitney U tests), progression, survival and radiation pneumonits (CTCAEv3). Progression-free and overall survival as well as radiation pneumonitis were compared with log-rank tests. Hazard ratios were estimated from Cox proportional hazard regression. RESULTS: No significant differences in stage (p = 0.36), histology (p = 0.35), PS (p = 0.12) and GTV volumes (p = 0.24) were observed. Concomitant chemotherapy was administered more frequently in the ART group (78%) compared to preART (64%), p < 0.001. Median[range] PTV volumes decreased from 456 [71;1262] cm3 (preART) to 270 [31;1166] cm3 (ART), p < 0.001, thereby significantly reducing mean doses to lungs (median, preART 16.4 [1.9;24.7] Gy, ART 12.1 [1.7;19.4] Gy, p < 0.001) and heart (median, preART 8.0 [0.1;32.1] Gy, ART 4.4 [0.1;33.9] Gy, p < 0.001). The incidence of RP at nine months decreased significantly with ART (50% to 20% for symptomatic RP (≥G2), 21% to 7% for severe RP (≥G3), 6% to 0.4% for lethal RP (G5), all p < 0.001). The two-year progression free survival increased from 22% (preART) to 30% (ART), while the overall survival increased from 43% (preART) to 56% (ART). The median overall survival time increased from 20 (preART) to 28 months (ART). CONCLUSION: Tumor match and adaptive radiotherapy significantly decreased radiation pneumonitis, while maintaining loco-regional control. Further, we observed a significantly improved progression-free and overall survival.

Strategies for Motion Robust Proton Therapy With Pencil Beam Scanning for Esophageal Cancer.

PURPOSE: Proton therapy of esophageal cancer is superior to photon radiation therapy in terms of normal tissue sparing. However, respiratory motion and anatomical changes may compromise target dose coverage owing to density changes, geometric misses, and interplay effects. Here we investigate the combined effect on clinical target volume (CTV) coverage and compare proton therapy with intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: This study includes 26 patients with esophageal cancer previously treated with IMRT planned on 4-dimensional computed tomography (4D-CT). For each patient, 7 proton pencil beam scanning (PBS) plans were created with different field configurations and optimization strategies. The effect of respiration was investigated by calculating the phase doses, 4D dose, and 4D dynamic dose (including interplay effects). The effect of anatomical changes was investigated by recalculating all plans on all phases of a 4D-CT surveillance scan. RESULTS: The most robust PBS plans were achieved using 2 posterior beams requiring coverage of planning target volume (PTV) and simultaneously using robust optimization (RO) of CTV (2PAPTVRO), resulting in only 1 patient showing V95%CTV <97% in 1 or more phases of the planning CT. For the least robust PBS plans obtained using lateral + posterior beams and CTV-RO, but not requiring PTV coverage (2LPRO), 10 patients showed underdosage. For IMRT, 2 patients showed underdosage. Interplay effects reduced V95%CTV significantly when delivering only 1 fraction, but the effects generally averaged out after 10 fractions. The effect of interplay was significantly larger for RO-only plans compared with plans optimized with RO combined with PTV coverage. Combining the effect of anatomical changes and respiration on the 4D-CT surveillance scan resulted in V95%CTV <97% for 3 2PAPTVRO, 16 2LPRO, and 8 IMRT patients. CONCLUSIONS: PBS using posterior beam angles was more robust to anatomical changes and respiration than IMRT. The effect of respiration was enhanced when anatomical changes were present. Single fraction interplay effects deteriorated the dose distribution but were averaged out after 10 fractions.

Prospectively scored pulmonary toxicities in non-small cell lung cancer: Results from a randomized phase II dose escalation trial.

PURPOSE: Prospectively scored radiation pneumonitis (RP) observed in a national, randomized phase II dose-escalation trial for patients with locally advanced non-small cell lung cancer (NSCLC) was investigated. METHODS: Patients with stage IIB-IIIB histologically proven NSCLC were treated with concomitant chemo-radiotherapy (oral Vinorelbine 3times/week) at 60 Gy/30fx (A-59pts) and 66 Gy/33fx (B-58pts) from 2009 to 2013 at five Danish RT centers. Grade 2 RP (CTCAEv3.0) was investigated with univariate analysis for association with clinical and dosimetric parameters, including dyspnea and cough at baseline and during RT. Multivariable logistic regression and Cox regression with regularization were used to find a multivariable model for RP ≥ G2. RESULTS: Despite a tendency of higher mean lung dose in the high-dose arm (median[range] A = 14.9 Gy[5.8,23.1], B = 17.5 Gy[8.6,24.8], p = 0.075), pulmonary toxicities were not significantly different (RP ≥ G2 41%(A) and 52%(B), p = 0.231). A Kaplan Meier analysis of the time to RP ≥ G2 between the two arms did not reach statistical significance (p = 0.180). Statistically significant risk factors for RP ≥ G2 were GTV size (OR = 2.091/100 cm3, p = 0.002), infection at baseline or during RT (OR = 8.087, p = 0.026), dyspnea at baseline (OR = 2.184, p = 0.044) and increase of cough during RT (OR = 2.787, p = 0.008). In the multivariable logistic regression and the Cox regression analysis, the deviances of the most predictive models were within one standard deviation of the null model. CONCLUSION: No statistical difference between the high- and low dose arm was found in the risk of developing RP. The univariate analysis identified target volume, infection, dyspnea at baseline, and increase of cough during RT as risk factors for RP. The number of patients was too small to establish a statistically sound multivariable model.

Validation of a robust strategy for proton spot scanning for oesophageal cancer in the presence of anatomical changes.

SFUD strategies with one or two posterior proton beams and three target coverage strategies are compared with IMRT and tested for robustness towards anatomical changes by recalculation on surveillance CTs during treatment. We find posterior beam SFUD combining PTV coverage with robust optimization increases robustness towards anatomical changes compared to IMRT.

The NARLAL2 dose escalation trial: dosimetric implications of inter-fractional changes in organs at risk.

BACKGROUND: Phase II trials suggested that survival rates for locally advanced lung cancer could be increased by radiotherapy dose escalation. However, results of the phase III RTOG 0617 trial illustrated an imminent risk of treatment-related death. This could be thwarted with strict constraints to organs at risk (OARs) and control of the delivered dose. This study investigates the impact of anatomical changes during radiotherapy on escalated dose distributions used in the Danish NARLAL2 dose escalation trial. MATERIAL AND METHODS: The phase III NARLAL2 trial randomizes patients between a standard and an escalated treatment plan. In the escalated arm, mean doses up to 95 Gy/33 fractions (tumour) and 74 Gy/33 fractions (lymph nodes) are delivered to the most 18fluorodeoxyglucose-positron emission tomography (18FDG PET) active regions. The dose distributions are limited by strict constraints to OARs. For a group of 27 patients, a surveillance scan (sCT) was acquired at fraction 11. The original-escalated treatment plans were recalculated on the sCTs and the impact of inter-fractional changes evaluated. RESULTS: A total of 13 patients (48%) had overdosage of least one OAR. Constraints for the oesophagus, trachea and aorta were violated in 26% of the patients. No overdosage was seen for heart or bronchi. For the connective tissue (all tissue in the mediastinum not identified as OAR or tumour) overdosage was seen in 41% of the patients and for the chest wall in 30% of the patients. The main reason for overdosage was tumour shrinkage. CONCLUSIONS: Anatomical changes during radiotherapy caused one or more OAR constraint violations for approximately half of the patient cohort. The main cause was tumour shrinkage. For lung cancer radiotherapy dose escalation trials, we recommend incorporation of adaptive radiotherapy strategies.

The potential benefits from respiratory gating for breast cancer patients regarding target coverage and dose to organs at risk when applying strict dose limits to the heart: results from the DBCG HYPO trial.

PURPOSE: The potential benefits from respiratory gating (RG) compared to free-breathing (FB) regarding target coverage and dose to organs at risk for breast cancer patients receiving post-operative radiotherapy (RT) in the DBCG HYPO multicentre trial are reported. MATERIAL AND METHODS: Patients included in the DBCG HYPO trial were randomized between 50 Gy in 25 fractions (normofractionated) versus 40 Gy in 15 fractions (hypofractionated). A tangential forward field-in-field dose planning technique was used to cover the clinical target volume (CTV) with the intent to limit dose to the left anterior descending coronary artery (LADCA) to 20 Gy and 17 Gy in the normo- and hypofractionated arms, respectively. Treatment plan data for 1327 patients from four Danish centres was retrospectively analyzed. FB right-sided patients served as control group for the left-sided patients regarding CTV V95% (relative volume receiving at least 95% of the prescribed dose), mean heart dose (MHD) and mean lung dose (MLD). RESULTS: Median CTV V95% was for FB right-sided, FB left-sided and RG left-sided patients 94.6, 92.6 and 94.7% for normofractionated therapy, respectively, and 94.6, 91.8 and 94.4% for hypofractionated therapy and did not differ significantly for RG left-sided plans compared to FB right-sided in either study arm. CTV V95% was significantly lower for FB versus RG for left-sided plans in both arms. Median MHD was 0.7, 1.8 and 1.5 Gy (normofractionated therapy) versus 0.6, 1.5 and 1.2 Gy (hypofractionated therapy), respectively. The corresponding median MLD was 9.0, 8.3 and 7.3 Gy versus 7.3, 6.4 and 5.8 Gy, respectively. CONCLUSIONS: RG for left-sided breast cancer patients ensured similar CTV V95% as for FB right-sided patients. MLD was lower for RG due to the increased lung volume. MHD was generally low due to strict protocol-defined maximum dose to LADCA, but for left-sided patients RG led to significantly lower MHD.

EGFR and Cortactin: Markers for potential double target therapy in oral squamous cell carcinoma.

Survival periods of patients following surgical therapy of oral squamous cell carcinoma (OSCC) have previously been demonstrated to decrease over recent decades. Epidermal growth factor receptor (EGFR) and Cortactin are molecular markers that are important in tumour progression and development, and interact within the EGF pathway. Although EGFR antibody therapy exists, sufficient efforts for increased survival are still lacking due to the present limited response rates. The aim of the present study was to examine the association between EGFR and Cortactin expression on survival rates of OSCC patients and to determine whether EGFR and Cortactin expression levels are associated with advanced tumor sizes and lymphnode-metastases. In total, 222 OSCC patients were included in the study. EGFR and Cortactin expression in tumor tissue was evaluated by immunohistochemistry. Cox regression was used for survival analysis. Categories were tested for associations by using cross tabs (Chi-square test). Groups were compared by the non-parametric Mann Whitney U-test. Probabilities of less than 0.05 were considered significant and significant expression of Cortactin was observed in Advanced Union Internationale Contre le Cancer stage (P=0.032), including advanced tumour stage (P=0.021) and lymph node metastasis (P=0.049). High Cortactin expression was significantly associated with poorer survival rates (P=0.037). Further Cortactin expression was not associated with extracapsular spread, however EGFR exhibited a significant association (P=0.034). Neither EGFR nor Cortactin expression was correlated to grading. EGFR and Cortactin co-expression was demonstrated to be significantly associated with poorer survival rates in OSCC patients, suggesting that identification of predictive biomarkers for adjuvant therapies are of primary concern in OSCC. In particular, efficient dual-target therapy may act as an appropriate therapy to improve survival time for patients at advanced OSCC tumor stages.

Short-Term and Long-Term Effects of an Exercise-Based Patient Education Programme in People with Multiple Sclerosis: A Pilot Study.

Background. Although people with Multiple Sclerosis (pwMS) benefit from physical exercise, they still show reduced physical activity and exercise behaviour. This study aimed to investigate short- and long-term effects of an exercise-based patient education programme (ePEP) that focuses on empowering pwMS to a sustainable and self-regulated exercise training management. Methods. Fourteen pwMS were randomly assigned to immediate experimental group (EG-I: n = 8) and waitlist-control group (EG-W: n = 6) and attended biweekly in a six-week ePEP. All participants were measured for walking ability, quality of life, fatigue, and self-efficacy towards physical exercise before and after the ePEP, after 12 weeks, and one year after baseline. Short-term effects were analysed in a randomised control trial and long-term effects of all ePEP participants (EG-I + EG-W = EG-all) in a quasi-experimental design. Results. Only functional gait significantly improved in EG-I compared to EG-W (p = 0.008, r = -0.67). Moderate to large effects were found in EG-all for walking ability. Not significant, however, relevant changes were detected for quality of life and fatigue. Self-efficacy showed no changes. Conclusion. The ePEP seems to be a feasible option to empower pwMS to a self-regulated and sustainable exercise training management shown in long-term walking improvements.

Heterogeneous FDG-guided dose-escalation for locally advanced NSCLC (the NARLAL2 trial): Design and early dosimetric results of a randomized, multi-centre phase-III study.

BACKGROUND AND PURPOSE: Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans. MATERIAL AND METHODS: Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue. RESULTS: The median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation. CONCLUSIONS: FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans.

Setup error and motion during deep inspiration breath-hold breast radiotherapy measured with continuous portal imaging.

BACKGROUND: The position and residual motion of the chest wall of breast cancer patients during treatment in deep inspiration breath-hold (DIBH) were investigated. MATERIAL AND METHODS: The study included 58 left-sided breast cancer patients treated with DIBH three-dimensional (3D) conformal radiotherapy in 15 or 25 fractions. The DIBH levels were monitored using an external marker block placed on the chest, either shifted 5 cm to the right at the level of the xiphoid process (Group 1, 27 consecutive patients) or placed medially on the inferior part of the sternum (Group 2, 31 consecutive patients). At every third treatment fraction, continuous portal images were acquired. The time-resolved chest wall position during treatment was compared with the planned position to determine the inter-fraction setup errors and the intra-fraction motion of the chest wall. RESULTS: The DIBH compliance was 95% during both recruitment periods. A tendency of smaller inter-fraction setup errors and intra-fraction motion was observed for group 2 (medial marker block position). However, apart from a significantly reduced inter-field random shift (σ = 1.7 mm vs. σ = 0.9 mm, p = 0.005), no statistically significant differences between the groups were found. In a combined analysis, the group mean inter-fraction setup error was M = - 0.1 mm, with random and systematic errors of σ = 1.7 mm and Σ = 1.4 mm. The group mean inter-field shift was M = 0.0 (σ = 1.3 mm and Σ = 1.1 mm) and the group mean standard deviation of the intra-field motion was 0.5 mm. The absolute setup error had a maximum of 16.3 mm, exceeding 5 mm in 2.2% of the imaged fields. CONCLUSION: Compared to free breathing treatments, the primary benefit of the DIBH technique was the separation of the heart from the target rather than more accurate targeting. Despite a small gating window, occasional large errors in the chest wall position were observed for some patients, illustrating limitations of the external marker block as surrogate in a broad patient population.

A pilot study of an exercise-based patient education program in people with multiple sclerosis.

There is increasing evidence that physical exercise leads to numerous positive effects in PwMS. However, long-term effects of exercise may only be achievable if training is implemented in daily routine. Enabling patients to exercise regularly, we developed a patient education program focused on evidence-based information of training. PwMS were educated in neurophysiological effects of physical exercise, exercise-induced benefits for PwMS, and risk factors (e.g., weather). Fifteen PwMS were analyzed before (T 0) and after (T 1) a 12-week patient education. Afterwards, participants performed their exercises autonomously for 32 weeks and were tested in sustainability tests (T 2). Guided interviews were carried out, additionally. Significant improvements from T 0 to T 1 were found in 6MWT, gait velocity, TUG, fatigue, and quality of life. Significant results of TUG and gait velocity from T 1 to T 2 demonstrated that participants kept few effects after the 32-week training phase. Qualitative analyses showed improved self-confidence and identified training strategies and barriers. This pilot study provides evidence that PwMS are able to acquire good knowledge about physical exercise and apply this knowledge successfully in training management. One might conclude that this exercise-based patient education seems to be a feasible option to maintain or improve patients' integral constitution concerning physical and mental health.

[Halitophobia--an under-recognized clinical picture]. / Halitophobie--das unterschätzte Krankheitsbild.

A large part of the population suffers from halitosis. Causes can be both oral and non-oral changes. Coating of the tongue as well as marginal periodontitis are the most frequent oral causes. Non-oral causes are primarily tonsillitis and sinusitis but also general diseases as well as special diet habits. Non-real halitosis or halitophobia is unterstood by the compulsive idea to suffer from bad breath and to irritate others by this. This compulsive idea can change the complete pattern of behavior of these patients which in itself can lead to self-isolation and even to suicide. Consultation hours for halitosis should be prepared for patients with non-real halitosis and build up corresponding interdisciplinary contacts.

Protein kinase C theta affects Ca2+ mobilization and NFAT cell activation in primary mouse T cells.

Protein kinase C (PKC)theta is an established component of the immunological synapse and has been implicated in the control of AP-1 and NF-kappaB. To study the physiological function of PKCtheta, we used gene targeting to generate a PKCtheta null allele in mice. Consistently, interleukin 2 production and T cell proliferative responses were strongly reduced in PKCtheta-deficient T cells. Surprisingly, however, we demonstrate that after CD3/CD28 engagement, deficiency of PKCtheta primarily abrogates NFAT transactivation. In contrast, NF-kappaB activation was only partially reduced. This NFAT transactivation defect appears to be secondary to reduced inositol 1,4,5-trisphosphate generation and intracellular Ca2+ mobilization. Our finding suggests that PKCtheta plays a critical and nonredundant role in T cell receptor-induced NFAT activation.

Evidence of functional modulation of the MEKK/JNK/cJun signaling cascade by the low density lipoprotein receptor-related protein (LRP).

Lipoprotein receptors, such as LRP, have been shown to assemble multiprotein complexes containing intracellular signaling molecules; however, in vivo, their signaling function is poorly understood. Using a novel LRP receptor fusion construct, a type I transmembrane protein chimera, termed sIgG-LRP (bearing the intracellular COOH-terminal tail of human LRP as recombinant fusion to a transmembrane region plus the extracellular IgG-F(c) domain), we here investigated LRP signal transduction specificity in intact cells. First and similar to activated alpha2-macroglobulin as agonist of endogenous LRP, expression of sIgG-LRP demonstrated significant apoptosis protection. Second and similar to alpha2-macroglobulin-induced endogenous LRP, sIgG-LRP is sufficient to negatively modulate mitogen-induced Elk-1 and cJun (but not NF-kappaB) transcriptional activity. Third, expression of sIgG-LRP also impaired cJun transactivation mediated by constitutive active mutants of Rac-1 and MEKK-1. Fourth and unexpectedly, sIgG-LRP expression was found to be associated with a marked enhancement of mitogen-induced cJun amino-terminal kinase (JNK) activation. Fifth, confocal microscopic examination and subcellular fractionation demonstrated that sIgG-LRP and JNK co-localize in transfected cells. Therefore, sIgG-LRP expression was found to significantly impair activation-induced translocation of JNK into the nucleus. Taken together, we here demonstrate that sIgG-LRP protein sequesters activated JNK into the plasma membrane compartment in intact cells, inhibiting nuclear activation of the JNK-dependent transcription factors Elk-1 and cJun.