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Objective To analyze the impact of nutritional counseling on the development of hypothyroidism after (chemo)radiotherapy in head and neck cancer patients to propose a new normal tissue complication probability (NTCP) model. Materials and methods At baseline, at the end of (chemo)radiotherapy, and during follow-up, thyroid-stimulating hormone (TSH) with free thyroxin (fT3 and fT4), nutritional status, and nutrient intake were prospectively analyzed in 46 out of 220 screened patients. Patients received (chemo)radiotherapy within an intervention (individual nutritional counseling every 2 weeks during therapy) and a control group (no nutritional counseling). Results Overall median follow-up was 16.5 [IQR: 12; 22] months. Fourteen patients (30.4%) presented with hypothyroidism after 13.5 [8.8; 17] months. During (chemo)radiotherapy, nutritional status worsened in the entire cohort: body mass index (p p p = 0.02) increased, and the baseline protein intake dropped (p = 0.028). The baseline selenium intake (p = 0.002) increased until the end of therapy. Application of the NTCP models by Rønjom, Cella, and Boomsma et al. resulted in good performance of all three models, with an AUC ranging from 0.76 to 0.78. Our newly developed NTCP model was based on baseline TSH and baseline ferritin. Model performance was good, receiving an AUC of 0.76 (95% CI: 0.61–0.87), with a sensitivity of 57.1% and specificity of 96.9% calculated for a Youden index of 0.73 (p = 0.004; area = 0.5). Conclusion Baseline TSH and ferritin act as independent predictors for radiotherapy-associated hypothyroidism. The exclusion of such laboratory chemistry parameters in future NTCP models may result in poor model performance.

von K. Culmann, Handschriftliches Geschenkexlibris: "Herrn Prof.Dr. Wolf freundschaftlichst der Verf." 004342724_0001 Exemplar der ETH-BIB

PURPOSE/OBJECTIVE(S) Patients with squamous cell carcinoma of the head and neck (HNSCC) under (chemo-)radiotherapy are at high risk of malnutrition. There are no studies investigating the influence of nutritional status on an altered side effect spectrum and only very few studies examining bioelectric impedance analysis (BIA) and its impact as a prognostic indicator in patients with HNSCC undergoing (chemo-)radiotherapy. Our prospective, randomized, and controlled HEADNUT-trial presented here aimed at preventing increasing malnutrition under radiotherapy or concurrent chemoradiotherapy through specialized and individualized nutritional counseling. Additionally, we investigated whether parameters from BIA were suitable indicators for (threatening) malnutrition and inspected their prognostic effect on (clinical) outcome. MATERIALS/METHODS Between October 2018 and October 2020, 61 patients were randomized into an intervention and control group. Questionnaires (MUST, NRS-2002, and Nutriscore), clinical examinations, laboratory analyses, and BIA were used to assess nutritional status for all patients at the beginning and end of therapy as well as every 2 weeks during therapy. The intervention consisted of an individualized nutritional counseling every 2 weeks during therapy. RESULTS Median baseline BMI for all participants was 23.8 (14.5-37.2) kg/m² and dropped to 22.9 (16.8-33) kg/m² after therapy (P < 0.001). In all patients, median baseline fat-free mass index (FFMI) was 18.1 (14-24.7) kg/m² and decreased to 17.8 (13.4-21.6) kg/m² till the end of therapy (P < 0.001). Compliant patients with a BMI < 22 kg/m² presented with less weight loss in the intervention group compared to the control (P = 0.015, CI: 0.33-2.95). At baseline, MUST was the only screening-test which showed both good sensitivity (86%) and specificity (88%) in detecting malnutrition. Median follow-up was 15 (1-26) months. 2-year overall survival rate was 70% in the control and 79% in the intervention group (log-rank P = 0.79). Pretherapeutic phase angle, posttherapeutic FFMI and albumin level were prognostic indicators for overall survival (log-rank P = 0.002, P = 0.008 and P = 0.016). CONCLUSION Malnutrition negatively impacts patients' outcome under (chemo-)radiotherapy. Baseline phase angle, posttherapeutic FFMI and albumin level are proposed as reliable indicators for overall survival.

Purpose/objective Patients with squamous cell carcinoma of the head and neck undergoing (chemo-)radiotherapy are at high risk of malnutrition. Nevertheless, there is still a lack of prospective, randomized trials investigating the influence of nutritional status on therapy-related toxicity and patients’ outcome. Materials and methods Between October 2018 and October 2020, 61 patients were randomized into an intervention and control group. Questionnaires (MUST, NRS-2002, and Nutriscore), clinical examinations, laboratory analyses, and bioelectrical impedance analysis (BIA) were used to assess nutritional status for all patients at the beginning and end of therapy as well as every 2 weeks during therapy. The intervention consisted of an individualized nutritional counseling every 2 weeks during therapy. Results Median baseline BMI for all participants was 23.8 (14.5–37.2) kg/m2 and dropped to 22.9 (16.8–33) kg/m2 after therapy (p Conclusions Malnutrition negatively impacts patients’ outcome under (chemo-)radiotherapy. Baseline phase angle, posttherapeutic FFMI and albumin level are proposed as reliable indicators for overall survival. This study was registered within the German Clinical Trials Register (DRKS00016862).

Aims Somatic mutations of the epigenetic regulators DNMT3A and TET2 causing clonal expansion of haematopoietic cells (clonal haematopoiesis; CH) were shown to be associated with poor prognosis in chronic ischaemic heart failure (CHF). The aim of our analysis was to define a threshold of variant allele frequency (VAF) for the prognostic significance of CH in CHF. Methods and results We analysed bone marrow and peripheral blood-derived cells from 419 patients with CHF by error-corrected amplicon sequencing. Cut-off VAFs were optimized by maximizing sensitivity plus specificity from a time-dependent receiver operating characteristic (ROC) curve analysis from censored data. 56.2% of patients were carriers of a DNMT3A- (N = 173) or a TET2- (N = 113) mutation with a VAF >0.5%, with 59 patients harbouring mutations in both genes. Survival ROC analyses revealed an optimized cut-off value of 0.73% for TET2- and 1.15% for DNMT3A-CH-driver mutations. Five-year-mortality was 18% in patients without any detected DNMT3A- or TET2 mutation (VAF Conclusion The present study defines novel threshold levels for clone size caused by acquired somatic mutations in the CH-driver genes DNMT3A and TET2 that are associated with worse outcome in patients with CHF.

To analyze the impact of nutritional counseling on the development of hypothyroidism after (chemo)radiotherapy in head and neck cancer patients to propose a new normal tissue complication probability (NTCP) model.At baseline, at the end of (chemo)radiotherapy, and during follow-up, thyroid-stimulating hormone (TSH) with free thyroxin (fT3 and fT4), nutritional status, and nutrient intake were prospectively analyzed in 46 out of 220 screened patients. Patients received (chemo)radiotherapy within an intervention (individual nutritional counseling every 2 weeks during therapy) and a control group (no nutritional counseling).Overall median follow-up was 16.5 [IQR: 12; 22] months. Fourteen patients (30.4%) presented with hypothyroidism after 13.5 [8.8; 17] months. During (chemo)radiotherapy, nutritional status worsened in the entire cohort: body mass index (p 0.001) and fat-free mass index (p 0.001) decreased, calorie deficit (p = 0.02) increased, and the baseline protein intake dropped (p = 0.028). The baseline selenium intake (p = 0.002) increased until the end of therapy. Application of the NTCP models by Rønjom, Cella, and Boomsma et al. resulted in good performance of all three models, with an AUC ranging from 0.76 to 0.78. Our newly developed NTCP model was based on baseline TSH and baseline ferritin. Model performance was good, receiving an AUC of 0.76 (95% CI: 0.61-0.87), with a sensitivity of 57.1% and specificity of 96.9% calculated for a Youden index of 0.73 (p = 0.004; area = 0.5).Baseline TSH and ferritin act as independent predictors for radiotherapy-associated hypothyroidism. The exclusion of such laboratory chemistry parameters in future NTCP models may result in poor model performance.

Purpose To compare two surgical approaches for treating encapsulated blebs after trabeculectomy with mitomycin C, in terms of the development of intraocular pressure and progression of glaucoma in a long-term follow up: 1. bleb needling alone vs. 2. a combined approach of needling with additional transconjunctival scleral flap sutures, to prevent early ocular hypotony. Methods Forty-six patients with failing blebs after trabeculectomy with mitomycin C were enrolled in this study. Patients received either needling revision alone (group 1; n = 23) or a combined needling with additional transconjuctival flap sutures, if intraoperatively the intraocular pressure was estimated to be low (group 2; n = 23). Intraocular pressure (IOP), visual acuity, visual fields, and optic nerve head configuration by means of Heidelberg Retina Tomograph (HRT®) were analysed over time. Results from both groups were compared using Mann-Whitney U-test for single timepoints. Results IOP did not differ significantly between the two groups during follow-up at three months (P = 0.13), six months (P = 0.12), one year (P = 0.92) and two years (P = 0.57) after surgery. Furthermore, there was no significant difference in the course of glaucoma concerning the optic nerve anatomy between the two groups (Rim Area Change in the Moorfields Regression Analysis of HRT®) till two years after surgery (P = 0.289). No functional impairment in visual acuity and visual fields was found in the groups of the study. Conclusions Single needling procedure is a standard successful method for restoring the function of encapsulated blebs. Postoperative hypotony represents a possible hazard, which can be minimized by additional transconjunctival flap sutures. Long-term results suggest that this modification is equally effective in lowering the IOP and preventing the progression of glaucoma as the standard needling procedure. To our knowledge this is the first study to investigate the long-term effect of tranconjunctival sutures for the prevention of hypotony.

The clinical value of imaging is well established for the follow-up of many lymphoid malignancies but not for chronic lymphocytic leukemia (CLL). A meta-analysis was performed with the dataset of 3 German CLL Study Group phase 3 trials (CLL4, CLL5, and CLL8) that included 1372 patients receiving first-line therapy for CLL. Response as well as progression during follow-up was reassessed according to the National Cancer Institute Working Group1996 criteria. A total of 481 events were counted as progressive disease during treatment or follow-up. Of these, 372 progressions (77%) were detected by clinical symptoms or blood counts. Computed tomography (CT) scans or ultrasound were relevant in 44 and 29 cases (9% and 6%), respectively. The decision for relapse treatment was determined by CT scan or ultrasound results in only 2 of 176 patients (1%). CT scan results had an impact on the prognosis of patients in complete remission only after the administration of conventional chemotherapy but not after chemoimmunotherapy. In conclusion, physical examination and blood count remain the methods of choice for staging and clinical follow-up of patients with CLL as recommended by the International Workshop on Chronic Lymphocytic Leukemia 2008 guidelines. These trials are registered at http://www.isrctn.org as ISRCTN 75653261 and ISRCTN 36294212 and at http://www.clinicaltrials.gov as NCT00281918.

The HIV-1 Nef protein down-modulates surface expression of MHC class I proteins. Primary infected T lymphocytes thus escape lysis by cytotoxic T lymphocytes (CTL). In contrast, during HIV-1 infection there are strong CTL responses to several HIV proteins, and there is mounting evidence that CTL are critical for controlling the virus. The present study was carried out to assess Nef protein-cell interaction as it occurs in naturally infected antigen-presenting cells. To evaluate the presentation of peptides derived from viral antigen to CTL, we transfected nef genes obtained from peripheral blood mononuclear cells of HIV-1-seropositive subjects into dendritic cells isolated from monocytes of healthy donors. We demonstrate that expression and subsequent processing of Nef by transfected dendritic cells did not alter the presentation of an immunodominant epitope of Nef to CTL of HIV+ subjects. However, mutations in nef gene sequences from primary isolates may abolish this presentation by a mechanism that probably interferes with protein processing.

The ionic composition of the HF–SbF5 superacid system has been investigated by 1H and 19F high field NMR. The anionic distribution over the whole composition range could be directly calculated from the 19F NMR spectra. The cationic distribution was then estimated on the basis of charge balance. When the concentration of SbF5 in HF was higher than 20 mol%, increasing amounts of nonassociated SbF5 appeared. This change in composition can be linked to the change in reactivity of the superacid system in the activation process of small alkanes.

AIM: To evaluate the influence of locally active Crohn's disease on systemic small-bowel motility in patients with chronic Crohn's disease compared to healthy individuals. MATERIAL AND METHODS: Fifteen healthy individuals (11 men, four women; mean age 37 years) and 20 patients with histopathologically proven active (n = 15; 10 women, 5 men; mean age 45 years) or chronic (n = 5; four women, one man; mean age 48 years) Crohn's disease were included in this institutional review board-approved, retrospective study. Magnetic resonance imaging (MRI; 1.5 T) was performed after standardized preparation. Two-dimensional (2D) cine sequences for motility acquisition were performed in apnoea (27 s). Motility assessment was performed using dedicated software in three randomly chosen areas of the small-bowel outside known Crohn's disease-affected hotspots. The main quantitative characteristics (frequency, amplitude, occlusion rate) were compared using Student's t-test and one-way analysis of variance (ANOVA). RESULTS: Three randomly chosen segments were analysed in each participant. Patients with active Crohn's disease had significantly (p < 0.05) reduced contraction frequencies (active Crohn's disease: 2.86/min; chronic: 4.14/min; healthy: 4.53/min) and luminal occlusion rates (active: 0.43; chronic: 0.70; healthy: 0.73) compared to healthy individuals and patients with chronic Crohn's disease. Contraction amplitudes were significantly reduced during active Crohn's disease (6.71 mm) compared to healthy participants (10.14 mm), but this only reached borderline significance in comparison to chronic Crohn's disease (8.87 mm). Mean bowel lumen diameter was significantly (p = 0.04) higher in patients with active Crohn's disease (16.91 mm) compared to healthy participants (14.79 mm) but not in comparison to patients with chronic Crohn's disease (13.68). CONCLUSION: The findings of the present study suggest that local inflammatory activity of small-bowel segments in patients with active Crohn's disease alters small-bowel motility in distant, non-affected segments. The motility patterns revealed reduced contraction-wave frequencies, amplitudes, and decreased luminal occlusion rates. Thus evaluation of these characteristics potentially helps to differentiate between chronic and active Crohn's disease.

Purpose A simple needling procedure is the standard method for restoring the function of an encapsulated bleb after trabeculectomy. However, postoperative hypotony represents a possible hazard. This study describes a new surgical approach for treating encapsulated blebs with reduced risk of early postoperative hypotony: bleb needling combined with transconjunctival sutures tightening the scleral flap directly. Methods The study included two groups of 23 patients with failing bleb following trabeculectomy: “Group 1” underwent simple needling revision of the filtering bleb and served as a control group, while “Group 2” received needling revision with additional transconjunctival scleral flap sutures, if intraoperatively the intraocular pressure was estimated to be very low. Intraocular pressure (IOP), postoperative management and complications were analyzed over a follow-up period of 4 weeks postoperatively. Results were compared using t-test or Mann-Whitney U-tests. Results Adverse effects occurred with a higher frequency after sole needling of the bleb (5 cases of choroidal effusion and 1 case of choroidal hemorrhage) than after the combined method with additional scleral sutures (1 case of choroidal effusion). The IOP on the first postoperative day was significantly lower in group 1, with 9.43 ± 9.01 mm Hg vs. 16.43 ± 8.35 mm Hg in group 2 (P = 0.01). Ten patients with ocular hypotony (IOD of 5 mmHg or lower) were found in group 1 and only two in group 2. One week and one month after surgery the intraocular pressure was similar in both groups (P>0.05). Conclusions This new needling technique with additional transconjunctival scleral flap sutures appears to reduce postoperative hypotony, and may thus protect from further complications, such as subchoroidal hemorrhage.

In human immunodeficiency virus (HIV) infection, sequence variations within defined cytotoxic T lymphocyte (CTL) epitopes may lead to escape from CTL recognition. In a previous report, we have shown that the variable central region of HIV Nef protein (amino acids 73-144) that contains potential CTL epitopes, can escape the CTL response. We suggested that this non recognition occurs through a variety of mechanisms. In particular, we provided evidence that HIV Nef sequences recovered from HLA-A11-expressing individuals have alterations in the major anchor residues essential for binding of the two Nef epitopes (amino acids 73-82 and 84-92) to the HLA-A11 molecule. Here, we investigate in more detail whether variations in autologous Nef sequences affect HLA binding, leading to CTL escape. Potential epitopes were sought by testing Nef peptides containing the HLA-A11-specific motif or related motifs. We confirmed that only the two previously described epitopes identified in cytolysis tests have optimal reactivity with the HLA-A11 molecule. We then sequenced several viral variants from donors that do not express the HLA-A11 molecule and compared the variability of these epitopes with those obtained from HLA-A11-expressing individuals. One substitution (Leu85) found in the sequences isolated from both populations increase the reactivity of the HLA-A11-restricted epitope 84-92, and might explain the difference in immunogenicity observed between the two HLA-A11-restricted epitopes from HLA-A11+ individuals. In addition, selective variations were only detected in virus isolated from HLA-A11-expressing individuals. Furthermore, examination of the association of variant peptides with the HLA-A11 molecule demonstrated that a single substitution within the minimal epitope could not always completely abrogate HLA binding, suggesting that multiple alterations within a particular epitope may accumulate during disease progression, allowing the virus to escape CTL recognition.