Radio(chemo)therapy in anaplastic thyroid cancer-high locoregional but low distant control rates-a monocentric analysis of a tertiary referral center.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a lethal disease with highly aggressive disease progression. This study analyses the influence of radio(chemo)therapy, R(C)T, on disease control, survival rates and predictors for survival. PATIENTS AND METHODS: A total of 33 patients with ATC, treated at a tertiary referral center between May 2001 and April 2020 were included. Univariate and multivariate analysis were used to investigate correlates of R(C)T and predictors on disease control and survival rates. RESULTS: Median follow-up was 4 months. In UICC stage IVA and IVB median overall survival (OS) was 8 months, median progression-free survival (PFS) was 6 months. Patients with UICC stage IVA and IVB and patients being irradiated with a radiation dose of more than 60 Gy showed increased OS. Of these patients, 3 were alive and free from disease. All of them receiving cisplatin-based radiochemotherapy and a minimum radiation dose of 66 Gy. UICC stage IVC showed a median OS of 2.5 months and a median PFS of 1 month. Only 2 of 16 patients had local failure. CONCLUSION: Depending on UICC stage, RT with high radiation dose can lead to improved OS or at least higher locoregional control. A limiting factor is the high incidence of distant metastases; therefore modern systemic treatment options should be integrated into multimodal therapy concepts.

[Salvage laryngectomy after primary radio- and radiochemotherapy : A retrospective study. German version]. / Salvage-Laryngektomie nach primärer Radio- und Radiochemotherapie : Eine retrospektive Fallzusammenfassung.

BACKGROUND: Recurrent and residual laryngeal cancer after organ-preserving radio- or radiochemotherapy is associated with a poor prognosis. Salvage surgery is the most important therapeutic option in these cases. OBJECTIVE: The study assessed rates of recurrence and residual tumor as well as survival and complication rates after salvage laryngectomy at the authors' academic cancer center. MATERIALS AND METHODS: A retrospective examination of all patients receiving laryngectomy between 2001 and 2019 due to tumor residuals or recurrence after primary radio- and radiochemotherapy was conducted. RESULTS: A total of 33 salvage procedures were performed. Defect reconstruction was performed by free flap surgery in 30.3% (n = 10) and regional flap surgery in 15.2% (n = 5) . One patient received regional flap surgery and free flap surgery simultaneously. Overall survival after 1, 2, and 5 years was 68.7, 47.9, and 24.2%, and disease-free survival was 81.6, 47.8, and 24.2%, respectively, with 48.5% (n = 16) postoperative tumor recurrences overall. Disease-free survival was significantly shorter for tumor extension into or onto the hypopharynx (p = 0.041). Postoperatively, 72.7% of patients developed a pharyngocutaneous fistula, of which 24.2% required surgical treatment. The hospital stay was 28.0 ± 16.1 days. CONCLUSION: Salvage laryngectomy is associated with a high rate of treatable complications and high morbidity. Nevertheless, considering the advanced tumor stages treated, it allows for respectable oncological results.

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.

Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far. METHODS: The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE. RESULTS: Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were "weight change", "difficulty to grip things", "bloody or mucous stool" and "insomnia". Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire. CONCLUSION: Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on "weight change" and "insomnia" may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03453892 . Registered on 05 March 2018.

Salvage laryngectomy after primary radio- and radiochemotherapy : A retrospective study.

BACKGROUND: Recurrent and residual laryngeal cancer after organ-preserving radio- or radiochemotherapy is associated with a poor prognosis. Salvage surgery is the most important therapeutic option in these cases. OBJECTIVE: The study assessed rates of recurrence and residual tumor as well as survival and complication rates after salvage laryngectomy at the authors' academic cancer center. MATERIALS AND METHODS: A retrospective examination of all patients receiving laryngectomy between 2001 and 2019 due to tumor residuals or recurrence after primary radio- and radiochemotherapy was conducted. RESULTS: A total of 33 salvage procedures were performed. Defect reconstruction was performed by free flap surgery in 30.3% (n = 10) and regional flap surgery in 15.2% (n = 5) . One patient received regional flap surgery and free flap surgery simultaneously. Overall survival after 1, 2, and 5 years was 68.7, 47.9, and 24.2%, and disease-free survival was 81.6, 47.8, and 24.2%, respectively, with 48.5% (n = 16) postoperative tumor recurrences overall. Disease-free survival was significantly shorter for tumor extension into or onto the hypopharynx (p = 0.041). Postoperatively, 72.7% of patients developed a pharyngocutaneous fistula, of which 24.2% required surgical treatment. The hospital stay was 28.0 ± 16.1 days. CONCLUSION: Salvage laryngectomy is associated with a high rate of treatable complications and high morbidity. Nevertheless, considering the advanced tumor stages treated, it allows for respectable oncological results.

[Thrombosis of sewn vs. coupled anastomoses in microvascular head and neck reconstructions]. / Thrombose genähter vs. gekoppelter Anastomosen bei mikrovaskulären Kopf- und Halsrekonstruktionen.

OBJECTIVE: The Anastomotic Coupling Device for microvascular anastomoses has become widely used in free tissue transplantation. This study compares the thrombosis rate and flap failure as a function of the anastomosis technique at a large head and neck cancer center. MATERIAL AND METHODS: Retrospective analysis of all patients receiving free flap reconstructions in the period 2001-2019. Reconstruction type, recipient vessels, number of venous anastomoses, coupler size, and operation time were investigated. We compared the rates of venous thrombosis between hand sewn and coupled anastomoses, as well as the rate of flap failure. RESULTS: A total of 403 free flap reconstructions were performed for over 17 years. The venous anastomosis was sewn in 113 flaps in single suture technique, and in 290 cases, coupler device was used. The rate of venous thrombosis requiring immediate surgical revision was 6.2 % (7/113) in the sewn group compared to 7.6 % in the coupled group (22/290; p = 0.627). With an overall success rate of 95.0 % (383/403), the rate of flap failure was 3.6 % (4/113) and 5.5 % (16/290; p = 0.421), respectively. Surgical time is comparable with 680 ±â€Š144 minutes in the hand-sewn group and 688 ± 167 minutes in the coupled group (p = 0.678). CONCLUSIONS: With similar success rates, the coupler device is an effective alternative to venous anastomosis in single suture technique. Due to the generally low rate of pedicle thrombosis in both groups, we cannot separate the influence of the anastomosis technique from possible interfering variables.

Single-cycle induction chemotherapy before chemoradiotherapy or surgery in functionally inoperable head and neck squamous cell carcinoma: 10-year results.

INTRODUCTION: The response to induction chemotherapy (IC) predicts local control after conservative treatment of laryngeal, meso- and hypopharyngeal head and neck squamous cell carcinoma (HNSCC) and can thus help to avoid surgery. Single-cycle induction chemotherapy may help to maintain a low local recurrence rate while keeping the overall toxicity manageable. However, long-term data on single-cycle IC response by tumor location is lacking. METHODS: N = 102 patients with functionally inoperable primary HNSCC of the larynx (n = 43), hypopharynx (n = 42) or mesopharynx/tongue (n = 17) received one cycle of docetaxel (75 mg/m2, d1) plus cisplatin (30 mg/m2, d1-3) or carboplatin (AUC 1.5, d1-3) and a response evaluation 3 weeks later. Responders (≥ 30% tumor size reduction and ≥ 20% SUVmax decrease in 18F-FDG PET/CT) were recommended chemoradiotherapy (CRT), and non-responders surgery. RESULTS: The overall response rate was 72.5%. All 74 responders and 10 non-responders received primary CRT, and 18 patients received primary surgery after single-cycle IC. Overall 10-year local recurrence-free survival (LRFS) was 73.7%. Three-year LRFS was 88.2% (mesopharynx/tongue), 88.2% (larynx), and 73.3% (hypopharynx); p = 0.17. 3-year distant metastasis-free survival (DMFS) was 94.1% (mesopharynx/tongue), 88.0% (larynx) and 76.4% (hypopharynx); p > 0.05. This influenced the 3-year cancer-specific survival (CSS) for larynx (91.2%) vs. hypopharynx tumors (60.8%); p = 0.003, but CSS was not different to tumors in the mesopharynx/tongue (81.4%); p > 0.05. CONCLUSIONS: A single-cycle induction chemotherapy for HNSCC enables surgery plus adjuvant therapy as well as chemoradiotherapy. The long-term local and distant disease control was good but varied between tumors in the larynx and mesopharynx/tongue vs. hypopharynx.

Sinonasal papillomas: A single centre experience on 137 cases with emphasis on malignant transformation and EGFR/KRAS status in "carcinoma ex papilloma".

Among the three major histological subtypes of sinonasal papillomas, inverted (ISP) and oncocytic (OSP) sinonasal papillomas tend to undergo malignant transformation to carcinoma. However, criteria determining risk of recurrence and malignant progression have not been established. Recently, EGFR and KRAS mutations were detected to be characteristic for ISP and OSP, respectively. In this study, we analyzed 137 sinonasal papilloma cases (132 ISP and 5 OSP) for clinicopathological characteristics, frequency of recurrences/malignant transformation, and histological types and genetic features of carcinoma ex Schneiderian papilloma. OSP presented at a higher age than ISP (median, 75 vs. 57 years) and affected predominantly females. Overall frequency of recurrences and malignant transformation was 23.1% and 9.5%, respectively. Rates of recurrence (33.3% vs. 22.0%) and malignant transformation (33.3% vs. 8.8%) were higher in OSP compared to ISP, respectively. Carcinomas (n = 10) occurred mostly synchronously, more frequently in females and mainly associated with ISP (n = 9). Squamous cell carcinoma (SCC) was the most frequently associated malignancy. Concordant EGFR (in ISP/associated carcinoma) and KRAS (in the OSP/associated carcinoma) mutations were detected in all successfully analyzed matching papilloma/carcinoma pairs, confirming their shared clonal origin. Results of this large study are in line with recent studies showing frequent EGFR and KRAS mutations in sinonasal carcinoma ex Schneiderian papilloma. As the papilloma component might on occasion be missed on biopsy of synchronous carcinoma ex papilloma, EGFR and KRAS mutation testing represents a promising molecular surrogate for sinonasal "carcinoma ex papilloma", at the same time offering an opportunity for targeting mutant EGFR in this rare cancer type.

Outcome and management of rare high-grade "salivary" adenocarcinoma: the important role of adjuvant (chemo)radiotherapy.

PURPOSE: To determine survival and management strategies for high-grade adenocarcinoma of salivary glands (ASG). METHODS: A retrospective analysis of cases diagnosed between 1998 and 2015 from our single tertiary referral center was performed. Multivariable logistic regression was used to determine factors associated with survival. RESULTS: Thirty-eight cases of high-grade ASG were identified. Most patients were men (68.4%) with a median age of 65.5 years (range 23-84 years). Most tumors were T3 and T4 (65.8%). Regional metastases were common (55.2%), and 42.1% developed distant metastases. The mean follow-up was 60.5 months. All patients received surgery as primary treatment, with 84.2% of patients receiving adjuvant radiation therapy or chemoradiotherapy ([C]RT). Cumulative overall survival was 89.1%, 50.9%, and 20.7% after 1, 5, and 10 years, respectively. Disease-specific survival was 94.4%, 69.8%, and 42.8%, and distant-metastases-free survival (DMFS) was 80.5%, 50.1%, and 40.1% after 1, 5, and 10 years. On multivariable analysis, advanced T status correlated with DMFS (hazard ratio 2.75, 95% CI 0.93-8.16). Postsurgical (C)RT reduced the locoregional recurrence rate by 23.9%, and it improved the locoregional-recurrence-free survival by 39% (p = 0.094). CONCLUSION: High-grade ASG is considered to have an unfavorable prognosis. Adjuvant (C)RT reduces the rate of locoregional recurrences. Distant metastases are common, and an advanced T stage has increased prognostic value for development of early distant lesions.

Automated setup for ex vivo larynx experiments.

Ex vivo larynx experiments are limited in time due to degeneration of the laryngeal tissues. In order to acquire a significant and comparable amount of data, automatization of current manual experimental procedures is desirable. A computer controlled, electro-mechanical setup was developed for time-dependent variation of specific physiological parameters, including adduction and elongation level of the vocal folds and glottal flow. The setup offers a standardized method to induce defined forces on the laryngeal cartilages. Furthermore, phonation onset is detected automatically and the subsequent measurement procedure is automated and standardized to improve the efficiency of the experimental process. The setup was validated using four ex vivo porcine larynges, whereas each validation measurement series was executed with one separate larynx. Altogether 31 single measurements were undertaken, which can be summed up to a total experimental time of about 4 min. Vocal fold elongation and adduction lead both to an increase in fundamental frequency and subglottal pressure. Measurement procedures like applying defined subglottal pressure steps and onset-offset detection were reliably executed. The setup allows for a computer-based parameter control, which enables fast experimental execution over a wide range of laryngeal configurations. This maximizes the number of measurements and reduces personal effort compared with manual procedures.

A novel nasopharyngeal stent for the treatment of obstructive sleep apnea: a case series of nasopharyngeal stenting versus continuous positive airway pressure.

The objective of the study was to investigate the first-night treatment success of a nasopharyngeal stent compared to standard nCPAP-titration. This is a case series and a single-center study. Eight participants (n = 8) were selected with untreated obstructive sleep apnea with a prestudy AHI ≥ 10. A newly developed nasopharyngeal stent was tested individually versus standard nCPAP-titration. Cardiorespiratory polysomnography was performed on two consecutive nights (random order: stent, nCPAP). The AHI, the number of obstructive apneas and hypopneas, the mean oxygen saturation, and the minimum oxygen saturation were compared before and after using the nasopharyngeal stent or standard nCPAP. The AHI value before treatment (AHIpre) was 31.1 ± 12.0 (mean ± standard deviation). After inserting the AlaxoStent, the mean AHIstent was 19 ± 12.0 compared to mean AHInCPAP 8.2 ± 11.9 with standard nCPAP-titration. Both nasopharyngeal stenting and nCPAP-titration could reduce the mean number of obstructive apneas by >94 %. Compared to responder rates of classic surgical interventions like uvulopalatopharyngoplasty or multi-level surgery, the nasopharyngeal stent seems to give a comparable responder rate of 50 %. There were no complications associated with the use of the stent and it was well tolerated by all subjects. Nasopharyngeal stenting widens the range of non-invasive mechanical treatment and seems to be an effective mechanical therapeutic alternative to surgery in nCPAP non-compliant patients with OSA. Careful selection of the patient population is a prerequisite of treatment and therefore it should be reserved for individual cases only.

The mechanisms of subharmonic tone generation in a synthetic larynx model.

The sound spectra obtained in a synthetic larynx exhibited subharmonic tones that are characteristic for diplophonia. Although the generation of subharmonics is commonly associated with asymmetrically oscillating vocal folds, the synthetic elastic vocal folds showed symmetrical oscillations. The amplitudes of the subharmonics decreased with an increasing lateral diameter of the supraglottal channel, which indicates a strong dependence of the supraglottal boundary conditions. Investigations of the supraglottal flow field revealed small cycle-to-cycle variations of the static pressure in the region of the pulsatile glottal jet as the origin of the first subharmonic tone. It is located at half the fundamental frequency of the vocal fold oscillation. A principle component analysis of the supraglottal flow field with the fully developed glottal jet revealed a large recirculation area in the second spatial eigenvector which deflected the glottal jet slightly in a perpendicular direction of the jet axis. The rotation direction of the recirculation area changed with different oscillation cycles between clockwise and counterclockwise. As both directions were uniformly distributed across all acquired oscillation cycles, a cycle-wise change can be assumed. It is concluded that acoustic subharmonics are generated by small fluctuations of the glottal jet location favored by small lateral diameters of the supraglottal channel.

SFTA3, a novel protein of the lung: three-dimensional structure, characterisation and immune activation.

The lung constantly interacts with numerous pathogens. Thus, complex local immune defence mechanisms are essential to recognise and dispose of these intruders. This work describes the detection, characterisation and three-dimensional structure of a novel protein of the lung (surfactant-associated protein 3 (SFTA3/SP-H)) with putative immunological features. Bioinformatics, biochemical and immunological methods were combined to elucidate the structure and function of SFTA3. The tissue-specific detection and characterisation was performed by using electron microscopy as well as fluorescence imaging. Three-dimensional structure generation and analysis led to the development of specific antibodies and, as a consequence, to the localisation of a novel protein in human lung under consideration of cystic fibrosis, asthma and sepsis. In vitro experiments revealed that lipopolysaccharide induces expression of SFTA3 in the human lung alveolar type II cell line A549. By contrast, the inflammatory cytokines interleukin (IL)-1ß and IL-23 inhibit expression of SFTA3 in A549. Sequence- and structure-based prediction analysis indicated that the novel protein is likely to belong to the family of lung surfactant proteins. The results suggest that SFTA3 is an immunoregulatory protein of the lung with relevant protective functions during inflammation at the mucosal sites.

Transporter gene expression in human head and neck squamous cell carcinoma and associated epigenetic regulatory mechanisms.

Expression levels of membrane transporters may affect the disposition, and thereby treatment efficacy, of anticancer drugs in human head and neck squamous cell carcinoma (HNSCC). Herein, we analyzed the gene expression profile of membrane transporters in HNSCC. In addition, we evaluated the mechanisms of transporter regulation in HNSCC and focused on the role of the nuclear pregnane X receptor (or NR1I2) and epigenetic mechanisms. Real-time RT-PCR revealed a significantly increased mRNA expression of membrane transporters SLCO1A2 and SLCO1B3 and a significantly decreased expression of transporters SLCO2B1, SLCO2A1, and ABCC3 in human HNSCC tumors compared with adjacent normal mucosa. An association between SLCO2B1 mRNA levels in tumors and 5-year survival of patients with HNSCC was observed (χ2 = 6.59, P = 0.010). Bisulfite sequencing revealed that promoter CpG islands of ABCC3 and SLCO2A1 were not hypermethylated, indicating that these genes were not epigenetically silenced in HNSCC tumors. In HNSCC-derived cell lines, transcript expression of transporters (e.g., ABCC3 or SLCO2A1; P < 0.001 for both) and NR1I2 (P < 0.001) was markedly induced by the DNA methyltransferase inhibitor, decitabine. Cotreatment with the prototypical pregnane X receptor activator, rifampicin, significantly reversed decitabine-induced ABCC3 and SLCO2A1 expression. In summary, the expression of drug transporters (i) is markedly changed in HNSCC tumor tissues compared with normal mucosa, (ii) might be predictive of the outcome of patients with HNSCC, and (iii) is affected by novel epigenetic therapies and is further modulated by nuclear receptor-mediated mechanisms.

Extracting continuous sleep depth from EEG data without machine learning.

The human sleep-cycle has been divided into discrete sleep stages that can be recognized in electroencephalographic (EEG) and other bio-signals by trained specialists or machine learning systems. It is however unclear whether these human-defined stages can be re-discovered with unsupervised methods of data analysis, using only a minimal amount of generic pre-processing. Based on EEG data, recorded overnight from sleeping human subjects, we investigate the degree of clustering of the sleep stages using the General Discrimination Value as a quantitative measure of class separability. Virtually no clustering is found in the raw data, even after transforming the EEG signals of each 30-s epoch from the time domain into the more informative frequency domain. However, a Principal Component Analysis (PCA) of these epoch-wise frequency spectra reveals that the sleep stages separate significantly better in the low-dimensional sub-space of certain PCA components. In particular the component C1(t) can serve as a robust, continuous 'master variable' that encodes the depth of sleep and therefore correlates strongly with the 'hypnogram', a common plot of the discrete sleep stages over time. Moreover, C1(t) shows persistent trends during extended time periods where the sleep stage is constant, suggesting that sleep may be better understood as a continuum. These intriguing properties of C1(t) are not only relevant for understanding brain dynamics during sleep, but might also be exploited in low-cost single-channel sleep tracking devices for private and clinical use.

Comparison of mucus and serum biomarker sampling in chronic rhinosinusitis with nasal polyps.

OBJECTIVE: The objective of this study was to analyze advantages and disadvantages of mucus and serum for biomarker analysis. METHODS: This study includes prospective study of 61 CRS with nasal polyps patients who were followed over 24 months and over nine time points after functional endoscopic sinus surgery. At each time points, the nasal polyp score (NPS) was assessed and mucus as well as serum was collected. Selected were measured in mucus and serum. Mean, standard deviation and variance, undetectable values, and the correlation of the biomarkers to the NPS over time and to early recurrences were calculated, and the effect of surgery on the biomarkers was assessed. Additionally, the diurnal rhythm of all biomarkers was measures in order to assure stable biomarker values during sampling times. RESULTS: All biomarkers showed stable values during sampling times. Serum biomarker levels displayed higher percentages of undetectable values compared to mucus biomarkers. Mucus periostin (p < 0.001, r = 0.89), mucus IgE (p < 0.001, r = 0.51), serum periostin (p < 0.001, r = 0.53), mucus CST1 (p < 0.001, r = 0.27), and serum IgE (p < 0.01, r = -0.18) were the best marker and medium combinations to track the NPS over time and to predict recurrences. Mucus serpinF2 was negatively correlated and predicted early recurrences (p = 0.026, R2  = 0.015). CONCLUSIONS: Serum and mucus both represent viable mediums for "liquid biopsies." The most promising biomarker/medium combinations over time to track disease severity were mucus periostin, mucus IgE, serum periostin, mucus CST1, and serum IgE. Mucus serpinF2 was the best biomarker to predict early recurrences.

Effect of postoperative systemic prednisolone on short-term and long-term outcomes in chronic rhinosinusitis with nasal polyps: A multi-centered randomized clinical trial.

Introduction: The objective of this study was to determine whether postoperative additive systemic steroid administration in chronic rhinosinusitis with nasal polyps (CRSwNP) impacted selected endoscopic, subjective and objective outcome measures. Methods: This was a prospective, randomized, double-blind, placebo-controlled, noninferiority multicenter trial of n=106 patients with CRSwNP. All patients underwent primary functional endoscopic sinus surgery (FESS) followed by topical nasal steroids. Patients were randomized to a systemic steroid or placebo for 1 month. Patients were followed up for 2 years over 9 time points. The primary outcome measures were the differences between groups with respect to the nasal polyp score (NPS) and sinonasal quality of life (SNQoL). Secondary outcome measures included interactions with respect to the Lund-Kennedy score (LKS), sinonasal symptoms, general quality of life (GQoL), 16-item odor identification test scores, recurrence rates, need for revision surgery and mucus biomarker levels. Results: 106 patients were randomized to either the placebo or the systemic steroid group (n=53 per group). Postoperative systemic steroids were not superior to placebo with respect to all primary (p= 0.077) and secondary outcome measures (p>0.05 for all). Reported adverse events were similar between the two groups. Conclusion: In conclusion, the addition of postoperative systemic steroids after primary FESS did not confer a benefit over topical steroid nasal spray alone with respect to NPS, SNQOL, LKS, GQOL, sinonasal symptoms, smell scores, recurrence rates, the need for revision surgery or biomarkers over a short-term follow-up of up to 9 months and a long-term follow-up of up to 24 months in CRSwNP patients. Functional endoscopic surgery did, however, show a strong effect on all outcome measures, which remained relatively stable up to the endpoint at 2 years.

Classification at the accuracy limit: facing the problem of data ambiguity.

Data classification, the process of analyzing data and organizing it into categories or clusters, is a fundamental computing task of natural and artificial information processing systems. Both supervised classification and unsupervised clustering work best when the input vectors are distributed over the data space in a highly non-uniform way. These tasks become however challenging in weakly structured data sets, where a significant fraction of data points is located in between the regions of high point density. We derive the theoretical limit for classification accuracy that arises from this overlap of data categories. By using a surrogate data generation model with adjustable statistical properties, we show that sufficiently powerful classifiers based on completely different principles, such as perceptrons and Bayesian models, all perform at this universal accuracy limit under ideal training conditions. Remarkably, the accuracy limit is not affected by certain non-linear transformations of the data, even if these transformations are non-reversible and drastically reduce the information content of the input data. We further compare the data embeddings that emerge by supervised and unsupervised training, using the MNIST data set and human EEG recordings during sleep. We find for MNIST that categories are significantly separated not only after supervised training with back-propagation, but also after unsupervised dimensionality reduction. A qualitatively similar cluster enhancement by unsupervised compression is observed for the EEG sleep data, but with a very small overall degree of cluster separation. We conclude that the handwritten letters in MNIST can be considered as 'natural kinds', whereas EEG sleep recordings are a relatively weakly structured data set, so that unsupervised clustering will not necessarily re-cover the human-defined sleep stages.

Depression and female gender associated with higher postoperative pain scores after sinonasal surgery.

BACKGROUND: Although it is extremely necessary to reduce the number of opioids taken postoperatively after sinonasal surgery, this is the subject of controversial discussion. OBJECTIVES: The objective of this study was to identify factors that predict higher postoperative pain scores (PPS) and the need for opioid analgesics after sinonasal surgery. MATERIAL AND METHODS: This was a retrospective study of n = 492 patients who underwent functional endoscopic sinus surgery (FESS), septoplasty or a combination of both in the Otolaryngology Department in Erlangen between January and December 2018. Postoperative pain using the numeric rating scale and the postoperative need for non-opioid and opioid analgesics in relation to demographic and surgical parameters were evaluated. RESULTS: Significant predictors for a higher pain score were depression (p = .009) and female gender (p < .001). A significant predictor of the need for postoperative opioids was the female gender (p < .001), whereas FESS alone showed a significantly lower need for opioids (p = .035) and a significantly lower PPS compared to septoplasty (p < .001). CONCLUSIONS AND SIGNIFICANCE: The study identified risk factors for a higher PPS and the need for opioids. The results indicated that reducing postoperative opioids might be possible in patients without these risk factors and might help guide individualized postoperative therapy.