The Addition of C-Reactive Protein and von Willebrand Factor to Model for End-Stage Liver Disease-Sodium Improves Prediction of Waitlist Mortality.

BACKGROUND AND AIMS: Patients with cirrhosis on the liver transplant (LT) waiting list may die or be removed because of complications of portal hypertension (PH) or infections. von Willebrand factor antigen (vWF-Ag) and C-reactive protein (CRP) are simple, broadly available markers of these processes. APPROACH AND RESULTS: We determined whether addition of vWF-Ag and CRP to the Model for End-Stage Liver Disease-Sodium (MELD-Na) score improves risk stratification of patients awaiting LT. CRP and vWF-Ag at LT listing were assessed in two independent cohorts (Medical University of Vienna [exploration cohort] and Mayo Clinic Rochester [validation cohort]). Clinical characteristics, MELD-Na, and mortality on the waiting list were recorded. Prediction of 3-month waiting list mortality was assessed by receiver operating characteristics curve (ROC-AUC). In order to explore potential mechanisms underlying the prognostic utility of vWF-Ag and CRP in this setting, we evaluated their association with PH, bacterial translocation, systemic inflammation, and circulatory dysfunction. In the exploration cohort (n = 269) vWF-Ag and CRP both improved the predictive value of MELD-Na for 3-month waitlist mortality and showed the highest predictive value when combined (AUC: MELD-Na, 0.764; MELD-Na + CRP, 0.790; MELD-Na + vWF, 0.803; MELD-Na + CRP + vWF-Ag, 0.824). Results were confirmed in an independent validation cohort (n = 129; AUC: MELD-Na, 0.677; MELD-Na + CRP + vWF-Ag, 0.882). vWF-Ag was independently associated with PH and inflammatory biomarkers, whereas CRP closely, and MELD independently, correlated with biomarkers of bacterial translocation/inflammation. CONCLUSIONS: The addition of vWF-Ag and CRP-reflecting central pathophysiological mechanisms of PH, bacterial translocation, and inflammation, that are all drivers of mortality on the waiting list for LT-to the MELD-Na score improves prediction of waitlist mortality. Using the vWFAg-CRP-MELD-Na model for prioritizing organ allocation may improve prediction of waitlist mortality and decrease waitlist mortality.

Generation of ductal organoids from normal mammary luminal cells reveals invasive potential.

Here we present an experimental model for human luminal progenitor cells that enables single, primary cells isolated from normal tissue to generate complex branched structures resembling the ductal morphology of low-grade carcinoma of no special type. Thereby, we find that ductal structures are generated through invasive branching morphogenesis via matrix remodeling and identify reduced actomyosin contractility as a prerequisite for invasion. In addition, we show that knockout of E-cadherin causes a dissolution of duct formation as observed in invasive lobular carcinoma, a subtype of invasive carcinomas where E-cadherin function is frequently lost. Thus, our model shows that invasive capacity can be elicited from normal luminal cells in specific environments, which results in low-grade no special type morphology. This assay offers a platform to investigate the dynamics of luminal cell invasion and unravel the impact of genetic and non-genetic aberrations on invasive morphology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Microfluidic Evolution-On-A-Chip Reveals New Mutations that Cause Antibiotic Resistance.

Microfluidic devices can mimic naturally occurring microenvironments and create microbial population heterogeneities ranging from planktonic cells to biofilm states. The exposure of such populations to spatially organized stress gradients can promote their adaptation into complex phenotypes, which are otherwise difficult to achieve with conventional experimental setups. Here a microfluidic chip that employs precise chemical gradients in consecutive microcompartments to perform microbial adaptive laboratory evolution (ALE), a key tool to study evolution in fundamental and applied contexts is described. In the chip developed here, microbial cells can be exposed to a defined profile of stressors such as antibiotics. By modulating this profile, stress adaptation in the chip through resistance or persistence can be specifically controlled. Importantly, chip-based ALE leads to the discovery of previously unknown mutations in Escherichia coli that confer resistance to nalidixic acid. The microfluidic device presented here can enhance the occurrence of mutations employing defined micro-environmental conditions to generate data to better understand the parameters that influence the mechanisms of antibiotic resistance.

The von Willebrand Factor Facilitates Model for End-Stage Liver Disease-Independent Risk Stratification on the Waiting List for Liver Transplantation.

BACKGROUND AND AIMS: The Model for End-Stage Liver Disease (MELD) is used for clinical decision-making and organ allocation for orthotopic liver transplantation (OLT) and was previously upgraded through inclusion of serum sodium (Na) concentrations (MELD-Na). However, MELD-Na may underestimate complications arising from portal hypertension or infection. The von Willebrand factor (vWF) antigen (vWF-Ag) correlates with portal pressure and seems capable of predicting complications in patients with cirrhosis. Accordingly, this study aimed to evaluate vWF-Ag as an adjunct surrogate marker for risk stratification on the waiting list for OLT. APPROACH AND RESULTS: Hence, WF-Ag at time of listing was assessed in patients listed for OLT. Clinical characteristics, MELD-Na, and mortality on the waiting list were recorded. Prediction of 3-month waiting-list survival was assessed by receiver operating characteristics and net reclassification improvement. Interestingly, patients dying within 3 months on the waiting list displayed elevated levels of vWF-Ag (P < 0.001). MELD-Na and vWF-Ag were comparable and independent in their predictive potential for 3-month mortality on the waiting list (area under the curve [AUC], vWF-Ag = 0.739; MELD-Na = 0.764). Importantly, a vWF-Ag cutoff at 413% identified patients at risk for death within 3 months of listing with a higher odds ratio (OR) than the previously published cutoff at a MELD-Na of 20 points (vWF-Ag, OR = 10.873, 95% confidence interval [CI], 3.160, 36.084; MELD-Na, OR = 7.594, 95% CI, 2.578, 22.372; P < 0.001, respectively). Ultimately, inclusion of vWF-Ag into the MELD-Na equation significantly improved prediction of 3-month waiting-list mortality (AUC, MELD-Na-vWF = 0.804). CONCLUSIONS: A single measurement of vWF-Ag at listing for OLT predicts early mortality. Combining vWF-Ag levels with MELD-Na improves risk stratification and may help to prioritize organ allocation to decrease waiting-list mortality.

Long-Term Results after Suprapubic ARC Procedure for the Treatment of Stress Urinary Incontinence in Women: A Retrospective Data Analysis.

INTRODUCTION: The aim of this study was to evaluate long-term safety and efficacy of the suprapubic arc (SPARC) procedure for the surgical treatment of stress urinary incontinence (SUI). MATERIALS AND METHODS: 139 female patients treated by SPARC were included in this retrospective analysis, whereby 126 patients were available for follow-up after 1 year, 70 after 6 years, and 41 after 9 years. The cough test, pad test, uroflowmetry, and post-void residual volume measurements were performed. Severity of bother (visual analogous scale [VAS] 0-10), continence, and the satisfaction rate were assessed. Objective cure was defined as a negative cough test and pad weight ≤1 g, subjective cure as no urine loss during daily activities and no usage of pads. The VAS, pad weight, number of pads per day, and maximal flow rate were compared preoperatively and postoperatively. RESULTS: Objective cure rates at 1, 6, and 9 years were 78.6, 71.4, and 70.7% and subjective cure rates were 72.2, 55.7, and 65.8%, respectively. The VAS, pad weight, number of pads, and maximal flow rate decreased significantly. Study limitations include a relatively small sample size and the retrospective fashion of the analysis. CONCLUSIONS: In the long-term context, SPARC showed to represent an efficient and safe procedure for treatment of female SUI.

The intercarotid or alar fascia, other cervical fascias, and their adjacent spaces - a plea for clarification of cervical fascia and spaces terminology.

Due to varying descriptions and terminology of fascias of the neck, medical advice relying on this basic knowledge is insufficient. Our goal was to provide a precise anatomical description of cervical fascias and spaces with special focus on the intercarotid fascia, or the alar fascia. One hundred bodies donated to science embalmed with Thiel's method were investigated, cervical fascias were dissected layer by layer, and the results were documented by photography, with a focus on the intercarotid fascia. In addition, we performed a review of recent literature concerning cervical surgical interventions, radiological diagnostic pathways, and basic anatomical works focusing on core information on anatomical relations of cervical fascias and spaces. In another 10 bodies donated to science, the spaces of the neck were injected with coloured latex under ultrasound guidance, dissected, and documented by photography. The intercarotid fascia was a constantly developed connective tissue interconnecting the carotid sheath of both sides. In 52 of 100 specimens (52%) it crossed to the opposite side without any fusion to the ventrally situated visceral fascia. Fusion with the visceral fascia was found in 48%, either at the lateral border of the pharynx or on its dorsal side. The results of our dissections strengthen the precise description of the cervical fascias provided by Grodinsky and Holyoke in 1938. Spaces can be confirmed as described by Hafferl in 1969. The international anatomical and ENT societies should codify a unified anatomical terminology of the cervical spaces and fascias to prevent varying interpretations in the future.

A systematic review and meta-analysis of rescue revascularization with arterial conduits in liver transplantation.

Although aortohepatic conduits (AHCs) provide an effective technique for arterialization in liver transplantation (LT) when the native recipient artery is unusable, various publications report higher occlusion rates and impaired outcome compared to conventional anastomoses. This systematic review and meta-analysis investigates the published evidence of outcome and risk of AHCs in LT using bibliographic databases and following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Primary and secondary outcome were artery occlusion as well as graft and patient survival. Twenty-three retrospective studies were identified with a total of 22 113 patients with LT, of whom 1900 patients (9%) received an AHC. An AHC was used in 33% of retransplantations. Early artery occlusion occurred in 7% (3%-16%) of patients with AHCs, compared to 2% (1%-3%) without conduit (OR 3.70; 1.63-8.38; P = .001). The retransplantation rate after occlusion was not significantly different in both groups (OR 1.46; 0.67-3.18; P = .35). Graft (HR 1.38; 1.17-1.63; P < .001) and patient (HR 1.57; 1.12-2.20; P = .009) survival was significantly lower in the AHC compared to the nonconduit group. In contrast, graft survival in retransplantations was comparable (HR 1.00; 0.82-1.22; P = .986). Although AHCs provide an important rescue option, when regular revascularization is not feasible during LT, transplant surgeons should be alert of the potential risk of inferior outcome.

Preoperative ultrasound improves patency and cost effectiveness in arteriovenous fistula surgery.

OBJECTIVE: We aimed to compare routine preoperative color-coded duplex ultrasound (DUS) to clinical examination (CE) alone in surgery for arteriovenous fistula (AVF) with special emphasis on long-term outcomes and cost effectiveness. METHODS: All patients undergoing an AVF formation or revision between January 1, 2011, and December 31, 2016, at our tertiary referral center were subject to analysis. Routine DUS was performed in 114 patients and CE alone in 217 patients. Primary and secondary patency, the need for revision or reintervention to obtain patency, and individual as well as overall costs were analyzed. RESULTS: Primary patency rate was higher in AVF after DUS compared with CE alone at 62% vs 26% (P < .05), respectively. Patients receiving DUS had significantly lower rates of revision and revisions per patient when compared with CE (25.4% vs 59.4% [P < .0001]; 0.36 ± 0.71 vs 1.06 ± 1.55 [P < .0001], respectively). Costs per patient were significantly lower in the DUS group compared with CE at 4074€ vs 6078€ (P < .0001). CONCLUSIONS: We were able to show that patients receiving preoperative DUS showed higher patency rates and needed fewer revisions. Standard preoperative ultrasound examination is an easy tool to improve outcomes and cost effectiveness in AVF surgery.

MiR-371a-3p Serum Levels Are Increased in Recurrence of Testicular Germ Cell Tumor Patients.

Metastatic testicular germ cell tumors (TGCTs) are a potentially curable disease by administration of risk-adapted cytotoxic chemotherapy. Nevertheless, a disease-relapse after curative chemotherapy needs more intensive salvage chemotherapy and significantly worsens the prognosis of TGCT patients. Circulating tumor markers (ß-subunit of human chorionic gonadotropin (ß-HCG), alpha-Fetoprotein (AFP), and Lactate Dehydrogenase (LDH)) are frequently used for monitoring disease recurrence in TGCT patients, though they lack diagnostic sensitivity and specificity. Increasing evidence suggests that serum levels of stem cell-associated microRNAs (miR-371a-3p and miR-302/367 cluster) are outperforming the traditional tumor markers in terms of sensitivity to detect newly diagnosed TGCT patients. The aim of this study was to investigate whether these miRNAs are also informative in detection of disease recurrence in TGCT patients after curative first line therapy. For this purpose, we measured the serum levels of miR-371a-3p and miR-367 in 52 samples of ten TGCT patients at different time points during disease relapse and during salvage chemotherapy. In our study, miR-371a-3p levels in serum samples with proven disease recurrence were 13.65 fold higher than levels from the same patients without evidence of disease (p = 0.014). In contrast, miR-367 levels were not different in these patient groups (p = 0.985). In conclusion, miR-371a-3p is a sensitive and potentially novel biomarker for detecting disease relapse in TGCT patients. This promising biomarker should be investigated in further large prospective trials.

Blood Platelet Volume Represents a Novel Prognostic Factor in Patients with Nonmetastatic Renal Cell Carcinoma and Improves the Predictive Ability of Established Prognostic Scores.

PURPOSE: The average size of blood platelets determined by mean platelet volume might represent a biologically meaningful parameter in carcinogenesis and potentially serve as a novel prognostic biomarker in renal cell carcinoma. MATERIALS AND METHODS: In this retrospective analysis of the records of 652 patients we evaluated the potential prognostic value of mean platelet volume and its ability to improve existing risk assessment tools used in adjuvant clinical trials in nonmetastatic renal cell carcinoma cases. Associations of mean platelet volume with baseline covariates and clinical outcomes (recurrence, and death from renal cell carcinoma and other causes) were assessed with the competing risk estimators of Kaplan-Meier, and Marubini and Valsecchi, respectively. Univariable and multivariable Cox proportional hazard models were constructed. The Harrell c-index was applied to test improvements in the predictive accuracy of the established Leibovich prognosis score. RESULTS: Small platelet volume was associated with large tumors (p = 0.043), high Fuhrman grade (p = 0.001), sarcomatoid components (p <0.0001), histological tumor necrosis (p = 0.044) and vascular invasion (p = 0.022). On univariable and multivariable analyses small platelet volume accurately predicted recurrent renal cell carcinoma (continuously and binary coded) and cancer specific survival. Adding mean platelet volume to the Leibovich prognosis score improved its discriminative performance (c-index = 0.83, p = 0.004). CONCLUSIONS: Mean platelet volume represented a highly significant predictor of recurrence and cancer specific death in patients with renal cell carcinoma. This parameter improved the accuracy of the Leibovich prognosis score to better predict long-term outcomes in localized renal cell carcinoma cases after curative surgical resection.

Impact of dynamic changes in MELD score on survival after liver transplantation - a Eurotransplant registry analysis.

BACKGROUND & AIMS: With restricted numbers of available organs, futility in liver transplantation has to be avoided. The concept of dynamic changes in MELD score (DeltaMELD) has previously been shown to be a simple tool to identify patients with the greatest risk of death after transplantation. Aim was to validate this concept with the Eurotransplant (ET) database. METHODS: A retrospective registry analysis was performed on all patients listed for liver transplantation within ET between 2006 and 2011. Patients <18 years of age, acute liver failure, malignancy and patients listed for retransplantation were excluded. Influence of MELD at listing (MELDon), MELD at transplantation (MELDoff), DeltaMELD, age, sex, underlying disease and time on the waiting list on overall survival after liver transplantation were evaluated. RESULTS: A total of 16 821 patients were listed for liver transplantation, 8096 met the inclusion criteria. Age, MELD on and DeltaMELD showed significant influence on survival on the waiting list. Age and DeltaMELD showed influence on survival after liver transplantation, with DeltaMELD>10 showing a 1.6-fold increased risk of death. CONCLUSION: The concept of DeltaMELD was validated in a large, prospective data set. It provides a simple tool to identify patients with increased risk of death after liver transplantation and might help improve long-term results.

Chiral symmetry breaking in QCD with two light flavors.

A distinctive feature of the presence of spontaneous chiral symmetry breaking in QCD is the condensation of low modes of the Dirac operator near the origin. The rate of condensation must be equal to the slope of M(π)(2)F(π)(2)/2 with respect to the quark mass m in the chiral limit, where M(π) and F(π) are the mass and the decay constant of the Nambu-Goldstone bosons. We compute the spectral density of the (Hermitian) Dirac operator, the quark mass, the pseudoscalar meson mass, and decay constant by numerical simulations of lattice QCD with two light degenerate Wilson quarks. We use lattices generated by the Coordinated Lattice Simulation (CLS) group at three values of the lattice spacing in the range 0.05-0.08 fm, and for several quark masses corresponding to pseudoscalar mesons masses down to 190 MeV. Thanks to this coverage of parameters space, we can extrapolate all quantities to the chiral and continuum limits with confidence. The results show that the low quark modes do condense in the continuum as expected by the Banks-Casher mechanism, and the rate of condensation agrees with the Gell-Mann-Oakes-Renner relation. For the renormalization-group-invariant ratios we obtain [Σ(RGI)](1/3)/F=2.77(2)(4) and Λ(M̅S)/F=3.6(2), which correspond to [Σ(M̅S)(2 GeV)](1/3)=263(3)(4) MeV and F=85.8(7)(20) MeV if F(K) is used to set the scale by supplementing the theory with a quenched strange quark.

Prevalence of genital dysplasia after kidney transplantation--a retrospective, non-interventional study from two centers.

OBJECTIVE: Renal transplant patients are at increased risk for human papillomavirus-related malignancies of the lower genital tract. Our aim was to describe the incidence of genital dysplasia, assess the most common cervical cancer screening intervals and identify independent risk factors for the development of genital dysplasia in renal transplant patients. DESIGN: Retrospective, non-interventional study from two centers. SETTING: Post-transplant nephrologic follow-up visit at the Medical University of Vienna and a Viennese teaching hospital. POPULATION: 262 consecutive female renal transplant patients with renal transplant performed between 1980 and 2012 at the Medical University of Vienna. METHODS: Sociodemographic patient characteristics, frequency of gynecological examinations, histo- and cytopathological test results were collected. MAIN OUTCOME MEASURES: Dysplasia rates in renal transplant patients. RESULTS: 16 patients (6.2%) with genital dysplasia after renal transplant were observed. The 1-year, 3-year and 10-year proportional incidence rates for genital dysplasia in general and cervical dysplasia in particular were 1.3 and 1.3%, 3.3 and 2.7%, and 13.6 and 12.0%, respectively. Patients attended cervical cancer screening on a regular basis once a year in 82.7% of cases. In multivariate analysis re-transplantation [odds ratio 12.1 (1.5-96.3)], and renal transplant at a young age [odds ratio 0.6 (0.4-0.9)] were identified as independent risk factors for the development of female genital dysplasia. CONCLUSIONS: Female renal transplant patients have an increased risk for the development of genital dysplasia in general and of cervical dysplasia in particular. Within this cohort, women at a young age at the time of transplantation and after re-transplantation are at highest risk for the development of genital dysplasia.

[Treatment planning with functional MRI]. / Strahlentherapieplanung mit der funktionellen MRT.

CLINICAL/METHODICAL ISSUE: The aim of magnetic resonance imaging (MRI) guided radiotherapy is high precision in treatment delivery. With new developments it is possible to focus the high dose irradiation on the tumor while sparing the surrounding tissue. The achievements in precision of the treatment planning and delivery warrant equally precise tumor definition. STANDARD RADIOLOGICAL METHODS: In conventional radiation therapy it is necessary to carry out a planning computed tomography (CT). For many tumors there is also need for an additional morphological MRI because of more accurate tumor definition. In standard radiotherapy the tumor volume is irradiated with a homogeneous dose. METHODICAL INNOVATIONS: The aim of functional multiparametric MRI is to visualize and quantify biological, physiological and pathological processes at the cellular and molecular levels. Based on this information it is possible to elucidate tumor biology and identify subvolumes of more aggressive behavior. They are often radiotherapy-resistant, leading to tumor recurrence thus requiring further dose escalation. The concept of inhomogeneous tumor irradiation according to its biological behavior is called dose painting. PERFORMANCE: Dose painting is technically feasible. The expected clinical benefit is motivated by selective treatment adaptations based on biological tumor characteristics. Tumors show variable response to therapy underlining the need for individual treatment plans. This approach may lead not only to higher local control but also to better sparing of normal surrounding tissue. ACHIEVEMENTS: With the clinical implementation of dose painting, improvements in the therapeutic outcome can be expected. PRACTICAL RECOMMENDATIONS: Due to the existing technical challenges, extensive collaboration between radiation oncologists, radiologists, medical physicists and radiation biologists is needed.

Distant metastasis in patients with cervical cancer after primary radiotherapy with or without chemotherapy and image guided adaptive brachytherapy.

OBJECTIVE: The aim of this study is to investigate patterns of distant relapse after primary radiochemotherapy in cervical cancer patients. METHODS: All patients with cervical cancer treated in curative intent with external beam radiotherapy +/- chemotherapy and image-guided adaptive brachytherapy between January 1998 and June 2009 at the Medical University of Vienna were included in this retrospective analysis. Patients with locoregional recurrences were excluded from this study. Presence, site of and time to distant metastases were recorded. For identifying prognostic factors, uni- and multivariate analyses using Cox regression analysis were performed. Based on the result from the multivariate analysis, patients were stratified into a high and a low risk group. The Kaplan-Meier method was used to estimate distant-metastasis-free-survival in the overall cohort, in the risk groups and for analysing the impact of chemotherapy within the risk groups. RESULTS: A total number of 189 patients were included in this study. After a median follow-up of 54 months, 49 patients developed distant metastases. Overall, distant-metastasis-free-survival 5 years after treatment was 73%. FIGO stage, lymph node status and the extent of tumour regression during treatment were significant predictors for distant metastasis. Distant-metastasis-free-survival 5 years after treatment was 91% and 60% in the low and high risk groups, respectively. The number of the cycles of chemotherapy had a significant impact on the occurrence of distant metastasis in high risk patients, but not in low risk patients. CONCLUSION: Patients with high risk factors have a 40% probability of developing distant metastasis within 5 years. In these patients, decreasing the number of cycles of cisplatin may increase their probability of developing distant metastasis.

Residual tumour volumes and grey zones after external beam radiotherapy (with or without chemotherapy) in cervical cancer patients. A low-field MRI study.

BACKGROUND: Grey zones, which are defined as tissue with intermediate signal intensity in the area of primary hyperintense tumour extension, can be seen during radiation with or without chemotherapy on the T2-weighted MRI in patients with cervical cancer. The purpose of this study was to systematically measure the tumour volume at the time of diagnosis and the residual tumour volume at the time of brachytherapy without and with consideration of the grey zones and to estimate tumour regression during external beam radiotherapy (EBRT). MATERIAL AND METHODS: T2-weighted MRI datasets of 175 patients with locally advanced cervical cancer (FIGO stage IB-IVA), who underwent combined external beam radiotherapy and brachytherapy with or without concomitant chemotherapy were available for this study. The gross tumour volume at the time of diagnosis (GTV(init)) and at the time of first brachytherapy without (GTV(res)) and with (GTV(res)+ GZ) consideration of grey zones were measured for each patient. A descriptive statistical analysis was performed and tumour regression rates without (R) and with consideration of grey zones (R(GZ)) were calculated. Further, the role of prognostic factors on GTV(init), GTV(res), GTV(res)+ GZ and tumour regression rates was investigated. RESULTS: The median GTV(init), GTV(res), GTV(res)+ GZ in all patients were 44.4 cm(3), 8.2 cm(3), 20.3 cm(3), respectively. The median R was 78.5% and the median R(GZ) was 50.1%. The histology and FIGO staging showed a significant impact on GTV(init), GTV(res) and GTV(res)+ GZ. CONCLUSION: Grey zones represent a substantial proportion of the residual tumour volume at the time of brachytherapy. Differentiation of high signal intensity mass and surrounding intermediate signal intensity grey zones may be reasonable.

Time course of late rectal- and urinary bladder side effects after MRI-guided adaptive brachytherapy for cervical cancer.

BACKGROUND AND PURPOSE: To analyze the time course of late rectal- and urinary bladder complications after brachytherapy for cervical cancer and to compare the incidence- and prevalence rates thereof. PATIENTS AND METHODS: A total of 225 patients were treated with external-beam radiotherapy (EBRT) and magnetic resonance imaging (MRI)-guided brachytherapy with or without chemotherapy. Late side effects were assessed prospectively using the Late Effects in Normal Tissue--Subjective, Objective, Management and Analytic (LENT/SOMA) scale. The parameters analyzed were time to onset, duration, actuarial incidence- (occurrence of new side effects during a defined time period) and prevalence rates (side effects existing at a defined time point). RESULTS: Median follow-up was 44 months. Side effects (grade 1-4) in rectum and bladder were present in 31 and 49 patients, 14 and 27 months (mean time to onset) after treatment, respectively. All rectal and 76 % of bladder side effects occurred within 3 years after radiotherapy. Mean duration of rectal events was 19 months; 81 % resolved within 3 years of their initial diagnosis. Mean duration of bladder side effects was 20 months; 61 % resolved within 3 years. The 3- and 5-year actuarial complication rates were 16 and 19 % in rectum and 18 and 28 % in bladder, respectively. The corresponding prevalence rates were 9 and 2 % (rectum) and 18 and 21 % (bladder), respectively. CONCLUSION: Late side effects after cervical cancer radiotherapy are partially reversible, but their time course is organ-dependent. The combined presentation of incidence- and prevalence rates provides the most comprehensive information.

The Recent Dangers for European Happiness: Is Homeostatic Resilience Sufficient?

In the literature on life satisfaction the author came across the hypothesis that happiness oscillates around a set point given by nurture and nature. This assumption implicitly supposes a homeostatic mechanism, which implies resilience against unhappiness. The present paper aims at the exploration and quantitative description of this resilience at the national level, which may be challenged by military conflicts, pandemics, energy crises, etc. In particular, the researcher would like to know, for which European countries the postulated resilience really exists, where the related national set points are, and whether there are limits of unhappiness below which the homeostatic set points cannot be reached anymore. In order to tackle these research questions, country-specific time series of annual happiness between 2007 and 2019 are analyzed by linear and quadratic regressions, where the current national happiness is the independent and the related following level of happiness the dependent variable. By analyzing the resulting regression equations, it is possible to identify and analyze its mathematical fixed points. Depending on whether they are stable or not, they are either homeostatic set points (equilibria) or critical limits, where homeostasis is destroyed. The present empirical analysis reveals that more than 50% of the analyzed European countries have no homeostasis of happiness. Consequently, these countries are psychologically vulnerable with regard to depressing developments like energy crises or pandemics. The remaining cases do often not display the classical form of homeostasis: they have either a shifting set point or only a narrow range, within which the homeostasis of happiness is maintained. Thus, there are only a few European countries with unlimited resilience against unhappiness and a set point that is stable over time.

Simultaneous integrated boost within the lymphatic drainage system in breast cancer: A single center study on toxicity and oncologic outcome.

Background and purpose: In breast cancer patients, the increasing de-escalation of axillary surgery and the improving resolution of diagnostic imaging results in a more frequent detection of residual, radiographically suspect lymph nodes (sLN) after surgery. If resection of the remaining suspect lymph nodes is not feasible, a simultaneous boost to the lymph node metastases (LN-SIB) can be applied. However, literature lacks data regarding the outcome and safety of this technique. Materials and methods: We included 48 patients with breast cancer and sLN in this retrospective study. All patients received a LN-SIB. The median dose to the breast or chest wall and the lymph node system was 50.4 Gy in 28 fractions. The median dose of the LN-SIB was 58.8 Gy / 2.1 Gy (56-63 Gy / 2-2.25 Gy). The brachial plexus was contoured in every case and the dose within the plexus PRV (+0.3-0.5mm) was limited to an EQD2 of 59 Gy. All patients received structured radiooncological and gynecological follow-up by clinically experienced physicians. Radiooncological follow-ups were at baseline, 6 weeks, 3 months, 6 months and subsequent annually after irradiation. Results: The median follow-up time was 557 days and ranged from 41 to 3373 days. Overall, 28 patients developed I°, 18 patients II° and 2 patients III° acute toxicity. There were no severe late side effects (≥ III°) observed during the follow-up period. The most frequent chronic side effect was fatigue. One patient (2.1 %) developed pain and mild paresthesia in the ipsilateral arm after radiotherapy. After a follow-up of 557 days (41 to 3373 days), in 8 patients a recurrence was observed (16.7%). In 4 patients the recurrence involved the regional lymph node system. Hence, local control in the lymph node drainage system after a median follow-up of 557 days was 91.6 %. Conclusion: If surgical re-dissection of residual lymph nodes is not feasible or refused by the patient, LN-SIB-irradiation can be considered as a potential treatment option. However, patients need to be informed about a higher risk of regional recurrence compared to surgery and an additional risk of acute and late toxicity compared to adjuvant radiotherapy without regional dose escalation.

Charlson-Deyo Comorbidity Index as a Novel Predictor for Recurrence in Non-Muscle-Invasive Bladder Cancer.

PURPOSE: To test the association between the Charlson-Deyo Comorbidity Index (CCI) and the recurrence of non-muscle-invasive bladder cancer (NMIBC). METHODS: NMIBC (Ta, T1, TIS) patients who underwent transurethral resection of bladder tumor (TURB) between 2010 and 2018 were identified within a retrospective data repository of a large university hospital. Kaplan-Meier estimates and uni- and multivariable Cox regression models tested for differences in risk of recurrence according to low vs. high comorbidity burden (CCI ≤ 4 vs. >4) and continuously coded CCI. RESULTS: A total of 1072 NMIBC patients were identified. The median follow-up time of the study population was 55 months (IQR 29.6-79.0). Of all 1072 NMIBC patients, 423 (39%) harbored a low comorbidity burden vs. 649 (61%) with a high comorbidity burden. Overall, the rate of recurrence was 10% at the 12-month follow-up vs. 22% at the 72-month follow-up. In low vs. high comorbidity burden groups, rates of recurrence were 6 vs. 12% at 12 months and 18 vs. 25% at 72 months of follow-up (p = 0.02). After multivariable adjustment, a high comorbidity burden (CCI > 4) independently predicted a higher risk of recurrence (HR 1.42, 95% confidence interval (CI) 1.06-1.92, p = 0.018). After multivariable adjustment, the hazard of recurrence increased by 5% per each one-unit increase on the CCI scale (HR 1.05, 95% CI 1.00-1.10, p = 0.04). CONCLUSIONS: Comorbidities in NMIBC patients are common. Our data suggest that patients with higher CCI have an increased risk of BC recurrence. As a consequence, patients with a high comorbidity burden should be particularly encouraged to adhere to NMIBC guidelines and conform to follow-up protocols.