Understanding an impact of patient enrollment pattern on predictability of central (unstratified) randomization in a multi-center clinical trial.

In a multi-center randomized controlled trial (RCT) with competitive recruitment, eligible patients are enrolled sequentially by different study centers and are randomized to treatment groups using the chosen randomization method. Given the stochastic nature of the recruitment process, some centers may enroll more patients than others, and in some instances, a center may enroll multiple patients in a row, for example, on a given day. If the study is open-label, the investigators might be able to make intelligent guesses on upcoming treatment assignments in the randomization sequence, even if the trial is centrally randomized and not stratified by center. In this paper, we use enrollment data inspired by a real multi-center RCT to quantify the susceptibility of two restricted randomization procedures, the permuted block design and the big stick design, to selection bias under the convergence strategy of Blackwell and Hodges (1957) applied at the center level. We provide simulation evidence that the expected proportion of correct guesses may be greater than 50% (i.e., an increased risk of selection bias) and depends on the chosen randomization method and the number of study patients recruited by a given center that takes consecutive positions on the central allocation schedule. We propose some strategies for ensuring stronger encryption of the randomization sequence to mitigate the risk of selection bias.

Estimation of treatment effects in early-phase randomized clinical trials involving external control data.

There are good reasons to perform a randomized controlled trial (RCT) even in early phases of clinical development. However, the low sample sizes in those settings lead to high variability of the treatment effect estimate. The variability could be reduced by adding external control data if available. For the common setting of suitable subject-level control group data only available from one external (clinical trial or real-world) data source, we evaluate different analysis options for estimating the treatment effect via hazard ratios. The impact of the external control data is usually guided by the level of similarity with the current RCT data. Such level of similarity can be determined via outcome and/or baseline covariate data comparisons. We provide an overview over existing methods, propose a novel option for a combined assessment of outcome and baseline data, and compare a selected set of approaches in a simulation study under varying assumptions regarding observable and unobservable confounder distributions using a time-to-event model. Our various simulation scenarios also reflect the differences between external clinical trial and real-world data. Data combinations via simple outcome-based borrowing or simple propensity score weighting with baseline covariate data are not recommended. Analysis options which conflate outcome and baseline covariate data perform best in our simulation study.

Translation and psychometric properties of the German version of the "Interprofessional Socialization and Valuing Scale" (ISVS-21-D).

Understanding of the processes associated with socialization into collaborative work plays an important role in interprofessional education and collaborative practice. In order to evaluate changes in socialization toward interprofessional collaborative practice a measure is needed that captures professional beliefs, attitudes and behaviors of individuals in learning activities and in workplace practice. This article presents the translation and psychometric properties of the German Version of the Interprofessional Socialization and Valuing Scale (ISVS-21). Following translation from English to German, data of the German version of the questionnaire (ISVS-21-D) was collected in six different interprofessional education and practice settings amongst undergraduate students and health professionals. In total, 494 responses were analyzed. Results showed high reliability with Cronbach's alpha .90. Although not all fit indices are in the desired range, results give preliminary indication of the underlying single factor of the ISVS-21-D and suggest that the German version of the ISVS-21-D is a reliable instrument that can be used to measure interprofessional socialization in German health professionals and health care students as well as within other disciplines.

GPs´ Personal Spirituality, Their Attitude and Spiritual Competence: A Cross-Sectional Study in German General Practices.

To understand if GPs' spiritual competence, their personal spirituality and attitude towards enquiring about spirituality in practice interrelate, we conducted a cross-sectional survey of 30 German GPs regarding issues of SC. We found correlations between GPs' personal spirituality, their spiritual competence and their attitudes towards SC. The ability to perceive spiritual needs of patients was the competence most strongly related to GPs' attitude towards SC. The competence with the strongest correlation to personal spirituality was Self-awareness and Proactive opening. No correlation was found between affiliation to a spiritual community and GPs' attitude towards SC. The results show that GPs' personal spirituality and spiritual competence are indeed related to addressing spirituality with their patients. To foster SC, training programmes should raise awareness for one's personal spirituality and encourage one to reflect on spiritual competence.

Protocol of the TREASURE study: Thoracic RadiothErapy with Atezolizumab in Small cell lUng canceR Extensive disease - a randomized, open-label, multicenter phase II trial.

BACKGROUND: Recently, the combination of the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab with first-line chemotherapy has demonstrated to improve outcome for patients with advanced small cell lung cancer (SCLC), leading to approval of this regimen. At the same time, accumulating (pre-)clinical data suggest synergisms of radiotherapy and immunotherapy via the radiation-mediated induction of anti-tumor immunogenicity. Combining the recent findings, the TREASURE trial aims at further enhancing response to upfront chemo-immunotherapy by the addition of thoracic radiotherapy (TRT). METHODS/DESIGN: The TREASURE trial is a randomized, multicenter, phase II clinical trial ( ClinicalTrials.gov identifier, NCT04462276). One hundred four patients suffering from extensive disease (ED) SCLC, with any response to the standard of care induction chemo-immunotherapy will be randomized to receive atezolizumab maintenance therapy with or without TRT. The primary endpoint of this study is overall survival (OS). Secondary endpoints include further measures of efficacy, safety, and the collection of biomarker samples. A safety interim analysis will take place after n = 23 patients receiving TRT have been observed for three months after the end of TRT. DISCUSSION: This trial will investigate whether treatment efficacy can be improved by adding TRT to atezolizumab maintenance therapy in ED SCLC patients with any response after chemo-immunotherapy. Safety and feasibility of such a regimen will be evaluated, and biomaterials for a translational research project will be collected. Together, the results of this trial will deepen our comprehension of how checkpoint inhibition and radiotherapy interact and contribute to the evolving landscape of SCLC therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04462276 (Date of initial registration: 8th July 2020), https://clinicaltrials.gov/ct2/show/NCT04462276 Eudra-CT Number: 2019-003916-29 (Date of initial registration: 30th March 2020), https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003916-29/DE.

A Comprehensive Comparison of Additional Benefit Assessment Methods Applied by Institute for Quality and Efficiency in Health Care and European Society for Medical Oncology for Time-to-Event Endpoints After Significant Phase III Trials-A Simulation Study.

OBJECTIVES: After a successful Marketing Authorization Application for clinical trials with time-to-event endpoints, the degree of the added benefit from new treatments remains unknown and needs to be assessed. Unfortunately, until now no clear definition for added benefit determination of a treatment exists. Nevertheless, European authorities / societies have developed 2 "additional benefit assessment" methods, which have up to now not been compared: the European Society for Medical Oncology (ESMO) developed a dual rule considering relative and absolute benefit. The German Institute for Quality and Efficiency in Health Care (IQWiG) developed a method using upper 95% hazard ratio confidence interval. METHODS: We evaluate and compare both methods in an extensive simulation study including different censoring rates, failure time distributions, and treatment effects for sample size calculation. The methods' performance is assessed via Receiver Operating Characteristic curves, Spearman correlation, and percentage of achieved maximal scores. RESULTS: The results show that IQWiG's method has in many situations a lower maximal scoring proportion than ESMO's rule, that is, up to 28.5% versus 94.7%. Various failure time distributions lead to strongly changed maximal scoring percentages for ESMO. High positive correlation between the methods is present for moderate treatment effects. CONCLUSIONS: IQWiG's method is usually more conservative than ESMO's. ESMO's rule tends to be more susceptible for various failure time distributions. Using the lower confidence interval limit seems to be a better solution resulting in a higher true-positive rate without increasing the false-positive rate. Thus, IQWiG's method might need to be adapted accordingly to achieve a better overall classification.

Communication with patients with limited prognosis-an integrative mixed-methods evaluation study.

PURPOSE: Oncological societies advocate the continuity of care, specialized communication, and early integration of palliative care. To comply with these recommendations, an interprofessional, longitudinally-structured communication concept, the Milestone Communication Approach (MCA), was previously developed, implemented, and evaluated. Our research question is: what are possible explanations from the patient perspective for prognosis and advance care planning being rarely a topic and for finding no differences between MCA and control groups concerning distress, quality of life, and mood? METHODS: A pragmatic epistemological stance guided the study. A mixed-methods design was chosen including a pragmatic randomized trial (n = 171), qualitative interviews with patients (n = 13) and caregivers (n = 12), and a content analysis (133 milestone conversations, 54 follow-up calls). Data analysis involved the pillar integration process. RESULTS: Two pillar themes emerged: 1 "approaching prognosis and advance care planning"; 2 "living with a life-threatening illness". Information on prognosis seemed to be offered, but patients' reactions were diverse. Some patients have to deal with having advanced lung cancer while nonetheless feeling healthy and seem not to be ready for prognostic information. All patients seemed to struggle to preserve their quality of life and keep distress under control. CONCLUSION: Attending to patients' questions, worries and needs early in a disease trajectory seems key to helping patients adjust to living with lung cancer. If necessary clinicians should name their predicament: having to inform about prognosis versus respecting the patients wish to avoid it. Research should support better understanding of patients not wishing for prognostic information to successfully improve communication strategies. TRIAL REGISTRATION: Registration: German Clinical Trial Register No. DRKS00013649, registration date 12/22/2017, ( https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013649 ) and No. DRKS00013469, registration date 12/22/2017, ( https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013469 ).

An adaptive design for early clinical development including interim decision for single-arm trial with external controls or randomized trial.

In early clinical development, randomized controlled trials (RCT) or single-arm trials with external controls (SATwEC) are design options, which allow adjustment for confounding: RCT via design, SATwEC via analysis using propensity score methods. SATwEC requires less investment than RCT. However, if the confounder space substantially differs between the experimental and external control group, the SATwEC might lead to inappropriate decisions for further development. We develop an adaptive two-stage design (ATD) for early clinical development that reduces the risk of unreliable decision-making at the end of a SATwEC. In Stage I, subjects are solely assigned to the experimental group. If at the interim the propensity score distributions of internal and external data are comparable based on the preference score, the subjects in stage II will again be solely assigned to the experimental arm; if not, a randomized stage II will be conducted. In a simulation study guided by a motivating example, data is generated using a time-to-event model with observable and unobservable confounders. The confounder space is varied to investigate the impact on false go/stop probabilities as well as a loss function, which reflects the quality of treatment effect estimates and decision-making. The proposed ATD provides a compromise between optimizing quality (as expressed by false go/stop probabilities and the loss function) and investment (defined by sample size and trial duration).

Monotonicity conditions for avoiding counterintuitive decisions in basket trials.

In a basket trial, a new treatment is tested in different subgroups, called the baskets. In oncology, the baskets usually comprise patients with different primary tumor sites but a common biomarker. Most basket trials are uncontrolled phase II trials and investigate a binary endpoint such as tumor response. To combine the data of baskets that show a similar response to the treatment, many basket trial designs use Bayesian borrowing methods. This increases the power compared to a basketwise analysis. However, it can lead to posterior probabilities that are not monotonically increasing in the number of responses. We show that, as a consequence, two types of counterintuitive decisions can arise-one that occurs within a single trial and one that occurs when the results are compared between different trials. We propose two monotonicity conditions for the inference in basket trials. Using a design recently proposed by Fujikawa and colleagues, we investigate the case of a single-stage basket trial with equal sample sizes in all baskets and show that, as the number of baskets increases, these conditions are violated for a wide range of different borrowing strengths. We show that in the investigated scenarios pruning baskets can help to ensure that the monotonicity conditions hold and investigate how this affects type I error rate and power.

Effects of an Interprofessional Communication Approach on Support Needs, Quality of Life, and Mood of Patients with Advanced Lung Cancer: A Randomized Trial.

BACKGROUND: To address the support needs of newly diagnosed patients with lung cancer with limited prognosis, the Milestone Communication Approach (MCA) was developed and implemented. The main elements of the MCA are situation-specific conversations along the disease trajectory conducted by an interprofessional tandem of physician and nurse. The aim of the study was to evaluate the effects of MCA on addressing support needs, quality of life, and mood as compared with standard oncological care. PATIENTS AND METHODS: A randomized trial was conducted with baseline assessment and follow-up assessments at 3, 6, and 9 months in outpatients with newly diagnosed lung cancer stage IV at a German thoracic oncology hospital. The primary outcome was the Health System and Information Needs subscale of the Short Form Supportive Care Needs Survey (SCNS-SF34-G) at 3-month follow-up. Secondary outcomes included the other subscales of the SCNS-SF34-G, the Schedule for the Evaluation of Individual Quality of Life, the Functional Assessment of Cancer Therapy lung module, the Patient Health Questionnaire for Depression and Anxiety, and the Distress Thermometer. RESULTS: At baseline, 174 patients were randomized, of whom 102 patients (MCA: n = 52; standard care: n = 50) provided data at 3-month follow-up. Patients of the MCA group reported lower information needs at 3-month follow-up (mean ± SD, 33.4 ± 27.5; standard care, 43.1 ± 29.9; p = .033). No effects were found for secondary outcomes. CONCLUSION: MCA lowered patient-reported information needs but did not have other effects. MCA contributed to tailored communication because an adequate level of information and orientation set the basis for patient-centered care. IMPLICATIONS FOR PRACTICE: By addressing relevant issues at predefined times, the Milestone Communication Approach provides individual patient-centered care facilitating the timely integration of palliative care for patients with a limited prognosis. The needs of patients with lung cancer must be assessed and addressed throughout the disease trajectory. Although specific topics may be relevant for all patients, such as information about the disease and associated health care, situations of individual patients and their families must be considered. Additionally, using the short form of the Supportive Care Needs Survey in clinical practice to identify patients' problems might support individually targeted communication and preference-sensitive care.

Brigatinib versus other second-generation ALK inhibitors as initial treatment of anaplastic lymphoma kinase positive non-small cell lung cancer with deep phenotyping: study protocol of the ABP trial.

BACKGROUND: Availability of potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) has pushed the median survival of ALK+ non-smallcell lung cancer (NSCLC) patients to over five years. In particular, second-generation ALK TKI have demonstrated superiority compared to the first-generation compound crizotinib and are meanwhile standard first-line treatment. However, clinical courses of individual patients vary widely, with secondary development of drug resistance and intracranial progression remaining important problems. While these limitations highlight the need for better disease monitoring and additional therapeutic tools, molecular tumor features are increasingly recognized as crucial determinants of clinical outcome. This trial aims to optimize management of ALK+ NSCLC by analyzing the efficacy of second-generation ALK inhibitors in conjunction with deep longitudinal phenotyping across two treatment lines. METHODS/DESIGN: In this exploratory prospective phase II clinical trial, newly diagnosed ALK+ NSCLC patients will be randomized into two treatment arms, stratified by presence of brain metastases and ECOG performance status: brigatinib (experimental arm) vs. any other approved second-generation ALK TKI. Tumor tissue and blood samples will be collected for biomarker analysis at the beginning and throughout the study period to investigate baseline molecular tumor properties and analyze the development of acquired drug resistance. In addition, participating investigators and patients will have the possibility of fast-track molecular tumor and ctDNA profiling at the time of disease progression using state-of-the-art next-generation sequencing (NGS), in order to support decisions regarding next-line therapy. DISCUSSION: Besides supporting therapeutic decisions for enrolled patients, the ABP trial primarily aims to deepen the understanding of the underlying biology and facilitate development of a framework for individualized management of ALK+ NSCLC according to molecular features. Patients with low molecular risk and the perspective of a "chronic disease" will be distinguished from "high-risk" cases, molecular properties of which will be utilized to elaborate improved methods of non-invasive monitoring and novel preclinical models in order to advance therapeutic strategies. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04318938. Registered March 182,020, https://www.clinicaltrials.gov/ct2/show/NCT04318938 Eudra-CT, 2019-001828-36. Registered September 302,019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-001828-36.

The impact of splinting mobile mandibular incisors on Oral Health-Related Quality of Life-Preliminary observations from a randomized clinical trial.

AIM: To compare the Oral Health-Related Quality of Life (OHRQoL) of patients with mobile mandibular incisors before and after full-mouth disinfection (FMD) with and without splinting. MATERIAL AND METHODS: Thirty-four periodontitis patients with ≥1 mobile mandibular incisor (degree II/III) were randomly allocated to the test or control group. All patients received FMD and the test group additional splinting of teeth 33-43. OHRQoL was assessed before (BL) and 3 months after FMD (RE) using the Oral Health Impact Profile (OHIP)-14. Data were compared within and between the groups (Wilcoxon test/Mann-Whitney U test). RESULTS: Twenty-eight patients (13 test group/15 control group) were re-evaluated. FMD led to a reduction of the mean probing pocket depth (PPD; in mm) (test group: BL-PPD 3.89 ± 1.03, RE-PPD 2.82 ± 0.53; control group: BL-PPD 3.58 ± 0.66, RE-PPD 2.77 ± 0.59; each p ≤ .001), the mean clinical attachment level (CAL; in mm) (test group: BL-CAL 5.22 ± 1.38, RE-CAL 4.79 ± 0.85; control group: BL-CAL 4.58 ± 1.10, RE-CAL 4.41 ± 0.96; each p ≤ .05), and the mean OHIP-14 summary scores (test group: BL-OHIP 21.7 ± 11.06, RE-OHIP 9.9 ± 8.96, p = .0046; control group: BL-OHIP 16.8 ± 8.27, RE-OHIP 11.7 ± 8.55; p = .0217). The reduction of the OHIP-G14 scores was considerably higher in the test group but statistically not significant (p = .080). CONCLUSIONS: The results show a positive impact of non-surgical periodontal treatment on OHRQoL and a possible tendency for further improvement by splinting mobile mandibular incisors.

Short and mid-term impact of community pharmacy-based medication reviews on medication- and patient-related outcomes in Germany.

OBJECTIVE: To assess the effect of a routine medication review service in German community pharmacies (ATHINA) on drug-related problems (DRPs) and patient-related outcomes. MATERIALS AND METHODS: From 2015 to 2017, ATHINA patients were invited by their pharmacists to participate in a prospective, observational trial, meaning that they needed to attend to a follow-up visit (T2) 3 - 6 months after the routine ATHINA baseline (T0) and concluding visit (T1) to assess implementation rates of the pharmacists' interventions. Moreover, they were asked to fill in 2 surveys on drug treatment-related quality of life and satisfaction with the amount of information received about medicines at T0, T1, and T2. RESULTS: Of 132 recruited patients, 115 completed T2. At T0, pharmacists documented a DRP or information need for 114 of 115 patients. About half of these issues were resolved leading to 43/115 patients without any DRP or information need at T1 and 50/115 patients without any DRP or information need at T2 (i.e., absolute reduction by 42.6%, p < 0.001). Also, the number of patients who felt that their daily life was not impaired at all or only very slightly by their drug treatment increased from 54.7% (58/106) at T0 to 67.6% (73/108, p = 0.011) at T2. While the overall satisfaction score with the amount of information on medicines increased from 10.2 ± 5.5 at T0 over 14.6 ± 3.8 (T1) to 15.4 ± 3.1 (T2, p < 0.001), this increase did not correlate with reduced information needs. CONCLUSION: The results suggest that the intervention improves medication- and patient-related outcomes. However, causal relationships are still questionable.

What do Germans really think about health-nudges?

BACKGROUND: In recent years, policymakers have increasingly used behaviourally informed policies, including 'nudges'. They have been implemented to produce desirable social outcomes such as healthier eating and physical activity. In Germany, a small research team at the Federal Chancellery acts as the central unit to promote the introduction of nudges in the design of public life. Despite this, the nudging concept itself as well as the understanding around it has not spread widely among German citizens. When reporting about the concept, German media is often very critical of the concept. METHODS: Using a for age, sex and educational level nationally representative online survey with 1000 participants, we investigate whether German citizens know about the concept of nudging. We also explore if they approve of the theoretical concept as well as a list of seven specific interventions regarding healthy eating and physical activity. A particular focus is placed on whether the level of approval is dependent on the target group of the intervention, as well as different intervention-initiators. RESULTS: We find that nearly 80% of the respondents have never heard of nudging. However when being provided with a definition, we find that a strong majority (90%) supports the concept of nudging as well as all the specific interventions. Acceptance rates are higher if interventions are targeted at the general population compared to only children. All initiators - statutory health insurers, the government, private companies, and independent experts - are accepted as nudge initiators. CONCLUSION: Amongst Germans nudges are an accepted method to promote health behaviours. Policy makers from various fields in Germany should take that into account to improve future health policy.

Effect of endodontic treatment on periodontal healing of grade 3 endo-periodontal lesions without root damage in periodontally compromised patients-a retrospective pilot study.

OBJECTIVES: There is little evidence about the effect of different treatment protocols for grade 3 endo-periodontal lesions without root damage in patients with periodontitis according to the new classification of periodontal disease. The aim of this study is to evaluate the impact of endodontic treatment on the achievement of periodontal healing. MATERIALS AND METHODS: Teeth with the initial diagnosis endo-periodontal lesion without root damage grade 3, treated with a standardized endodontic treatment protocol, were included in this study. A retrospective analysis was performed to assess the impact on periodontal healing by evaluating probing pocket depth (PPD), clinical attachment gain (CAL), and periapical index score (PAI). RESULTS: Nineteen teeth and 13 patients were included. A mean reduction of 3.19 ± 3.41 mm in PPD was recorded. The mean CAL gain was 2.33± 3.75 mm. Five teeth (45.4%) showed an improvement of PAI and were classified as treatment success. CONCLUSIONS: The results failed to show a highly predictable treatment outcome for endo-periodontal lesion grade 3 without root damage in patients with periodontitis. However, endodontic therapy alone resulted in treatment success for some of the teeth, which would otherwise have had a poor prognosis. CLINICAL RELEVANCE: Endo-periodontal lesions can often be challenging for dentists in daily clinical practice. To date, there is not much evidence for practitioners to rely on. Therefore, this study aims to strengthen the evidence for the management and treatment of endo-periodontal lesions. Although the outcome is not highly predictable yet, teeth with the initial diagnosis endo-periodontal lesion without root damage grade 3 can benefit from an endodontic treatment.

Categories, components, and techniques in a modular construction of basket trials for application and further research.

Basket trials have become a virulent topic in medical and statistical research during the last decade. The core idea of them is to treat patients, who express the same genetic predisposition-either personally or their disease-with the same treatment irrespective of the location of the disease. The location of the disease defines each basket and the pathway of the treatment uses the common genetic predisposition among the baskets. This opens the opportunity to share information among baskets, which can consequently increase the information of the basket-wise response with respect to the investigated treatment. This further allows dynamic decisions regarding futility and efficacy of individual baskets during the ongoing trial. Several statistical designs have been proposed on how a basket trial can be conducted and this has left an unclear situation with many options. The different designs propose different mathematical and statistical techniques, different decision rules, and also different trial purposes. This paper presents a broad overview of existing designs, categorizes them, and elaborates their similarities and differences. A uniform and consistent notation facilitates the first contact, introduction, and understanding of the statistical methodologies and techniques used in basket trials. Finally, this paper presents a modular approach for the construction of basket trials in applied medical science and forms a base for further research of basket trial designs and their techniques.

Diagnostic accuracy of the Diagnostic Criteria for Temporomandibular Disorders for children aged 8-12 years.

BACKGROUND AND OBJECTIVE: Objective of this study was to determine whether the diagnostic accuracy of the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) is sufficient for use among schoolchildren aged 8-12 years. METHODS: This prospective cohort study on diagnostic accuracy with calibrated examiners was conducted among 533 children of both sexes aged 8-12 years, with and without TMD symptoms, selected randomly from the Rhein-Neckar district. Self-reporting of non-dental facial pain was used as the reference standard, against which we calculated the following for the pain-related items of the DC/TMD (index test): sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, accuracy and 95% Wilson Score confidence intervals. We also calculated the area under the receiver-operating characteristic (AUROC) curve displaying sensitivity and specificity. RESULTS: Our final sample consisted of 282 children, half of whom reported having facial pain and 3.2% reported sounds from the temporomandibular joints (TMJs). Despite high specificity (90.78%; 95% confidence interval (CI): [84.86%; 94.53%]), sensitivity of the adapted DC/TMD for pain on maximum jaw opening was poor (37.59%; 95% CI: [30.02%; 45.81%]). For pain on palpation, more similar values were recorded for sensitivity (74.47%; 95% CI: [66.69%; 80.95%]) and specificity (70.21%; 95% CI: [62.21%; 77.14%]). The diagnostic odds ratio was >1 for both examinations. The AUROC for pain on opening was 68.39% (95% CI: [62.62%; 74.16%]), and for pain on palpation, it was 74.63% (95% CI: [69.45%; 79.81%]), whereas the combination of both resulted to an AUROC of 74.09% (95% CI: [68.96%; 79.21%]). It was not possible to measure the diagnostic accuracy of the DC/TMD regarding TMJ sounds or jaw-opening limitations, as they occurred too rarely in our sample. CONCLUSION: In this study, the diagnostic accuracy of the DC/TMD for TMD-related pain in children was lower than that recorded for adults in previous studies.

Acute exacerbation of idiopathic pulmonary fibrosis: international survey and call for harmonisation.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an often deadly complication of IPF. No focussed international guidelines for the management of AE-IPF exist. The aim of this international survey was to assess the global variability in prevention, diagnostic and treatment strategies for AE-IPF.Pulmonologists with ILD expertise were invited to participate in a survey designed by an international expert panel.509 pulmonologists from 66 countries responded. Significant geographical variability in approaches to manage AE-IPF was found. Common preventive measures included antifibrotic drugs and vaccination. Diagnostic differences were most pronounced regarding use of Krebs von den Lungen-6 and viral testing, while high-resolution computed tomography, brain natriuretic peptide and D-dimer are generally applied. High-dose steroids are widely administered (94%); the use of other immunosuppressant and treatment strategies is highly variable. Very few (4%) responders never use immunosuppression. Antifibrotic treatments are initiated during AE-IPF by 67%. Invasive ventilation or extracorporeal membrane oxygenation are mainly used as a bridge to transplantation. Most physicians educate patients comprehensively on the severity of AE-IPF (82%) and consider palliative care (64%).Approaches to the prevention, diagnosis and treatment of AE-IPF vary worldwide. Global trials and guidelines to improve the prognosis of AE-IPF are needed.

Thoracic radiotherapy plus Durvalumab in elderly and/or frail NSCLC stage III patients unfit for chemotherapy - employing optimized (hypofractionated) radiotherapy to foster durvalumab efficacy: study protocol of the TRADE-hypo trial.

BACKGROUND: Non-small cell lung cancer is the most common cause of cancer death worldwide, highlighting the need for novel therapeutic concepts. In particular, there is still a lack of treatment strategies for the group of elderly and frail patients, who are frequently not capable of receiving standard therapy regimens. Despite comprising the majority of lung cancer patients, this group is underrepresented in clinical trials. This applies also to elderly and frail patients suffering from unresectable stage III NSCLC, who are unfit for chemotherapy, and, therefore, cannot receive the standard therapy comprising of radiochemotherapy and the recently approved subsequent durvalumab consolidation therapy. These patients often receive radiotherapy only, which raises the concern of undertreatment. The TRADE-hypo trial aims at optimizing treatment of this patient group by combining radiotherapy with concomitant durvalumab administration, thereby employing the immune-promoting effects of radiotherapy, and determining safety, feasibility, and efficacy of this treatment. METHODS/ DESIGN: In this prospective phase II clinical trial, durvalumab therapy will be combined with either conventionally fractionated (CON-group) or hypofractionated (HYPO-group) thoracic radiotherapy. A safety stop-and-go lead-in phase will assess safety of hypofractionated radiotherapy with respect to severe pneumonitis in small patient cohorts before opening full enrollment. Tumor tissue, blood and stool samples will be collected before and during the study period to investigate the immunological mechanisms responsible for checkpoint inhibitor efficacy and immune-promoting effects of radiotherapy. DISCUSSION: Preclinical data suggests that irradiation-induced immunogenicity can be further increased if applied in a hypofractionated setting, potentially boosting the expected synergistic effect with immune checkpoint inhibition in restoring the immune anti-tumor response. If proven safe and efficient, a hypofractionated radiation schedule can provide a considerably more practicable option for the patient. Taking into consideration the intend to develop a combination treatment strategy that can be made available to patients soon after proving to be efficient and the potentially elevated toxicity of a hypofractionated radiotherapy approach, this trial was designed as a two-trials-in-one design. An accompanying translational research program is planned striving to gain insights into the tumor-host biology and to identify suitable biomarkers to predict therapy response. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04351256 . Registered 17 April 2020, Eudra-CT, 2019-002192-33 . Registered 24 October 2019.

Intrafractional vaginal dilation in anal cancer patients undergoing pelvic radiotherapy (DILANA) - a prospective, randomized, 2-armed phase-II-trial.

BACKGROUND: The incidence of anal cancer is rising in the last decades and more women are affected than men. The prognosis after chemoradiation is very good with complete remission rates of 80-90%. Thus, reducing therapy-related toxicities and improving quality of life are of high importance. With the development of new radiotherapy techniques like IMRT (Intensity-modulated radiotherapy), the incidence of acute and chronic gastrointestinal toxicities has already been reduced. However, especially in female anal cancer patients genital toxicities like vaginal fibrosis and stenosis are of great relevance, too. Up to now, there are no prospective data reporting incidence rates, techniques of prevention or impact on quality of life. The aim of the DILANA trial is to evaluate the incidence and grade of vaginal fibrosis, to optimize radiotherapy by reducing dose to the vaginal wall to minimize genital toxicities and improve quality of life of anal cancer patients. METHODS: The study is designed as a prospective, randomized, two-armed, open, single-center phase-II-trial. Sixty patients will be randomized into one of two arms, which differ only in the diameter of a tampon used during treatment. All patients will receive standard (chemo) radiation with a total dose of 45-50.4 Gy to the pelvic and inguinal nodes with a boost to the anal canal up to 54-60 Gy. The primary objective is the assessment of the incidence and grade of vaginal fibrosis 12 months after (chemo) radiation depending on the extent of vaginal dilation. Secondary endpoints are toxicities according to the CTC AE version 5.0 criteria, assessment of clinical feasibility of daily use of a tampon, assessment of compliance for the use of a vaginal dilator and quality of life. DISCUSSION: Prospective studies are needed evaluating the incidence and grade of vaginal fibrosis after (chemo) radiation in female anal cancer patients. Furthermore, the assessment of techniques to reduce the incidence of vaginal fibrosis like intrafractional vaginal dilation as well as other radiotherapy-independent methods like using a vaginal dilator are essential. Additionally, implementation of a systematic assessment of vaginal stenosis is necessary to grant reproducibility and comparability of future data. TRIAL REGISTRATION: The trial is registered with clinicaltrials.gov (NCT04094454, 19.09.2019).