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Background: Treatment paradigms for management of metastatic renal cell carcinoma (mRCC) are evolving. We examined impact of surgical metastasectomy on survival across in mRCC stratified by risk-group., Methods: Multicenter retrospective analysis from the Registry of Metastatic RCC database. The cohort was subdivided utilizing Motzer criteria (favorable-, intermediate-, high-risk). Primary outcome was all-cause mortality (ACM)/overall survival (OS); secondary outcome was cancer-specific mortality (CSM)/cancer-specific survival (CSS). Impact of metastasectomy was analyzed via Cox-Regression analysis adjusting for potential prognostic variables and Kaplan-Meier analysis (KMA) within each risk-group., Results: Four hundred thirty-one patients (59 favorable-risk, 274 intermediate-risk, 98 high-risk; median follow-up 27.2 months) were analyzed. Metastasectomy was performed in 22 (37%), 66 (24%), and 32 (16%) of favorable-, intermediate- and high-risk groups (P = .012). Median number of metastases at diagnosis differed significantly (favorable-risk 2, intermediate-risk 3.4, high-risk 5.1, P < .001). On Cox-regression, high-risk (HR = 1.72, P = .002) was associated with worsened ACM, while metastasectomy was associated with improved ACM (HR = 0.56, P = .005). On KMA, median OS (months) was longer with metastasectomy in favorable- (92.7 vs. 25.8, P = .003) and intermediate-risk (26.3 vs. 20.1, P = .038), but not high-risk (P = .911) groups. Metastasectomy was associated with longer CSS in favorable- (76.1 vs. 32.8, P = .004) but not intermediate- (P = .06) and high-risk (P = .595) groups., Conclusions: Metastasectomy was independently associated with improved ACM and CSM, as well as improved CSS and OS in favorable- and intermediate-risk mRCC patients. Metastasectomy may be considered as component of multimodal management strategy in favorable and intermediate-risk subgroups. In high-risk patients, metastasectomy should be deferred except in select circumstances., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: To evaluate the impact of PSMA PET (prostate specific membrane antigen positron emission tomography) findings prior to salvage radiotherapy (SRT) in recurrent prostate cancer (PCa) after radical prostatectomy (RP) on metastasis-free survival (MFS)., Patients and Methods: Between 01/2012 and 12/2018, 1,599 patients received SRT for biochemical recurrence after RP at our institution. Five-year MFS of "positive PSMA PET" (n = 49) vs. "negative PSMA PET" (n = 106) vs. "no PSMA PET" (n = 1,599) prior to SRT was determined. For all time to event analyses, uni- and multivariable Cox's proportional hazards models and univariable Kaplan-Meier analyses were applied, with a significance threshold of P < 0.05. Further 4:1 propensity score matching for patient, cancer and treatment characteristics was performed to account for residual differences between groups., Results: Of PSMA PET patients, 106 patients exhibited "negative PSMA PET" (68.4%) and 49 exhibited "positive PSMA PET" (31.6%). Median PSA at recurrence did not differ between groups (0.2 ng/ml; P= 0.4). After 4:1 propensity score matching, 5-year MFS between "no PSMA PET" and "negative PSMA PET" was 94.4 vs. 93.0%, respectively (P = 0.8). For "no PSMA PET" versus "positive PSMA PET", 5-year MFS was significantly lower in "positive PSMA PET" (92.3 vs. 48.5%, respectively P < 0.0001). Finally, "positive PSMA PET" was independently associated with worse MFS compared to "no PSMA PET" after multivariable adjustment in the overall cohort (HR 13.8, CI 7.5-25.2, P < 0.001)., Conclusions: Locoregional positive PSMA PET findings in recurrent patients after RP are highly predictive of worse MFS in the setting of SRT., Competing Interests: Conflict of interest None. The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Rapid case ascertainment (RCA) refers to the expeditious and detailed examination of patients with a potentially rapidly fatal disease shortly after diagnosis. RCA is frequently performed in resource-rich settings to facilitate cancer research. Despite its utility, RCA is rarely implemented in resource-limited settings and has not been performed for malignancies. One cancer and context that would benefit from RCA in a resource-limited setting is HIV-related Kaposi sarcoma (KS) in sub-Saharan Africa., Methods: To determine the feasibility of RCA for KS, we searched for all potential newly diagnosed KS among HIV-infected adults attending three community-based facilities in Uganda and Kenya. Searching involved querying of electronic medical records, pathology record review, and notification by clinicians. Upon identification, a team verified eligibility and attempted to locate patients to perform RCA, which included epidemiologic, clinical and laboratory measurements., Results: We identified 593 patients with suspected new KS. Of the 593, 171 were ineligible, mainly because biopsy failed to confirm KS (65%) or KS was not new (30%). Among the 422 remaining, RCA was performed within 1 month for 56% of patients and within 3 months for 65% (95% confidence interval: 59 to 70%). Reasons for not performing RCA included intervening death (47%), inability to contact (44%), refusal/unsuitable to consent (8.3%), and patient re-location (0.7%)., Conclusions: We found that RCA - an important tool for cancer research in resource-rich settings - is feasible for the investigation of community-representative KS in East Africa. Feasibility of RCA for KS suggests feasibility for other cancers in Africa., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Low-grade inflammation has been associated with cancer related fatigue (CRF). However, most studies focused on CRF during or shortly after treatment. Longitudinal studies are rare with inconsistent results. We assessed the association of inflammatory biomarkers with total CRF and all subdomains (physical, cognitive, affective) in long-term breast cancer survivors., Method: Patients recruited between 2002 and 2005 provided information on CRF at first follow-up (FU1) (N = 1292) and second follow-up (FU2) (N = 1205), after a median of 6.2 years and 11.7 years, respectively. Associations of 11 inflammatory biomarkers with CRF at FU1 and at FU2 were assessed using linear regression models. Logistic regression models were used to compare patients fatigued at both time-points and those never fatigued (N = 932)., Results: C-reactive protein (CRP) was significantly associated with total CRF at FU1 (β = 1.47, 95%CI = 0.62-2.31, p = 0.0007), at FU2 (β = 1.98, 95 %CI = 0.96-2.99, p = 0.0001) and with persistent CRF (OR = 1.29, 95%CI = 1.13-1.47, p < 0.0001). IL-6 levels were associated with total CRF at FU1 (β = 1.01, 95%CI = 0.43-1.59, p = 0.0006), but not with CRF at FU2 or persistent CRF. No association remained significant after adjustment for relevant covariates., Discussion: CRP and Il-6 were associated with risk of CRF in long-term breast cancer survivors, but were not independent of other known risk factors, suggesting that currently studied inflammatory markers are not suitable to identify patients at risk of long-term CRF., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Intermediate-risk prostate cancer (IR PCa) phenotypes may vary from favorable to unfavorable. National Comprehensive Cancer Network (NCCN) criteria help distinguish between those groups. We studied and attempted to improve this stratification., Patients and Methods: A total of 4048 (NCCN favorable: 2015 [49.8%] vs. unfavorable 2033 [50.2%]) patients with IR PCa treated with radical prostatectomy were abstracted from an institutional database (2000-2018). Multivariable logistic regression models predicting upstaging and/or upgrading (Gleason Grade Group [GGG] IV-V and/or ≥ pT3 or pN1) in IR PCa were developed, validated, and directly compared with the NCCN IR PCa stratification., Results: All 4048 patients were randomly divided between development (n = 2024; 50.0%) and validation cohorts (n = 2024; 50.0%). The development cohort was used to fit basic (age, prostate-specific antigen, clinical T stage, biopsy GGG, and percentage of positive cores [all P < .001]) and extended models (age, prostate-specific antigen, clinical T stage, biopsy GGG, prostate volume, and percentage of tumor within all biopsy cores [all P < .001]). In the validation cohort, the basic and the extended models were, respectively, 71.4% and 74.7% accurate in predicting upstaging and/or upgrading versus 66.8% for the NCCN IR PCa stratification. Both models outperformed NCCN IR PCa stratification in calibration and decision curve analyses (DCA). Use of NCCN IR PCa stratification would have misclassified 20.1% of patients with ≥ pT3 or pN1 and/or GGG IV to V versus 18.3% and 16.4% who were misclassified using the basic or the extended model, respectively., Conclusion: Both newly developed and validated models better discriminate upstaging and/or upgrading risk than the NCCN IR PCa stratification., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to investigate the impact of lymph-node involvement on oncological outcomes in patients with pathologically organ-confined prostate cancer (pT2 CaP) after radical prostatectomy (RP)., Methods: We retrospectively analyzed 9,631 pT2 CaP patients who underwent RP at a single institution between 1998 and 2018. Kaplan-Meier plots and Cox regression models (CRMs) assessed biochemical recurrence (BCR)-free survival and metastasis-free survival (MFS) according to N-stage. In subgroup analyses of N1 patients, Kaplan-Meier plots and CRMs were stratified according to adjuvant treatment., Results: Of 9,631 pT2 staged patients, 241 (2.5%) harbored lymph-node metastases after RP (pN1). The median follow-up was 60.8 months. No pT2 N1-staged patient died due to CaP. The 5-year BCR-free survival rates were 54.7 vs. 88.4% in pT2 N1 vs. pT2 N0 patients, respectively (P < 0.001). The 5-year MFS rates were 92.5 vs. 98.9% in pT2 N1 vs. pT2 N0 patients, respectively (P < 0.001). Within pT2 N1 patients, presence of ≥3 positive lymph nodes was an independent risk factor for BCR (hazard ratio [HR] 3.4, P < 0.001) and for metastatic progression (HR 1.7, P = 0.04). Finally, 3-year BCR-free survival was improved in pT2 N1 patients treated with adjuvant radiation therapy (87.1% vs. 63.7% for patients who received other treatment options [P < 0.001])., Conclusion: Patients with pathologically organ-confined but lymph node-positive CaP exhibited favorable oncological outcomes after RP. Presence of ≥3 positive LNs predicted higher rates of BCR and metastatic progression. In consequence, in pT2 N1 patients treated with RP with ≥3 positive LNs, adjuvant treatment may be considered.9., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Pulmonary vein isolation (PVI) using the second-generation cryoballoon (CB2) for atrial fibrillation (AF) treatment has demonstrated encouraging procedural success rates and mid-term results. However, long-term follow-up data on outcome is sparse. The current study is reporting on five-year clinical outcomes following CB2-based PVI in patients with paroxysmal AF (PAF) and persistent AF (PersAF)., Methods: A total of 139 patients underwent index CB2-based PVI patients (PAF: n = 105, 76% and PersAF: n = 34, 34%) in two electrophysiology centers. Freeze-cycle duration was 240 s. After successful PVI a bonus freeze-cycle of the same duration was applied in the first 71 patients while the bonus-freeze was omitted in 68 following patients. Three patients (2.2%) were lost to follow-up., Results: After a median follow-up duration of 60 months (interquartile range: 46, 72 months) 74/136 (54.4%) patients remained in stable sinus rhythm (PAF: 62/104, 59.6%; PersAF: 15/32, 46.9%). Significant differences were observed concerning 5-year clinical outcome between PAF and PersAF patients (p = 0.0315). After a mean of 1.32 ± 0.6 procedures (2nd and 3rd procedure by radiofrequency ablation) and a median follow-up duration of 60 (37, 68) months 90/136 (66.2%) patients remained in stable sinus rhythm (PAF: 72/104 (69.2%), PersAF: 21/32 (65.6%), p = 0.0276). For the comparison of bonus-freeze vs no-bonus-freeze protocols no differences were observed (53.5% vs 57.4%, p = 0.650)., Conclusions: The five-year single-procedure success rate for CB2-based PVI was 54.4% and increased to 66.2% following repeat RF-based procedures. No differences were detected comparing bonus-freeze and no-bonus-freeze protocols., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: The purpose of this study was to investigate adherence to recommended adjuvant radiotherapy (aRT) in radical prostatectomy (RP) patients with adverse pathologic features and to analyse the outcome of patients who followed or denied this recommendation., Patients and Methods: We included 1140 consecutive RP patients (2006-2015) with non-organ confined (pT3) prostate cancer and either positive surgical margins (R1) and/or lymph node involvement (pN1) and non-detectable postoperative prostate-specific antigen who received multidisciplinary aRT recommendations. Patients were stratified into adherence versus non-adherence to recommendations. Additionally, subgroups within pathologic criteria (pT3R1N0, pT3R0N1, pT3R1N1) were analyzed. Kaplan-Meier, as well as multivariable Cox regression analyses were used to assess biochemical recurrence (BCR)-free survival, metastasis-free survival, cancer-specific survival, and overall survival., Results: Overall, 508 (44.6%) patients were non-adherent. Of those, 273 (53.6%) did not receive any RT, and 235 (46.4%) received salvage RT. At 8 years, BCR-free survival was 57.7 versus 20.1%, metastasis-free survival was 76.5 versus 75.4%, cancer-specific survival was 91.7 versus 87.4%, and overall survival was 80.4 versus 75.8% in adherent versus non-adherent patients, respectively (P < .001). In multivariable Cox regression predicting BCR, metastatic progression, cancer-specific mortality, and overall mortality, non-adherence to aRT recommendation represented an independent predictor (hazard ratio [HR], 3.8; 95% confidence interval [CI], 3.1-4.5; HR, 1.6; 95% CI, 1.2-2.2; HR, 2.8; 95% CI, 1.5-5.3; and HR, 1.8; 95% CI, 1.2-2.8, respectively)., Conclusions: Only about 55% of patients followed our multidisciplinary recommendations. Adherent patients were significantly less likely to experience BCR, metastatic progression, cancer-specific mortality, and overall mortality. Thus, patients with high risk of recurrence may be advised about the possibility of improved oncologic outcomes in case of adherence to aRT recommendations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Scabies is a parasitic disease of the skin that disproportionately affects disadvantaged populations. The disease causes considerable morbidity and leads to severe bacterial infection and immune-mediated disease. Scientific advances from the past 5 years suggest that scabies is amenable to population-level control, particularly through mass drug administration. In recognition of these issues, WHO added scabies to the list of neglected tropical diseases in 2017. To develop a global control programme, key operational research questions must now be addressed. Standardised approaches to diagnosis and methods for mapping are required to further understand the burden of disease. The safety of treatments for young children, including with ivermectin and moxidectin, should be investigated. Studies are needed to inform optimum implementation of mass treatment, including the threshold for intervention, target, dosing, and frequency. Frameworks for surveillance, monitoring, and evaluation of control strategies are also necessary., (Copyright © 2019 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Background: The prevalence of atrial fibrillation (AF) increases with age. Second-generation cryoballoon (CB2)-based PVI has demonstrated encouraging clinical results in the treatment of paroxysmal (PAF) and persistent atrial fibrillation (PersAF). The objective of this study was to assess data on safety, efficacy and long-term clinical success of CB2-based pulmonary vein isolation (PVI) in patients ≥75 years of age., Methods: CB2-based PVI was performed in 104 patients ≥75 years of age (elderly group) and symptomatic AF (PersAF: n = 44, 42.3%) in three highly experienced German EP centers. The data was compared to propensity score matched patients with age <75 years (n = 104, control group; PersAF: n = 45, 43.3%, p = 0.956)., Results: The median age of the elderly group was 77.5 [75, 80] years while it was 63 [52, 70] years of control group patients (p = 0.0001). The median procedure time was 92.5 [75, 120] minutes (elderly group) and 100 [75, 120] (control group), p = 0.124. Major complications were registered in 7/104 (6.7%) elderly patients and 7/104 (6.7%) control group patients (p = 0.999). Clinical success in terms of freedom from AF recurrence after one-year follow-up was 80% (95% CI: 72-88) and 82% (95% CI: 75-90) and after three-year follow-up 59% (95% CI: 47-74) and 49% (95% CI: 37 64) for the elderly group and the control group, respectively (p = 0.7)., Conclusions: CB2-based PVI in patients ≥75 years of age appears safe, is associated with low procedure times and shows promising clinical success rates equal to patients of the younger population., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) is less effective in patients with atrial fibrillation (AF) because of impaired ventricular CRT capture., Objective: We investigated the effects of catheter ablation in patients with AF and previous nonresponse to CRT., Methods: Consecutive patients with AF and CRT nonresponse who underwent catheter ablation for AF were analyzed. CRT nonresponse was defined as one of the following: (1) reduced biventricular capture <95% due to rapidly conducted AF, (2) <1 point improvement in New York Heart Association (NYHA) class after CRT implantation, or (3) insufficient increase in left ventricular ejection fraction (LVEF; ≤5%) after CRT implantation., Results: Thirty-eight patients (8 women [21%]; mean age 68 ± 10 years; LVEF 30% ± 7%, biventricular capture 88.0% [25th, 75th percentile 75.3%, 98.5%]) underwent catheter ablation. One major and 1 minor complication occurred (1 lethal atrioesophageal fistula and 1 hemodynamically nonrelevant pericardial effusion). The Kaplan-Meier estimates for arrhythmia-free survival after single and multiple ablation procedures were 29% (95% confidence interval 16%-51%) and 67% (95% confidence interval 53%-86%) after 24 months. After a median follow-up of 817 days (25th, 75th percentile 179, 1741 days), biventricular capture and LVEF were significantly higher (median [25th, 75th percentile] 99% [96%, 99%], difference 8% [0.2%, 3.75%], P < .0001; mean 32.1% ± 9.1%, difference 2.2% ± 7.1%, P = .0225) and patients had a significantly lower functional NYHA class (28 of 37 patients with improvement of at least 1 point; P < .0001)., Conclusion: Catheter ablation of AF significantly improves CRT response in patients with heart failure and concomitant AF in terms of increased biventricular capture and LVEF and improved functional NYHA class., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Second-generation cryoballoon (CB2)-based pulmonary vein isolation (PVI) has demonstrated encouraging clinical results for the treatment of paroxysmal atrial fibrillation (AF) and persistent AF. However, rhythm follow-up after PVI is mainly based on Holter electrocardiography of limited duration., Objective: The purpose of this study was to assess the real AF burden following CB2-based PVI in patients with implanted cardiac devices., Methods: A total of 670 consecutive patients underwent CB2-based PVI at 3 electrophysiology centers. In 66 patients (9.9%), an implantable cardiac device with continuous monitor function was independently implanted before the procedure (device group). This patient cohort was compared to propensity score-matched patients without cardiac devices (n = 66; control group)., Results: A total of 254 of 258 PVs (98.4%0 in the device group were successfully isolated using only CB2. Postprocedural device interrogation found no device or lead malfunction related to the procedure. Periprocedural complications were registered in 7 of 66 patients (11%) in the device group and in 6 of 66 patients (9%) in the control group (P = .770). Phrenic nerve palsy occurred in 6 of 66 patients (9%) in the device group) and in 2 of 66 patients (3%) in the control group) (P = .274). Clinical success in terms of freedom from AF recurrence after a 1-year follow-up period was 63.8% (95% confidence interval 53-77) in the device group and 77.3% (95% confidence interval 68-88) in the control group (P = .038). In the device group, AF/AT burden decreased from 41.8% ± 35.0% before the procedure to 10.2% ± 22.4% after 1 year (P <.0001)., Conclusion: CB2-PVI seems safe and feasible in patients with an implanted cardiac device. A significantly higher AF/AT burden was seen in patients with an implanted cardiac device compared to a control group., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To analyze the contribution of Wnt signaling pathway to bladder cancer growth in order to identify suitable target molecules for therapy., Material and Methods: Expression of Wnt 2/4/7, LRP5/6, TCF1/2/4, LEF-1, and β-actin was detected by reverse transcription polymerase chain reaction in a panel of 9 and for Wntless (WLS) in 17 bladder cancer cell lines. Protein expression of WLS was detected in 6 cell lines. Wnt/β-catenin activity was analyzed using the TOPflash/FOPflash luciferase reporter assay. Expression level of β-catenin, WIF1, Dickkopf proteins (DKK), HSulf-2, sFRP4, and WLS was modulated by transfecting or infecting cells transiently or stably with respective shRNAs, siRNAs, or cDNAs. For protein detection, whole cell lysates were applied to sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by immunoblots. Effects on cell growth were determined by cell viability assays and BrdU/APC incorporation/staining. For 3-dimensional tumor growth, the chicken chorioallantoic membrane model was used. Tumor growth was characterized by weight., Results: Expression of molecular components and activation of the Wnt signaling pathway could be detected in all cell lines. Expression level of β-catenin, WIF1, DKK, WLS, and HSulf-2 influenced Wnt activity. Expression of WLS was confirmed in 17 cell lines by reverse transcription polymerase chain reaction and in 6 cell lines by immunoblotting. WLS positively regulates Wnt signaling, cell proliferation, and tumor growth in vitro and in vivo. These effects could be reversed by the expression of the Wnt antagonist WIF1 and DKK. Synergistic activity of cisplatin and WLS inactivation by genetic silencing could be observed on cell viability., Conclusion: The Wnt signaling pathway is ubiquitously activated in bladder cancer and regulates tumor growth. WLS might be a target protein for novel therapies in combination with established chemotherapy regimens., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Second-generation cryoballoon (CB2)-based pulmonary vein isolation (PVI) has demonstrated encouraging clinical results in the treatment of paroxysmal (PAF) and persistent atrial fibrillation (PersAF). However, the CB2 features a maximal diameter of 28 mm, and its adaptability to anatomic variations of the pulmonary veins (PVs) might be challenging., Objective: The purpose of this study was to assess the acute efficacy, safety, and long-term clinical results of CB2-based PVI in patients with a left common pulmonary vein (LCPV)., Methods: Six hundred seventy consecutive patients underwent CB2-based PVI in 3 electrophysiology centers. In 74 patients (11%), an LCPV was identified (LCPV group). The data were compared to those from matched patients (n = 74) with normal PV anatomy and comparable baseline characteristics (control group). An antral occlusion of the complete LCPV ostium was feasible in 50% of patients in the LCPV group. If an antral occlusion could not be obtained, a sequential isolation of the first superior and inferior branches was applied., Results: All 74 LCPVs were successfully isolated. A total of 64% patients (LCPV group) and 66% patients (control group) remained in sinus rhythm after mean follow-up of 1.9 ± 0.9 years (P = .820). In 18 of 26 patients (69%) with atrial tachyarrhythmia recurrence, a repeat procedure using radiofrequency energy was performed, and a total of 56% LCPVs were found to be persistently isolated (control group: 61% of left-sided PVs, P = .801)., Conclusion: Patients with an LCPV undergoing CB2-based PVI demonstrate a high acute success rate. Comparable results with regard to clinical success and durability of PVI were shown when comparing patients of the LCPV group and the control group., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Although often overlooked, passive mechanisms can lead to significant accumulation or restriction of drugs to intracellular sites of drug action. These mechanisms include lipoidal diffusion of ionized species and pH partitioning according to the electrochemical potential and to pH gradients that exist across subcellular compartments, respectively. These mechanisms are increasingly being exploited in the design of safe and effective drugs for the treatment of a wide variety of diseases. In this work, the authors review these efforts and the associated passive mechanisms of cellular drug permeation. A generic mathematical model of the cell is provided and used to illustrate concepts relevant to steady-state intracellular distribution. Finally, the authors review methods for estimating determinant parameters and measuring the net effect at the level of unbound intracellular drug concentrations., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Extensive ablation strategies are currently performed in addition to pulmonary vein isolation (PVI) to improve the clinical outcome of patients with drug-refractory persistent atrial fibrillation (AF). Ablation of complex fractionated atrial electrograms (CFAEs), linear lesions, and/or isolation of the left atrial appendage (LAA) are thought to improve arrhythmia-free survival., Objective: The purpose of this study was to assess the durability of wide-area left atrial appendage isolation (LAAI) achieved by PVI, an anterior line, and a mitral isthmus line., Methods: Seventy-one patients with intentional or incidental LAAI during repeat catheter ablation for treatment of persistent AF were included. The initial ablation strategy was PVI. Additional ablation strategies were performed only if PVI failed to maintain stable sinus rhythm. Durability of LAAI was assessed during a subsequent ablation procedure for arrhythmia recurrences (n = 23) or a subsequent percutaneous LAA closure (n = 48)., Results: LAAI was performed after a mean of 3 ± 1 procedures. Ablation strategies included circumferential PVI in 71 patients (100%), mitral isthmus line in 64 (90%), anterior line in 60 (85%), CFAE in 27 (38%), and roof line in 13 (18%). LAAI occurred after ablation and bidirectional block of LA linear lesions in 63 patients (89%) and during extensive CFAE ablation in 8 patients (11%). After a median of 105 [61;426] days, the LAA remained electrically isolated in 52 of 71 patients (73%)., Conclusion: Wide-area LAAI after extensive catheter ablation for persistent AF is durable in the majority of patients. The potential clinical benefit of LAAI for maintaining stable sinus rhythm requires further investigation., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

In considering the challenges of approaches to clinical imaging, we are faced with choices that sometimes are impacted by rather dogmatic notions about what is a better or worse technology to achieve the most useful diagnostic image for the patient. For example, is PET or SPECT most useful in imaging any particular disease dissemination? The dictatorial approach would be to choose PET, all other matters being equal. But is such a totalitarian attitude toward imaging selection still valid? In the face of new receptor targeted SPECT agents one must consider the remarkable specificity and sensitivity of these agents. (99m)Tc-Tilmanocept is one of the newest of these agents, now approved for guiding sentinel node biopsy (SLNB) in several solid tumors. Tilmanocept has a Kd of 3×10(-11)M, and it specificity for the CD206 receptor is unlike any other agent to date. This coupled with a number of facts, that specific disease-associated macrophages express this receptor (100 to 150 thousand receptors), that the receptor has multiple binding sites for tilmanocept (>2 sites per receptor) and that these receptors are recycled every 15 min to bind more tilmanocept (acting as intracellular "drug compilers" of tilmanocept into non-degraded vesicles), gives serious pause as to how we select our approaches to diagnostic imaging. Clinically, the size of SLNs varies greatly, some, anatomically, below the machine resolution of SPECT. Yet, with tilmanocept targeting, the SLNs are highly visible with macrophages stably accruing adequate (99m)Tc-tilmanocept counting statistics, as high target-to-background ratios can compensate for spatial resolution blurring. Importantly, it may be targeted imaging agents per se, again such as tilmanocept, which may significantly shrink any perceived chasm between the imaging technologies and anchor the diagnostic considerations in the targeting and specificity of the agent rather than any lingering dogma about the hardware as the basis for imaging approaches. Beyond the elements of imaging applications of these agents is their evolution to therapeutic agents as well, and even in the neo-logical realm of theranostics. Characteristics of agents such as tilmanocept that exploit the natural history of diseases with remarkably high specificity are the expectations for the future of patient- and disease-centered diagnosis and therapy., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Novel strategies for the treatment of advanced prostate cancer (CaP), including immunotherapy or gene therapy, are currently under evaluation with Sipuleucel-T as first FDA-approved immunotherapeutic. Here, we examine cytosine-phosphorothioate-guanine (CpG)-DNA oligonucleotides (ODN) to boost cytokine responses and costimulatory molecule expression on murine bone marrow-derived dendritic cells (mBMDC). Furthermore, we evaluate the potency of a PSA-peptide based vaccine in combination with CpG-DNA to elicit specific cytotoxic T cell (CTL) responses., Materials and Methods: mBMDC were stimulated with CpG-DNA (1668: 5'-TCCATGACGTTCCTGATGCT-3') or non-stimulatory control-ODN (1720: 5'-TCCATGAGCTTCCTGATGCT-3'). Subsequently, expression of the costimulatory molecules CD40 and CD86 and induction of proinflammatory cytokines (interleukin (IL)-6 and IL-12) were analyzed. For induction of PSA-peptide specific CTL, female C57BL/6 mice were immunized with PSA-peptide 65-73 (HCIRNKSVI) alone or in combination with 1668 or 1720-ODN. In vivo cytotoxicity assay determined PSA-peptide specific cytotoxicity 1 week after vaccination., Results: Treatment of mBMDC with stimulatory CpG-DNA ODN resulted in pronounced up-regulation of costimulatory molecule expression on mBMDC in a dose-dependent manner. CpG-ODN significantly increased production of IL-6 and IL-12 in mBMDC (P < 0.001). Induction of PSA-peptide specific CTL responses in mice immunized with PSA-peptide and CpG-DNA were significantly greater than those of PSA-peptide and control-ODN immunized mice or PSA-peptide only vaccination., Conclusions: CpG-DNA acts as potent adjuvant for vaccination therapies and elicits profound PSA-peptide specific CTL responses in combination with an immunodominant PSA-peptide. CpG-ODN mediated immunotherapy represents a potentially inexpensive, safe, easy-to-produce, and easy-to-handle treatment alternative. Therefore, further evaluation of CpG-DNA in immunization therapies against CaP is warranted., (Copyright © 2013. Published by Elsevier Inc.)

Background: Inguinal lymph node dissection (LND) is often associated with wound complications. The aim of this study was to evaluate epidermal vacuum therapy for the prevention of wound complications following inguinal LND., Methods: From January 2009 to March 2012, a total of 24 patients with penile cancer or cancer of the urethra received uni- or bilateral inguinal lymphadenectomy in our institution. Postoperative wound care consisted of conventional wound care (CWC) in 16 patients or epidermal vacuum dressings (VAC) in eight patients. Maximum drained fluid per day, duration of drainage, duration of hospitalisation and inguinal complications (formation of lymphocele, persistent lymphorrhoea or lymphoedema of the lower extremity) as well as rate of reinterventions were evaluated retrospectively. Mann-Whitney U-tests were performed to compare treatment groups for maximal drained fluid per day, duration of drainage and duration of hospitalisation. Binary data were compared with Fisher's exact test. Statistical calculations were performed on a patient level., Results: Patients treated with CWC showed a slight tendency to higher values of maximum drained fluid per day (p=0.632), duration of drainage (p=0.496) and a significantly longer time of hospitalisation (p=0.049). Epidermal VAC treatment resulted in significantly fewer complications such as formation of lymphoceles (62% vs. 20%), persistent lymphorrhoea (45% vs. 7%) or lymphoedema of the lower extremity (46% vs. 0%) (p=0.032). Reinterventions had to be performed in 23% of inguinal wounds (four patients) treated with CWC and for 7% of inguinal wounds (one patient) treated with epidermal VAC (p=0.631)., Conclusions: Epidermal VAC following inguinal LND might be advantageous for the prevention of postoperative wound complications. Prospective, controlled studies are warranted to further evaluate efficacy and cost-effectiveness., (Copyright © 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Purpose: The ZOTECT study assesses the effect of zoledronic acid (ZOL) on bone-marker levels and potential correlations with disease outcomes in bisphosphonate-naive patients., Methods: This prospective, single-arm, open-label study in bisphosphonate-naive (≥6 months) patients with bone metastases from prostate cancer (PC; n=301) or breast cancer (BC; n=99) enrolled at 98 German sites (May 2006 to July 2008) investigated the effect of ZOL (4 mg intravenously every 4 weeks×4 months, with a final follow-up at 12 months) on bone-marker levels. Secondary assessments: skeletal-related event (SRE) rate, pain, quality of life (QoL), and prostate-specific antigen levels. Endpoints were assessed using summary statistics by visit/tumor type and Kaplan-Meier analyses., Results: ZOL treatment significantly decreased bone-marker levels (amino-terminal propeptide of type I collagen [P1NP], C-terminal cross-linking telopeptide of type I collagen [CTX]; P<0.0001), and this decrease was maintained through the final 1-year follow-up visit. Baseline P1NP and CTX levels correlated with extent of bone disease (P<0.0001, each) and on-treatment decreases in marker levels. Skeletal disease burden and bone-marker levels were similar between PC and BC patients, and ZOL did not significantly influence osteoprotegerin/receptor activator of nuclear factor-κB ligand levels. Only 13 SREs occurred in 11 patients, supporting the known ZOL-mediated reduction in SREs. On-treatment bone-marker level changes did not correlate with SRE rate, pain scores, or QoL. Generally, ZOL was well tolerated and adverse events were consistent with its known safety profile., Conclusions: This study confirms that ZOL therapy significantly reduces bone turnover (measured as P1NP and CTX levels) in patients with bone metastases from PC or BC.

The leech protein Saratin from Hirudo medicinalis prevents thrombocyte aggregation by interfering with the first binding step of the thrombocytes to collagen by binding to collagen. We solved the three-dimensional structure of the leech protein Saratin in solution and identified its collagen binding site by NMR titration experiments. The NMR structure of Saratin consists of one alpha-helix and a five-stranded beta-sheet arranged in the topology betabetaalphabetabetabeta. The C-terminal region, of about 20 amino acids in length, adopts no regular structure. NMR titration experiments with collagen peptides show that the collagen interaction of Saratin takes place in a kind of notch that is formed by the end of the alpha-helix and the beta-sheet. NMR data-driven docking experiments to collagen model peptides were used to elucidate the putative binding mode of Saratin and collagen. Mainly, parts of the first and the end of the fifth beta-strand, the loop connecting the alpha-helix and the third beta-strand, and a short part of the loop connecting the fourth and fifth beta-strand participate in binding.

The original local lymph node assay (LLNA) is based on the use of radioactive labelling to measure cell proliferation. Other endpoints for the assessment of proliferation are also authorized by the OECD Guideline 429 provided there is appropriate scientific support, including full citations and description of the methodology (OECD, 2002. OECD Guideline for the Testing of Chemicals; Skin Sensitization: Local Lymph Node Assay, Guideline 429. Paris, adopted 24th April 2002.). Here, we describe the outcome of the second round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in nine laboratories in Europe. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products (Swissmedic) in Bern. Ear-draining lymph node (LN) weight and cell counts were used to assess LN cell proliferation instead of [3H]TdR incorporation. In addition, the acute inflammatory skin reaction was measured by ear weight determination of circular biopsies of the ears to identify skin irritation properties of the test items. The statistical analysis was performed in the department of statistics at the university of Bern. Similar to the EC(3) values defined for the radioactive method, threshold values were calculated for the endpoints measured in this modification of the LLNA. It was concluded that all parameters measured have to be taken into consideration for the categorisation of compounds due to their sensitising potencies. Therefore, an assessment scheme has been developed which turned out to be of great importance to consistently assess sensitisation versus irritancy based on the data of the different parameters. In contrast to the radioactive method, irritants have been picked up by all the laboratories applying this assessment scheme.

The new OECD guideline 429 (skin sensitization: local lymph node assay) is based upon a protocol, which utilises the incorporation of radioactivity into DNA as a measure for cell proliferation in vivo. The guideline also enables the use of alternative endpoints in order to assess draining lymph node (LN) cell proliferation. Here we describe the first round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in seven laboratories. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products, Swissmedic. Statistical analyses of all data were performed by an independent centre at the University of Bern, Department of Statistics. Ear-draining, LN weight and cell count were used to assess proliferation instead of radioactive labeling of lymph node cells. In addition, the acute inflammatory skin reaction was measured by ear swelling and weight of circular biopsies of the ears to identify skin irritating properties of the test items. Hexylcinnamaldehyde (HCA) and three blinded test items were applied to female, 8--10 weeks old NMRI and BALB/c mice. Results were sent via the independent study coordinator to the statistician. The results of this first round showed that the alternative endpoints of the LLNA are sensitive and robust parameters. The use of ear weights added an important parameter assessing the skin irritation potential, which supports the differentiation of pure irritative from contact allergenic potential. There were absolute no discrepancies between the categorisation of the three test substances A--C determined by each single participating laboratories. The results highlighted also that many parameters do have an impact on the strength of the responses. Therefore, such parameters have to be taken into consideration for the categorisation of compounds due to their relative sensitizing potencies.

The chemotactic signalling chain to the flagellar motor of Sinorhizobium meliloti features a new type of response regulator, CheY2. CheY2 activated by phosphorylation (CheY2-P) controls the rotary speed of the flagellar motor (instead of reversing the sense of rotation), and it is efficiently dephosphorylated by phospho-retrotransfer to the cognate kinase, CheA. Here, we report the NMR solution structures of the Mg(2+)-complex of inactive CheY2, and of activated CheY2-BeF(3), a stable analogue of CheY2-P, to an overall root mean square deviation of 0.042 nm and 0.027 nm, respectively. The 14 kDa CheY2 protein exhibits a characteristic open (alpha/beta)(5) conformation. Modification of CheY2 by BeF(3)(-) leads to large conformational changes of the protein, which are in the limits of error identical with those observed by phosphorylation of the active-centre residue Asp58. In BeF(3)-activated CheY2, the position of Thr88-OH favours the formation of a hydrogen bond with the active site, Asp58-BeF(3), similar to BeF(3)-activated CheY from Escherichia coli. In contrast to E.coli, this reorientation is not involved in a Tyr-Thr-coupling mechanism, that propagates the signal from the incoming phosphoryl group to the C-terminally located FliM-binding surface. Rather, a rearrangement of the Phe59 side-chain to interact with Ile86-Leu95-Val96 along with a displacement of alpha4 towards beta5 is stabilised in S.meliloti. The resulting, activation-induced, compact alpha4-beta5-alpha5 surface forms a unique binding domain suited for specific interaction with and signalling to a rotary motor that requires a gradual speed control. We propose that these new features of response regulator activation, compared to other two-component systems, are the key for the observed unique phosphorylation, dephosphorylation and motor control mechanisms in S.meliloti.

From 1985 to 2001 a group consisting of thirty experts including dermatologists from universities, representatives from the chemical industry and from regulatory authorities elaborated and consequently decided on the potency ranking of chemicals with contact allergenic properties. These chemicals were defined either as synthetic chemicals or as chemicals identified as ingredients in natural products. On 244 substances clinical and experimental data on humans and results of animal tests as documented in the scientific literature were carefully collected and evaluated. This careful evaluation and assessment of these chemicals clearly demonstrate that ranking of substances according to their allergenic potency is possible and justified. It was decided to rank the most potent contact allergens in Category A of substances having significant allergenic properties. Substances with a solid-based indication of a contact allergenic potential and substances with the capacity of cross-reactions were listed in Category B and substances with insignificant or questionable allergenic effects were listed in Category C. An assessment of these compiled data is published here. Three Appendices give a comprehensive overview of the 98 substances listed in Category A, the 77 substances listed in Category B and the 69 substances listed in Category C.

The European Commission has characterised and certified a set of six European soils (the EUROSOILS) under the number IRMM-443. After a successful validation and trial period with a preliminary batch it was decided to produce a new batch of certified reference materials. Part I of this paper describes the certification of adsorption coefficients for atrazine, 2,4-D and lindane in these soils. The adsorption coefficients were determined according to OECD Test Guideline 106. Additionally, the underlying principles for the value assignment process according to the GUM and their practical application to the numerical data obtained during the certification exercise according to ISO Guide 34 and 35 are discussed.

IRMM-443 re-groups a set of six European Reference Soils (EUROSOILS), which had been certified for their adsorption coefficients for atrazine, 2,4-D and lindane (Certification of the European Reference Soil Set (IRMM-443-EUROSOILS)-Part I. Adsorption coefficients for atrazine, 2,4-D and lindane. Sci Total Environ, in press). The certification of these parameters was complemented by an additional certification of pH in suspension as well by the determination of indicative values for total nitrogen, organic and total carbon content. While Part I explained the principles of the value assignment process and discussed their application to the adsorption coefficients, Part II presents the certified values for pH as well as the indicative values for N(tot), C(tot) and C(org). In addition, the assessment of uncertainty components for stability and homogeneity, which have been included in the final uncertainty budget, is discussed.

Time to revision is an important criterion describing the quality of implants in total joint surgery. Estimates of failure probabilities are required to inform a patient about the risk of suffering a reoperation. Also, regression models are used for comparing different prosthesis designs. Typically, patients dying before a revision are considered as censored for time to prosthesis failure. We argue that this technique is inadequate for estimation of failure probabilities and insufficient for comparison of different designs. We propose a new approach based on a competing risk model to account for concurrent mortality. We describe differences in the estimation of failure probabilities and in the interpretation of regression models for implant failure. Additionally, we introduce a random effects term in the regression model to account for potential dependencies in the failure times of bilaterally treated patients. The new approach is illustrated with fictitious data and data from an observational study conducted at a specialized hospital in Switzerland.

Mechanism-based enzyme inactivators (MBEIs) have unique kinetic actions that make predictions of potency, selectivity, and potential for metabolic drug interactions more complex than for competitive antagonists. We have derived a mathematical relationship that links the influence of substrate concentration and binding constant ([S] and K(m), respectively), inhibitor concentration and binding constant ([I] and K(I), respectively), and inactivation rate constant (k(inact)) to enzyme activity (v) and maximal activity (V(max)) at any time (t). The kinetic behavior of this relationship was validated in murine-macrophage cell cultures using MBEIs of nitric oxide synthase (NOS). This initial equation was also used in the derivation of a new relationship that directly links the kinetic parameters of mechanism-based inactivation to inhibitory potency at a particular time (IC((t))(50)). Using this direct relationship, we observed that the predicted rank inhibitory potency of a series of MBEIs was improved over that predicted by the K(I) parameter alone. These relationships offer a fundamental understanding of the kinetics of MBEI action and may be useful in the evaluation of these compounds during the discovery process., (Copyright 2000 Wiley-Liss, Inc.)

The binding affinity (K(I)) and inactivation rate (k(inact)) parameters of nitric oxide synthase (NOS) inhibitors are typically estimated by kinetic activity studies. Methods currently used in the estimation of these parameters frequently employ radiolabeled materials and require intensive sample preparation. We have devised a simple, reproducible, and sensitive method for the kinetic analysis of NOS activity and inhibition kinetics using chemiluminescence. We have used this method to characterize enzyme activity for purified murine macrophage nitric oxide synthase (NOS II). Using this method, we have also estimated the inhibitory parameters for a series of competitive antagonists and mechanism-based inactivators of NOS II. The estimated parameters are in agreement with those reported using other methods. We conclude that the chemiluminescence method can be used for kinetic studies of NOS activity and inhibition. This method represents a more efficient means for conducting kinetic studies of NOS inhibition., (Copyright 2000 Academic Press.)

Backbone torsional angles are a characteristic and useful parameter for the description and characterisation of protein structures determined by x-ray crystallography or NMR spectroscopy. For the comparison of an ensemble of three-dimensional structures the calculation of the statistical parameters mean and standard deviation would be very useful. However, they are not defined unambiguously for periodic quantities such as the dihedral angles. In this paper a plausible and unique definition of these parameters is introduced and a straightforward method for their calculation is given., (Copyright 1999 Academic Press.)

After reviewing general aspects and the historical development of predictive animal skin sensitization tests, the recommended tests of the OECD and EC are discussed. Background information is given on the changes which occurred in the last 2 years. From the many factors known to influence induction and challenge of contact allergy in animals, the discussion is focused on the choice of induction concentration and the vehicle. The difference of general screening strategies in Europe and the USA is presented and discussed. The paper closes with a discussion on the importance of inhouse validation of the methods used for proper prediction of the sensitizing potential of chemicals and with remarks on predictive in vitro tests.

The local lymph node assay in the mouse is a novel predictive test for the identification of contact sensitizing chemicals. The purpose of the studies described was to determine whether a similar local lymph node assay could be performed successfully in guinea pigs; currently the species of choice for assessment of sensitizing potential for regulatory purposes. Ten sensitizing chemicals (oxazolone, picryl chloride, 2,4-dinitrofluorobenzene, benzocaine, cinnamic aldehyde, 2,4,-dinitrothiocyanobenzene, p-nitrosodimethylaniline, formaldehyde, p-phenylenediamine and cyanuric chloride) and equal concentrations of sodium lauryl sulphate were examined in a guinea pig local lymph node assay. Animals received three consecutive daily applications of various concentrations of the test chemical on the dorsum of both ears. Control animals were untreated. Five days following the initiation of exposure, draining auricular lymph nodes were excised and weighed. Suspensions of lymph node cells (LNC) were prepared and cultured for 24 or 48 h and proliferation measured by incorporation of [3H]thymidine. Exposure to at least one concentration of all sensitizing chemicals, other than benzocaine, induced proliferation by draining LNC. Responses were higher at 24 h rather than 48 h. Evidence is presented that guinea pig LNC proliferation may be enhanced or maintained by addition to culture of an exogenous source of the T cell growth factor interleukin 2 (IL-2). Draining lymph node weight was increased following exposure to some sensitizing chemicals but, compared with LNC proliferation, provided a less sensitive correlate of lymph node activation. Exposure to sodium lauryl sulphate failed to induce changes in either lymph node weight of LNC proliferation. Data are compared with three-day murine local lymph node assays performed concurrently. The available information indicates that the local lymph node assay may be performed in guinea pigs.

The allergenicity of various compounds was tested by means of the optimization procedure in the guinea-pig. Results with antibiotics, preservatives, fragrance raw materials and miscellaneous contactants are reported. Their relevance is critically discussed in relation to other animal sensitization methods (Draize, Bühler, open epicutaneous and maximization tests). Predictive animal tests are compared with those used in human allergy (Shelanski & Shelanski; maximization test). The importance of animal methods entailing the use of adjuvants is underlined.

In order to determine the validity of reported alleged differences in the susceptibility of various strains of guinea pigs to the sensitizing action of known allergens, three unrelated strains of guinea pigs, namely Pirbright White, Hartley and Himalayan spotted strain, were selected. In our investigation, 3 haptens differing in their sensitization potential were used. The results showed that the sensitivity of the 3 given guinea pig strains was comparable. Furthermore, the sensitivity of a given guinea pig strain can only be determined by comparison of the sensitization reaction of several known contact allergens of various sensitizing potential.