SMARCA4 ‐deficient thoracic tumours have shown poor prognosis in clinical settings. Although the optimal treatment for SMARCA4‐deficient thoracic tumours remains unclear, existing studies indicate a favourable response of these tumours to immune checkpoint inhibitors (ICIs). However, there are no reports of fatality in SMARCA4‐deficient small‐cell lung carcinoma (SCLC) with hyper‐progressive disease (HPD) upon treatment with ICIs. Herein, we report a patient with SMARCA4‐deficient SCLC who had HPD after the first ICI treatment. A 35‐year‐old man was treated with nivolumab, subsequent to cytotoxic chemotherapy. A week after nivolumab initiation, chest computed tomography revealed marked increase in pleural effusion in the right lung and chest wall dissemination of the tumour, which concur with the definition of HPD. This is the first study to report the occurrence of HPD after treatment with ICIs in a patient with SMARCA4‐deficient SCLC. Analysis of additional data is necessary to determine the optimal treatment for these patients. Herein, we report a patient with SMARCA4 ‐deficient small‐cell lung carcinoma (SCLC) who had hyper‐progressive disease (HPD) after the first immune checkpoint inhibitors (ICI) treatment. A 35‐year‐old man was treated with nivolumab, subsequent to cytotoxic chemotherapy. A week after nivolumab initiation, chest computed tomography revealed marked increase in pleural effusion in the right lung and chest wall dissemination of the tumour, which concur with the definition of HPD. This is the first study to report the occurrence of HPD after treatment with ICIs in a patient with SMARCA4‐deficient SCLC. Analysis of additional data is necessary to determine the optimal treatment for these patients. SMARCA4  is a catalytic subunit essential for the function of the switch/sucrose non‐fermentable complex that plays important roles in transcription, differentiation, and DNA repair. SMARCA4 mutations were detected in 5% of non‐small cell lung carcinoma (NSCLC) patients .Recently, SMARCA4‐deficient thoracic tumours have clinically been recognized because of its poor prognosis in clinical settings. The correlation of the loss of SMARCA4 with poor prognosis is remarkable in thoracic tumours compared with that in other tumours . Althoug3 with 63.9% neutrophils and 24.2% lymphocytes; haemoglobin, 9.2 g/dL; albumin, 3.4 g/dL; lactate dehydrogenase (LDH), 341 IU/L; calcium, 9.4 mg/dL; C‐reactive protein, 3.32 mg/dL; carcinoembryonic antigen, 122.7 ng/mL; and pro‐gastrin‐releasing peptide, 2850 pg/mL. Chest radiography and high‐resolution computed tomography (HRCT) showed a right hilar lung mass in the right upper lobe with pleural dissemination and multiple hilar, para‐tracheal and subcarinal lymphadenopathies. Fluorodeoxyglucose‐positron emission tomography with CT showed positive accumulation  in these thoracic lesions with high‐uptake lesions in multiple bones . The target lesions were decided by Response Evaluation Criteria in Solid Tumours version 1.1 (RECISTv1.1).A 35‐year‐old male current smoker (22.5 pack‐years) visited our hospital with facial oedema and persistent productive cough. Upon admission to our hospital, physical examination revealed a height of 170 cm, body weight of 51 kg, body temperature of 37.0°C, heart rate of 108 bpm, blood pressure of 107/64 mmHg, and oxygen saturation of 99% . Analysis of chest auscultation revealed attenuated respiratory sounds in the upper right lung field. The laboratory findings were as follows: white blood cells, 9000/mmEGFR, ALK, or ROS1.Pathological examinations of the right S3 lung tumour under bronchoscopic guidance revealed proliferation of small round cells focally with prominent nucleoli and larger nuclei in sheets, nests, or cords with necrotic foci. The observations such as prominent nucleoli and larger nuclei were unusual, as these were not included in the descriptions of any categories of the World Health Organization classification of NSCLC based on histological types. Thus, the observations from the present case were indicative of SCLC. Immunohistochemistry  results showed that the tumour cells were diffusely positive for thyroid transcription factor‐1 (Dako), cytokeratin markers , and synaptophysin (Dako) and negative for chromogranin A (Dako), CD56 (Leica Biosystems), nuclear protein in the testis , and SMARCA4 (Epitomics)  was used as the second‐line therapeutic regimen for. After two cycles of chemotherapy with carboplatin plus paclitaxel (protein‐bound) and palliative radiation therapy (right upper lobe: 30 Gy/10 fr and right ilium: 30 Gy/10 fr), the sites of radiotherapy showed response. However, multiple new bone metastases were evident.The subject was treated with nivolumab as a next‐line treatment. A week after initiating nivolumab, the patient appeared febrile (38–39°C) with pain in the right chest. Chest HRCT performed on day 15 after nivolumab administration showed a marked increase in pleural effusion in the right lung and chest wall dissemination of the tumour Fig. .HPD was considered to have been caused by treatment with nivolumab. The patient's Eastern Cooperative Oncology Group performance status score had rapidly deteriorated from 1 to 3, necessitating switching of the treatment regimen to docetaxel and ramucirumab. However, tumour progression was uncontrollable, and the patient died due to respiratory failure, 27 days after docetaxel and ramucirumab administration.Small cell carcinoma is a highly aggressive cancer that arises within the lung, cervix, ovary, prostate, and gastrointestinal tract. SMARCA4‐deficient small cell carcinoma of the ovary, hypercalcaemic type, which is a rare and aggressive form of ovarian cancer, is described to be oncogenically driven exclusively by inactivating mutations in SMARCA4 . HoweverIn this patient, platinum‐doublet chemotherapy was ineffective, and the nivolumab therapy caused HPD. HPD is a novel pattern of progression with an unexpected and fast progression in both tumour volume and rate. According to the RECISTv1.1, HPD is indicated by disease progression with tumour growth rate (TGR) exceeding 50% during PD‐1/PD‐L1 inhibitor therapy, and 13.8% of patients with advanced NSCLC treated with PD‐1/PD‐L1 inhibitors had advanced HPD associated with a high number of metastatic sites and poor survival [While the aetiology and pathogenesis of HPD are unclear, associations with a lower frequency of effector/memory subsets  and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD‐1+ CD8+ T cells) have been reported . In a meAlthough patients with an SMARCA4‐deficient thoracic tumour have an extremely poor survival outcome, there are some reports of patients with an SMARCA4‐deficient thoracic tumour being successfully treated with ICIs. This suggested that ICIs could be effective against SMARCA4‐deficient thoracic tumours . HoweverIn conclusion, our patient showed fatal HPD after the first nivolumab. The accumulation of further clinical information is necessary to determine the optimal treatment of SMARCA4‐deficient thoracic tumour.Appropriate written informed consent was obtained for publication of this case report and accompanying images.


Information on steroids derived from the adrenal glands, gonads, or fetoplacental unit is minimal in newborn foals.To measure androgen concentrations in serum and determine their association with disease severity and outcome in hospitalized foals.Hospitalized (n = 145) and healthy (n = 80) foals.Prospective, multicenter, cross‐sectional study. Foals of ≤3 days of age from 3 hospitals and horse farms were classified as healthy and hospitalized  based on physical exam, medical history, and laboratory findings. Serum androgen and plasma ACTH concentrations were measured with immunoassays. Data were analyzed by nonparametric methods and univariate analysis.P <  .05), were associated with nonsurvival, decreased to 4.9‐10.8%, 5.7‐31%, and 30.8‐62.8% admission values in healthy, SNS, and septic foals, respectively (P < .05), but remained unchanged or increased in nonsurviving foals. ACTH:androgen ratios were higher in septic and NMS foals (P < .05). Foals with decreased androgen clearance were more likely to die .Serum dehydroepiandrosterone (DHEA), androstenedione, testosterone, and dihydrotestosterone (DHT) concentrations were higher upon admission in hospitalized foals (Similar to glucocorticoids, mineralocorticoids, and progestagens, increased serum concentrations of androgens are associated with disease severity and adverse outcome in hospitalized newborn foals. In healthy foals, androgens decrease over time, however, remain elevated longer in septic and nonsurviving foals. Androgens could play a role in or reflect a response to disorders such as sepsis or NMS in newborn foals. CBGcortisol binding globulinCIconfidence intervalCIRCIcritical illness‐related corticosteroid insufficiencyDHEAdehydroepiandrosteroneDHEA‐Sdehydroepiandrosterone sulfateDHPdihydroprogesteroneDHTdihydrotestosteroneGABAAgamma‐aminobutyric acid (GABA) type AGABAARGABAA receptorLC/MSliquid chromatography mass spectrometryNMDAN‐methyl‐D‐aspartateNMDARNMDA receptorNMSneonatal maladjustment syndromeORodds ratioRAIrelative adrenal insufficiencySHBGsex steroid binding globulinSNSsick nonseptic1Sepsis remains the leading cause of death in newborn foals.Pregnenolone and dehydroepiandrosterone (DHEA) are the main steroid precursors in the equine fetus and their source are the fetal gonads and adrenal glands.Cortisol, aldosterone, progestogens, and DHEA concentrations are elevated in sick foals and linked to disease severity,Progestogens are neuroprotective and could play a role in the pathogenesis of equine neonatal maladjustment syndrome (NMS).A and N‐methyl‐D‐aspartate receptors (NMDAR).DHEA and androstenedione are the main androgen precursors found in circulation of pregnant mares and foals, whereas testosterone and dihydrotestosterone  are considered the most active androgenic metabolites. They modulate GABAIn this study, we aimed to investigate androgens in healthy and sick neonatal foals over time and to determine their association with severity of disease and outcome. The ACTH to androgen relationship (ACTH:androgen ratios) were also investigated. We hypothesized that septic foals will have higher serum androgen concentrations that will remain elevated longer than in sick nonseptic (SNS) and healthy foals. We also proposed that steroid elevation would be associated with likelihood of death.22.1A total of 225 newborn foals ≤3 days of age of any breed and sex from the 2017‐2019 foaling seasons were included in this prospective study. Hospitalized foals (n = 145) were admitted to 3 equine referral hospitals (masked for review), whereas healthy foals (n = 80) were evaluated at the farm or hospitals.Hospitalized foals with a positive blood culture or a sepsis score ≥12 were considered septic (n = 81),Foals ≤3 days of age with normal physical examination, CBC, serum biochemistry profile, serum immunoglobulin G >800 mg/dL, and sepsis scores <4 were classified as healthy. Foals were also classified into NMS (n = 63) or sick non‐NMS (n = 82) groups based on clinical diagnosis.This study was approved by (masked for review) and adhered to the principles of humane treatment of animals in veterinary research, as stated by the American College of Veterinary Internal Medicine and the National Institutes of Health Guidelines.2.2g for 10 minutes, aliquoted and stored at −80°C until analysis.Blood samples from hospitalized foals were collected upon admission (0 hour) and at 24, 48, and 72 hours after admission. Blood from healthy foals were collected during their routine newborn foal examination at 18 to 30 hours of age (time 0) and 24, 48, and 72 hours later. Blood samples were collected into serum clot and EDTA‐aprotinin tubes, centrifuged at 20002.3Radioimmunoassays were used to measure serum concentrations of DHEA , testosterone , and androstenedione . Serum concentrations of DHT were measured using an ELISA . All assays measured total concentrations and had ≤6% cross‐reactivity to other androgens. These assays showed linearity for equine serum samples at dilutions up to 1:8 and had intra‐ and interassay coefficients of variation of <10%. Plasma ACTH concentrations were determined using a human‐specific immunochemiluminometric assay previously validated for equine samples .2.4U test. Proportions were compared with the Chi‐square test. Comparison of hormone changes over time was carried out with the Friedman's test. Sick foals were categorized as having low, high, and within normal hormone concentrations by using 95% confidence interval (CI) values from healthy foals as cutoff points.Data were assessed for normality using the Shapiro‐Wilk test and found to be not normally distributed. Therefore, results are presented as medians, interquartile ranges, and 95% ranges. Comparisons among 3 groups  were performed using the Kruskal‐Wallis ANOVA with Dunn's post hoc analysis. Comparisons between 2 groups  were done with the Mann‐Whitney 0‐24, Δ24‐48, Δ48‐72, Δ0‐72) were calculated by subtracting the later time from the earlier time concentration. Therefore, foals with decreases in serum androgen concentrations over time will have Δ values >0, whereas foals with increases or no changes in serum androgen concentrations over time will have Δ values ≤0. In addition, androgen percentage changes for each group at 24, 48, and 72 hours were calculated relative to time zero. ACTH:androgen ratios were calculated by dividing the plasma ACTH concentration by its matching androgen concentration at a given time point.Based on previous studies showing that serum progestogen and androgen concentrations are high in healthy newborn foals, and decrease steadily a few days after birth,P < .05.Univariate logistical regression and crude odds ratios (OR) for nonsurvival were determined. The referent was the high‐end of the healthy foal 95% CI. Statistical and graphical software used included IBM SPSS 26 , GraphPad Prism 8 , and SigmaPlot 14.0 . Significance was set at 33.1P = .20). Healthy foals (n = 80) comprised 45 fillies, 25 colts, and 10 unknowns. Hospitalized foals comprised 58 fillies, 80 colts, and 7 unknowns. The proportion of colts to fillies was higher in hospitalized than in healthy foals (P = .0005). The median age at first sampling for healthy foals was 24 hours (1‐72 hours) and for hospitalized foals was 9 hours (1‐72 hours), which were not statistically different (P = .22). Hormone concentrations between sex within groups were not statistically different.Of the hospitalized foals (n = 145), 55.8% (81/145) were septic and 44.2% (64/145) were SNS. In addition, 43.4% (63/145) and 56.6% (82/145) of the hospitalized foals were classified as NMS and sick non‐NMS, respectively. Blood culture was performed in 69 septic foals, of which 63.8% (44/69) were positive. Within NMS foals, 61.9% (39/63) were septic and 38.1% (24/63) were SNS foals. In the sick non‐NMS group, 51.2% (42/82) were septic and 48.8% (40/82) SNS foals. Proportions of septic and SNS foals between NMS and sick non‐NMS were not statistically different , Standardbreds (n = 19), American Paint Horses (n = 2), and Quarter Horse (n = 1). Hospitalized foals included Thoroughbreds (n = 121), Standardbreds (n = 9), Quarter Horses (n = 5), Saddlebreds (n = 5), Belgians (n = 2), Warmbloods (n = 2), American Paint Horse (n = 1), and Arabian (n = 1).P < .01). Sixty‐two (74.6%) sick non‐NMS and 47 (75.8%) NMS foals survived, and this proportion was not statistically different (P = .91). Of the 36 nonsurviving foals, 27.8% (10/36) died between admission and 24 hours, 19.4% (7/36) between 24‐48 hours, and 11.1% (4/36) between 48‐72 hours.The survival rate in hospitalized foals was 75.2% (109/145). Forty‐nine (61.2%) septic and 60 (93.7%) SNS foals survived, and this proportion was statistically different (3.2P = .02). NMS foals had higher DHEA concentrations than sick non‐NMS foals at all time points (P < .003) and healthy foals at 0, 24, and 72 hours . Nonsurviving foals had higher DHEA at 24 and 48 hours than surviving foals . Apart from nonsurviving foals, DHEA concentrations decreased over time among all foal groups .Serum DHEA concentrations were not significantly different at admission, 24, or 48 hours among healthy, SNS, and septic foals. However, at 72 hours, septic foals had a significantly higher DHEA compared to healthy foals Figure ; P = .02s Figure ; P < .05P < .01). Androstenedione concentrations did not differ between surviving and nonsurviving foals at admission, but were higher in nonsurviving foals at later time points . Excluding nonsurviving foals, androstenedione concentrations decreased over time among all foal groups .Serum androstenedione concentrations were higher at all time points in septic and NMS compared to healthy and sick non‐NMS foals Figures ; P < .01s Figure ; P < .01 Figures ; P < .05P < .05). Serum testosterone concentrations decreased over time in healthy, SNS, sick non‐NMS and septic foals , but remained elevated in NMS and nonsurviving foals .Serum testosterone concentrations were higher in septic compared to SNS foals at admission and 72 hours Figure ; P < .05 Figures ; P < .05 Figures  and 2. SP = .009). Nonsurviving foals had higher serum DHT concentrations than survivors at 24 hours . Serum DHT concentrations decreased over time in healthy, SNS, and sick non‐NMS foals (P < .05), but did not in septic, NMS, and nonsurviving foals  than healthy foals (Supplementary Table P < .05). Clearance among healthy foals was significantly greater at earlier time points (Δ0‐24 vs Δ24‐48), whereas septic foals had higher DHEA clearance at later time points (Δ24‐48 vs Δ0‐24) (Supplementary Table P < .03). Nonsurviving foals had decreased DHEA clearance (Δ0‐24) . Median percentage DHEA concentrations from baseline to 72 hours decreased to 8% to 84% among healthy, SNS, septic, sick non‐NMS, NMS, and surviving foals, but increased to 207% in nonsurviving foals .Septic foals had less DHEA clearance Δ0‐2 than heas Figure ; P < .050‐24) was significantly lower in septic foals than healthy foals (Supplementary Table P < .05). Androstenedione clearance in SNS foals was greater at earlier time points (Supplementary Table P < .05). The androstenedione clearance  was significantly lower in nonsurviving than surviving foals . From baseline to 72 hours, the median percentage change in androstenedione concentrations decreased to 20% to 55% among healthy, SNS, septic, sick non‐NMS, NMS, surviving foals, but increased to 136% in nonsurviving foals .Serum androstenedione clearance Δ0‐2 was signs Figure ; P < .05P < .02). Nonsurviving foals had lower testosterone clearance  than surviving foals . The median percentage change in testosterone concentrations decreased from baseline to 72 hours to 18% to 44% in healthy, SNS, septic, sick non‐NMS, NMS, and surviving foals whereas in nonsurviving foals increased to 195% .Serum testosterone clearance did not differ between healthy and septic foals, but did between septic and SNS foals  was lower in septic than healthy foals (Supplementary Table P < .05). Clearance in healthy foals was higher at earlier time points (Supplementary Table P < .01). Serum DHT clearance (Δ0‐24) was significantly lower in nonsurvivors compared to survivors . From baseline to 72 hours, median percentage DHT concentrations decreased to 9% to 53% among healthy, SNS, sick non‐NMS and surviving foals, with minimal changes in septic and NMS foals, but increased in nonsurviving foals to 257% .Serum DHT clearance Δ0‐2 was lowe% Figure ; P < .053.4P < .001). Plasma ACTH concentrations were not different when comparing healthy to SNS and sick non‐NMS foals at any time point. Plasma ACTH concentrations were not different in surviving and nonsurviving foals at admission or 48 hours, but were higher in nonsurvivors at 24 hours (P = .04). Over time, ACTH concentrations decreased in NMS foals (Supplementary Table P = .007), but did not change significantly in other groups. ACTH concentrations decreased in all hospitalized foals, but were not statistically different than time 0.Plasma ACTH concentrations at admission were higher in septic and NMS than healthy foals (Supplementary Table P < .01). The ACTH:DHEA ratio increased over time in healthy foals (P = .002), whereas no change was seen among other groups.The ACTH:androgen ratios are listed in Supplementary Table P = .03). Healthy foals experienced a significant increase from admission to 48 hours (P < .01). SNS and NMS foals had a significant decrease in the ACTH:androstenedione ratio from 0 to 24 hours (P < .04).The ACTH:androstenedione ratio was not different among foal groups upon admission. However, the ratio was significantly lower in NMS compared to healthy foals at 48 hours (P < .02), but not in SNS or sick non‐NMS foals. NMS foals had significantly higher ACTH:testosterone ratios at admission compared to 24 and 48 hours (P < .05).The ACTH:testosterone ratio was significantly higher in septic and NMS compared to healthy foals upon admission (P = .02). NMS foals had a significantly lower ACTH:DHT ratios at 24 hours than at admission (P < .05).At admission, the ACTH:DHT ratio was higher in septic and NMS compared to healthy foals . Hospitalized foals with serum testosterone concentrations >12.31 ng/mL at admission and >5 ng/mL at 72 hours were >3 times more likely to die (Table P < .05). Foals with serum DHT concentrations >680 pg/mL at 72 hours were >3.6 times more likely to die (Table P = .04). Androstenedione concentrations were not associated with mortality at any time point.Results of univariate analysis for survival are listed in Table 0‐24 values ≤0  for DHEA, androstenedione, and DHT were >4 times more likely to die (Table P < .05). In addition, foals with a Δ24‐48 ≤ 0 for androstenedione and DHT, a Δ48‐72 ≤ 0 for DHT, and a Δ0‐72 ≤ 0 for androstenedione and DHT had a >3.3 times higher chance of mortality (Table P < .05).Table 4This study shows that increased serum androgen concentrations, similar to progestogens, are associated with disease severity and outcome in hospitalized neonatal foals. Healthy foals showed a steady decrease in serum androgen concentrations over the study period that was not evident in severely affected or nonsurviving foals. These results indicate that steroid dynamics in the immediate postpartum period are linked to organ function and viability, which have clinical and prognostic implications.Progestogens, androgens, and estrogens play key roles in pregnancy establishment, maintenance and termination, as well as fetal tissue differentiation and maturation.Steroid concentrations in the newborn foal reflect placental as well as fetal adrenocortical and gonadal steroidogenic activity.The delayed decrease in serum androgen concentrations, which was more evident in critically ill and nonsurviving foals, suggests that impaired clearance rather than increased secretion is central to these abnormal steroid patterns. These findings could be reflecting a combination of impaired hepatic processing, altered protein binding, and reduced renal excretion. We speculate that impaired steroid metabolism and excretion are the main reasons because concentrations and time to decrease for most androgens were associated with disease severity. Pathologic processes specific to steroid metabolism in foals remain to be investigated. Hepatic or renal dysfunction leading to failure to metabolize or excrete steroids was proposed as potential explanations for increased progestogens in premature foals.In this study, we used delta values to evaluate the dynamics of androgen concentrations in blood because they are easy to calculate, can be generated with 2 time points, and provide information in short time segments. We also calculated percentage changes to adjust concentrations to baseline values to facilitate result interpretation. Calculation of steroid half‐lives could have been an alternative method to evaluate clearance. However, around half of nonsurviving foals did not live beyond 2 sampling points and a quarter did not have delta values because of mortality after initial sampling. Thus, determination of half‐lives would have been challenging because this calculation requires 3 or more time points and steroid half‐lives may have been biased to foals that lived longer. Based on the higher delta values and percentage change from baseline in critically ill compared to healthy foals, one would predict that that the sicker foals would have longer steroid half‐lives.Recent work found that cortisol and progesterone concentrations remained elevated in sick foals born to mares with experimental placentitis.Another question that remains unanswered is what are the consequences of increased serum androgen concentrations in the sick equine neonate. In our study, elevated androgen concentrations were associated with nonsurvival, which could potentially contribute to disease progression since androgens have immunosuppressive effects. Testosterone suppresses T‐cell immune response via IL‐10 and TGF‐β.Because of their lipophilic nature, the majority of steroids in circulation are bound to transport proteins. Cortisol circulates free and bound to cortisol binding globulin (CBG) and albumin. Critically ill foals have increased cortisol concentrations,A receptor agonists, DHEA is an antagonist,A inhibitor than DHEA.In our study, serum androgen concentrations were higher in NMS compared to healthy and sick non‐NMS foals, which is a pattern similar to progestogens.Testosterone has pro‐ or anticonvulsant effects, which are attributable to its metabolism to other androgens or aromatization to estrogens.Elevated ACTH concentrations could have increased androgen concentrations in the sick foals of this study. However, that seems less likely based on differing longitudinal changes in ACTH and androgen concentrations between healthy and sick foals. Similar to a previous study,The ACTH:cortisol is a practical tool that has been used to assess hypothalamic‐pituitary‐adrenal axis activity and adrenocortical insufficiency (RAI/CIRCI) in hospitalized foals.One potential limitation of this study was the use of the sepsis score to categorize foals, which is known to have poor sensitivity and predictive value.5Authors declare no conflict of interest.Authors declare no off‐label use of antimicrobials.Approved by The Ohio State University IACUC. This was not an interventional study. Blood samples collected from healthy and sick foals were collected with owner consent.Authors declare human ethics approval was not needed for this study.Supplementary Table 1 Androgen and ACTH concentrations in healthy and hospitalized foals over time. Data expressed as medians and ranges.Supplementary Table 2: Androgen concentrations in surviving and non‐surviving foals over time. Data expressed as medians and ranges.Supplementary Table 3: Androgen delta values in healthy, SNS, and septic foals. . Data expressed as medians and ranges.Supplementary Table 4: Androgen delta values in surviving and non‐surviving foals. Data expressed as medians and ranges.Supplementary Table 5: ACTH:androgen ratios in healthy and hospitalized foals over time. Data expressed as median and ranges.Click here for additional data file.


Intraperitoneal/intravenous chemotherapy (IP/IV) was associated with improved survival for ovarian cancer (OC) patients in several randomized clinical trials. However, the uptake of IP/IV in clinical practice is varied due to conflicting evidence about its impact on survival and recurrence. The aim of this study was to explore the uptake of IP/IV treatment and to evaluate its impact on survival and recurrence in OC patients.Demographic and clinical information on OC patients (N = 2916) who underwent treatment for OC between 2000 and 2017 was obtained from the large healthcare system cancer registry. Duplicate records, grade 1, rare , and non‐epithelial  tumors were excluded. Kaplan‐Meier survival curves were constructed to compare 5‐ and 10‐year survival based on the chemotherapy type, surgery type, and stage. Multivariable Gray's piecewise constant time‐varying coefficient models were fitted to evaluate the effect of IP/IV on adjusted hazard ratio (AHR) of OC survival and recurrence adjusting for potential confounders.P < .001). Multivariable Gray's model demonstrated that IP/IV therapy significantly reduced the AHR of death  with the beneficial effect gradually declining over time. Use of IP/IV chemotherapy had no impact on OC recurrence.The final sample consisted of 1846 OC patients, 14% (250/1846) of which received IP/IV chemotherapy. IP/IV was significantly associated with improved 10‐year survival (These findings demonstrated that only a small fraction of eligible patients underwent IP/IV chemotherapy. We report a significant 10‐year survival, but not necessarily recurrence benefit is associated with IP/IV chemotherapy compared to IV only, suggesting the need for novel ways of identifying patients who may benefit from IP/IV chemotherapy. Only one of seven eligible patients underwent intraperitoneal chemotherapy in our large heterogenous health system. Intraperitoneal chemotherapy use has been associated with improved 10‐year survival, but not necessarily recurrence benefit compared to intravenous chemotherapy. In addition, we analyzed factors associated with OC survivorship and recurrence. In this study, we provide valuable additional information to practitioners, patients, and policy makers by improving our understanding of IP/IV effectiveness and treatment outcomes in the real‐world clinical population not driven by clinical trial restrictions.22.1The hospital Registry Information Services is a cancer registry designed for the collection, management, and analysis of patient demographic, grading, staging, treatment, and progression data on cancer patients. American Joint Commission on Cancer (AJCC TNM) and Surveillance, Epidemiology, and End Results (SEER) General Summary are used for cancer staging. The Registry Information Services is architected on the North American Association of Central Cancer Registries (NAACCR) data standard. The primary sources for documentation are both paper and electronic medical records, from which data are abstracted into the cancer registry by certified cancer registrars.The data for our study was abstracted from the Registry Information Services for all women with confirmed OC who underwent treatment between 2000 and 2017 using honest broker service system. The exclusion criteria were as follows: duplicate records; women not eligible for IP/IV therapy, including grade 1, rare , and non‐epithelial ; and patients with unknown chemotherapy status. Our study was approved by the university's Human Research Protection Office through the exempt study protocol.2.2The independent variables used in our analyses were as follows: demographic and lifestyle factors ; tumor ; surgery type ; histology ; and chemotherapy type (IP/IV and IV only). We also extracted information on the primary treatment facility where each patient received most of her treatment .2.3Our outcomes of interest were overall survival defined as time from diagnosis to death and recurrence defined as time from diagnosis to recurrence, censoring for death. Both outcomes were censored at last follow‐up in the absence of an event, time was expressed in months. Vital status was confirmed by the National Death Index.2.4Analyses were performed on a cohort of patients eligible for IP/IV chemotherapy (n = 1846) to compare survival and recurrence among IP/IV treated patients in comparison to IV only patients. Descriptive statistics were performed using two‐sample t‐test for continuous variables and Fisher exact test or Chi‐squared test for categorical variables, as appropriate. Univariable comparison of 1‐year survival across groups was done using Kaplan‐Meier curves with log‐rank test or Peto‐Peto‐Prentice tests used for statistical significance, as appropriate.Two outcomes were assessed in univariable and multivariable analyses: (i) overall survival (OS), defined as time from diagnosis to death; and (ii) recurrence‐free interval (RFI), defined as time from diagnosis to recurrence, censoring for death. Both outcomes were censored at last follow‐up in the absence of an event. Univariable and multivariable Gray's piecewise constant time‐varying coefficient (TVC) models were used instead of Cox regression analysis when proportional hazard assumption was violated, which occurred for several risk factors, including treatment type (IP/IV vs IV only). Unlike Cox regression, Gray's TVC models allow for time‐varying hazard ratio (HR), which provides assessment of the HR between groups (eg IP/IV and IV only) of patients when the proportional hazards assumption required for Cox regression does not hold, ie the HR is not constant over time.P value less than or equal to 0.10. We used the same final set of covariates to refit the data using Gray's model to achieve the estimates of adjusted hazard ratio (AHR) for these covariates. In all cases, if the HR varied over time for a given variable, the results are presented using the range (minimum – maximum) of HR, otherwise a constant HR is presented. All data management and data analyses were implemented in SAS version 9.4  and R version 3.5.1.In the univariable analysis, each potential covariate was individually fitted using Gray's model with 4 degrees of freedom as was suggested by Gray.3Between 2000 and 2017, all of the patients with OC (n = 2916) who underwent treatment at large hospital system facilities were identified through the cancer registry. Duplicated records (n = 285), non‐epithelial and rare cancers (n = 105), non‐chemotherapy or unknown chemotherapy status (n = 564), and tumor grade 1 (n = 116) were excluded to a final sample size of 1846 , though the effect decreased with time  differed across cancer stages, with 77% 10‐year survival for stage 1 OC compared to 49% for stage 2 OC, 15% for stage 3 OC, and 5% for stage 4 OC  women received IP/IV chemotherapy. Patients treated with IP/IV chemotherapy had significantly better 10‐year survival pattern compared to IV only patients  Figure . SurvivaC Figure .P = .082), with 41% and 53% 10‐year recurrence free rate for the IP/IV and IV only chemotherapy groups respectively , such that recurrence free percentage at 10 years were 40%, 65%, and 73% for advanced debulking, hysterectomy, oophorectomy, and other surgery groups respectively  different between OC stages with 83% recurrence free for stage 1 OC, 60% for stage 2 OC, 32% for stage 3 OC, and 42% for stage 4 OC , as well as other potential confounders for OC survival including age at diagnosis , surgery type ,tobacco use , histology , and cancer stage  were significantly associated with survival with the beneficial effect being largest right after the chemotherapy, but gradually declining , as well as hysterectomy and oophorectomy , were significantly associated with reduced hazard of death compared to other surgeries with the effect significantly decreasing in the following 2 years , histology , and higher stage  significantly increased the hazard of death for OC patients.The final multivariable Gray's model for survival included IP/IV therapy, age at diagnosis, surgery type, and stage. IP/IV therapy, surgery type, and stage violated proportional assumption Figure , and theg Figure . AdvanceP = .052) (Table P = .003), race , BMI , surgery type , histology , and cancer stage .Time‐varying HRs for univariable Gray's model for recurrence are presented in Figure 2) Table . FactorsP = .020), histology , and higher stage  significantly increased the hazard of recurrence for OC patients after adjusting for other confounding variables  patients eligible for IP/IV received this chemotherapy in specialized hospitals, despite the NCI Clinical Announcement of survival benefit of IP/IV chemotherapy. Use of IP/IV chemotherapy has not been universally implemented, likely due to excessive toxicity, inpatient infusion of paclitaxel, and/or intraperitoneal port complications. Less than half of patients eligible for IP/IV chemotherapy were receiving it, which has resulted in the development of modified GOG 172 and outpatient regimens with similar retrospective outcomes.In our cohort, IP/IV patients were younger and had lower stage, which is corroborated by a previous report,P < .001), which was similar to what was reported in GOG‐114 P = .01).The 5‐year survival rates observed in this study were higher for IP/IV treated patients compared to the national average of 48% reported by SEER, while the 5‐year survival for IV only treated patients was lower.One of the strengths of this study was its ability to evaluate survival outcomes in OC patients treated at a large heterogeneous healthcare system representing an entire regional cancer network. The size of the system allowed for the comparison of survival advantage between hospitals with possible structural barriers to IP/IV use (no trained staff and resources) and large specialty hospitals without structural barriers to offering IP/IV therapy. The strengths of this study also include large sample size, inclusion of all eligible OC patients treated in a large healthcare system for 17 years, and the focus on a patient population that was not necessarily captured by previous research. Additionally, very few existing publications on OC survival had such a long follow‐up period.This study had some limitations. As with any registry based research, data quality, reporting of the same cases by more than one facility, missing data, and type I errors can become potential problems associated with the interpretation of the results obtained with registry data.This nearly 20‐year data from a large healthcare system demonstrates that IP/IV delivery of chemotherapy provides a survival benefit to OC patients. Our analysis is based on the community level data that is similar to the original randomized control trials. Toxicity, catheter related complications, and increased use of neoadjuvant chemotherapy are potentials reasons explaining why so few patients received IP/IV chemotherapy in our cohort. While GOG 252 did not show benefits of IP/IV due to several issues that limited the interpretation of the trial's data, the current study adds to the understanding that IP/IV therapy should remain an option for selected patients. Regional delivery of IP/IV chemotherapy has consistently been shown to improve survival, although its use is limited by adverse side effects, need for specialized facilities, and lack of acceptance by physicians. Despite the survival advantage, utilization of traditional IP/IV utilization failed to become widely implemented and its use is decreasing. The accumulated retrospective and randomized data of heated intraperitoneal chemotherapy (HIPEC)The authors report no conflict of interest.Shalkar Adambekov: Methodology, formal analysis, writing ‐ original draft, investigation, validation. Samia Lopa: Methodology, formal analysis, writing ‐ review & editing. Robert P. Edwards: Conceptualization, investigation, writing ‐ review & editing, validation. Lara Lemon: Investigation, writing ‐ review & editing, validation. Shu Wang: Methodology, formal analysis, writing ‐ review & editing. Sarah E. Taylor: Investigation, writing ‐ review & editing, validation. Brian Orr: Conceptualization, investigation, writing ‐ review & editing, validation. Faina Linkov: Conceptualization, validation, resources, writing ‐ review & editing, project administration.Fig S1Click here for additional data file.Fig S2Click here for additional data file.


High dose LT4 or LT4/paracetamol absorption test is used in such cases. Hence, establishment of an optimal test protocol and timing of sample collection is of utmost importance.Levothyroxine (LT4) 0.13 ng/dl (ref. range 0.93–1.7)] despite apparently taking 1000 μg of LT4 a day. Autoimmune hypothyroidism had been diagnosed 4 years before during post-partum thyroiditis. Subsequently, it was not possible to control her hypothyroidism despite several admissions to two University Hospitals and despite vehement denial of compliance problems. There was no evidence of coeliac disease or other malabsorption problems, though gluten-free and lactose-free diet was empirically instigated without success. A combined paracetamol (1000 mg)/LT4 (1000 μg) absorption test was performed in one of these Hospitals. This showed good paracetamol absorption (from < 2 μg/ml to 14.11 μg/ml at 120 min), with inadequate LT4 absorption (FT4 increase from 5.95 pmol/l to 9.92 pmol/l at 0 and 120 min respectively). About 2 years prior to admission to our Department the patient was treated with escalating doses of levothyroxine [up to 3000 μg of T4 and 40 μg of triiodothyronine (T3) daily] without significant impact on TSH .A 34-year old woman was admitted to our Department because of severe hypothyroidism [on admission thyrotropin (TSH) > 100 μIU/ml, free thyroxine  is the key for successful implementation of LT Furthermore, such cases are also characterised by poor attendance for follow-up appointments, by some patients, once poor-adherence to medication is mentioned  despite apparently taking 1000 μg of LT4 a day. Her skin was dry and ankle reflexes were markedly delayed. She seemed, however, to be very well adopted to her hypothyroid state, blood pressure was 116/74 mmHg, heart rate 70 beats/minute, with a history of only 3 kg weight gain over 2 year period. Her periods were heavy and mildly irregular (every 34–45 days). Interestingly, no third party was authorised by the patient to be informed about her medical condition, even though she admitted that she was living with a partner. As an initial part of investigation we performed serial TSH dilution test, in order to rule out possible assay interference  LT4 absorption tests was performed. She received crushed tablets of standard LT4 preparation (Euthyrox N®), with a lactose-containing base. The test was, however, performed under strict supervision. In particular, the patient was told to remain for an entire duration of the test in the room, where endocrine dynamic tests are performed in our Department. Blood samples were taken every 30 min. Several nurses and other patients undergoing dynamic tests of pituitary function (such as glucagon stimulation test) were also present in the same room.Taking into account that she had been apparently taking 1000 μg of LT4 absorption test revealed an excellent absorption of LT4, with FT4 concentrations surpassing upper limit of FT4 reference range at 60 min and reaching concentrations about 25 times above the baseline FT4 concentration at 120 min of the test  with iron deficiency, standard gastroscopy with duodenal biopsies was performed. This showed evidence of Helicobacter pylori infection, but failed to demonstrate any histological evidence of villous atrophy  .4 (Euthyrox N®) 200 μg/day (still a high dose of about 3.5 μg/kg of body weight), as well as Helicobacter pylori eradication course, with an outpatient check-up of thyroid function after 4–5 weeks. We also suggested a possibility of supervised weekly ingestion of 1400 μg of LT4 once a week, with possible further decrease of the dose to about 1.6 μg/kg/day (~ 90–100 μg/day) in the outpatient setting, depending on her TSH and fT4 concentrations.The patient was subsequently informed that we had managed to overcome her “absorption problems”. In such circumstances she discharged herself against medical advice. She declined any psychological or psychiatric consultation. We suggested LT4 pseudomalabsorption due to do non-compliance linked with manipulative behaviour. This psychiatric disorder, known as factitious disorder, is characterised by lying, sometimes involving the use of aliases, multiple hospital admissions without specific reasons, and extensive knowledge of medical symptomatology [Our study demonstrates a case of severe and prolonged LTmatology , 11. Thematology  suggests4 treatment, a LT4 absorption test may be used [4 are typically observed about 120 min after test dose [4 may be observed as soon as between 60 and 90 min after the test dose. It is not entirely clear what extent of FT4 increase should be considered an adequate response during LT4 absorption test. Soares et al. [In such cases, if associated with non-adherence to LT be used , 11, 13.est dose , though s et al.  suggest s et al. .4 despite evidence of rather poor absorption during previous LT4 absorption tests performed in other institutions. In one of these tests quite good absorption of paracetamol was observed despite rather inadequate absorption of LT4  (Table ). Prolonged ingestion of such high doses of LT4 might have been potentially very dangerous, if the patient had suddenly decided to follow the prescribed regimen.In our case, we have documented, however, an excellent absorption of LTLT4 Fig. . This has) Table . Prolong4 and paracetamol (i.e. a combined LT4/paracetamol absorption test) was suggested as a good method to check for LT4 malabsorption [max) is about 1.58 h for standard tablets, but it decreases to as much as 0.42 h (about 25 min), if co-administered with bicarbonate [It should be noted that paracetamol absorption test has widely been validated as a marker of gastric emptying , while csorption . It is narbonate . Indeed arbonate  suggests4 and paracetamol concentrations were performed rather late, i.e. 2 h after ingestion of test doses. In our opinion, such timing impeded adequate supervision of the patient during the crucial absorption period (i.e. the first hour after tablet ingestion). In such cases a possibility of a manipulative behaviour must be always suspected. Notably, in a study by Thynne and Doogue [In our case, the first assessment of FTd Doogue  sampling4 that is absorbed more slowly. This, in turn could result in misleading test result.In our case there is a strong suspicion that the patient had not been supervised correctly, i.e. she was likely to swallow the tablets in a supervised manner, but must have been subsequently left unsupervised till the first blood sampling (i.e. after 120 min). There is a possibility that if subsequently she had managed to provoke vomiting, e.g. 20–25 min after the test dose, then most of the paracetamol dose might have been already absorbed, in contrast to LT4, when the patient was prevented from leaving the area, where blood samples were being collected at 30 min intervals. She was instructed that all patients who require frequent blood testing, e.g. during dynamic tests for pituitary function, had to remain in the nurse-supervised Endocrine Dynamic Test Room for the entire duration of the test. Importantly, she was aware that such procedure was not “designed” particularly for her, as other patients were also present. As a result of such approach, we have managed to ensure an adequate patient supervision and clearly demonstrated normal absorption of LT4. In such circumstances we have also demonstrated that there is no need to co-administer paracetamol. Furthermore, paracetamol absorption test without adequate supervision may be indeed misleading. In our case, though the patient discharged herself against medical advice, the diagnosis of deliberate non-compliance with medication regimen was established and her General Practitioner was informed about the outcome of our investigations. Furthermore, we offered a possibility of a supervised ingestion of her LT4 dose once a week. Such an approach was found to be safe and validated by several authors [In contrast, in our Institution we have observed a very rapid absorption of LT authors –22.4 absorption test in manipulative patients with deliberate medication non-adherence. Such an approach should obviate the need for several readmissions associated with enourmous costs for health service and multitude of unnecessary investigations. Furthermore, adequate supervision and frequent sampling during initial part of the test renders paracetamol coadministration superfluous.In summary, we have demonstrated that adequate supervision and frequent sampling is the key for successful implementation of LT


The extracellular matrix protein fibronectin contains a domain that is rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumours, particularly in solid tumours, different types of lymphoma and some leukaemias. This domain, called the extra domain B (ED‐B), thus has broad therapeutic potential. The antibody L19 has been developed to specifically target ED‐B and has shown therapeutic potential when combined with cytokines, such as IL‐2. In this review article, we discuss the preclinical research and clinical trials that highlight the potential of ED‐B targeting for the imaging and treatment of various types of cancer. ED‐B‐centred studies also highlight how proper patient stratification is of utmost importance for the successful implementation of novel antibody‐based targeted therapies. The extracellular matrix protein fibronectin contains a domain that is rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumours, the extra domain B (ED‐B). This review summarizes preclinical research and clinical trials on the potential of antibody‐based ED‐B targeting for tumour visualization and treatment. It was discovered by Borsi et al.  and is aet al., et al., et al., Fibronectin is an extracellular matrix (ECM) protein that binds to integrins and to other ECM proteins , which makes it easy to detect. By contrast, cFN is synthesized and secreted with ED‐A and/or ED‐B segments by various cell types, including endothelial cells, macrophages, smooth muscle cells and fibroblasts as a disulfide‐linked, tail‐to‐tail dimer  and cellular FN (cFN), which is present in the ECM. pFN is synthesized and secreted without ED‐A or ED‐B segments by hepatocytes in the liver as double polypeptide chains, which are joined together by disulfide bridges at their C termini  tissue, by using noninvasive (SPECT or PET) or invasive  imaging methods, the latter necessitating a biopsy. Based on these results, several L19 antibody variants have been coupled to different radioisotopes for use in imaging  was seven times higher in tumours than was L19‐(scFv)2, even after 144 h postinjection. Studies carried out using these different forms of L19 have shown that L19‐SIP has a tumour‐to‐blood ratio (TBR) of 70 which means very low concentrations of L19 in blood compared with tumour uptake, L19‐(scFv)2 has a ratio of 10 and L19‐IgG as a ratio of 3 2 evaluating its uptake in patients with brain, lung or colorectal cancer. L19‐(scFv)2 was chosen based on its higher TBR compared with that of L19‐IgG, and on its faster clearance from the blood compared with both SIP and IgG, which improves image quality. No adverse effects were observed in response to L19‐(scFv)2 in this safety clinical trial ] in relapsed Hodgkin lymphoma patients at different time points after injection. A favourable tumour to bone marrow ratio (TBMR) dosimetry of 14 Gy/1.3 Gy, 22.7 Gy/0.85 Gy and 18 Gy/0.99 Gy for all three patients was observed, with 2/3 patients demonstrating partial remissions. These results support the potential use of 131I‐L19SIP as a therapeutic option in the context of radioimmunotherapy (RIT). In 2012, Erba et al. confirmed the differential dosimetry of 131I‐L19SIP (185 MBq) in tumour to bone marrow with ratios of 10 : 1 in 14/18 treated lymphoma patients using SPECT/CT  or breast carcinoma, to test if the accuracy of dosimetric results were better than those achieved using 131I‐L19SIP SPECT. The uptake of 124I‐L19SIP was highly variable in tumour lesions within the same patient and might explain the short beneficial effects of positive RIT responses 2 and SIP] that target ED‐B were tested for their ED‐B binding capacity before they were coupled to therapeutic drugs. In 2002, Borsi , et al.  analysedet al. demonstrated the specific binding of a newly developed peptide, ZD2, to ED‐B  tissues can be done using a variety of methods, including ELISA, western blot, qPCR and immunohistochemistry Fig. . Using E4et al.  as part of their radiotherapy (RIT) , which emits high doses of radiation on and in the tumour microenvironment. Seven lymphoma patients have received a therapeutic dose of 4.24.2.1et al., et al., et al., Following antigenic or mitogenic stimulation, T cells typically excrete pro‐inflammatory cytokines, such as IL‐2, to induce the proliferation of T and B lymphocytes, natural killer cells, macrophages and monocytes . This combination has produced long‐lasting therapeutic benefit, depending on ED‐B expression levels, RT dose and schedule, and the levels of cytotoxic T cells . The first clinical trial (NCT01253096) tested the effect of L19‐IL‐2 as an IIT in stage 3–stage 4 melanoma patients  expression and major histocompatibility complex I (MHCI) processing and presentation . TNF‐α has pro‐inflammatory activities as it inhibits angiogenesis, increases cytotoxic T‐cell activity and promotes apoptosis. However, it can also promote tumour progression by regulating stromal cell types and by increasing the expression of cytokines, such as CCL2 and IL‐6 (both recruiting myeloid cells), CCL7 and VEGF (both promoting angiogenesis), and TNFR1 and TNFR2 (which are important for regulating tumour‐promoting activities of TNF‐α)  in metastatic melanoma patients. However, no therapeutic activity was observed  is produced by many different cells, such as T cells, macrophages, endothelial cells and even tumour cells. GM‐CSF can act as a hematopoietic growth factor and can stimulate hematopoietic progenitor cells to proliferate  interacts with coagulation factor VIIa to form an VIIa‐TF complex that initiates blood coagulation  to investigate the safety and specificity of this new delivery system in F9 mice , and all showed 62–90% tumour shrinkage on days 5 and 8, compared with free liposome‐treated animals. Despite these very promising results, no clinical follow‐up of L19‐ML (drug or cytokine) has taken place.Liposomes are being increasingly used as a carrier for drugs, vitamins and cytokines. In 2005, Marty Overall, we can conclude that L19 has been successfully coupled to different therapeutic agents, from which some (daromun) has already advanced in phase 3 clinical trials. Others are in different stages of development, from preclinical studies into early clinical testing.5Extra domain B is well‐described, preclinically and clinically, and has known applications in imaging and in targeting therapeutics in cancer, as shown by several ongoing phase 2 and phase 3 clinical trials in the context of novel drug development. To further advance the use of ED‐B targeting as a cancer therapeutic and its testing in clinical trials  licensed to Oncoradiomics and one issue patent on mtDNA (PCT/EP2014/059089) licensed to ptTheragnostic/DNAmito, three nonpatented invention (softwares) licensed to ptTheragnostic/DNAmito, Oncoradiomics and Health Innovation Ventures and three nonissues, nonlicensed patents on Deep Learning‐Radiomics and Lymphocytes Sparing Radiotherapy .PL reports, within the submitted work, a status of PI of the trial ImmunoSABR. PL reports outside the submitted work grants/sponsored research agreements from Varian medical, Oncoradiomics, ptTheragnostic/DNAmito and Health Innovation Ventures. He received an advisor/presenter fee and/or reimbursement of travel costs/external grant writing fee and/or RIYL and LJD wrote this manuscript. LJD, PL, AY, JT and RIYL conceived the need of the present review. DM, AMAW and EJVL verified with their expertise literature findings regarding ED‐B. All authors read and approved the final manuscript.


There are many atrial fibrillation (AF) screening devices available. Validation studies have mainly been performed in optimal settings in the young population.We aim to compare the yield of AF detection, compliance, and patient‐based experience in an ambulatory elderly population by using intermittent electrocardiogram (ECG) recordings and continuous event recording simultaneously.The study participants were part of the STROKESTOP II study, a Swedish screening study for AF. All participants were 75/76 years of age, were clinically free of AF, and had N‐terminal pro b‐type natriuretic peptides levels ≥125 ng/L. AF screening was performed in parallel during a 2‐week period, using a continuous event recording device  and 30‐second intermittent recordings using a handheld ECG device (Zenicor II) four times daily. Participants were asked to fill out a questionnaire with regard to compliance and ease of use of the devices.P = .002). No new cases of AF were detected using intermittent ECG monitoring only, but some episodes were detected in parallel for patients. On a graded ordinal scale of 1 to 5, with 1 reflecting “very easy to use”, continuous monitoring was graded 2 (interquartile range [IQR]: 1‐3) compared to intermittent 1 (IQR: 1‐1) (P < .001).During continuous event recording, 6% (n = 15/269) were diagnosed with AF and intermittent ECG detected AF in 2% (n = 5/269) of the participants (Continuous event recording detected three times more AF compared to intermittent ECG in an elderly ambulatory population. Compliance and user‐friendliness were rated higher for the intermittent ECG device. The prevalence of clinically diagnosed AF is approximately 3% in the adult population,AF can be asymptomatic, and individuals with asymptomatic AF have been suggested to have a higher risk of stroke than those with symptomatic AF.With the advent of new technology, many new devices for AF detection have been developed. The validation of these devices is commonly performed in an optimal in‐office setting, in the young population.We aim to compare the yield of AF detection, compliance, and patient‐based experience in population screening in elderly individuals, by using intermittent ECG recordings vs continuous event recording.22.1This is a substudy of STROKESTOP II, a Swedish mass‐screening study for AF in individuals aged 75 and 76 years. The study protocol has been published previously.2.2Consecutive participants were included during the last 8 months of the STROKESTOP II study. All participants were free of AF at baseline and had NT‐proBNP ≥125 ng/L. All participants received oral and written information about the substudy and provided informed consent.2.3During inclusion in the STROKESTOP II study, all participants filled out a health questionnaire from which baseline medical data were gathered. In addition to the one‐lead ambulatory handheld Zenicor II device used in STROKESTOP II, participants were equipped with a one‐lead continuous event recorder, R‐test 4 evolution , and were instructed to use the recording devices in parallel for 2 weeks. Both devices had buttons for activation if symptomatic arrhythmia occurred. The participants were also asked to fill out a questionnaire with regards to their experience of the two different AF screening devices including information on completion of the 2‐week registration (yes/no), problems leading to discontinuation (free text), ease of use , and effect on daily life. They were also asked to fill out a symptom diary during the 2 weeks.2.4To identify ECGs with suspected AF, all intermittent recordings were inspected manually in addition to the validated computerized algorithm used by Zenicor.2.5The R‐test 4 evolution device was programmed to store not only AF suspicious activity, but also other significant arrhythmias Table . The R‐t2.6p‐waves, and duration of at least 30 seconds.The diagnostic criteria for AF used in the study are according to ESC guidelines: absolute irregular rate‐to‐rate intervals, no discernable, distinct 2.7Participants with other significant bradyarrhythmias such as second‐degree atrioventricular block Mobitz type II, sinoatrial block or sinoatrial arrest for >2 seconds during daytime or >3 seconds at night‐time, or sinus bradycardia with a frequency of less than 30 beats/min were offered cardiologist follow‐up. Similar follow‐up was offered to participants with multifocal or broad complex tachycardia consisting of eight or more consecutive beats.2.8U test. Chi‐square test was used for proportions. Comparisons of the two screening methods were performed using McNemar's test for dichotomous variables and paired sample t‐test for continuous variables. All tests were two‐sided, and a value of P < .05 was regarded as significant. All analyses were performed using IBM SPSS Statistics, version 24 software .All continuous variables were analyzed according to non‐normal distribution, as most variables were non‐normally distributed. Together with all ordinal data, they were reported as median with interquartile range (IQR), and analyzed using Mann‐Whitney 2.9The study complies with the Declaration of Helsinki. The protocol was approved by the regional ethics committee . All participants provided informed consent.3Of the 3763 participants in STROKESTOP II, 269 (7%) were included in this comparison study between June 2017 and January 2018.3.1P = .002). Using parallel monitoring, no new cases of AF were detected using intermittent ECG monitoring only. Using continuous event recording, AF was detected on average day 4 (IQR: 1‐8) compared to day 8 (IQR: 4‐14) using intermittent ECG (P = .135). There was a significant difference in AF detection between the two devices already after 3 days of monitoring  of the participants and intermittent ECG detected AF in 2% (n = 5)  reported symptoms in their diaries.Individuals diagnosed with AF had lower systolic blood pressure compared to those free of AF. AF was more common in patients reporting diabetes, but was less commonly associated with hypertension, vascular disease, and previous stroke/transient ischemic attack Table .3.2In total, other significant arrhythmias were overall more commonly detected using continuous monitoring compared to intermittent recordings Table .3.3The detection algorithm for the intermittent ECG device detected all episodes manually interpreted as AF. For the continuous recorder, 73% (n = 11) of episodes manually interpreted as AF were categorized as AF by the algorithm of the device, and 27% (n = 4) were categorized as other arrhythmias. Hence, for intermittent ECGs, only episodes marked as AF needed manual interpretation, whereas for continuous ECG all categories marked as arrhythmia needed to be interpreted to detect all AF cases.The number of ECG strips that needed manual interpretation per participant was 3 (IQR: 1‐8) for intermittent ECG compared to 55 (IQR: 40‐70) for continuous event recorder. The average time spent on analysis of ECG recordings per participant was 4.5 minutes for continuous event recording and 0.75 minutes for intermittent ECG. For continuous event recording, 4 (IQR: 0‐10)% of the ECGs were non‐interpretable compared to 0 (IQR: 0‐2)% of intermittent ECGs.3.4P = .559 for intermittent ECG and P = .804 for continuous event recording).Intermittent ECG was graded as easier to tolerate compared to continuous ECG by the participants Figure . Median 4In this ambulatory elderly population, continuous event recording detected three times more new cases of AF compared to intermittent ECG. Both methods were well tolerated and, even in this ambulatory setting, ECG quality was good. The device‐based algorithms differed in categorization of AF events, leading to a more time‐consuming interpretation for the continuous event recording device.Continuous event recording detected more AF cases during the first 3 days than intermittent ECG did during 2 weeks. Overall, the detection of 6% new AF is significantly higher than the outcomes of previous screening studies using intermittent ECGs (3‐4%).One might speculate that in order to increase the ease of use and reduce the interpretation burden for the investigator, the duration of continuous event recording could be reduced.An important aspect of AF screening is to diagnose AF in asymptomatic patients. It might be possible that patients who experienced symptoms of palpitations were more keen to participate in our study, which might have had an impact on generalization and compliance. In a real‐world setting, compliance might be lower and the perceived differences in ease of use between the devices might lead to lower compliance for continuous monitoring.To our knowledge, there are no prior studies comparing continuous event recording and intermittent ECG, except our smaller pilot study, where the two devices were used in parallel for 2 weeks; according to our previous results, continuous event recording detected >2.5 times more participants with AF compared to the intermittent ECG.p‐waves.In prior studies, both devices have shown an increased detection of AF compared to 24‐ to 48‐hour Holter monitoring. When intermittent ECG recordings, using the Zenicor device, for 10 seconds twice daily during 30 days were compared to 24‐hour continuous ECG recording, AF episodes were detected in 82% using intermittent recordings compared to 32% using continuous recording.In our study, intermittent ECG was graded as more user‐friendly than continuous event recording, and previous studies have shown similar results.There is an ongoing discussion regarding the stroke risk in screening‐detected AF, as patients with screening‐detected AF may have short and rare AF episodes. In our study, screening‐detected AF was treated equally to clinically detected AF as we hypothesized that patients with AF detected during such short monitoring period are likely to have a high AF burden. In a large matched cohort study of stroke risk in incidentally detected ambulatory AF, individuals with incidentally diagnosed AF were found to have twice as high incidence of stroke compared to individuals with no AF. Anticoagulant treatment reduced stroke risk by >60% and mortality by >40% in these individuals with incidentally detected AF.4.1The participants were all part of the STROKESTOP II study. It is possible that they were healthier than the general population, as participation in screening studies is known to be higher in healthier individuals.Participants with high NT‐proBNP levels are more likely to have AF, and this could lead to an increased detection, with a detection bias. As the participants are their own control, this will not affect the results of this study.p‐wave analysis difficult. This could introduce a misclassification bias by underestimation of true cases. Neither of the screening devices used have 100% sensitivity for AF detection; hence, we may have underestimated the true AF prevalence.Both AF screening methods used in the study are one‐lead ECGs, making 5Continuous event recording detected three times more new cases of AF compared to intermittent ECG when performed simultaneously in an ambulatory setting for 2 weeks. In our elderly population, both methods were well tolerated, although intermittent ECG was graded as more user‐friendly. The ECG quality was good for both methods, but device‐based algorithms differed in categorization of AF events, leading to a more time‐consuming interpretation for the continuous event recording device.Tove Fredriksson has received unrestricted research grants from Boehringer‐Ingelheim and Stiftelsen Hjärtat. Katrin Kemp Gudmundsdottir has received a research grant from Stiftelsen Hjärtat. Viveka Frykman has received lecture fees from MSD, Boehringer‐Ingelheim, Bayer, and Medtronic. Leif Friberg has received consultancy fees from Bayer, Boehringer‐Ingelheim, BMS/Pfizer, and Sanofi. Faris Al‐Khalili has received lecture fees from Bayer, Boehringer‐Ingelheim, and BMS/Pfizer. Johan Engdahl has received consultancy fees from Sanofi and Pfizer; lecture fees from Bayer, Boehringer‐Ingelheim, Astra Zeneca, and Medtronic; and unrestricted research grants from Pfizer and Boehringer‐Ingelheim. Emma Svennberg has received lecture fees from Bayer, Bristol‐Myers Squibb‐Pfizer, Boehringer‐ Ingelheim, and Sanofi.Table S1. Settings for R‐test 4 evolution.Click here for additional data file.


Establishing and maintaining interpersonal trust is often difficult for patients with Borderline Personality Disorder (BPD). How we trust is influenced by prior trust experiences.n = 36 patients with BPD and n = 99 non-clinical controls were examined. Trust objects and interaction partners, emotional valence, perceived relevance and memory specificity were analyzed.For the investigation of trust experiences, autobiographical memories of Content analyses revealed that patients with BPD recalled mostly situations in which their trust was failed by family members or romantic partners. In addition, patients with BPD considered memories with trust and mistrust more relevant for their current lives than the control group. Our results correspond with findings that BPD patients have difficulties trusting close others as well as with theoretical assumptions about deficits in mentalizing and epistemic trust in patients with BPD.In conclusion, our findings should encourage clinical practitioners to address trust deficits towards close others, as well as omniscient negative memory retrieval and interpretation biases which might influence current trust behavior. The capacity to mentalize has received most attention in patients with BPD  as theseDifferent studies suggest that trust experiences influence a person’s trust behavior to a large degree , 12–15. Autobiographical memories (ABMs) are personal memories about events an individual has experienced and are therefore always self-referential. ABMs hold an identity-establishing function  because For a comprehensive understanding of trust memories and alterations in trust behavior, it is interesting to investigate also the content of ABMs. So far, only one published study examined thematic content of memories of patients with BPD. Guruprasad and Bohla  examinedTo our knowledge, there are no studies on ABMs of trust in BPD yet. However, for a deeper understanding of alterations in trust behavior in BPD, it seems necessary to examine trust experiences. Having in mind that patients with BPD do not seem to display trust alterations on all facets of interpersonal trust  we wantN = 36 patients with Borderline Personality Disorder  participated in our study, of whom five  had both a comorbid MDD and PTSD, seven (33.3%) had a comorbid MDD only and one  had a comorbid PTSD only. All patients were diagnosed using the Structured Clinical Interview for DSM-IV Axis-I and Axis-II [n = 99 non-clinical controls  participated. Patients with BPD were recruited at a borderline-specific inpatient treatment facility. Non-clinical controls were recruited in different settings: the majority of non-clinical control participants was recruited at a public event (Lange Nacht der Wissenschaften / Long Night of the Sciences) at Freie Universität Berlin, a smaller part (n = 15) was recruited via emails and postings in internet forums and on social media platforms. Eligible for the study were people over 18 years of age with sufficient knowledge of the German language to understand the questionnaires. Current mood in non-clinical controls was assessed via the 5-item World Health Organization Well-Being Index (WHO-5) [D, seven .3% had a Axis-II . Further (WHO-5) . ControlThe WHO-5 is a short self-report measure for the assessment of well-being and at the same time serves as a screening instrument for current depressive symptoms. The measure has good construct validity as a unidimensional scale measuring well-being .In the self-report questionnaire, participants were asked to describe two memories of interpersonal trust situations. For situation 1, participants were asked to describe a situation in which they actually showed trust . For situation 2, participants were asked to describe a situation in which trust could have been shown but was not . Furthermore, participants were instructed to write down their emotions related to these situations, how important the situation is for their current life on a scale from 1  to 5 (very relevant) and indicate for the first situation whether their trust was failed or not.n = 135), most participants (n = 120) completed a paper-pencil version of the questionnaire. Only a small number of the control group (n = 15) participated online. The groups (online vs paper-pencil version) did not differ significantly from each other in age, gender, and length of the texts. First, basic demographic information (age and gender) was completed, followed by the WHO-5 and the questions on ABMs, associated emotions, relevance and – for situation 1 – whether trust was failed or not. Two trained research assistants transcribed all handwritten situation descriptions in Microsoft Excel. Spelling errors were not corrected as we analyzed content only (in opposite to linguistic patterns for example). Text analysis was run in MaxQDA and the analysis was conducted based on the qualitative text analysis approach by Mayring [Of the complete sample ( Mayring .n = 6) on interpersonal trust [Category systems for trust objects and interaction partners were developed. Deductive categories for trust objects were derived using facets of published questionnaires . Agreement between raters κ = .89 was reached.Specificity of memories was categorized as specific , categorical  or extended . Very good agreement of Frequencies and percentages of trust objects and interaction partners were determined, first for overall participants and then for each group separately. Relationships between group  and trust objects, interaction partners, valence of emotions, specificity and whether the trust in situation 1 was failed or not were conducted using Chi Square Tests of Independence because data were categorical. Last, comparison of the relevance of the described ABMs was conducted using non-paired t-tests.Our main focus was to analyze the content of trust memories of patients with BPD and non-clinical control participants. To provide a comprehensive picture of our results, we also report frequencies of named trust objects and interaction partners as well as the emotional valence, specificity and perceived relevance of the reported trust memories.χ 2(1) = 5.23, p = .02, φ = −.19. All other comparisons were non-significant (p > .05).Frequencies  of trust objects are presented in Fig. χ2(1) =4.10, p = .04, φ = −.17. All other comparisons were non-significant (p > .05).Frequencies  of trust objects are presented in Fig. χ2(1) = 6.14, p = .01, φ = .21 and romantic partners χ2(1) = 4.71, p = .03, φ = .18 whereas non-clinical controls reported significantly more trust memories with friends χ2(1) =5.16, p = .02, φ = −.19 and strangers χ2(1) = 6.14, p = .01, φ = −.21 as interaction partners. All other comparisons were non-significant (p > .05).Frequencies  of interaction partners are presented in Fig. χ2(1) = 4.14, p = .04, φ = .18. All other comparisons were non-significant (p > .05), however, the differences within the categories of romantic partners and strangers followed the same pattern like in situation 1 – a situation in which trust was shown. This means that patients with BPD reported more situations with romantic partners than non-clinical controls, and non-clinical controls reported more situations with strangers than patients with BPD.Frequencies  of interaction partners are presented in Fig. p = .015, φ = .27. Post-hoc tests revealed that patients with BPD reported significantly less positive emotions χ 2(1) = 7.67, p = .01, φ = −.25 compared to non-clinical controls. Both other comparisons were non-significant (p > .05).Patients with BPD reported more negative and mixed emotions in situations where they showed trust, whereas non-clinical controls reported more positive emotions for situations in which they showed trust . The overall difference was significant χ 2(1) = 8.46, p > .05; CG vs. BPD percentages of positive emotions: 7.9% vs. 0.0%; negative emotions: 90.8% vs. 100.0%; extended memories: 1.3% vs. 0.0%).Both groups rated the emotional valence of memories of situations in which they did not show trust as negative. Non-clinical controls and patients with BPD did not differ significantly from each other  compared to non-clinical controls  χ 2(1) = 21.36, p > .05; CG vs. BPD percentages of specific memories: 67.8% vs. 60.0%; categorical memories: 13.3% vs. 20.0%; extended memories: 18.9% vs. 20.0%).The specificity of memories of situations in which trust was shown did not differ between the groups .The specificity of memories of situations in which trust was not shown did not differ between the groups  for their current lives than non-clinical controls  t = − 3.81, p < .001, d =. -.89.Patients with BPD rated their memories of situations in which they showed trust as significantly more relevant  for their current lives than non-clinical controls  t = − 2.66, p = .01, d = −.62.Patients with BPD rated their memories of situations in which they did not show trust as significantly more relevant  of trust in patients with BPD compared to non-clinical controls. To our knowledge, our study is the first to provide information about ABMs of trust in patients with BPD.The main result suggests that patients with BPD, when remembering trust, mainly recall memories in which their trust was failed by family members or romantic partners. Interestingly, they also recalled memories where they themselves failed to trust their family members. This result corresponds with findings on self-reported difficulties in trusting close others by patients with BPD .The main focus of the current study was to analyze content of trust memories of patients with BPD and non-clinical control participants. To provide a comprehensive picture of such memories, we additionally reported frequencies of named trust objects  and interaction partners as well as emotional valence, specificity and perceived relevance of trust memories.The first aim of our study was to provide insight into what and about whom patients with BPD and non-clinical controls trusted. Current results suggest that especially trust into a person’s emotional reliability (30.1%) followed by trust into a person’s dependability (21.9%) and competency (24.0%) were the major trust objects named. Similarly, competency (14.4), dependability (16.6), and emotional reliability (14.4) were also the most frequently named categories in trust situations in which individuals did not show trust (situation 2). Participants of both groups reported most often to trust friends (27.6%) and romantic partners (20.3%). Besides this, they reported most often friends (20.0%), family (18.9%), acquaintances (15.5%) and romantic partners (14.4%) in situations in which they could have trusted but did not (situation 2). Emotional factors like empathetic listening and practical aspects like trusting into each other’s competencies make trust one of the most important factors for beneficial human relationships.Our second aim was to examine differences in trust objects and interaction partners between patients with BPD and non-clinical controls. Patients with BPD did not report memories of trust into a person’s benevolence at all, while non-clinical controls did. This difference was significant.Interestingly, in both groups, participants’ trust into a person’s benevolence was always related to unknown interaction partners. One explanation for this might be that benevolence  is something that is usually expected as given in relationships with close others, while in interactions with unknown people one does not have any information about the entrusted person’s intentions. Patients with BPD do not seem to expect the benevolence of close others as given, however.Patients with BPD showed a pattern to remember family members and romantic partners as interaction partners more often than non-clinical controls, while non-clinical controls remembered friends and strangers more often than patients with BPD. These differences were significant. In fact, patients with BPD did not remember any situation at all in which strangers were their interaction partners, which corresponds with the above described result on trust into someone’s benevolence. The result that patients with BPD remembered mostly situations with family members and romantic partners corresponds with the results from a study about memories of rejection . In a liIn the current study, an illustrative example of such a situation from a patient with BPD was:“My car was broken and standing in front of my house. I had to go to the hospital and could not take care of it, so my dad promised to me to bring it to the garage. When I returned from the hospital, the car was still standing in the same place and my father obviously again did not stick to his word.”It is striking that the patient who described this memory seems to have frequently experienced similar situations (my father obviously again did not stick to his word). As trust behavior is influenced by trust experiences , it doesThe two groups differed in situations in which trust could have been shown but was not (situation 2). Patients with BPD recalled fewer memories about failing to trust into someone’s competency than non-clinical controls. One explanation for this finding could be that patients generally experience more situations in which they have to trust in a person’s competency, such as those in psychotherapy for example:“During sessions with my therapist. I trust that we can take breaks whenever I want to. That we can do things without any pressure. That I can even say negative things out loud and still I will not be abandoned. That I am even allowed to scream. That he will not blame me, even if I will not accomplish my goals. That he will approach me. That there is not so much I can do wrong.”Besides, in situations in which trust could have been shown but was not (situation 2), differences within interaction partner categories followed a similar pattern like in situation 1 – a situation in which trust was shown: here too, patients with BPD named family members and romantic partners as interaction partners more often than the control participants did. The difference within the category of family members was significant.This result supports the idea that patients with BPD develop difficulties in trusting family members already early in life. Besides, this corresponds with research results indicating a high amount of childhood maltreatment in BPD , 48, 49 The third aim of our study was to investigate whether alterations in ABMs from patients with BPD - for example, emotional valence of memories - can be found in ABMs of trust. In line with our hypotheses, patients with BPD related their ABMs of trust mostly to negative emotions and considered those memories as more relevant for their current lives than non-clinical controls. Prior studies on ABMs of patients with BPD found a tendency to recall mostly negatively valenced memories –30. BechConcerning relevance ratings, our results correspond with the results from Rosenbach and Renneberg  who alsoLimitations of the current study are that generalization of the current results is limited due to the small number of male patients in our study. Furthermore, BPD symptomatology was not assessed in the control group, as our assessment took place in a public and anonymous setting in which task duration was limited, which made it difficult to assess more sensitive information.Current results emphasize the role of family members and romantic partners within memories of trust in patients with BPD. More specifically, patients with BPD mainly recall trust situations in which their trust was failed by family members and romantic partners. This is highly relevant for the current lives of the patients, as indicated by relevance ratings. Consequently, patients with BPD report mostly negative emotions when recalling ABMs of trust.Taken together, our study is the first to provide insights into the nature of ABMs of trust from patients with BPD. Our work contributes to a better understanding of alterations in interpersonal trust and especially their possible origins. Specifically, our findings encourage addressing difficulties to trust close others such as family members or romantic partners, omniscient negative memory and interpretation biases.


In patients with atrial fibrillation (AF), left atrial (LA) enlargement, and the presence of low‐voltage areas (LVAs) indicate an advanced disease stage. NT‐proANP is a biomarker, which is significantly higher in both phenotypes. Prediction of LVAs before catheter ablation could impact the prognosis and therapeutical management in AF patients.The aim of this study was to (a) analyze the predictive value of a novel biomarker‐based AF substrate prediction score, and (b) compare it with DR‐FLASH and APPLE scores.Age ≥ 65 years, NT‐proANP > 17 ng/mL, and Persistent AF) was calculated at baseline.Patients undergoing first AF catheter ablation were included. LA volume (LAV) was analyzed prior to ablation using cardiovascular magnetic resonance imaging (CMR). Blood plasma samples from the femoral vein were collected before AF ablation. NT‐proANP was analyzed using commercially available assays. LVAs were determined using high‐density maps during catheter ablation and defined as <0.5 mV. The novel ANP score (one point for P < .001), the ANP score significantly predicted LVAs presence. There were no differences between novel ANP score – which is a new one ‐ is described in the Abstract; with APPLE  and DR‐FLASH  scores.The study population included 156 AF patients . The cut‐off ANP score ≥ 2 demonstrated 77% sensitivity and 70% specificity. On logistic regression (odds ratio [OR] 3.469) and receiver operating characteristic (ROC) analysis (area under the curve [AUC] 0.778, The novel biomarker‐based ANP score demonstrates good prediction of LVAs. Interventional AF ablation is a key treatment for highly symptomatic AF patients.Pathophysiological, electrical, and structural atrial remodeling plays an important role in AF pathogenesis,The LVAs prediction remains challenging and is not widely available.Therefore, the aim of this study was to (a) analyze the predictive value of novel biomarker‐based AF substrate prediction score, and (b) compare it with APPLE and DR‐FLASH scores.2In the present study, we included 156 patients who underwent AF catheter ablation between October 2015 and April 2017 at the Heart Center Leipzig (Germany). Inclusion criterion was a highly symptomatic and refractory to antiarrhythmic treatment AF. Exclusion criteria were pregnancy, age <18 or >75, valvular AF, cancer, acute, or systemic inflammatory diseases. The studies were approved by the local Ethical Committee  and patients provided written informed consent for participation. Paroxysmal and persistent AF were defined according to the current guidelines.2.1Prior to AF ablation, patients underwent 1.5 T CMR  1 to 2 days before the intervention as previously described.2.2The electro‐anatomical mapping was performed as previously described.2.3g for 10 minutes at 20°C) and aliquots were stored at −70°C for subsequent analysis. NT‐proANP levels were studied using Luminex Screening Assay .Blood samples were obtained in ethylenediaminetetraacetic acid (EDTA) test tubes in fasting state prior ablation procedure from the femoral vein and processed within 1 hour of collection. Blood plasma was prepared  diameter ≥ 43 mm, EF < 50%) and the DR‐FLASH score , which was developed for the prediction of LVAs, were calculated before catheter ablation using baseline patients' characteristics.Age ≥ 65 years, NT‐proANP over 75th percentile in peripheral circulation [≥17 ng/mL], and Persistent AF type) was built at baseline prior to ablation. The cut‐off ≥2 had been chosen to facilitate comparison of all scores and enable interpretation of previous and current results.The APPLE score  for skewed continuous variables, and as proportions for categorical variables. The differences between continuous values were assessed using an unpaired P‐value <.05 found on univariable analysis, was performed to identify independent predictors for the presence of LVAs.Logistic regression analysis was used to identify factors associated with LVAs. Multivariable analysis, which included variables with a Receiver operating characteristic (ROC) curves were generated for a graphical illustration of ANP, DR‐FLASH, and APPLE scores' performance in predicting LVAs, with the area under the curve (AUC) being equivalent to the c‐index for determining the predictive value for a score. The c indices  for the two scores were compared by using DeLong's method.P‐value <.05 was considered statistically significant, and all analyses were performed with SPSS statistical software version 25 .A 33.1P < .01), and were more often women (P = .041). CMR derived LAV was significantly higher in patients with LVAs (median 68 mL/m2 (interquartile range (IQR) 55‐79) vs 52 mL/m2(IQR 43‐67), P < .001), and NT‐proANP levels were significantly higher in patients with LVAs (median 14 ng/mL (IQR 8‐21) vs 10 ng/mL (IQR 6‐14), P = .003).In total, 156 patients  undergoing primary AF ablation were included in the study. Clinical characteristics of the study population are summarized in Table P = .019), persistent AF , and higher NT‐proANP levels  remained significant predictors for LVAs. These variables were used to build the novel biomarker‐based AF substrate prediction—the ANP score.In the logistic regression univariable (unadjusted) analysis, age, female gender, persistent AF, LA volume, and NT‐proANP were significantly associated with LVAs Table . In mult.There were n = 33 21%), n = 55 (35%), n = 50 (32%), and n = 19 (12%) patients with ANP scores 0, 1, 2, and 3, respectively. The LVAs presence increased with each ANP score point and was 6%, 14%, 44%, and 67% for ANP scores 0 to 4 %, n = 553.2P = .378 between ANP and APPLE scores, P = .856 between ANP and DR‐FLASH scores). The novel ANP score  ≥ 2 demonstrated a good sensitivity and specificity for the LVAs presence . The sensitivity/specificity for APPLE and DR‐FLASH scores >2 were 73/63% and 93/65%, respectively.All scores were significantly associated with LVAs Figure . The preThe predictive value of the scores was similar in the subgroup of patients with persistent AF Table .4To the best of our knowledge, this is the first study demonstrating the predictive value of the novel biomarker‐based score for prediction of electro‐anatomical remodeling (LVAs) prior to catheter ablation. We found that LVAs prediction using the novel ANP score was non‐inferior or even better than the DR‐FLASH and APPLE scores. Compared to other scores, the ANP score demonstrated better specificity. Importantly, using only three variables mirroring atrial myopathy with its structural changes, it was possible to build an LVAs score with a good predictive value.4.1The presence of LVAs is a key characteristic of AF progression and pathogenesis. Usually, LVAs are determined invasively using LA voltage mapping.A recent study reported that age and persistent AF are clinical significant predictors associated with LVAs.Renal dysfunction is another controversial clinical factor associated with LVAs. Compared to other observations, where impaired renal function was associated with atrial fibrosis,LA enlargement had been used as a marker of advanced electro‐anatomical remodeling because of its strong association with AF progression and related success of different AF management strategies.4.22 and CHA2DS2‐VASc scores by adding TGF‐ß1 did not improve the prediction of arrhythmia recurrences.Besides NT‐proANP in our current analysis and in the previously published study by Yin et al,≥17 ng/mL was associated with almost 3‐fold risk for the LVAs presence. This finding is in line with a previous study, which proved an association of NT‐proANP levels with LVAs and persistent AF.In current study, NT‐proANP 4.3There is a vast majority of different scores for the prediction of AF incidence, thromboembolic complications, AF recurrences, or mortality associated with AF.Male sex, Bundle brunch block, Left Atrium ≥ 47 mm, clinical Type of AF, and Early Recurrent AF) has been tested for LVAs prediction.P < .001) and the DR‐FLASH score  showed a good prediction for LVAs, whereas the MB‐LATER score did not show a significant association with LVAs. Also, in a small analysis using the CHADS2 score , the cutoff ≥3 was found to be associated with a decreased left atrial voltage.Besides APPLE and DR‐FLASH scores, the MB‐LATER score , imaging , peri‐interventional  data, and blood samples of patients undergoing AF ablation. Despite the advantage of such unique phenotyping, this could be considered as a disadvantage, because validation of our results in an external cohort is problematic—not all ablation centers analyze electro‐anatomical mapping or have available blood biobanking. Therefore, missing validation of the novel score is the major limitation of the present study.Also, since quantitative measurements  were not performed in this cohort, a correlation analyses between LVAs areas' size and NT‐proANP concentration was not possible.Another limitation is not consistently obtained follow‐up data as many patients were followed by general practitioners or cardiologists in the outpatient setting. Also, compared to our previous studies, there were significant differences in follow‐up management among those patients, who presented to our clinic after 2014.5The novel biomarker‐based ANP score demonstrated good prediction of LVAs. Compared to other established AF substrate scores, the ANP score includes parameters associated with atrial myopathy and demonstrates better specificity.The authors declare no potential conflict of interests.