Fibroblast activation protein inhibitor-positron emission tomography in aortitis: fibroblast pathology in active inflammation and remission.

OBJECTIVES: Epigenetically modified fibroblasts contribute to chronicity in inflammatory diseases. Reasons for the relapsing character of large vessel vasculitis (LVV) remain obscure, including the role of fibroblasts, in part due to limited access to biopsies of involved tissue.68Ga FAPI-46 (FAPI)-PET/CT detects activated fibroblasts in vivo. In this exploratory pilot study, we tested the detection of fibroblast activation in vessel walls using FAPI-PET/CT in LVV with aortitis. METHODS: Eight LVV patients with aortitis and eight age- and gender-matched controls were included. The distribution of FAPI uptake was evaluated in the aorta and large vessels. FAPI-uptake was compared with MRI inflammatory activity scores. Imaging results were compared with clinical parameters such as serum inflammatory markers, time of remission and medication. RESULTS: Three aortitis patients were clinically active and five in remission. Irrespective of activity, FAPI uptake was significantly enhanced in aortitis compared with controls. Patients in remission had a mean duration of remission of 2.8 years (range 1-4 years), yet significant FAPI uptake in the vessel wall was found. In remitted aortitis, MRI inflammatory scores were close to be negative, while in 4/5 patients visually identifiable FAPI uptake was observed. CONCLUSIONS: This pilot feasibility study shows significant tracer uptake in the aortic walls in LVV. FAPI positivity indicates ongoing fibroblast pathology in clinically remitted LVV.

Impact of age on the prognosis of patients with ventricular tachyarrhythmias and aborted cardiac arrest.

BACKGROUND: This study evaluated the prognostic impact of age on patients presenting with ventricular tachyarrhythmias (VTA) and aborted cardiac arrest. MATERIAL AND METHODS: The present registry-based, monocentric cohort study included all consecutive patients presenting at the University Medical Center Mannheim (UMM) between 2002 and 2016 with ventricular tachycardia (VT), ventricular fibrillation (VF) and aborted cardiac arrest. Middle-aged (40-60 years old) were compared to older patients (> 60 years old). Furthermore, age was analyzed as a continuous variable. The primary endpoint was all-cause mortality at 2.5 years. The secondary endpoints were cardiac death at 24 h, all-cause mortality at index hospitalization, all-cause mortality after index hospitalization and the composite endpoint at 2.5 years of cardiac death at 24 h, recurrent VTA, and appropriate implantable cardioverter defibrillator (ICD) treatment. RESULTS: A total of 2259 consecutive patients were included (28% middle-aged, 72% older). Older patients were more often associated with all-cause mortality at 2.5 years (27% vs. 50%; hazard ratio, HR = 2.137; 95% confidence interval, CI 1.809-2.523, p = 0.001) and the secondary endpoints. Even patient age as a continuous variable was independently associated with mortality at 2.5 years in all types of VTA. Adverse prognosis in older patients was demonstrated by multivariate Cox regression analyses and propensity score matching. Chronic kidney disease (CKD), systolic left ventricular dysfunction (LVEF) < 35%, cardiopulmonary resuscitation (CPR) and cardiogenic shock worsened the prognosis for both age groups, whereas acute myocardial infarction (STEMI/NSTEMI) and the presence of an ICD improved prognosis. CONCLUSION: The results of this study suggest that increasing age is associated with increased mortality in VTA patients. Compared to the middle-aged, older patients were associated with higher all-cause mortality at 2.5 years and the secondary endpoints.

Cardiac disease and prognosis associated with ventricular tachyarrhythmias in young adults and adults.

BACKGROUND: This study evaluates cardiac diseases and prognosis in young adults and adults presenting with ventricular tachyarrhythmias (VTA). METHODS: The present longitudinal, observational, registry-based, monocentric cohort study includes all consecutive patients 45 years old or younger presenting with VTA at admission from 2002 to 2016. Rates of coronary angiography, coronary artery disease (CAD) and need for percutaneous coronary intervention (PCI), cardiac diseases associated with VTA, and differences in long-term prognostic endpoints for young adults (20-34 years old) were analyzed and compared to those of adults (35-45 years old), for whom multivariable risk prediction models were developed. Kaplan-Meier analyses were performed according to age and type of VTA. RESULTS: A total of 259 consecutive patients were included in the study (36% young adults and 64% adults). At admission, 38% of young adults had VTA due to CAD that required PCI. Furthermore, VTA in young adults was commonly idiopathic (27%), or had underlying channelopathies (18%), primary cardiomyopathies (13%) or acute myocardial infarction (AMI, 11%). In adults, VTA was mostly associated with AMI (28%), though the rate of idiopathy was still high (20%). A total 41% of all patients received cardiopulmonary resuscitation (CPR), for whom AMI (STEMI 17%, NSTEMI 24%) was most frequently observed. Irrespective of the type of VTA, all-cause mortality was similar for young adults and adults. In young adults, left ventricular ejection fraction (LVEF) < 35% (HR = 33.590) was associated with increased long-term all-cause mortality. CONCLUSION: Despite high rates of idiopathic ventricular tachyarrhythmias, CAD and AMI are common causes of VTA and CPR in adults 45 years old and younger. Young adults and adults had comparable survival at index hospitalization and after 2.5 years irrespective of the type of VTA. Clinical trial registration clinicaltrials.gov identifier: NCT02982473.

Impact of chronic kidney disease on recurrent ventricular tachyarrhythmias in ICD recipients.

The study sought to assess the impact of chronic kidney disease (CKD) on recurrences of ventricular tachyarrhythmias in implantable cardioverter defibrillator (ICD) recipients. Data regarding the outcome of patients with CKD in ICD recipients is limited. A large retrospective registry was used including consecutive ICD recipients surviving episodes of ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2016. CKD patients were compared to non-CKD patients. The primary endpoint was the first recurrence of ventricular tachyarrhythmias at 5 years. Secondary endpoints were ICD-related therapies, rehospitalization and all-cause mortality at 5 years. Kaplan-Meier, multivariable Cox regression and propensity score matching were applied. A total of 585 consecutive patients were included (non-CKD: 57%, CKD: 43%). CKD had higher rates of the primary endpoint of recurrent ventricular tachyarrhythmias compared to non-CKD patients (50% vs. 40%; log rank p = 0.008; HR = 1.398; 95% CI 1.087-1.770; p = 0.009), which was irrespective of a primary or secondary preventive ICD and mainly attributed to recurrent VF (11% vs. 5%; p = 0.007) and electrical storm (ES) (10% vs. 5%; p = 0.010). Accordingly, CKD patients had higher rates of the secondary endpoint of appropriate ICD therapies (41% vs. 30%; log rank p = 0.002; HR = 1.532; 95% CI 1.163-2.018; p = 0.002), mainly attributed to appropriate ICD shocks (19% vs. 11%; p = 0.005). After multivariable Cox regression CKD was associated with a 1.4-fold higher risk of appropriate device therapies (HR = 1.353; 95% CI 1.001-1.825; p = 0.049), but not with first recurrence of ventricular tachyarrhythmias (p = 0.177). Irrespective of propensity score matching, CKD was associated with increasing all-cause mortality at 5 years (p = 0.001). The presence of CKD is associated with increased rates of recurrent ventricular tachyarrhythmias, appropriate device therapies, mainly attributed to appropriate shock, and all-cause mortality in ICD recipients at 5 years.

Male sex increases mortality in ventricular tachyarrhythmias.

BACKGROUND: Ventricular tachyarrhythmias are still associated with poor clinical outcomes. Therefore, it is important to stratify high-risk patients presenting with ventricular tachyarrhythmias for their individual risk of future outcomes. AIM: To assess the impact of male sex on survival in patients presenting with ventricular tachyarrhythmias. METHODS: All consecutive patients surviving ventricular tachycardia (VT) and fibrillation (VF) on admission from 2002 to 2016 were included and stratified according to sex differences by propensity score matching. The primary prognostic end-point was all-cause mortality at 30 months. Secondary end-points were all-cause mortality at 30 days, at index hospitalisation, after discharge, the composite of recurrent ventricular tachyarrhythmias and appropriate implantable cardioverter defibrillator (ICD) therapies, and finally rehospitalisation related to ventricular tachyarrhythmias. RESULTS: A total of 784 (392 males and 392 females) matched patients was included. The rate of VT and VF was similar in both groups (VT: male 65% vs female 62%; VF: male 35% vs female 38%). Male sex was independently associated with the primary end-point of all-cause mortality at 30 months (31% vs 23%; hazard ratio (HR) = 1.432; 95% confidence interval (CI) 1.089-1.883; P = 0.010) as well as with the secondary end-point of all-cause mortality at index hospitalisation (mortality rate 31% vs 23%; log-rank P = 0.010; HR = 1.432; 95% CI 1.089-1.883; P = 0.010; mortality rate 10% vs 15%; HR = 1.685; 95% CI 1.117-2.542; P = 0.013). No differences in further secondary end-points were found. Sex differences of the primary end-point were predominantly observed in patients with VT at index (mortality rate 28% versus 20%; HR = 1.512; 95% CI 1.040-2.189; P = 0.028), without an ICD and with left ventricular ejection fraction ≥35% (log-rank values, P < 0.05). CONCLUSION: Males presenting with ventricular tachyarrhythmias on admission were associated with higher all-cause mortality at 30 months and all-cause mortality at index hospitalisation.

Type 2 diabetes is independently associated with all-cause mortality secondary to ventricular tachyarrhythmias.

OBJECTIVES: The study sought to assess the prognostic impact of type 2 diabetes in patients presenting with ventricular tachyarrhythmias on admission. BACKGROUND: Data regarding the prognostic outcome of diabetics presenting with ventricular tachyarrhythmias is limited. METHODS: A large retrospective registry was used including all consecutive patients presenting with ventricular tachycardia (VT) and fibrillation (VF) on admission from 2002 to 2016. Patients with type 2 diabetes (diabetics) were compared to non-diabetics applying multivariable Cox regression models and propensity-score matching for evaluation of the primary prognostic endpoint of long-term all-cause mortality at 2 years. Secondary prognostic endpoints were cardiac death at 24 h, in-hospital death at index, all-cause mortality at 30 days, all-cause mortality in patients surviving index hospitalization at 2 years (i.e. "after discharge") and rehospitalization due to recurrent ventricular tachyarrhythmias at 2 years. RESULTS: In 2411 unmatched high-risk patients with ventricular tachyarrhythmias, diabetes was present in 25% compared to non-diabetics (75%). Rates of VT (57% vs. 56%) and VF (43% vs. 44%) were comparable in both groups. Multivariable Cox regression models revealed diabetics associated with the primary endpoint of long-term all-cause mortality at 2 years (HR = 1.513; p = 0.001), which was still proven after propensity score matching (46% vs. 33%, log rank p = 0.001; HR = 1.525; p = 0.001). The rates of secondary endpoints were higher for in-hospital death at index, all-cause mortality at 30 days, as well as after discharge, but not for cardiac death at 24 h or rehospitalization due to recurrent ventricular tachyarrhythmias. CONCLUSION: Presence of type 2 diabetes is independently associated with an increase of all-cause mortality in patients presenting with ventricular tachyarrhythmias on admission.

Design and validation of a German version of the GSRS-IBS - an analysis of its psychometric quality and factorial structure.

BACKGROUND: Currently, a suitable questionnaire in German language is not available to monitor the progression and evaluate the severity of irritable bowel syndrome (IBS). Therefore, this study aimed to translate the Gastrointestinal Symptom Rating Scale for Irritable Bowel Syndrome (GSRS-IBS) into German and to evaluate its psychometric qualities and factorial structure. METHODS: This study is based on a total sample of 372 participants [62.6% female, mean age = 41 years (SD = 17 years)]. 17.5% of the participants had a diagnosis of IBS, 19.9% were receiving treatment for chronic inflammatory bowel disease, 12.1% of the participants were recruited from a psychosomatic clinic, and 50.5% belonged to a control group. All participants completed the German version of GSRS-IBS (called Reizdarm-Fragebogen, RDF), as well as the Gießen Subjective Complaints List (GBB-24) and the Hospital Anxiety and Depression Scale - German version (HADS-D). RESULTS: The internal consistency of the RDF total scale was at least satisfactory in all subsamples (Cronbach's Alpha between .77 and .92), and for all subscales (Cronbach's Alpha between .79 and .91). The item difficulties (between .25 and .73) and the item-total correlations (between .48 and .83) were equally satisfactory. Principal axis analysis revealed a four-factorial structure of the RDF items, which mainly resembled the structure of the English original. Convergent validity was established based on substantial and significant correlations with the stomach-complaint scale of the GBB-24 (r = .71; p < .01) and the anxiety (r = .42; p < .01) and depression scales (r = .43; p < .01) of the HADS-D. CONCLUSION: The German version of the GSRS-IBS RDF proves to be an effective, reliable, and valid questionnaire for the assessment of symptom severity in IBS, which can be used in clinical practice as well as in clinical studies.

Diagnostic Potential of Supplemental Static and Dynamic 68Ga-FAPI-46 PET for Primary 18F-FDG-Negative Pulmonary Lesions.

PET using 68Ga-labeled fibroblast activation protein (FAP) inhibitors (FAPIs) holds high potential for diagnostic imaging of various malignancies, including lung cancer (LC). However, 18F-FDG PET is still the clinical gold standard for LC imaging. Several subtypes of LC, especially lepidic LC, are frequently 18F-FDG PET-negative, which markedly hampers the assessment of single pulmonary lesions suggestive of LC. Here, we evaluated the diagnostic potential of static and dynamic 68Ga-FAPI-46 PET in the 18F-FDG-negative pulmonary lesions of 19 patients who underwent surgery or biopsy for histologic diagnosis after PET imaging. For target validation, FAP expression in lepidic LC was confirmed by FAP immunohistochemistry. Methods: Hematoxylin and eosin staining and FAP immunohistochemistry of 24 tissue sections of lepidic LC from the local tissue bank were performed and analyzed visually. Clinically, 19 patients underwent static and dynamic 68Ga-FAPI-46 PET in addition to 18F-FDG PET based on individual clinical indications. Static PET data of both examinations were analyzed by determining SUVmax, SUVmean, and tumor-to-background ratio (TBR) against the blood pool, as well as relative parameters (68Ga-FAPI-46 in relation to18F-FDG), of histologically confirmed LC and benign lesions. Time-activity curves and dynamic parameters (time to peak, slope, k 1, k 2, k 3, and k 4) were extracted from dynamic 68Ga-FAPI-46 PET data. The sensitivity and specificity of all parameters were analyzed by calculating receiver-operating-characteristic curves. Results: FAP immunohistochemistry confirmed the presence of strongly FAP-positive cancer-associated fibroblasts in lepidic LC. LC showed markedly elevated 68Ga-FAPI-46 uptake, higher TBRs, and higher 68Ga-FAPI-46-to-18F-FDG ratios for all parameters than did benign pulmonary lesions. Dynamic imaging analysis revealed differential time-activity curves for LC and benign pulmonary lesions: initially increasing time-activity curves with a decent slope were typical of LC, and steadily decreasing time-activity curve indicated benign pulmonary lesions, as was reflected by a significantly increased time to peak and significantly smaller absolute values of the slope for LC. Relative 68Ga-FAPI-46-to-18F-FDG ratios regarding SUVmax and TBR showed the highest sensitivity and specificity for the discrimination of LC from benign pulmonary lesions. Conclusion: 68Ga-FAPI-46 PET is a powerful new tool for the assessment of single 18F-FDG-negative pulmonary lesions and may optimize patient stratification in this clinical setting.

Prognostic impact of age and gender on patients with electrical storm.

BACKGROUND: Electrical storm (ES) is a severe and life-threatening heart rhythm disorder. Age and male gender have been identified as independent risk factors for cardiovascular diseases. However, data regarding the prognostic impact of age and gender on ES patients is limited. METHODS: The present study included retrospectively consecutive patients presenting with ES from 2002 to 2016. Patients 67 years old or older were compared to patients younger than 67, males were also compared to females. Receiver operating characteristic analyses were performed to find the optimum age cut-off value. The primary endpoint was all-cause mortality at 3 years. The secondary endpoints were in-hospital mortality, rehospitalization rates, ES recurrences, and major adverse cardiac events (MACE) at 3 years. RESULTS: Eighty-seven ES patients with implantable cardioverter-defibrillators were included. Age ≥ 67 years was associated with increased all-cause mortality at 3 years (48% vs. 20%, hazard ratio = 3.046; 95% confidence interval 1.316-7.051; p = 0.008; log-rank p = 0.006). MACE, in-hospital mortality, rehospitalization rates, and ES recurrences were not affected by age. Even after multivariate adjustment, age ≥ 67 years was associated with increased long-term mortality at 3 years, besides left ventricular ejection fraction < 35%. In contrast, gender was not associated with primary and secondary endpoints. CONCLUSIONS: Patients 67 years old and older presenting with ES are associated with poor long-term prognosis. Increased long-term mortality was still evident after multivariate adjustment. In contrast, gender was not associated with primary and secondary endpoints.

Static and Dynamic 68Ga-FAPI PET/CT for the Detection of Malignant Transformation of Intraductal Papillary Mucinous Neoplasia of the Pancreas.

Pancreatic ductal adenocarcinoma (PDAC) may arise from intraductal papillary mucinous neoplasms (IPMN) with malignant transformation, but a significant portion of IPMN remains to show benign behavior. Therefore, it is important to differentiate between benign IPMN and IPMN lesions undergoing malignant transformation. However, nonoperative differentiation by ultrasound, CT, MRI, and carbohydrate antigen 19-9 (CA19-9) is still unsatisfactory. Here, we assessed the clinical feasibility of additional assessment of malignancy by PET using 68Ga-labeled fibroblast activation protein inhibitors (68Ga-FAPI PET) in 25 patients with MRI- or CT-proven cystic pancreatic lesions. Methods: Twenty-five patients with cystic pancreatic lesions who were followed up in the European Pancreas Center of Heidelberg University hospital and who were led to surgical resection or fine-needle aspiration due to suspicious clinical, laboratory chemistry, or radiologic findings were examined by static (all patients) and dynamic (20 patients) 68Ga-FAPI PET. Cystic pancreatic lesions were delineated and SUVmax and SUVmean were determined. Time-activity curves and dynamic parameters (time to peak, K 1, k 2, K3, k 4) were extracted from dynamic PET data. Receiver-operating curves of static and dynamic PET parameters were calculated. Results: Eleven of the patients had menacing IPMN (high-grade IPMN with [6 cases] or without [5 cases] progression into PDAC) and 11 low-grade IPMN; 3 patients had other benign entities. Menacing IMPN showed significantly elevated 68Ga-FAPI uptake compared with low-grade IPMN and other benign cystic lesions. In dynamic imaging, menacing IPMN showed increasing time-activity curves followed by slow decrease afterward; time-activity curves of low-grade IPMN showed an immediate peak followed by rapid decrease for about 10 min and slower decrease for the rest of the time. Receiver-operating curves showed high sensitivity and specificity (area under the curve greater than 80%) of static and dynamic PET parameters for the differentiation of IPMN subtypes. Conclusion: 68Ga-FAPI PET is a helpful new tool for the differentiation of menacing and low-grade IPMN and shows the potential to avoid unnecessary surgery for nonmalignant pancreatic IPMN.

Comparison of early and late 68Ga-FAPI-46-PET in 33 patients with possible recurrence of pancreatic ductal adenocarcinomas.

Positron emission tomography with 68Gallium (68Ga) labeled inhibitors of fibroblast activation protein (68Ga-FAPI-PET) is a promising imaging technique for patients with recurrent pancreatic ductal adenocarcinomas (PDAC). To date, it is not clear if different acquisition timepoints for 68Ga-FAPI-PET may result in comparable imaging information and if repetitive 68Ga-FAPI-PET imaging may add diagnostic value to single timepoint acquisition for recurrent PDAC. Here we analyzed retrospectively early (20 min p.i.) and late (60 min p.i.) 68Ga-FAPI-PET imaging using FAPI-46 of 33 patients with possible recurrence of PDAC concerning detection rates and uptake over time of local recurrences, metastases, inflammatory lesions of the pancreas, cholestatic lesions of the liver and reactive tissue. 33 patients with histologically confirmed PDAC after complete or partial resection of the pancreas and possible recurrence were examined by 68Ga-FAPI-46-PET acquired 20- and 60-min post injection (p.i.) of the radiotracer. FAPI-positive lesions were classified as local recurrences, metastases, inflammatory lesions of the pancreas (ILP), cholestatic lesions of the liver and reactive tissue based on histology, PET- and CT-morphology and clinical information. Lesions were contoured, and standardized uptake values (SUVmax and SUVmean) and target-to-background ratios (TBR) were analyzed for both acquisition timepoints. In total, 152 FAPI-positive lesions (22 local relapses, 47 metastases, 26 inflammatory lesions of the pancreas, 28 reactive tissues, and 29 cholestatic lesions) were detected. Detection rates for the early and late acquisition of 68Ga-FAPI-46-PET were almost identical except cholestatic lesions, which showed a higher detection rate at early imaging. SUV parameters and TBRs of ILP significantly decreased over time. Cholestatic lesions showed a tendency towards decreasing uptake. All other types of lesions showed relatively stable uptake over time. Early and late acquisition of 68Ga-FAPI-PET results in comparable imaging information in patients with possible recurrence of PDAC. Two timepoint imaging offers additional diagnostic potential concerning differential diagnoses.

Subclass Analysis of Malignant, Inflammatory and Degenerative Pathologies Based on Multiple Timepoint FAPI-PET Acquisitions Using FAPI-02, FAPI-46 and FAPI-74.

PURPOSE: FAPI-PET is a promising imaging technique for various malignant as well as non-malignant pathologies. In a recent retrospective analysis, we evaluated the diagnostic value of repetitive early FAPI-PET-imaging with FAPI-02, FAPI-46 and FAPI-74 for malignant, inflammatory/reactive and degenerative pathologies. Here, we apply a subgroup analysis to that dataset and describe the tracer-wise uptake kinetic behavior of multiple types of FAPI-positive lesions, which are encountered frequently during clinical routine. METHODS: A total of 24 cancer patients underwent whole-body FAPI-PET scans, and images were acquired at 10, 22, 34, 46 and 58 min after the administration of 150-250 MBq of 68Ga-FAPI tracer molecules (eight patients each regarding FAPI-02, FAPI-46 and FAPI-74). Standardized uptake values (SUVmax and SUVmean) of healthy tissues, cancer manifestations and non-malignant lesions were measured and target-to-background ratios (TBR) versus blood and fat were calculated for all acquisition timepoints. RESULTS: Differential uptake behavior over time was observed in several subclasses of malignant lesions, inflammatory/reactive lesions and degenerative lesions. These differences over time were particularly manifested in the direct comparison between the uptakes associated with pancreatic carcinoma (stable or increasing over time) and inflammatory lesions of the pancreas (markedly decreasing over time). Furthermore, marked differences were found between the three tracer variants regarding their time-dependent uptake and TBRs within different subclasses of malignant, inflammatory/reactive and degenerative pathologies. CONCLUSION: Multiple timepoint FAPI-PET/CT is a promising innovative imaging technique that provides additional imaging information compared to single timepoint imaging. Differences in the kinetic behavior of malignant and benign pathologies can facilitate the interpretation of FAPI-positive lesions.

Repetitive Early 68Ga-FAPI PET Acquisition Comparing 68Ga-FAPI-02, 68Ga-FAPI-46, and 68Ga-FAPI-74: Methodologic and Diagnostic Implications for Malignant, Inflammatory/Reactive, and Degenerative Lesions.

68Ga-labeled fibroblast activation protein (FAP) inhibitor (68Ga-FAPI) PET targets 68Ga-FAPI-positive activated fibroblasts and is a promising imaging technique for various types of cancer and nonmalignant pathologies. However, discrimination between malignant and nonmalignant 68Ga-FAPI-positive lesions based on static PET with a single acquisition time point can be challenging. Additionally, the optimal imaging time point for 68Ga-FAPI PET has not been identified yet, and different 68Ga-FAPI tracer variants are currently used. In this retrospective analysis, we evaluate the diagnostic value of repetitive early 68Ga-FAPI PET with 68Ga-FAPI-02, 68Ga-FAPI-46, and 68Ga-FAPI-74 for malignant, inflammatory/reactive, and degenerative lesions and describe the implications for future 68Ga-FAPI imaging protocols. Methods: Whole-body PET scans of 24 cancer patients were acquired at 10, 22, 34, 46, and 58 min after the administration of 150-250 MBq of 68Ga-FAPI tracer molecules (8 patients each for 68Ga-FAPI-02, 68Ga-FAPI-46, and 68Ga-FAPI-74). Detection rates and SUVs (SUVmax and SUVmean) for healthy tissues, cancer manifestations, and nonmalignant lesions were measured, and target-to-background ratios (TBR) versus blood and fat were calculated for all acquisition time points. Results: For most healthy tissues except fat and spinal canal, biodistribution analysis showed decreasing uptake over time. We analyzed 134 malignant, inflammatory/reactive, and degenerative lesions. Detection rates were minimally reduced for the first 2 acquisition time points and remained at a constant high level from 34 to 58 min after injection. The uptake of all 3 variants was higher in malignant and inflammatory/reactive lesions than in degenerative lesions. 68Ga-FAPI-46 showed the highest uptake and TBRs in all pathologies. For all variants, TBRs versus blood constantly increased over time for all pathologies, and TBRs versus fat were constant or decreased slightly. Conclusion: 68Ga-FAPI PET/CT is a promising imaging modality for malignancies and benign lesions. Repetitive early PET acquisition added diagnostic value for the discrimination of malignant from nonmalignant 68Ga-FAPI-positive lesions. High detection rates and TBRs over time confirmed that PET acquisition earlier than 60 min after injection delivers high-contrast images. Additionally, considering clinical feasibility, acquisition at 30-40 min after injection might be a reasonable compromise. Different 68Ga-FAPI variants show significant differences in time-dependent biodistributional behavior and should be selected carefully depending on the clinical setting.

Chronic kidney disease impairs prognosis in electrical storm.

BACKGROUND: The study sought to assess the prognostic impact of chronic kidney disease (CKD) in patients with electrical storm (ES). ES represents a life-threatening heart rhythm disorder. In particular, CKD patients are at risk of suffering from ES. However, data regarding the prognostic impact of CKD on long-term mortality in ES patients is limited. METHODS: All consecutive ES patients with an implantable cardioverter-defibrillator (ICD) were included retrospectively from 2002 to 2016. Patients with CKD (MDRD-GFR < 60 ml/min/1.73 m2) were compared to patients without CKD. The primary endpoint was all-cause mortality at 3 years. Secondary endpoints were in-hospital mortality, cardiac rehospitalization, recurrences of electrical storm (ES-R), and major adverse cardiac events (MACE) at 3 years. RESULTS: A total of 70 consecutive ES patients were included. CKD was present in 43% of ES patients with a median glomerular filtration rate (GFR) of 43.3 ml/min/1.73 m2. CKD was associated with increased all-cause mortality at 3 years (63% vs. 20%; p = 0.001; HR = 4.293; 95% CI 1.874-9.836; p = 0.001) and MACE (57% vs. 30%; p = 0.025; HR = 3.597; 95% CI 1.679-7.708; p = 0.001). In contrast, first cardiac rehospitalization (43% vs. 45%; log-rank p = 0.889) and ES-R (30% vs. 20%; log-rank p = 0.334) were not affected by CKD. Even after multivariable adjustment, CKD was still associated with increased long-term mortality (HR = 2.397; 95% CI 1.012-5.697; p = 0.047), as well as with the secondary endpoint MACE (HR = 2.520; 95% CI 1.109-5.727; p = 0.027). CONCLUSIONS: In patients with ES, the presence of CKD was associated with increased long-term mortality and MACE.

Effect of Anemia on the Prognosis of Patients with Ventricular Tachyarrhythmias.

This study evaluates the prognostic impact of anemia in patients presenting with ventricular tachyarrhythmias. The present longitudinal, observational, registry-based, monocentric cohort study included retrospectively all consecutive patients presenting with ventricular tachyarrhythmias on admission from 2002 to 2016. Anemic patients (hemoglobin levels <12.0 g/dl) were compared with non-anemic patients (hemoglobin levels ≥12.0 g/dl). The primary endpoint was all-cause mortality at 2.5 years. Secondary endpoints were cardiac death at 24 hours, all-cause mortality at index hospitalization, and the composite endpoint of cardiac death at 24 hours, recurrent ventricular tachyarrhythmias, and appropriate ICD therapies at 2.5 years. A total of 2,184 consecutive patients were included, of whom 30% were anemic and 70% non-anemic. Anemia was associated with the primary endpoint of all-cause mortality at 2.5 years (65% vs 29%, p = 0.001; HR = 2.441; 95% CI 2.086 to 2.856), cardiac death at 24 hours (26% vs 11%, p = 0.001), all-cause mortality at index hospitalization (45% vs 20%, p = 0.001), and the composite endpoint (35% vs 27%, p = 0.001; HR = 2.923; 95% CI 2.564 to 4.366). After multivariable adjustment, anemia was no longer associated with the composite endpoint. Predictors of adverse prognosis for anemics were CKD (HR = 2.191), LVEF <35% (HR = 1.651), cardiogenic shock (HR = 1.591), CPR (HR = 1.460), male gender (HR = 1.379), and age (HR = 1.017). In conclusion, anemic patients presenting with ventricular tachyarrhythmias were associated with increased long-term mortality at 2.5 years but not with the composite arrhythmic endpoint at 2.5 years. Predictors of adverse prognosis at 2.5 years were CKD, LVEF <35%, cardiogenic shock, CPR, male gender, and age.

Risk factor paradox: No prognostic impact of arterial hypertension and smoking in patients with ventricular tachyarrhythmias.

BACKGROUND: Data regarding the outcome of patients with ventricular tachyarrhythmias related to arterial hypertension (AHT) and smoking is limited. The study sought to assess the prognostic impact of AHT and smoking on survival in patients presenting with ventricular tachyarrhythmias. METHODS: All consecutive patients surviving ventricular tachycardia (VT) and ventricular fibrillation (VF) upon admission to the University Medical Center Mannheim (UMM), Germany from 2002 to 2016 were included and stratified according to AHT and smoking by propensity score matching. The primary prognostic endpoint was all-cause mortality at 30 months. RESULTS: A total of 988 AHT-matched patients (494 each, with and without AHT) and a total of 872 smoking-matched patients (436 each, with and without smoking) were included. The rates of VT and VF were similar in both groups (VT: AHT 60% vs. no AHT 60%; smokers 61% vs. non-smokers 62%; VF: AHT 35% vs. no AHT 38%; smokers 39% vs. non-smokers 38%). Neither AHT nor smoking were associated with the primary endpoint of long-term all-cause mortality at 30 months (long-term mortality rates: AHT/no AHT, 26% vs. 28%; log-rank p = 0.525; smoking/non-smoking, 22% vs. 25%; log-rank p = 0.683). CONCLUSIONS: Paradoxically, neither AHT nor smoking were associated with differences of long-term all-cause mortality in patients presenting with ventricular tachyarrhythmias.

Prognostic impact of chronic kidney disease and renal replacement therapy in ventricular tachyarrhythmias and aborted cardiac arrest.

BACKGROUND: The study sought to assess the prognostic impact of chronic kidney disease (CKD) and renal replacement therapy (RRT) in patients with ventricular tachyarrhythmias and sudden cardiac arrest (SCA) on admission. METHODS: A large retrospective registry was used including all consecutive patients presenting with ventricular tachycardia (VT), fibrillation (VF) and SCA on admission from 2002 to 2016. Non-CKD vs. "CKD without RRT", and "CKD without RRT" vs. "CKD with RRT" were compared applying multivariable Cox regression models and propensity-score matching for evaluation of the primary prognostic endpoint defined as long-term all-cause mortality at 2 years. Secondary prognostic endpoints were cardiac death at 24 h, in-hospital death at index and the composite endpoint of recurrent ventricular tachyarrhythmias, appropriate ICD therapies and cardiac death at 24 h. RESULTS: In 2686 unmatched high-risk patients with ventricular tachyarrhythmias and SCA, non-CKD was present in 46%, "CKD without RRT" in 46% and "CKD with RRT" in 8%. Each, VT and VF occurred in about one-third of CKD patients. Multivariable Cox regression models revealed that "CKD without RRT" (HR = 2.118; p = 0.001) and "CKD with RRT" (HR = 3.043; p = 0.001) patients were associated with the primary endpoint of long-term mortality at 2 years, which was also proven after propensity-score matching (non-CKD vs. "CKD without RRT": 43% vs. 27%, log rank p = 0.001; HR = 1.847; "CKD without RRT" vs. "CKD with RRT": 74% vs. 51%, log rank p = 0.001; HR = 2.129). The rates of secondary endpoints were higher for cardiac death at 24 h, in-hospital death at index and the composite of recurrent ventricular tachyarrhythmias, appropriate ICD therapies and  cardiac death at 24 h, respectively, for "CKD without RRT" and "CKD with RRT" patients.  CONCLUSION: In patients presenting with ventricular tachyarrhythmias and aborted SCA on admission, the presence of CKD, especially combined with RRT, is independently associated with an increase of long-term all-cause mortality at 2 years, cardiac death at 24 h, in-hospital death and the composite of recurrent ventricular tachyarrhythmias, appropriate ICD therapies and  cardiac death at 24 h.

Chromosomal breakpoints affecting immunoglobulin loci are recurrent in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma.

Chromosomal breakpoints affecting immunoglobulin (IG) loci are recurrent in many subtypes of B-cell lymphomas. However, despite the predominant B-cell origin of the Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL), the presence of chromosomal translocations in IG loci has not yet been systematically explored. Therefore, we have investigated a series of cHL for chromosomal breakpoints in the IGH (n = 230), IGL (n = 139), and IGK (n = 138) loci by interphase cytogenetics. Breakpoints in the IGH, IGL, or IGK locus were observed in the HRS cells of 26 of 149 (17%), 2 of 70, and 1 of 77 evaluable cHLs, respectively. The IG partners could be identified in eight cHLs and involved chromosomal bands 2p16 (REL), 3q27 (BCL6, two cases), 8q24.1 (MYC), 14q24.3, 16p13.1, 17q12, and 19q13.2 (BCL3/RELB). In 65 of 85 (76%) cHLs evaluable for an IGH triple-color probe, the HRS cells showed evidence for a (partial) deletion of the IGH constant region, suggesting the presence of class switch recombination (CSR). Furthermore, analyses with this probe in cases with IGH breakpoints indicated that at least part of them seem to be derived from CSR defects. Our results show that chromosomal breakpoints affecting the IG loci are recurrent in cHL.

COPD increases cardiac mortality in patients presenting with ventricular tachyarrhythmias and aborted cardiac arrest.

OBJECTIVES: The study sought to assess the prognostic impact of COPD in patients presenting with ventricular tachyarrhythmias and sudden cardiac arrest (SCA) on admission. BACKGROUND: Data regarding the outcome of patients with COPD presenting with ventricular tachyarrhythmias and SCA is limited. METHODS: A large retrospective registry was used including all consecutive patients presenting with ventricular tachycardia (VT), fibrillation (VF) and SCA from 2002 to 2016. Patients with COPD were compared to patients without COPD applying multivariable Cox regression models and propensity-score matching for evaluation of the primary prognostic endpoint defined as long-term all-cause mortality at 2 years. Secondary endpoints were all-cause mortality at index, at 30 days and after discharge, cardiac death at 24 h, rehospitalization related to cardiac causes and the composite endpoint of cardiac death at 24 h, recurrences of ventricular tachyarrhythmias and appropriate ICD therapies at 2 years. RESULTS: In 2813 unmatched high-risk patients with ventricular tachyarrhythmias and SCA, COPD was present in 9%. VF was less common in COPD (28% versus 39%; p = 0.001). Multivariable Cox regression models revealed that COPD was associated with the primary endpoint of long-term all-cause mortality (HR = 1.245; 95% CI 1.001-1.549; p = 0.001), which was also proven after propensity score matching (log rank p = 0.001). The secondary endpoints of all-cause mortality at index, at 30 days, after discharge, cardiac death at 24 h, as well as the composite endpoint of cardiac death at 24 h, recurrences of ventricular tachyarrhythmias and appropriate ICD therapies were higher in COPD (p < 0.033). CONCLUSION: In high-risk patients presenting with ventricular tachyarrhythmias and SCA, COPD was associated with higher long-term all-cause mortality, cardiac death at 24 h and higher rates of the composite endpoint of cardiac death at 24 h, recurrences of ventricular tachyarrhythmias and appropriate ICD therapies at 2 years.