Neoadjuvant irradiation of extremity soft tissue sarcoma with ions (Extrem-ion): study protocol for a randomized phase II pilot trial.

BACKGROUND: The standard of care treatment for soft tissue sarcoma of the extremities is a wide resection in combination with pre- or postoperative radiotherapy with high local control rates, sparing patients the necessity of amputation without compromising on overall survival rates. The currently preferred timing of radiotherapy is under debate. Albeit having higher rates of acute wound complications, late side effects like fibrosis, joint stiffness or edema are less frequent in preoperative compared to postoperative radiotherapy. This can be explained in smaller treatment volumes and a lower dose in the preoperative setting. Particles allow better sparing of surrounding tissues at risk, and carbon ions additionally offer biologic advantages and are preferred in less radiosensitive tumors. Hypofractionation allows for a significantly shorter treatment duration. METHODS: Extrem-ion is a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the extremities will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5-6 fractions per week] in each arm). The primary objective is the proportion of therapies without wound healing disorder the first 120 days after surgery or discontinuation of treatment for any reason related to the treatment. The secondary endpoints of the study consist of local control, local progression-free survival, disease-free survival, overall survival, and quality of life. DISCUSSION: The aim of this study is to confirm that hypofractionated, preoperative radiotherapy is safe and feasible. The potential for reduced toxicity by the utilization of particle therapy is the rational of this trial. A subsequent randomized phase III trial will compare the hypofractionated proton and carbon ion irradiation in regards to local control. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04946357 ; Retrospectively registered June 30, 2021.

MR-guided adaptive versus ITV-based stereotactic body radiotherapy for hepatic metastases (MAESTRO): a randomized controlled phase II trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an established local treatment method for patients with hepatic oligometastasis or oligoprogression. Liver metastases often occur in close proximity to radiosensitive organs at risk (OARs). This limits the possibility to apply sufficiently high doses needed for optimal local control. Online MR-guided radiotherapy (oMRgRT) is expected to hold potential to improve hepatic SBRT by offering superior soft-tissue contrast for enhanced target identification as well as the benefit of gating and daily real-time adaptive treatment. The MAESTRO trial therefore aims to assess the potential advantages of adaptive, gated MR-guided SBRT compared to conventional SBRT at a standard linac using an ITV (internal target volume) approach. METHODS: This trial is conducted as a prospective, randomized, three-armed phase II study in 82 patients with hepatic metastases (solid malignant tumor, 1-3 hepatic metastases confirmed by magnetic resonance imaging (MRI), maximum diameter of each metastasis ≤ 5 cm (in case of 3 metastases: sum of diameters ≤ 12 cm), age ≥ 18 years, Karnofsky Performance Score ≥ 60%). If a biologically effective dose (BED) ≥ 100 Gy (α/ß = 10 Gy) is feasible based on ITV-based planning, patients will be randomized to either MRgRT or ITV-based SBRT. If a lesion cannot be treated with a BED ≥ 100 Gy, the patient will be treated with MRgRT at the highest possible dose. Primary endpoint is the non-inferiority of MRgRT at the MRIdian Linac® system compared to ITV-based SBRT regarding hepatobiliary and gastrointestinal toxicity CTCAE III or higher. Secondary outcomes investigated are local, locoregional (intrahepatic) and distant tumor control, progression-free survival, overall survival, possible increase of BED using MRgRT if the BED is limited with ITV-based SBRT, treatment-related toxicity, quality of life, dosimetric parameters of radiotherapy plans as well as morphological and functional changes in MRI. Potential prognostic biomarkers will also be evaluated. DISCUSSION: MRgRT is known to be both highly cost- and labor-intensive. The MAESTRO trial aims to provide randomized, higher-level evidence for the dosimetric and possible consecutive clinical benefit of MR-guided, on-table adaptive and gated SBRT for dose escalation in critically located hepatic metastases adjacent to radiosensitive OARs. TRIAL REGISTRATION: The study has been prospectively registered on August 30th, 2021: Clinicaltrials.gov, "Magnetic Resonance-guided Adaptive Stereotactic Body Radiotherapy for Hepatic Metastases (MAESTRO)", NCT05027711.

Association of the advanced lung cancer inflammation index (ALI) with immune checkpoint inhibitor efficacy in patients with advanced non-small-cell lung cancer.

BACKGROUND: The advanced lung cancer inflammation index [ALI: body mass index × serum albumin/neutrophil-to-lymphocyte ratio (NLR)] reflects systemic host inflammation, and is easily reproducible. We hypothesized that ALI could assist guidance of non-small-cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: This retrospective study included 672 stage IV NSCLC patients treated with programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy in 25 centers in Greece and Germany, and a control cohort of 444 stage IV NSCLC patients treated with platinum-based chemotherapy without subsequent targeted or immunotherapy drugs. The association of clinical outcomes with biomarkers was analyzed with Cox regression models, including cross-validation by calculation of the Harrell's C-index. RESULTS: High ALI values (>18) were significantly associated with longer overall survival (OS) for patients receiving ICI monotherapy [hazard ratio (HR) = 0.402, P < 0.0001, n = 460], but not chemo-immunotherapy (HR = 0.624, P = 0.111, n = 212). Similar positive correlations for ALI were observed for objective response rate (36% versus 24%, P = 0.008) and time-on-treatment (HR = 0.52, P < 0.001), in case of ICI monotherapy only. In the control cohort of chemotherapy, the association between ALI and OS was weaker (HR = 0.694, P = 0.0002), and showed a significant interaction with the type of treatment (ICI monotherapy versus chemotherapy, P < 0.0001) upon combined analysis of the two cohorts. In multivariate analysis, ALI had a stronger predictive effect than NLR, PD-L1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. Among patients with PD-L1 tumor proportion score ≥50% receiving first-line ICI monotherapy, a high ALI score >18 identified a subset with longer OS and time-on-treatment (median 35 and 16 months, respectively), similar to these under chemo-immunotherapy. CONCLUSIONS: The ALI score is a powerful prognostic and predictive biomarker for patients with advanced NSCLC treated with PD-L1 inhibitors alone, but not in combination with chemotherapy. Its association with outcomes appears to be stronger than that of other widely used parameters. For PD-L1-high patients, an ALI score >18 could assist the selection of cases that do not need addition of chemotherapy.

Clinical effect of stannous fluoride and amine fluoride containing oral hygiene products: A 4-year randomized controlled pilot study.

This 4-year randomized controlled trial (RCT) aimed at investigating whether routine home use of both a SnCl2/AmF/NaF-containing mouth rinse and toothpaste has a preventive effect on oral health. Fifty-four test subjects were examined in biannual intervals. The primary endpoint "dental erosion" was determined by the Basic Erosive Wear Examination (BEWE). The secondary endpoints were "saliva pH", "dentin hypersensitivity" generated by Visual Analogue Scale (VAS), and "discoloration" measured by the Lobene Stain Index (LSI). A mixed model for repeated measures (MMRM) was used to analyze the primary endpoint "dental erosion". Primary analysis showed a significant intervention effect of the SnCl2/AmF/NaF-containing test product (p1 = 0.0242). This result was confirmed by two additional MMRM-based sensitivity analyses. Comparison of all models showed "dental erosion" values of the intervention group  below values of the control group. Discoloration of the teeth was significantly higher in the intervention than in the control group at all time points. Saliva pH and dentin hypersensitivity were not significantly different between groups over four years. In summary, this RCT is the first to indicate a possible preventive effect of SnCl2/AmF/NaF-containing oral hygiene products on dental erosion over a follow-up period of four years.

Diagnostic Value of the Basic Erosive Wear Examination for the Assessment of Dental Erosion on Patients, Dental Photographs, and Dental Casts.

OBJECTIVES: The aim of this trial was to investigate the diagnostic value of the basic erosive wear examination (BEWE) in clinical use, on dental photographs, and on dental casts over a two-year follow-up period (2013-2015). According to the main hypothesis for longitudinal monitoring of dental erosion, the BEWE is equally reproducible by the three assessment methods. METHODS AND MATERIALS: The clinical assessment included intraoral photographic documentation, dental impressions, oral examination, and assessment of BEWE. Clinical assessment of BEWE was done by one blinded examiner, whereas assessment on photographs and dental casts was performed by three calibrated examiners and repeated after 14 days. The three assessment methods were analyzed separately by longitudinal agreement and inter- and intrarater reliability (intraclass correlation coefficient) alongside 95% confidence intervals (CIs). RESULTS: Comparing the longitudinal data of the years 2013-2015, clinical use and photographs showed no significant difference (p=0.0681-0.9963), whereas the statistical analysis showed a significant difference for dental casts by comparing data from 2013 vs 2014 (p=0.0266) as well as data from 2013 vs 2015 (p=0.0001). Statistical evaluation of overall BEWE showed an intrarater reliability of 0.79-0.91 for photographs and 0.60-0.87 for dental casts. The interrater reliability was 0.77 (95% CI=[0.69; 0.84]) for photographs and 0.63 (95% CI=[0.52; 0.72]) for dental casts. CONCLUSION: This investigation showed that in longitudinal clinical monitoring, the assessment of the BEWE on patients and dental photographs yielded comparable results. In addition, based on these findings, the assessment of the BEWE on dental casts showed moderate reproducibility. Therefore, dental casts may be better used for laboratory assessment techniques.

Clinical management and prevention of dental caries in athletes: A four-year randomized controlled clinical trial.

The aims of this four-year randomized controlled clinical trial were to gain insights into management and prevention of dental caries and the effect of stannous fluoride products in athletes. Fifty-four participants were randomized into test and control groups. The test group used special stannous fluoride products. The primary endpoint dental caries was assessed by the ICDAS-II-System and analyzed both by a linear mixed model for repeated measures and a generalized linear mixed model. During the observation period an increase in caries-free surfaces from 64.91 ± 6.42 at baseline to 73.22 ± 4.43 was observed. In surfaces with caries superficialis and caries media, a decrease from 13.94 ± 5.70 and 2.96 ± 2.55 surfaces at baseline to 7.89 ± 3.18 and 0.46 ± 0.78 after 2.5 years was noted, respectively. The analysis showed no effect of stannous fluoride products, but a significant difference for the time of examination (p < 0.0001). In addition, it could be shown that at any time of examination, the odds of developing caries media on a new surface was significantly lower than at baseline (up to 25-times). Due to biannual dental examinations, professional tooth cleaning and restorative treatment the number of caries-free surfaces increased and the odds of a new surface to be afflicted with caries media decreased 25-fold.

Evaluation of small-group education on the shade determination ability of preclinical dental students-A controlled clinical trial.

OBJECTIVES: To evaluate the effect of small-group education including practical training on dental students' shade determination performance compared with a control group. METHODS: Sixty-three non-colour-blind preclinical students were asked to participate and belonged to an intervention (n = 31) and a control (n = 32) group, respectively. All students received a lecture on dental shade determination. The members of the intervention group were educated and practically trained in small groups in addition. Ten volunteers, each with unrestored upper right middle and lateral incisors, were recruited. The students of both the intervention and control groups were then asked to determine the colour of the volunteers' test teeth using the 3D-Master shade guide (Vita Zahnfabrik, Bad Säckingen, Germany) under artificial daylight illumination. For analytical purposes, the CIE L*a*b* coordinates were obtained using a spectrophotometer. Colour differences, ΔE, between all shade tabs selected by the students and the natural teeth were calculated. ΔE observed in the intervention and control groups were compared using t tests. In addition, a multi-level regression model was adjusted for age and gender. RESULTS: Mean (SD) ΔE between the shade tabs selected by the students and the natural teeth in the intervention and control groups were 3.8 (2.1) and 4.3 (2.3), respectively (P < .001). The effect of group membership was reproduced in multivariate analysis whereas age and gender did not reach statistical significance. CONCLUSIONS: With more intensive education and practical training the ability to perform clinical shade determinations improved for students without previous clinical experience. The results obtained support the idea of implementing thematic small-group education in the dental curriculum.

Prospective phase-II-study evaluating postoperative radiotherapy of cervical and endometrial cancer patients using protons - the APROVE-trial.

BACKGROUND: The prognosis for patients with cervical or endometrial cancer has improved over the last decades. Thus, reducing therapy-related toxicity and impact on quality of life have become more and more important. With the development of new radiotherapy techniques like IMRT (Intensity-modulated radiotherapy) the incidence of acute and chronic toxicities has already been reduced. Nevertheless, rates of complications requiring medical treatment range from 0.7-8% according to literature. 7.7% of patients develop severe complications after 5 years with an increasing risk for complications of 0.3%/year. Particularly, the volume of the small and large bowel receiving low doses (15 Gy) has been shown to be a predictive factor for the development of higher bowel toxicity. With the introduction of proton therapy into clinical practice, there are new opportunities for optimization of organ at risk-sparing thus possibly reducing toxicity. METHODS/DESIGN: The APROVE study is a prospective single-center one-arm phase-II-study. Patients with cervical or endometrial cancer after surgical resection who have an indication for postoperative pelvic radiotherapy will be treated with proton therapy instead of the commonly used photon radiation. A total of 25 patients will be included in this trial. Patients will receive a dose of 45-50.4 GyE in 1.8 GyE fractions 5-6 times per week using active raster-scanning pencil beam proton radiation. Platinum-based chemotherapy can be administered if indicated. For treatment planning, rectum, sigma, large and small bowel, bladder and femoral heads are defined as organs at risk. The CTV is defined according to the RTOG consensus guidelines. DISCUSSION: The primary endpoint of the study is the evaluation of safety and treatment tolerability of pelvic radiation using protons defined as the lack of any CTC AE Grade 3 or 4 toxicity. Secondary endpoints are clinical symptoms and toxicity, quality of life and progression-free survival. The aim is to explore the potential of proton therapy as a new method for adjuvant pelvic radiotherapy to decrease the dose to the bowel, rectum and bladder thus reducing acute and chronic toxicity and improving quality of life. TRIAL REGISTRATION: Registered at https://clinicaltrials.gov , ClinicalTrials.gov Identifier: NCT03184350 , registered 09 June 2017, enrolment of the first participant 19 June 2017.

In vitro investigation on extensively destroyed vital teeth: is fracture force a limiting factor for direct restoration?

To evaluate the in vitro fracture load of extensively damaged vital teeth after either direct or indirect restauration, severe tooth substance loss was simulated for 96 molars. Subsequently, two cavities were prepared with little (design 1) or more substantial (design 2) residual tooth support. All molars were provided with a 2-mm ferrule design and then divided into 12 test groups based on their occlusal surface size. They were restored with composite or with either of two types of single crown (cast metal or milled zirconia). After thermal ageing (10,000 cycles at 6.5 and 60 °C), 1.2 million cycles of chewing simulation were applied (64 N). Maximum fracture load was determined with a loading angle of 45°. Statistical analysis was performed by use of Kaplan-Meier modelling, Student's t-tests, one-way anova, post hoc Tukey's HSD tests and linear regression analysis. Regarding mean fracture load without ageing, the indirect restorations outperformed composite (design 1: direct: 508 ± 123 N, indirect: 741 ± 248 N; design 2: direct: 554 ± 167 N, indirect: 903 ± 221 N). After artificial ageing, however, these differences were no longer significant (design 1: direct: 328 ± 189 N, indirect: 506 ± 352 N; design 2: direct 399 ± 208 N, indirect 577 ± 292 N). Instead, the fracture load of the aged composite restorations was comparable with that for zirconia (design 1) and cast metal (design 2) crowns. Fracture loads of direct composite restorations after artificial ageing might fulfil clinical requirements.