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Christoffer Valdorff Madsen,1,2 Lars Nannestad Jørgensen,3 Bonna Leerhøy,3 Ismail Gögenur,4 Sarah Ekeloef,4 Ahmad Sajadieh,1 Helena Domínguez1,2 1Department of Cardiology, Bispebjerg-Frederiksberg Hospital, Frederiksberg, Denmark; 2Department of Biomedical Science, Copenhagen University, Copenhagen, Denmark; 3Digestive Disease Center, Bispebjerg Hospital, Copenhagen, Denmark; 4Department of Surgery, Zealand University Hospital, Køge, DenmarkCorrespondence: Helena DomínguezDepartment of Cardiology, Bispebjerg-Frederiksberg Hospital, Nordre Fasanvej 57, Frederiksberg 2000, DenmarkTel +45 38166068Fax +45 22989343Email mdom0002@regionh.dkAbstract: Postoperative atrial fibrillation (POAF) in relation to abdominal surgery can cause clinical deterioration, prolonged hospitalization, admittance to intensive care units, stroke and increased mortality. The current review focus on patients developing POAF in relation to abdominal surgery and aims to present the current knowledge on predictors of this condition. Furthermore, predictors identified in other surgical populations that may be transferable and guide future research within the field of abdominal surgery will be presented. A systematic literature search of patients undergoing abdominal surgery and developing POAF was performed on PubMed and Embase. All types of study interventions, comparators and designs were included. All studies included reported POAF as primary or secondary outcome. All peer-reviewed English full-text manuscripts regardless of publication date were included. We included five studies out of the 149 unique records identified. Age, congestive heart failure, hypertension, vascular disease and surgical approach are risk factors associated with the development of POAF. Furthermore, inflammation biomarkers, dobutamine stress echocardiography and cardiac single-photon emission computed tomography can predict POAF. Insights from other surgical cohorts reveal that other biomarkers (ie, brain natriuretic peptide (BNP) and N-terminal pro-BNP), electrocardiography and echocardiography can be used to predict POAF and may be applied in future research projects within the field of abdominal surgery. In conclusion, very scarce evidence is currently available in predicting POAF after abdominal surgery. However, predicting POAF seems possible and feasible, why the authors encourage readers to initiate new research to close the current knowledge gap and improve clinical management.Keywords: postoperative atrial fibrillation, surgery, biomarkers, electrocardiogram, echocardiography, complications

Metastatic castration resistant prostate cancer (mCRPC) is still the lethal stage for the whole spectrum of prostate cancer disease. Even though different treatment options have been introduced in the last decade with a significant survival improvement for this population, a lack of more reliable prognostic and predictive markers is still one of the main clinical challenges in management of mCRPC. The aim of this study was to investigate the correlation between Natural Killer cell activity (NKA) and both treatment effect and outcomes in patients with mCRPC treated with enzalutamide. A total of 87 patients with mCRPC treated with enzalutamide as the first line treatment were enrolled. NKA was estimated at baseline and prior to each treatment cycle. Endpoints included both treatment effect with biochemical response (BR), biochemical progression (BP) and radiological progression (RP), as well as outcome data with overall survival (OS), radiologic progression free survival (rPFS), and time to next treatment (TTT). At the time of BR, interferon-gamma (IFNγ) decreased significantly compared to levels detected at baseline (z-score = 2.33, p = 0.019). Regarding outcome data, the whole cohort was divided into four groups according to the change of IFNγ level during the first 3 cycles of enzalutamide treatment. In group 1 (n = 42) the IFNγ level remained within a normal range (≥ 250 pg/mL),while in group 2 (n = 7) it increased from an abnormal (< 250 pg/mL) to a normal level. In group 3 (n = 13) it dropped to an abnormal level, and it remained at an abnormal level during treatment in group 4 (n = 17). Patients in group 2 showed the worst prognosis with shorter both rPFS and TTT (HR 4.30, p = 0.037; and HR 6.82, p = 0.011, respectively). In this study inverse correlations between NKA and both treatment response and outcomes was observed in mCRPC patients receiving enzalutamide, suggesting an unfavourable role of NK cells in the late stage of PCa., (© 2023. Springer Nature Limited.)

Background: Secondary lymphedema is a known side effect to radiotherapy (RT), but limited information regarding prevalence and risk factors for lower limb edema (LLE) after curative radiotherapy in patients with prostate cancer (PCa) is available. This study provides a descriptive analysis of patient-reported LLE with analysis of risk factors in a cohort of patients with PCa treated with curative RT., Material and Methods: A total of 302 patients with PCa with prospective registration of patient-reported LLE (EORTC QLQ-PR25 (Question 46)) were included. Analysis of LLE was done with the calculation of prevalence rates and Kaplan-Meier statistics. Risk factors for LLE were analyzed multivariate with Cox regression analysis., Results: At a median follow-up of 15 (3-51) months, the overall crude incidence of patients reporting 'quite a bit' or 'a lot' of LLE was 49 (16.2%) and 21 (7.0%), respectively. The baseline prevalence rate of 'quite a bit' and 'a lot' of LLE was 5.0% and 0.8%, respectively. During follow-up the prevalence rate for 'quite a bit' or 'a lot' of LLE increased significantly and remained constant from 6 months where 11.5% (±1.7%) reported 'quite a bit' and 2.9% (±0.5%) reported 'very much' LLE ( p  < 0.001), respectively.Significant risk factors ( p  < 0.10) for LLE in univariate analysis included lymph node irradiation (HR:2.325), baseline Body Mass Index (BMI) (HR:1.100), Charlson Comorbidity Index (HR:1.227), Androgen Deprivation Therapy (HR:2,979), and Performance Status (HR:0.594). Only high BMI (HR:1.091) remained significant in multivariate analysis with a three-fold increase in LLE in patients with BMI ≥ 30 compared to normal weight patients., Conclusion: Severe patient-reported LLE after curative RT for PCa is rare. Significantly more patients with a high BMI report 'quite a bit' or 'very much' LLE compared to patients with a normal BMI. Obese PCa patients could be offered a rehabilitation program for early detection and management of LLE.

Following open-heart surgery, atrial fibrillation and stroke occur frequently. Left atrial appendage closure added to elective open-heart surgery could reduce the risk of ischemic stroke. We aim to examine if routine closure of the left atrial appendage in patients undergoing open-heart surgery provides long-term protection against cerebrovascular events independently of atrial fibrillation history, stroke risk, and oral anticoagulation use. Long-term follow-up of patients enrolled in the prospective, randomized, open-label, blinded evaluation trial entitled left atrial appendage closure by surgery (NCT02378116). Patients were stratified by oral anticoagulation status and randomized (1:1) to left atrial appendage closure in addition to elective open-heart surgery vs standard care. The primary composite endpoint was ischemic stroke events, transient ischemic attacks, and imaging findings of silent cerebral ischemic lesions. Two neurologists blinded for treatment assignment adjudicated cerebrovascular events. In total, 186 patients (82% males) were reviewed. At baseline, mean (standard deviation (SD)) age was68 (9) years and 13.4% (n = 25/186) had been diagnosed with atrial fibrillation. Median [interquartile range (IQR)] CHA 2 DS 2 -VASc was 3 [2,4] and 25.9% (n = 48/186) were receiving oral anticoagulants. Mean follow-up was 6.2 (2.5) years. The left atrial appendage closure group experienced fewer cerebrovascular events; intention-to-treat 11 vs 19 (P = 0.033, n = 186) and per-protocol 9 vs 17 (P = 0.186, n = 141). Left atrial appendage closure as an add-on open-heart surgery, regardless of pre-surgery atrial fibrillation and oral anticoagulation status, seems safe and may reduce cerebrovascular events in long-term follow-up. More extensive randomized clinical trials investigating left atrial appendage closure in patients without atrial fibrillation and high stroke risk are warranted., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: COVID-19 can cause cardiopulmonary involvement. Physical activity and cardiac complications can worsen prognosis, while pulmonary complications can reduce performance., Aims: To determine the prevalence and clinical implications of SARS-CoV-2 cardiopulmonary involvement in elite athletes., Methods: An observational study between 1 July 2020 and 30 June 2021 with the assessment of coronary biomarkers, electrocardiogram, echocardiography, Holter-monitoring, spirometry, and chest X-ray in Danish elite athletes showed that PCR-tested positive for SARS-CoV-2. The cohort consisted of male football players screened weekly (cohort I) and elite athletes on an international level only tested if they had symptoms, were near-contact, or participated in international competitions (cohort II). All athletes were categorized into two groups based on symptoms and duration of COVID-19: Group 1 had no cardiopulmonary symptoms and duration ≤7 days, and; Group 2 had cardiopulmonary symptoms or disease duration >7 days., Results: In total 121 athletes who tested positive for SARS-CoV-2 were investigated. Cardiac involvement was identified in 2/121 (2%) and pulmonary involvement in 15/121 (12%) participants. In group 1, 87 (72%), no athletes presented with signs of cardiac involvement, and 8 (7%) were diagnosed with radiological COVID-19-related findings or obstructive lung function. In group 2, 34 (28%), two had myocarditis (6%), and 8 (24%) were diagnosed with radiological COVID-19-related findings or obstructive lung function., Conclusions: These clinically-driven data show no signs of cardiac involvement among athletes who tested positive for SARS-CoV-2 infection without cardiopulmonary symptoms and duration <7 days. Athletes with cardiopulmonary symptoms or prolonged duration of COVID-19 display, exercise-limiting cardiopulmonary involvement., Competing Interests: None of the authors has any conflict of interest., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Autonomic imbalance reflected by higher resting heart rate and reduced parasympathetic tone may be driven by low-grade inflammation (LGI) and impaired glycemic control in type 2 diabetes mellitus (T2DM) and pre-diabetes. We examined the interaction of parasympathetic components of heart rate variability (HRV), variables of LGI, and glucose metabolism in people with T2DM, pre-diabetes, and normal glucose metabolism (NGM). We recorded HRV by Holter (48 h) in 633 community-dwelling people of whom T2DM n = 131, pre-diabetes n = 372, and NGM n = 130 and mean HbA1c of 7.2, 6.0 and 5.3%, respectively. Age was 55-75 years and all were without known cardiovascular disease except from hypertension. Fasting plasma glucose, fasting insulin, HOMA-IR, HbA1c and LGI (CRP, Interleukin-18 (IL-18), and white blood cells) were measured. Root-mean-square-of-normal-to-normal-beats (RMSSD), and proportion of normal-to-normal complexes differing by more than 50 ms (pNN50) are accepted measures of parasympathetic activity. In univariate analyses, RMSSD and pNN50 were significantly inversely correlated with level of HbA1c and CRP among people with T2DM and pre-diabetes, but not among NGM. RMSSD and pNN50 remained significantly inversely associated with level of HbA1c after adjusting for age, sex, smoking, and BMI among people with T2DM (β = - 0.22) and pre-diabetes (β = - 0.11); adjustment for LGI, HOMA-IR, and FPG did not attenuate these associations. In backward elimination models, age and level of HbA1c remained associated with RMSSD and pNN50. In people with well controlled diabetes and pre-diabetes, a lower parasympathetic activity was more related to age and HbA1c than to markers of LGI. Thus, this study shows that the driver of parasympathetic tonus may be more the level of glycemic control than inflammation in people with prediabetes and well controlled diabetes., (© 2022. The Author(s).)

Background Left atrial (LA) volumes and emptying fraction in the general population may address structural and functional aspects of atrial cardiomyopathy associated with long-term risk of ischemic stroke in the absence of atrial fibrillation or prior stroke. We investigated the association between LA volumes and function and ischemic stroke. Methods and Results In a community-based cohort, we measured LA minimal volume, LA maximal volume, and LA emptying fraction by transthoracic echocardiography. The primary end point was ischemic stroke. Participants with known atrial fibrillation or prior ischemic stroke were excluded, which resulted in 1866 participants. The mean age was 58±16 years, and 57% were women. During a median follow-up of 16.5 years (interquartile range: 11.4-16.8 years), 176 (9.4%) ischemic strokes occurred. In multivariable cause-specific regression models and competing risk models with death as a competing risk, LA emptying fraction was associated with ischemic stroke (hazard ratio [HR], 1.14 per 10% decrease [95% CI, 1.02-1.28]) and (subdistribution HR, 1.14 [95% CI, 1.01-1.29]). This association remained when adjusting for participants who developed atrial fibrillation during follow-up (HR, 1.12 per 10% decrease [95% CI, 1.00-1.26]). Indexed LA volumes were not associated with ischemic stroke in the same models. LA emptying fraction and indexed LA volumes were not associated with all-cause mortality. Conclusions Lower LA emptying fraction measured by transthoracic echocardiography was associated with future ischemic stroke independently of incident atrial fibrillation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993172.

Introduction: Atrial fibrillation (AF) management in primary care often requires a referral to cardiology clinics, which can be strenuous for frail patients. We developed " cardio-share " (CS), a new cross-sector collaboration model, to ease this process. General practitioners (GPs) can use a compact Holter monitor (C3 from Cortrium) to receive remote advice from the cardiologist. Objective: To test the feasibility and acceptability of the CS model to manage suspected AF in frail elderly patients. Methods: We used a mixed methods design, including the preparation of qualitative semistructured interviews of GPs and nurses. Results: Between MAR-2019 and FEB-2020, 54 patients were consulted through the CS model, of whom 35 underwent C3 Holter monitoring. The time from referral to a final Holter report was shortened from a mean (SD) of 117 (45) days in usual care to 30 days (13) with the CS model. Furthermore, 90% of the patients did not need to attend visits at the cardiology clinic. The GPs and nurses highlighted the ease of using the C3 monitor. Their perception was that patients were confident in the GPs' collaboration with cardiologists. Conclusions : The CS model using a C3 monitor for AF is both feasible and seems acceptable to GPs. The elapsed time from referral to the Holter report performed for the diagnosis was significantly reduced.

Background: Fabry disease (FD) is a lysosomal storage disorder resulting in systemic accumulation of globotriaosylceramide (Gb 3 ) causing multi-organ dysfunction. The audiologic involvement in FD has been neglected in previous studies; while not a lethal aspect of the disease, hearing loss can have a significantly negative impact on quality of life., Objective: To investigate hearing loss from baseline through 16 years follow-up of the Danish FD cohort and to compare audiometric data to other clinical variables., Methods: Data was collected prospectively and assessed retrospectively during a period of 16 years from 83 patients (age: 9-72 years; sex: 29 males and 54 females). 55 patients underwent treatment. Air conduction thresholds was assessed at six frequencies between 0.25 and 8 kHz bilaterally. Data was analyzed using multilinear models., Results: Mean follow-up period for patients undergoing a FD specific treatment was 7.8 years (0-12.8 years, SD 3.8 years, n  = 55). Hearing thresholds for FD patients deviated from healthy individuals at all frequencies for both sexes ( p  < 0.001). Males had more profound hearing loss than females at high frequencies (4,8 kHz) ( p  = 0.025). There was no improvement in hearing with treatment ( p  = 0.343♂, p  = 0.256♀). No associations between hearing loss and measured glomerular filtration rate, left ventricular wall thickness or cerebral white matter lesions were found. Lower plasma Gb 3 concentration correlated with better hearing ( p  = 0.046) in males., Conclusion: Our findings demonstrated significant hearing loss in FD patients compared to audiologically healthy individuals at all frequencies, and no change in hearing during treatment. Lower plasma Gb 3 concentrations correlated with better hearing in males., Competing Interests: U·F-R. has received Advisory Board honoraria from Amicus Therapeutics, Freeline Therapeutics, 10.13039/100013995Sanofi Genzyme, and Takeda, speaker honoraria from Amicus Therapeutics, 10.13039/100013995Sanofi Genzyme, and Takeda, grant support from 10.13039/100007343Shire and 10.13039/100013995Sanofi Genzyme, and is a member of the European Advisory Board of the Fabry and FollwMe Registries., (© 2022 Published by Elsevier Inc.)

Background/aim: Treatment of recurrent platinum-resistant ovarian cancer remains challenging due to the development of resistance to chemotherapy. Cabazitaxel is a new taxane that has demonstrated beneficial effect in prostate cancer patients resistant to docetaxel. Therefore, it could be anticipated to possibly also have an effect on chemotherapy resistant ovarian cancer., Patients and Methods: Twenty-six patients with chemotherapy-resistant epithelial ovarian cancer, fallopian tube or peritoneal cancer were treated with cabazitaxel at a dose of 25 mg/m 2 (on day 1 of each 3-week cycle), until progression or inacceptable toxicity, between September 2015 and April 2018. The fraction of patients without progression after three months of treatment was the primary endpoint. Prophylaxis with granulocyte colony-stimulating factor (G-CSF) was prescribed to all patients., Results: The median number of cabazitaxel infusions was 4 (range=1-18). In general, cabazitaxel was well-tolerated. The fraction of patients alive and without progression after 3 months of treatment was 54% (14/26). The response rate was 46% (12/26) according to the Gynecological Cancer Intergroup (GCIG) criteria for CA125. Partial response (PR), evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST), was found in 4/26 patients (15%). By intention-to-treat analysis, the median progression-free survival (PFS) was 3.9 months (95% CI=1.9-4.4) using the combination of CA125 or RECIST (whichever came first), while the median overall survival (OS) was 8.4 months (95% CI=5.1-11.0)., Conclusion: Cabazitaxel holds promise as a drug in recurrent platinum-resistant ovarian cancer. It demonstrated efficacy and in general, the toxicity was manageable., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Fabry disease (FD) is a lysosomal storage disorder resulting in systemic accumulation of globotriaosylceramide resulting in multi-organ dysfunction e.g. cerebral, cardiac, renal and audiologic complications. The audiologic involvement in FD has often been neglected; while not a lethal aspect of the disease, hearing loss can have a significantly negative impact on quality of life., Objectives: To investigate baseline hearing status of the Danish Fabry cohort prior to treatment, compared to sex- and age-expected hearing levels and correlating hearing to renal and cerebral findings., Material and Methods: Retrospective study of baseline hearing status of the Danish Fabry cohort (n = 83, 9-72 years). Air conduction and speech discrimination scores were assessed at 6 frequencies between 0.25-8 kHz bilaterally. Data were collected between 2001-2014 and compiled in STATA using multilinear mixed modelling for statistical evaluation., Results: Hearing thresholds at all frequencies deviated from the expected thresholds of an otologically normal cohort (p<0.001) and ranged 0.5 to 1.5 standard deviations below expected values. In total 29 males and 54 females were included. Hearing loss was more pronounced in the higher frequencies. There was a trend of association between hearing loss and measured glomerular filtration rate (mGFR) (p = 0.084). No association was present between hearing loss and albuminuria (p = 0.90), Fabry related cerebral abnormalities (p = 0.84) and cardiac left ventricular mass index, (LVMi) (p = 0.67) independent of sex. Hearing thresholds were poorer for men compared to women (p = 0.001). Sex differences were present at 0.25, 4 and 8 kHz., Conclusion: Our findings demonstrated significant hearing loss in Danish FD patients before treatment initiation, being more profound than in otologically healthy individuals at all frequencies. Additionally, we observed no association between hearing loss and LVMi, albuminuria or FD cerebral abnormalities, with a trend of association to mGFR., Synopsis: Patients with Fabrys disease have hearing loss of all frequencies and most prominently at high frequencies (4-8 kHz), with no association between the hearing loss and cerebral abnormalities, and cardiac mass but with a trend of association to measured glomerular filtration rate., Competing Interests: The authors have declared that no competing interests exist.

Background: Nephropathy is common in Fabry disease (FD). Prior studies of renal function during enzyme replacement therapy (ERT) have primarily used estimated glomerular filtration rate (eGFR). We studied the attrition of renal function in FD by measured GFR (mGFR) and urine protein excretion, and explored the influence of age., Methods: This was a long-term observational study of a nationwide, family-screened cohort of FD patients. All Danish genetically verified FD patients on ERT, without end-stage renal disease at baseline and with three or more mGFR values were included., Results: In all, 52 patients with consecutive mGFR values (n = 841) over median 7 years (range 1-13) were evaluated. Blood pressure remained normal and urine protein excretion was unchanged. Plasma globotriaosylceramide (Gb-3) levels normalized while plasma lyso-Gb-3 remained abnormal in 34% of patients. Baseline mGFR was 90 ± 3 mL/min/1.73 m2 and rate of renal function loss 0.9 ± 0.2 mL/min/1.73 m2/year. Baseline eGFR was 97 ± 5 mL/min/1.73 m2 and rate of renal function loss 0.8 ± 0.3 mL/min/1.73 m2/year. mGFR was age- adjusted to renal healthy non-FD subjects, giving a standard deviation score of -0.8 ± 0.2 with an annual slope of -0.03 ± 0.01 (P = 0.099), without differences between genders. Age grouping of age-adjusted data showed exaggerated renal function loss with age. Urine albumin-creatinine ratio (UACR) >300 mg/g was associated with faster renal function loss, independent of baseline mGFR, age and gender., Conclusions: ERT-treated FD patients did not have a faster attrition of renal function than renal healthy non-FD subjects (background population). The rate of renal function loss with age was independent of gender and predicted by high UACR. We suggest cautious interpretation of non-age-adjusted FD renal data., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Fabry disease (FD) is an X-linked, lysosomal storage disease. Mutations in the gene coding for alpha-galactosidase A lead to globotriaosylceramide (Gb-3) accumulation in lysosomes and in placenta and umbilical cord. Impact of FD and treatment with enzyme replacement (ERT) on foetal development is undisclosed.A 38-year-old primigravida with FD (G85N) is reported. She has 50% reduced alpha-galactosidase A activity and elevated plasma and urine-Gb-3. She was severely affected with ischaemic stroke at age 23, hypertension, albuminuria and moderately reduced renal function. ERT was initiated at age 23 years in 2001 and continued during spontaneous pregnancy at age 38. In third trimester she developed moderate-to-severe pre-eclampsia, successfully managed by methyldopa. Chorion villus sampling revealed a male foetus without the maternal gene mutation. Planned Caesarean section was performed without complications at gestational age week 38 + 6, delivering a healthy boy. Histopathological placental examination showed no sign of Gb-3 accumulation. Literature survey disclosed a total of 12 cases, 8 were treated with ERT during pregnancy and 5 infants inherited the family mutation. All outcomes were successful. In the six cases with available placental histopathological examination, Gb-3 accumulation was only seen on the foetal side if the foetus had the inherited mutation.In conclusion, the present case, describing the first data from a severely affected FD patient receiving ERT during pregnancy complicated by pre-eclampsia, together with all other published cases, has emphasized that ERT is safe during pregnancy and resulting in successful foetal outcome; despite this, ERT is by the health authorities advised against during pregnancy.

Purpose of Review: Stroke is the most feared complication of atrial fibrillation. To prevent stroke, left atrial appendage exclusion has been targeted, as it is the prevalent site for formation of heart thrombi during atrial fibrillation. We review the historic development of methods for exclusion of the left atrial appendage and the evidence to support its amputation during routine cardiac surgery., Recent Findings: Evidence is not yet sufficient to routinely recommend left atrial exclusion during heart surgery, despite a high prevalence of postoperative atrial fibrillation. Observational studies indicate that electrical isolation of scarring from clip or suture techniques reduces the arrhythmogenic substrate. Randomized studies comparing different methods of closure of the left atrial appendage before amputation do not exist. Such studies are therefore warranted, as well as studies that can elucidate whether amputation is superior to leaving the left atrial appendage stump. Potentially, thrombogenic remaining pouch after closure should be addressed.

Fabry disease is a rare progressive X-linked lysosomal storage disorder which leads to neuropathic pain, organ dysfunction and cerebral pathology. Few studies have investigated cognitive impairment in Fabry disease and these previous studies are difficult to compare due to heterogeneous methodological designs and small cohorts. The objective was to investigate the frequency of cognitive impairment in the Danish nationwide cohort of Fabry patients. Further, we examined if subjective cognitive complaints were associated with objective cognitive performances in this patient group. Neuropsychological tests (17 measures) and evaluation of subjective complaints with the Perceived Deficits Questionnaire (PDQ) were applied in 41 of 63 patients. According to an a priori definition, 12 patients (29.3%) were cognitively impaired. Tests tapping psychomotor speed, attention and executive functions had the highest frequency of impairment. In general, disease related variables as Mainz Severity Score Index, enzyme activity and years since onset and depression did not have a significant impact on the categorisation of patients as being cognitively impaired or non-impaired. Thus, cognitive impairment in Fabry disease does not seem to occur solely by having symptoms for many years or by having high disease burden. However, impaired neuropsychological test results were significantly more common in patients with cerebrovascular disease. Only three patients had scores in the abnormal range of the PDQ scale and subjective perceptions of cognition were not associated with cognitive performances. The levels of subjective cognitive complaints were generally very low in the studied patients demonstrating that the absence of subjective cognitive complaints does not exclude the presence of objective cognitive problems.

Objectives: In patients with Fabry disease (FD), left ventricular hypertrophy and arrhythmias are frequently observed and cardiac involvement is the leading cause of death. Long-term efficacy of enzyme replacement therapy (ERT) on cardiac involvement is unclear. We assessed and compared long-term progression of cardiac involvement according to ERT and non-ERT., Methods: We retrospectively assessed and compared long-term progression of cardiac involvement in adult patients with FD in the nationwide Danish cohort. We followed clinical signs, symptoms and findings by echocardiography, electrocardiography and Holter-monitoring., Results: We included 66 patients; 47 patients (27 women) received ERT (ERT group) and 19 patients (15 women) did not (non-ERT group). The groups were followed for a median of 8 [0-12] years and 6 [0-13] years, respectively. Comparison between ERT and non-ERT receiving patients by left ventricular mass (echocardiographic assessment) and Sokolow-Lyon voltage- and Cornell product criteria (electrocardiographic assessment) revealed no significant differences. In the ERT group, we observed no change in left ventricular mass but a decrease in Sokolow-Lyon voltage- and Cornell product criteria from baseline to follow-up; 30 mm [15-53] vs. 25 mm [3-44], p < 0.005 and 1710 mm·ms [480-3740] vs. 1520 mm·ms [550-5740], p < .05, respectively. There were no changes within the non-ERT group. During follow-up, cardiac symptoms and use of cardiovascular procedures and -medication increased significantly in the ERT group, whereas no differences were observed within the non-ERT group., Discussion: We raise concerns regarding the efficacy and benefit of ERT on cardiac involvement in Fabry disease and stress the need for further research.

Background: The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA (α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B)., Methods and Results: Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations., Conclusions: Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities., (© 2017 American Heart Association, Inc.)

Objective: YKL-40 is a proangiogenic glycoprotein that is secreted by cancer cells and inflammatory cells. The expression of YKL-40 is induced by vascular endothelial growth factor inhibition. We tested the hypothesis that low baseline plasma YKL-40 is associated with improved outcomes in patients with ovarian cancer treated with bevacizumab., Methods: One hundred forty patients with chemotherapy-refractory epithelian ovarian cancer were treated with single-agent bevacizumab 10 mg/kg every 3 weeks in a prospective trial. Plasma YKL-40 was determined by enzyme-linked immunosorbent assay before and during treatment. Both raw YKL-40 concentrations and age-corrected percentiles of normal YKL-40 level were used. Associations between plasma YKL-40 level and progression-free survival (PFS) and overall survival were tested using univariate and multivariate Cox proportional hazards models., Results: Baseline plasma YKL-40 levels were higher in patients with poor performance status, less differentiated tumors, residual disease after primary surgery, higher than the median serum CA-125 level, and higher than the median serum vascular endothelial growth factor level. Age-corrected percentile of normal plasma YKL-40 greater than the lowest quartile (Q1, 85th percentile) was associated with shorter PFS in univariate (hazard ratio, 1.83; 95% confidence interval, 1.15-2.89; P = 0.010) and multivariate analyses and shorter overall survival in univariate analysis (hazard ratio, 1.96; 95% confidence interval, 1.27-3.03; P = 0.003). Increase in plasma YKL-40 during bevacizumab treatment, with correction for baseline plasma YKL-40, was a predictor of shorter PFS. Using normal versus elevated plasma YKL-40 as a cutoff did not provide the same discriminative value., Conclusions: Low plasma YKL-40 at baseline and during treatment is associated with improved outcomes in patients with chemotherapy-refractory advanced ovarian cancer treated with single-agent bevacizumab.

Purpose: Enzyme replacement therapy (ERT) was offered from year 2001 to patients with Fabry disease. The ophthalmic experience was analysed, as part of a general 10-year status., Methods: A retrospective observational series comprising 39 patients (25 females, 14 males) closely followed by the endocrinologists, and with regular ophthalmic control. Time of inclusion was when the option of ERT was started, at age 11-60 years. Eye data (standard eye examination, including retinal imaging) were incomplete in five, due to death or non-attendance, and five patients had refused treatment., Results: Vision was normal throughout, except in two young males with total unilateral central retinal artery occlusion, prior to and during enzyme replacement, respectively. Cornea verticillata and conjunctival vessel ectasies were common. Tortuosity of retinal arterioles and venules was recorded in eight and 18 patients, respectively, and phlebopathy in 22, although generally without evidence of loss of vessel wall integrity. Systemic vascular lesions with or without loss of function were recorded for kidney (n = 23), heart (n = 17) and brain (n = 7), and an association was suggested between nephropathy and abnormal morphology of retinal vessels., Conclusions: Thirteen of 32 patients on ERT showed a reduction of corneal deposits over the study period. Abnormal ocular vessel morphology was a frequent finding. In contrast to the function loss related to systemic ischaemic lesions, we found no indication of impairment of visual parameters in 37. Compared to other Fabry series, two of 39 patients with serious unilateral occlusive retinal disease may appear a high number. The presence of retinal tortuosity is discussed, possibly reflecting haemodynamic events related to vessel wall deposits, but could also be 'constitutional', as part of the Fabry inheritance., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Aim: Treatment of multiresistant epithelial ovarian cancer (EOC) is palliative and patients who have become resistant after multiple lines of chemotherapy often have an unmet need for further and less toxic treatment. Anti-angiogenic therapy has attracted considerable attention in the treatment of EOC in combination with chemotherapy. However, only a minor subgroup will benefit from the treatment and there is an obvious need for new markers to select such patients. The purpose of this study was to investigate the effect of single-agent bevacizumab in multiresistant EOC and the importance of circulating cell-free DNA (cfDNA) in predicting treatment response., Methods: One hundred and forty-four patients with multi-resistant EOC were treated with single-agent bevacizumab 10mg/kg every three weeks. Baseline plasma samples were analysed for levels of cfDNA by real-time polymerase chain reaction (PCR)., Results: Eighteen percent responded to treatment according to CA125 and 5.6% had partial response by Response Evaluation Criteria in Solid Tumours (RECIST). Stable disease was seen in 53.5% and 48.6% of the patients by CA125 and RECIST, respectively. Median progression free survival (PFS) and overall survival (OS) were 4.2 and 6.7 months, respectively. Cell-free DNA was highly correlated to PFS (p=0.0004) and OS (p=0.005) in both univariate and multivariate analyses (PFS, hazard ratio (HR)=1.98, p=0.002; OS, HR=1.66, p=0.02), as patients with high cfDNA had a poor outcome., Conclusions: Single-agent bevacizumab treatment in multiresistant EOC appears to be a valuable treatment option with acceptable side-effects. Cell-free DNA showed independent prognostic importance in patients treated with bevacizumab and could be applied as an adjunct for treatment selection., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Anti-VEGF treatment has proven effective in recurrent ovarian cancer. However, the identification of the patients most likely to respond is still pending. It is well known that the angiogenesis is regulated by several other pro-angiogenic proteins, e.g. the platelet - derived growth factor (PDGF) system and the fibroblast growth factor (FGF) system. These other signaling pathways may remain active or become upregulated during anti-VEGF treatment.The aim of the present study was to investigate if potential changes of PDGF-BB, PDGF-AA, and FGF2 before and during bevacizumab treatment had predictive value for early progression or survival. Furthermore, we wanted to investigate the importance of serum VEGF in the same cohort., Methods: This study included 106 patients with chemotherapy-resistant epithelial ovarian cancer who were treated with single agent bevacizumab as part of a biomarker protocol. Patients were evaluated for response by the Response Evaluation Criteria In Solid Tumors (RECIST) and/ or Gynecologic Cancer Intergroup (GCIG) CA125 criteria. Serum samples were collected at baseline and prior to each treatment. FGF2, PDGF-BB, PDGF-AA were quantified simultaneously using the Luminex system, and VEGF-A was measured by ELISA. Eighty-eight baseline samples were avaliable for FGF2, PDGF-BB, PDGF-AA analysis, and 93 baseline samples for VEGF., Results: High baseline serum VEGF was related to poor overall survival. Furthermore, high serum PDGF-BB and FGF2 was of prognostic significance. None of the markers showed predictive value, neither at baseline level nor during the treatment.

Background: New biological markers with predictive or prognostic value are highly warranted in the treatment of ovarian cancer. The platelet-derived growth factor (PDGF) system and fibroblast growth factor (FGF) system are important components in tumor growth and angiogenesis., Materials and Methods: Pre-surgery peripheral blood samples were collected consecutively from 213 patients (42 with normal ovaries, 54 with benign, 21 with borderline, and 96 with malignant ovarian tumors) undergoing surgery for an untreated pelvic mass. Serum PDGF-AA, PDGF-BB, and FGF2 were quantified on a Luminex analyzer., Results: Median PDGF-AA, PDGF-BB, and FGF2 levels were higher in patients with ovarian cancer than in those with borderline tumors, and normal ovaries, and PDGF-BB and FGF2 were also higher as compared to patients with benign tumors. PDGF-AA and PDGF-BB were associated with FIGO stage and residual tumor and PDGF-BB was associated with histological subtype., Conclusion: PDGF-AA, PDGF-BB, and FGF2 are up-regulated in ovarian cancer and levels of serum PDGF-AA and PDGF-BB seem to be associated with stage and residual tumor in ovarian cancer.

Introduction. The well-documented role of the PDGF system in tumor growth and angiogenesis has prompted the development of new biological agents targeting the PDGF system. The aim of the present study was to analyze the expression of the PDGF-receptors in ovarian cancer and to investigate its relation to histopathological parameters and long-term overall survival. Methods. The immunohistochemical expression of PDGFR-α and PDGFR-β was investigated in tumor and stromal cells in 170 patients with histologically verified epithelial ovarian cancer. Results. Almost half of the tumor specimens showed high expression of PDGFR-α and PDGFR-β in tumor cells (43% and 41%) and in stromal compartments (32% and 44%). There was a significant association between high expression of PDGFR-α and high expression of PDGFR-β in both tumor and stromal cells. Coexpression of PDGFR-α and PDGFR-β in stromal cells was seen more often in serous adenocarcinomas than in nonserous adenocarcinomas. No clear correlation between PDGFR expression and longterm overall survival or clinical parameters was found. Conclusions. PDGFR-α and PDGFR-β were expressed in a subset of ovarian carcinomas but did not show significant prognostic importance in this material.