Perioperative anticoagulation in free microvascular flaps - a comparison of different prophylactic regimes in oncologic reconstructive surgery.

OBJECTIVE: Free tissue transfer has an established place in oncologic head and neck surgery. However, the necessity and specific regimen of perioperative thromboprophylaxis remain controversial. Here, the risk of postoperative hemorrhage contrasts with vascular pedicle thrombosis and graft loss. This work compares three different heparin protocols (A-C) with regard to postoperative complications. PATIENTS AND METHODS: A retrospective analysis of our free flap transplants between 2004 and 2023 was conducted. Inclusion criteria were thromboprophylaxis with (A) 500 IU/h unfractionated heparin (UFH), (B) low-molecular-weight heparin (LMWH) once daily, and (C) LMWH once daily with additional immediate preoperative administration. Primary endpoints were the incidence of postoperative bleeding and hematoma and the appearance of flap thrombosis. RESULTS: We evaluated 355 cases, 87 in group A, 179 in group B, and in group C 89 patients. Overall, postoperative bleeding occurred in 8.7% of patients, and 83% underwent hemostasis under intubation anesthesia, with no significant difference between groups (p = 0.784). Hematoma formation requiring revision was found in 3.7% of patients (p = 0.660). We identified postoperative hematoma as a significant influencing factor for venous pedicle thrombosis (OR 3.602; p = 0.001). Venous and arterial flap thrombosis in the graft vessel showed no difference between the groups (p = 0.745 and p = 0.128). CONCLUSIONS: The three anticoagulation regimens appear to be equivalent therapy for the prevention of thrombosis without significant differences in postoperative bleeding. The use of LMWH with additional preoperative administration can, therefore, be administered in free flap reconstruction.

A (Sub)field Guide to Quality Control in Hippocampal Subfield Segmentation on Highresolution T2-weighted MRI.

Inquiries into properties of brain structure and function have progressed due to developments in magnetic resonance imaging (MRI). To sustain progress in investigating and quantifying neuroanatomical details in vivo, the reliability and validity of brain measurements are paramount. Quality control (QC) is a set of procedures for mitigating errors and ensuring the validity and reliability of brain measurements. Despite its importance, there is little guidance on best QC practices and reporting procedures. The study of hippocampal subfields in vivo is a critical case for QC because of their small size, inter-dependent boundary definitions, and common artifacts in the MRI data used for subfield measurements. We addressed this gap by surveying the broader scientific community studying hippocampal subfields on their views and approaches to QC. We received responses from 37 investigators spanning 10 countries, covering different career stages, and studying both healthy and pathological development and aging. In this sample, 81% of researchers considered QC to be very important or important, and 19% viewed it as fairly important. Despite this, only 46% of researchers reported on their QC processes in prior publications. In many instances, lack of reporting appeared due to ambiguous guidance on relevant details and guidance for reporting, rather than absence of QC. Here, we provide recommendations for correcting errors to maximize reliability and minimize bias. We also summarize threats to segmentation accuracy, review common QC methods, and make recommendations for best practices and reporting in publications. Implementing the recommended QC practices will collectively improve inferences to the larger population, as well as have implications for clinical practice and public health.

Predictive factors for abscessing tonsillitis: a retrospective analysis.

OBJECTIVE: In clinical practice, identifying abscesses in tonsillar infections is crucial for early therapeutic management. Diagnosis of a peritonsillar abscess is usually based on clinical symptoms. Complementary examination procedures, such as laboratory parameters and imaging, are available for confirmation. PATIENTS AND METHODS: A retrospective analysis was carried out of data for 752 patients who presented with acute tonsillar infection and were hospitalized between January 2012 and February 2021. The data analyses involved evaluating the patient's clinical symptoms, inflammatory parameters, and previous medical history in relation to the predictive power of these factors for the presence of an abscess. RESULTS: Predictor analysis for the presence of an abscess showed significant values for trismus (OR 2.392; 95% CI, 1.305 to 4.383; p=0.005) and palatal arch protrusion (OR 29.679; 95% CI, 17.460 to 50.447; p=0.000). The inflammatory parameter C-reactive protein and the leukocyte count were not statistically significant as predictors. CONCLUSIONS: The presence of a tonsillar abscess can be diagnosed from the clinical presentation alone if the findings are clear. Further diagnostic procedures are indicated in case of inconclusive findings, and ultrasound should be the primary noninvasive method. Computed tomography is only required in selected cases. Inflammatory parameters can be assessed in order to monitor therapy, but do not predict the presence of an abscess. However, if defined action sequences are being considered, tonsillar abscesses can be differentiated at an early point.

Overall and disease-specific survival of sinonasal adenoid cystic carcinoma: a systematic review and meta-analysis.

This meta-analysis aims to investigate the outcome of sinonasal adenoid cystic carcinoma (snAdCC). We followed PRISMA guidelines and included studies reporting 5-year overall survival (OS) rates for snAdCC. Eligible studies were identified through a literature search and assessed using JBI critical appraisal checklist. A total of 17 studies were included comprising 2259 patients (mean age: 58.1 years, 52.7% female, 47.3% male). The meta-analysis demonstrated that the 5-year OS, 10-year OS, and 5-year disease-free survival (DFS) were 68%, 40%, and 47.2%, respectively. Descriptive statistics on study level showed high rates of locally advanced tumor stages at diagnosis: 23% cT3, 53% cT4, 3.4% N+, and 4.2% M+. 29.7% of the tumors were in the nasal cavity, 67.6% in the paranasal sinuses. The maxillary, ethmoid, sphenoid, and frontal sinus were affected in 50.9%, 7.2%, 4%, and 0.5%, of cases. A combination of surgery and radiotherapy was used in 45.4% of the patients and 19.3% of patients received surgery only. In conclusion, these findings emphasize the significance of thorough surveillance for individuals with snAdCC to identify any potential recurrence or progression of the disease.

EAONO/JOS classification for acquired cholesteatoma: evaluating the impact of the number of affected sites on treatment and outcomes.

PURPOSE: The European and Japanese system for cholesteatoma classification proposed an anatomical differentiation in five sites. In stage I disease, one site would be affected and in stage II, two to five. We tested the significance of this differentiation by analyzing the influence of the number of affected sites on residual disease, hearing ability and surgical complexity. METHODS: Cases of acquired cholesteatoma treated at a single tertiary referral center between 2010-01-01 and 2019-07-31 were retrospectively analyzed. Residual disease was determined according to the system. The air-bone gap mean of 0.5, 1, 2, 3 kHz (ABG) and its change with surgery served as hearing outcome. The surgical complexity was estimated regarding the Wullstein's tympanoplasty classification and the procedure approach (transcanal, canal up/down). RESULTS: 513 ears (431 patients) were followed-up during 21.6 ± 21.5 months. 107 (20.9%) ears had one site affected, 130 (25.3%) two, 157 (30.6%) three, 72 (14.0%) four and 47 (9.2%) five. An increasing number of affected sites resulted in higher residual rates (9.4-21.3%, p = 0.008) and surgical complexity, as well poorer ABG (preoperative 14.1 to 25.3 dB, postoperative 11.3-16.8 dB, p < 0.001). These differences existed between the means of cases of stage I and II, but also when only considering ears with stage II classification. CONCLUSION: The data showed statistically significant differences when comparing the averages of ears with two to five affected sites, questioning the pertinence of the differentiation between stages I and II.

Cellular density and variability in laryngeal and pharyngeal squamous cell carcinoma using confocal laser endomicroscopy.

OBJECTIVE: Confocal laser endomicroscopy (CLE) allows the visualization of epithelium in a thousand-fold magnification. This study analyzes the architectural differences at the cellular level of the mucosa and squamous cell carcinoma (SCC). PATIENTS AND METHODS: A total of 60 CLE sequences recorded in 5 patients with SCC undergoing laryngectomy between October 2020 and February 2021 were analyzed. The corresponding histologic sample derived from H&E staining was assigned to each sequence, capturing CLE images of the tumor and healthy mucosa. In addition, the cellular structure analysis was performed to diagnose SCC by measuring the total number of cells and cell size in 60 sequences in a fixed field of view (FOV) with 240 µm in diameter (45,239 µm2). RESULTS: Out of 3,600 images, 1,620 (45%) showed benign mucosa and 1,980 (55%) SCC. The automated analysis yielded a difference in cell size, with healthy epithelial cells being 171.9±82.0 µm2 smaller than SCC cells, which were 246.3±171.9 µm2 and showed greater variability in size (p=0.037). In addition, due to the probe's fixed FOV, there was a difference in cell count with a total of 188.7±38.3 and 124.8±38.6 cells in images of normal epithelium and SCC (p<0.001), respectively. Regarding cell density as a criterion for the differentiation of benign/malign, using a cut-off value of 145.5 cells/FOV, we obtained sensitivity and specificity of 88.0% and 71.9%, respectively. CONCLUSIONS: SCC reveals marked differences at a cellular level compared to the healthy epithelium. Our results further support the importance of this feature for identifying SCC during CLE imaging.

The influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome.

OBJECTIVE: The aim of this study was to investigate the influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome. PATIENTS AND METHODS: Endonasal swabs from the olfactory groove of 22 patients with moderate and severe obstructive sleep apnea (OSA) and a control group of 17 healthy controls were obtained at the Department of Otorhinolaryngology of the Friedrich-Alexander-Universität Erlangen-Nürnberg. 16S rRNA gene sequencing was performed to further evaluate the endonasal microbiome. In a second step, the longitudinal influence of continuous positive airway pressure (CPAP) therapy on the nasal microbiome was investigated (3-6 and 6-9 months). RESULTS: Analysis of the bacterial load and ß-diversity showed no significant differences between the groups, although patients with severe OSA showed increased α-diversity compared to the control group, while those with moderate OSA showed decreased α-diversity. The evaluation of longitudinal changes in the nasal microbiota during CPAP treatment showed no significant difference in α- or ß-diversity. However, the number of bacteria for which a significant difference between moderate and severe OSA was found in the linear discriminant analysis decreased during CPAP treatment. CONCLUSIONS: Long-term CPAP treatment showed an alignment of the composition of the nasal microbiome in patients with moderate and severe OSA as well as an alignment of biodiversity with that of the healthy control group. This change in the composition of the microbiome could be both part of the therapeutic effect in CPAP therapy and a promoting factor of the adverse side effects of the therapy. Further studies are needed to investigate whether the endonasal microbiome is related to CPAP compliance and whether CPAP compliance can be positively influenced in the future by therapeutic modification of the microbiome.

TIMP-1 as a biomarker in obstructive sleep apnea: screening, monitoring, risk stratification, and a step towards precision medicine.

OBJECTIVE: The diagnosis of obstructive sleep apnea (OSA) is a complex time- and resource-intensive diagnostic procedure. Since tissue inhibitors of matrix metalloproteinases (TIMP's) are involved in various pathophysiological processes and are correlated with a high cardiovascular risk, TIMP's appear to be a suitable candidate for an OSA-biomarker. PATIENTS AND METHODS: In a prospective controlled diagnostic study, TIMP-1 serum levels of 273 OSA-patients and controls were analyzed for correlation with OSA severity, BMI, age, sex, cardio-/ cerebrovascular comorbidities. Furthermore, longitudinal medium- and long-term effects of CPAP-treatment (n=15) on TIMP-1-levels were investigated. RESULTS: TIMP-1 was clearly linked to OSA as well as to disease severity (mild, moderate, severe; each p<0.001) and was not influenced by age, gender, BMI, or cardio-/cerebrovascular comorbidities. ROC curve analysis revealed an AUC of 0.91 ± 0.017 SE (p<0.001), suggesting a TIMP-1 cut-off value of 75 ng/ml (sensitivity 0.78; specificity 0.91) being especially sensitive for patients with severe OSA (sensitivity 0.89; specificity 0.91). The likelihood ratio was 8.88, while the diagnostic odds ratio was 37.14. CPAP-treatment led to a significant decrease of TIMP-1 after 6-8 months (p=0.008). CONCLUSIONS: TIMP-1 seems to fulfill the preconditions for a circulating OSA-biomarker: disease-specific with a mandatory presence in affected patients, reversible on treatment, reflects disease severity and provides a cutoff value between the healthy state and disease. In the clinical routine, TIMP 1 may help to stratify the individual OSA-associated cardiovascular risk and to monitor the treatment response to CPAP-therapy as a further step towards providing a personalized therapy.

Auto-commissioning of a Monte Carlo electron beam model with application to photon MLC shaped electron fields.

Objective.Presently electron beam treatments are delivered using dedicated applicators. An alternative is the usage of the already installed photon multileaf collimator (pMLC) enabling efficient electron treatments. Currently, the commissioning of beam models is a manual and time-consuming process. In this work an auto-commissioning procedure for the Monte Carlo (MC) beam model part representing the beam above the pMLC is developed for TrueBeam systems with electron energies from 6 to 22 MeV.Approach.The analytical part of the electron beam model includes a main source representing the primary beam and a jaw source representing the head scatter contribution each consisting of an electron and a photon component, while MC radiation transport is performed for the pMLC. The auto-commissioning of this analytical part relies on information pre-determined from MC simulations, in-air dose profiles and absolute dose measurements in water for different field sizes and source to surface distances (SSDs). For validation calculated and measured dose distributions in water were compared for different field sizes, SSDs and beam energies for eight TrueBeam systems. Furthermore, a sternum case in an anthropomorphic phantom was considered and calculated and measured dose distributions were compared at different SSDs.Main results.Instead of the manual commissioning taking up to several days of calculation time and several hours of user time, the auto-commissioning is carried out in a few minutes. Measured and calculated dose distributions agree generally within 3% of maximum dose or 2 mm. The gamma passing rates for the sternum case ranged from 96% to 99% (3% (global)/2 mm criteria, 10% threshold).Significance.The auto-commissioning procedure was successfully implemented and applied to eight TrueBeam systems. The newly developed user-friendly auto-commissioning procedure allows an efficient commissioning of an MC electron beam model and eases the usage of advanced electron radiotherapy utilizing the pMLC for beam shaping.

Efficiency enhancements of a Monte Carlo beamlet based treatment planning process: implementation and parameter study.

Objective.The computational effort to perform beamlet calculation, plan optimization and final dose calculation of a treatment planning process (TPP) generating intensity modulated treatment plans is enormous, especially if Monte Carlo (MC) simulations are used for dose calculation. The goal of this work is to improve the computational efficiency of a fully MC based TPP for static and dynamic photon, electron and mixed photon-electron treatment techniques by implementing multiple methods and studying the influence of their parameters.Approach.A framework is implemented calculating MC beamlets efficiently in parallel on each available CPU core. The user can specify the desired statistical uncertainty of the beamlets, a fractional sparse dose threshold to save beamlets in a sparse format and minimal distances to the PTV surface from which 2 × 2 × 2 = 8 (medium) or even 4 × 4 × 4 = 64 (large) voxels are merged. The compromise between final plan quality and computational efficiency of beamlet calculation and optimization is studied for several parameter values to find a reasonable trade-off. For this purpose, four clinical and one academic case are considered with different treatment techniques.Main results.Setting the statistical uncertainty to 5% (photon beamlets) and 15% (electron beamlets), the fractional sparse dose threshold relative to the maximal beamlet dose to 0.1% and minimal distances for medium and large voxels to the PTV to 1 cm and 2 cm, respectively, does not lead to substantial degradation in final plan quality compared to using 2.5% (photon beamlets) and 5% (electron beamlets) statistical uncertainty and no sparse format nor voxel merging. Only OAR sparing is slightly degraded. Furthermore, computation times are reduced by about 58% (photon beamlets), 88% (electron beamlets) and 96% (optimization).Significance.Several methods are implemented improving computational efficiency of beamlet calculation and plan optimization of a fully MC based TPP without substantial degradation in final plan quality.

Predictors of olfactory improvement after endoscopic sinus surgery in chronic rhinosinusitis with nasal polyps.

OBJECTIVE: This study aimed to determine the predictors of olfactory improvement after endoscopic sinus surgery among patients with chronic rhinosinusitis with nasal polyps. METHOD: This prospective cohort study included patients admitted to a university hospital between 2006 and 2012. Assessment using odour identification testing, a sinonasal symptom questionnaire, the Rhinosinusitis Disability Index and mucus biomarker levels was performed at various time points. Correlation of variables with identification score differences at six post-operative time points and at baseline was performed, followed by multiple linear regression to determine significant predictors at each of the six post-operative time points. RESULTS: Baseline absence of acute sinusitis, elevated serpin F2 and anterior rhinorrhoea predict early olfactory improvement, whereas baseline allergic rhinitis predicts late olfactory improvement. Baseline odour identification score was the strongest predictor across all time points. CONCLUSION: Patients with chronic rhinosinusitis and nasal polyps with worse disease or baseline olfactory function may benefit more from endoscopic sinus surgery in terms of olfactory improvement.

The pantomime of mental rotation: Left-handers are less lateralized.

INTRODUCTION: The conceptualization of skilled hand movements (praxis) may be grounded in hemispherically specialized functions. However, a left-hemispherical advantage of (tool-use) pantomime gestures and a right-hemispherical advantage of spatial gestures may be more prominent in right-handed than left-handed individuals. We therefore investigated the hypothesis that right-handed but not left-handed individuals show a superiority of the left hemisphere (/right-hand preference) for the execution of pantomime (rotation of an object) gestures as well as a right-hemispherical superiority (/left-hand preference) for gestures that depict spatial information (/positioning of an object). METHODS: 20 right- and 20 left-handed participants were asked in two experiments to demonstrate with their two hands how to move tachistoscopically (in the left (LVF) or right visual hemifields (RVF)) presented geometric objects of different rotations into an identical final position. Two independent blind raters evaluated the videotaped hand gestures employing the Neuropsychological Gesture (NEUROGES) Coding System. RESULTS: In contrast to left-handed individuals, right-handed individuals present increased pantomime - rotation gestures with the right hand and pantomime - position gestures with the left hand during stimuli presentation in either visual field. Left-handers showed significantly increased left-hand pantomime - rotation gestures during stimulus presentation within the LVF (only). DISCUSSION: Right-handed individuals increase their pantomime - rotation gestures with the right hand to depict motion but use their left hand for pantomime - position gestures to describe spatial relations of the objects. Left-handers do not show a clear lateralization of the right and left hand with regards to either handedness or hemispherically lateralized motor functions. The hemispherical lateralization of praxis functions is therefore more pronounced in right-handed than left-handed individuals.

Enabling non-isocentric dynamic trajectory radiotherapy by integration of dynamic table translations.

Objective.The purpose of this study is to develop a treatment planning process (TPP) for non-isocentric dynamic trajectory radiotherapy (DTRT) using dynamic gantry rotation, collimator rotation, table rotation, longitudinal, vertical and lateral table translations and intensity modulation and to validate the dosimetric accuracy.Approach.The TPP consists of two steps. First, a path describing the dynamic gantry rotation, collimator rotation and dynamic table rotation and translations is determined. Second, an optimization of the intensity modulation along the path is performed. We demonstrate the TPP for three use cases. First, a non-isocentric DTRT plan for a brain case is compared to an isocentric DTRT plan in terms of dosimetric plan quality and delivery time. Second, a non-isocentric DTRT plan for a craniospinal irradiation (CSI) case is compared to a multi-isocentric intensity modulated radiotherapy (IMRT) plan. Third, a non-isocentric DTRT plan for a bilateral breast case is compared to a multi-isocentric volumetric modulated arc therapy (VMAT) plan. The non-isocentric DTRT plans are delivered on a TrueBeam in developer mode and their dosimetric accuracy is validated using radiochromic films.Main results.The non-isocentric DTRT plan for the brain case is similar in dosimetric plan quality and delivery time to the isocentric DTRT plan but is expected to reduce the risk of collisions. The DTRT plan for the CSI case shows similar dosimetric plan quality while reducing the delivery time by 45% in comparison with the IMRT plan. The DTRT plan for the breast case showed better treatment plan quality in comparison with the VMAT plan. The gamma passing rates between the measured and calculated dose distributions are higher than 95% for all three plans.Significance.The versatile benefits of non-isocentric DTRT are demonstrated with three use cases, namely reduction of collision risk, reduced setup and delivery time and improved dosimetric plan quality.

Neoadjuvant chemoradiotherapy is superior to chemotherapy alone in surgically treated stage III/N2 non-small-cell lung cancer: a retrospective single-center cohort study.

BACKGROUND: There is lack of consensus whether neoadjuvant chemoradiotherapy (CHT/RT) is superior to neoadjuvant chemotherapy (CHT) alone in patients with potentially resectable stage III/N2 non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively evaluated clinical parameters and outcomes in patients with clinical stage III/N2 NSCLC treated with neoadjuvant CHT/RT versus CHT followed by surgery. Nearest-neighbor propensity score (PS) matching was used to correct for pretreatment differences. RESULTS: A total of 84 patients were enrolled. Thirty-four (40%) and 50 (60%) patients received CHT/RT or CHT followed by curative-intent surgery, respectively. Overall 90-day mortality and morbidity were 0% versus 0.04% and 21% versus 18%, respectively, with no significant difference between the CHT/RT and the CHT-alone cohorts (P = 0.51 and P = 0.70). In the PS-matched cohort, complete pathological response was recorded in 25% after CHT/RT versus 0% after CHT at the time of surgery. Patients receiving neoadjuvant CHT/RT exhibited significantly better 5-year disease-free survival (DFS) [45% versus 16% CHT group; hazard ratio (HR) 0.43, P = 0.04]; 5-year overall survival (OS) was 75% after CHT/RT and 21% after CHT (HR 0.37, P = 0.001). CHT/RT more often induced pathological mediastinal downstaging (P = 0.007), but CHT/RT remained the only independent factor for DFS and OS and did not depend on mediastinal downstaging. CONCLUSIONS: In this retrospective PS-matched long-term analysis, neoadjuvant CHT/RT conferred improved DFS and OS compared with CHT alone in stage III/N2 NSCLC. These highly challenging results require confirmation in well-designed randomized controlled trials conducted at highly specialized thoracic oncology centers.

Phantom-based prospective analysis of the accuracy of photo registration technology in electromagnetic navigation of the frontal skull base.

OBJECTIVE: This prospective study compared the accuracy of two different company-specific registration methods (Fiagon GmbH, Hennigsdorf, Germany) in the electromagnetic navigation of the frontal skull base. A newly developed photo registration technology (Fiagon tracey©) promises an increase in accuracy and user-friendliness, but there is no phantom-based prospective study comparing the new method with the classic approach of tactile surface registration. MATERIALS AND METHODS: A phantom skull was prepared with 27 markers in the sagittal, axial and coronary planes, and their reference coordinates were determined using a navigational CT (low dose, slice 0.6 mm). Subsequently, 20 runs of automatic photo registration and tactile surface registration were carried out, and the resulting marker coordinates were compared with the reference coordinates. The target registration error (TRE) of the 27 markers was assessed and compared between the two methods using a 2-factor ANOVA with repeated measures. RESULTS: The mean TRE using surface registration was 1.97 mm ± 0.57, while the mean TRE of the automatic photo registration was 1.54 mm ± 0.24 (p < 0.001). In a subgroup analysis limited to markers in anatomical regions of clinical relevance in terms of paranasal sinus surgery, the mean TRE for the photo registration procedure can even be reduced to 1.29 mm (± 0.43) compared to tactile registration (1.80 mm; ±0.50; p=0.01). CONCLUSIONS: Photo registration is a promising new technology in the field of electromagnetic navigation in paranasal sinus surgery. This prospective phantom-based study showed that the photo registration method achieves a significantly lower target registration error (1.29 mm) compared to the surface-based tactile registration procedure (1.80 mm).

A hybrid column generation and simulated annealing algorithm for direct aperture optimization.

The purpose of this work was to develop a hybrid column generation (CG) and simulated annealing (SA) algorithm for direct aperture optimization (H-DAO) and to show its effectiveness in generating high quality treatment plans for intensity modulated radiation therapy (IMRT) and mixed photon-electron beam radiotherapy (MBRT). The H-DAO overcomes limitations of the CG-DAO with two features improving aperture selection (branch-feature) and enabling aperture shape changes during optimization (SA-feature). The H-DAO algorithm iteratively adds apertures to the plan. At each iteration, a branch is created for each field provided. First, each branch determines the most promising aperture of its assigned field and adds it to a copy of the current apertures. Afterwards, the apertures of each branch undergo an MU-weight optimization followed by an SA-based simultaneous shape and MU-weight optimization and a second MU-weight optimization. The next H-DAO iteration continues the branch with the lowest objective function value. IMRT and MBRT treatment plans for an academic, a brain and a head and neck case generated using the CG-DAO and H-DAO were compared. For every investigated case and both IMRT and MBRT, the H-DAO leads to a faster convergence of the objective function value with number of apertures compared to the CG-DAO. In particular, the H-DAO needs about half the apertures to reach the same objective function value as the CG-DAO. The average aperture areas are 27% smaller for H-DAO than for CG-DAO leading to a slightly larger discrepancy between optimized and final dose. However, a dosimetric benefit remains. The H-DAO was successfully developed and applied to IMRT and MBRT. The faster convergence with number of apertures of the H-DAO compared to the CG-DAO allows to select a better compromise between plan quality and number of apertures.

Relevance of the time interval between surgery and adjuvant radio (chemo) therapy in HPV-negative and advanced head and neck carcinoma of unknown primary (CUP).

INTRODUCTION: In contrast to head and neck squamous cell carcinoma (HNSCC), the effect of treatment duration in HNSCC-CUP has not been thoroughly investigated. Thus, this study aimed to assess the impact of the time interval between surgery and adjuvant therapy on the oncologic outcome, in particular the 5-year overall survival rate (OS), in advanced stage, HPV-negative CUPs at a tertiary referral hospital. 5-year disease specific survival rate (DSS) and progression free survival rate (PFS) are defined as secondary objectives. MATERIAL AND METHODS: Between January 1st, 2007, and March 31st, 2020 a total of 131 patients with CUP were treated. Out of these, 59 patients with a confirmed negative p16 analysis were referred to a so-called CUP-panendoscopy with simultaneous unilateral neck dissection followed by adjuvant therapy. The cut-off between tumor removal and delivery of adjuvant therapy was set at the median, i.e. patients receiving adjuvant therapy below or above the median time interval. RESULTS: Depending on the median time interval of 55 days (d) (95% CI 51.42-84.52), 30 patients received adjuvant therapy within 55 d (mean 41.69 d, SD = 9.03) after surgery in contrast to 29 patients at least after 55 d (mean 73.21 d, SD = 19.16). All patients involved in the study were diagnosed in advanced tumor stages UICC III (n = 4; 6.8%), IVA (n = 27; 45.8%) and IVB (n = 28; 47.5%). Every patient was treated with curative neck dissection. Adjuvant chemo (immune) radiation was performed in 55 patients (93.2%), 4 patients (6.8%) underwent adjuvant radiation only. The mean follow-up time was 43.6 months (SD = 36.7 months). The 5-year OS rate for all patients involved was 71% (95% CI 0.55-0.86). For those patients receiving adjuvant therapy within 55 d (77, 95% CI 0.48-1.06) the OS rate was higher, yet not significantly different from those with delayed treatment (64, 95% CI 0.42-0.80; X2(1) = 1.16, p = 0.281). Regarding all patients, the 5-year DSS rate was 86% (95% CI 0.75-0.96). Patients submitted to adjuvant treatment in less than 55 d the DSS rate was 95% (95% CI 0.89-1.01) compared to patients submitted to adjuvant treatment equal or later than 55 d (76% (95% CI 0.57-0.95; X2(1) = 2.32, p = 0.128). The 5-year PFS rate of the entire cohort was 72% (95% CI 0.59-0.85). In the group < 55 d the PFS rate was 78% (95% CI 0.63-0.94) and thus not significantly different from 65% (95% CI 0.45-0.85) of the group ≥55 d; (X2(1) = 0.29, p = 0.589). CONCLUSIONS: The results presented suggest that the oncologic outcome of patients with advanced, HPV-negative CUP of the head and neck was not significantly affected by a prolonged period between surgery and adjuvant therapy. Nevertheless, oncologic outcome tends to be superior for early adjuvant therapy.

Brainstem Dysfunction in Healthy Aging.

The brainstem controls sub-cortical and cortical activity and influences the processing of incoming information. The goal of this study was to characterize age related alterations of brainstem-brain interactions during different brain states detected by dynamic analysis of task-free fMRI. 79 young (20-40 years) and 51 older adults (55-80 years) were studied. Internal brainstem structures were segmented using a new multi-contrast segmentation approach. Brain and brainstem gray matter segmentations were warped onto a population template. The ICV-corrected Jacobian determinants were converted into z-score maps and the means from 420 cortical/subcortical/brainstem rois extracted. The fMRI was preprocessed in SPM12/Conn18 and the BOLD signal from 420 cortical/subcortical/brainstem rois extracted. A dynamic task-free analysis approach based on hierarchical cluster analysis was used to identify 15 brain states that were characterized using graph analysis (strength, diversity, modularity). Kruskal-Wallis tests and Spearman correlations were used for statistical analysis. One brain state (cluster 21) occurred more often in older adults (p=0.008). It was characterized by a lower mean modular strength and brainstem-cortical strength in older adults compared to younger adults. Global age related gray matter differences were positively correlated with brain state 21's modular strength. Furthermore, brain state 21 duration was negatively correlated with working memory (r = -0.28, p=0.002). The findings suggest an age related weakening of the within and between network synchronization at the brainstem level during brain state 21 in older adults that negatively affects cortical and subcortical synchronization and working memory performance.