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1.
Clin Lab ; 66(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32162892

RESUMO

BACKGROUND: Only few data evaluating the prognostic impact of blood-derived potassium levels (K) on arrhythmic endpoints in patients with implantable cardioverter-defibrillators (ICD) is available. Therefore, this study evaluates the prognostic impact of potassium levels on recurrences of ventricular tachyarrhythmias in consecutive ICD recipients. METHODS: A large retrospective registry was used including all consecutive patients presenting with ventricular tachyarrhythmias on admission from 2002 to 2016 at one institution. Patients were divided into three subgroups: hypokalemia (i.e., K < 3.3 mmol/L), normokalemia (i.e., K 3.3 - 4.5 mmol/L), and hyperkalemia (i.e., K > 4.5 mmol/L). Kaplan-Meier and Cox regression analyses were applied for the evaluation of the primary endpoint of first recurrences of ventricular tachyarrhythmias at one year. Secondary endpoints comprised of first appropriate ICD therapy, first cardiac rehospitalization, and all-cause mortality at one year. RESULTS: Five hundred and thirty ICD recipients with a median potassium level of 4.23 mmol/L were included (67%: normokalemia, 27%: hyperkalemia, and 6%: hypokalemia). Whereas hyperkalemia was not associated with increasing risk of recurrent ventricular tachyarrhythmias, hypokalemia was associated with decreasing freedom from recurrent ventricular tachyarrhythmias (HR = 2.135; 95% CI 1.158 - 3.937; p = 0.015), even after mul-tivariable adjustment (HR = 2.577; 95% CI 1.236 - 5.372; p = 0.012). Higher risk of recurrences was especially attributed to higher rates of electrical storm in the presence of hypokalemia (15% vs. 3 - 4%). Negative impact of hypokalemia was mainly attributed to secondary preventive ICD (HR = 2.637; 95% CI 1.325 - 5.248; p = 0.006). Moreover, hypokalemia was associated with increasing risk of appropriate ICD therapies (HR = 1.920; 95% CI 0.912 - 4.042; statistical trend: p = 0.086), which was still demonstrated after multivariable adjustment. In contrast, risk of first cardiac rehospitalization and all-cause mortality were not affected by potassium levels. CONCLUSIONS: In consecutive ICD recipients with ventricular tachyarrhythmias at index, hypokalemia - but not hyperkalemia - was associated with increasing risk of recurrent ventricular tachyarrhythmias and appropriate ICD therapies.

2.
Sci Eng Ethics ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32026268

RESUMO

In recent years, tech evangelists have made headlines predicting that in the future manual driving will be outlawed. This essay will investigate the question whether a ban of human driven cars can be defended on moral grounds in a future scenario in which autonomous cars are going to be significantly safer than manually driven cars. This article will argue that in such a future scenario manually driven cars, for moral reasons, indeed should be banned from participating in regular traffic. Since the moral argument for outlawing manually driven cars will likely be met by resistance by car-aficionados, in the final part of the paper, we are devising a proposal for reconciling the strong moral case for a ban of manually driven cars with the widespread fondness of manual driving.

3.
J Antimicrob Chemother ; 75(5): 1194-1205, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32025716

RESUMO

BACKGROUND: Epidemiological cut-off values and clinical interpretive breakpoints have been developed for a number of antifungal agents with the most common Candida species that account for the majority of infections due to pathogenic yeasts species. However, less-common species, for which susceptibility data are limited, are increasingly reported in high-risk patients and breakthrough infections. METHODS: The UK National Mycology Reference Laboratory performs routine antifungal susceptibility testing of clinical yeast isolates submitted from across the UK. Between 2002 and 2016, >32 000 isolates representing 94 different yeast species were referred to the laboratory. Here we present antifungal susceptibility profiles generated over this period for amphotericin B, fluconazole, voriconazole, itraconazole, anidulafungin and flucytosine against 35 species of uncommon yeast using CLSI methodologies. MIC data were interpreted against epidemiological cut-off values and clinical breakpoints developed with Candida albicans, in order to identify species with unusually skewed MIC distributions that potentially indicate resistance. RESULTS: Potential resistance to at least one antifungal agent (>10% of isolates with MICs greater than the epidemiological cut-off or clinical breakpoint) was evidenced for 29/35 species examined here. Four species exhibited elevated MICs with all of the triazole antifungal drugs against which they were tested, and 21 species exhibited antifungal resistance to agents from at least two different classes of antifungal agent. CONCLUSIONS: This study highlights a number of yeast species with unusual MIC distributions and provides data to aid clinicians in deciding which antifungal regimens may be appropriate when confronted with infections with rarer yeasts.

4.
J Nucl Med ; 61(2): 194-201, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31375566

RESUMO

A first analysis of simultaneous 68Ga-prostate-specific membrane antigen (PSMA)-11 PET/MRI showed some improvement in the detection of recurrent disease at low serum prostate specific antigen (PSA) values below 0.5 ng/mL compared with the already high detection rate of 68Ga-PSMA-11 PET/CT. We therefore focused on all patients with biochemical recurrence and PSA values no higher than 0.5 ng/mL to assess the detection rate for 68Ga-PSMA-11 PET/MRI. Methods: We retrospectively analyzed a cohort of 66 consecutive patients who underwent 68Ga-PSMA-11 PET/MRI for biochemical recurrence with a PSA value no higher than 0.5 ng/mL at our institution. Median PSA level was 0.23 ng/mL (range, 0.03-0.5 ng/mL). Detection of PSMA-positive lesions within the prostate fossa, local and distant lymph nodes, bones, or visceral organs was recorded. In addition, all scans with 68Ga-PSMA-11 PET/MRI-positive lesions were retrospectively assessed to analyze if lesions were detected inside or outside a standard salvage radiotherapy volume. Results: Overall, in 36 of 66 patients (54.5%) PSMA-positive lesions were detected; in 26 of 40 (65%) patients with a PSA level between 0.2 and 0.5 ng/mL and in 10 of 26 (38.5%) patients with a PSA level less than 0.2 ng/mL. Even at those low PSA values, only 8 of 66 (12.1%) patients had exclusive local recurrence. Lymph nodes were detected in 23 patients and bone metastases in 5 on 68Ga-PSMA-11 PET/MRI. In 26 of 66 patients (39.4%), PSMA-positive lesions were located outside a standard salvage radiotherapy volume. Conclusion: Our data confirm that 68Ga-PSMA-11 PET/MRI has a high detection rate for recurrent prostate cancer, even at low PSA levels no higher than 0.5 ng/mL. In addition, we show that 68Ga-PSMA-11 PET/MRI detected PSMA-positive lesions outside a standard salvage radiotherapy volume in 39.4% of all patients.

5.
Eur J Nucl Med Mol Imaging ; 47(3): 652-664, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31802175

RESUMO

BACKGROUND: Accurate staging is of major importance to determine the optimal treatment modality for patients with prostate cancer. Positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) is a promising technique that outperformed conventional imaging in the detection of nodal and distant metastases in previous studies. However, it is still unclear whether the superior sensitivity and specificity also translate into improved patient management. The aim of this study was to assess the performance of 68Ga-PSMA-11 PET for staging of intermediate and high-risk prostate cancer and its potential impact on disease management. METHODS: In this retrospective analysis, 116 patients who underwent 68Ga-PSMA-11 PET/CT or MRI scans for staging of their intermediate or high-risk prostate cancer between April 2016 and May 2018 were included. The potential impact of 68Ga-PSMA-11 PET staging on patient management was assessed within a simulated multidisciplinary tumour board where hypothetical treatment decisions based on clinical information and conventional imaging alone was determined. This treatment decision was compared with the treatment recommendation based on clinical information and 68Ga-PSMA-11 PET imaging. RESULTS: The primary tumour was positive on 68Ga-PSMA-11 PET in 113 patients (97%). Nodal metastases were detected in 28 patients (24%) and bone metastases in 14 patients (12%). Compared with clinical staging and conventional imaging, 68Ga-PSMA-11 PET resulted in new information in 42 of 116 patients (36%). In 32 of 116 patients (27%), this information would most likely have changed the management into a different therapy modality (15 patients, 13%) or adjusted treatment details (e.g. modification of radiotherapy field or lymph node dissection template; 17 patients, 14%). CONCLUSION: Information from 68Ga-PSMA-11 PET staging has the potential to change the management in more than a fourth of the patients who underwent PET staging for their intermediate to high-risk prostate cancer. Whether these more personalized 68Ga-PSMA-11 PET-based treatment decisions will improve patient outcome needs further investigation.

6.
Cardiology ; 144(1-2): 9-17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31527375

RESUMO

BACKGROUND: Data regarding the prognostic impact of atrial fibrillation (AF) in patients with electrical storm (ES) is rare. OBJECTIVES: This study sought to assess the prognostic impact of AF in patients with ES on mortality, rehospitalization, major adverse cardiovascular events (MACE) and recurrence of ES (ES-R). METHODS: All consecutive implantable cardioverter defibrillator (ICD) patients presenting with ES were included retrospectively from 2002 to 2016. Patients with AF were compared to non-AF patients. The primary prognostic endpoint was all-cause mortality. Secondary endpoints were in-hospital mortality, rehospitalization rates, MACE and ES-R. RESULTS: A total of 87 ES patients with ICD were included and followed up to 2.5 years; 43% suffered from AF. The presence of AF was associated with increased all-cause mortality (47 vs. 29%, log-rank p = 0.052; hazard ratio [HR] 1.969, 95% confidence interval [CI] 0.981-3.952, p = 0.057), which was no longer present after multivariable adjustment for age, diabetes and dilated cardiomyopathy. Furthermore, AF was associated with increased rates of overall rehospitalization (61 vs. 31%, log-rank p = 0.013; HR 2.381, 95% CI 1.247-4.547, p = 0.009), especially due to AF (14 vs. 0%, p = 0.001) and acute heart failure (AHF) (28 vs. 10%, p = 0.018; HR 3.754, 95% CI 1.277-11.038, p = 0.016). Notably, AF was not associated with differences in MACE (55 vs. 37%, log rank p = 0.339) and ES-R (28 vs. 25%, log rank p = 0.704). CONCLUSION: In ES patients, presence of AF was univariably associated with increased rates of all-cause mortality at 2.5 years. Furthermore, AF was multivariably associated with overall rehospitalization, especially due to AF and AHF.

7.
Radiology ; 293(2): 350-358, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31502937

RESUMO

Background Recent studies have reported the additive value of combined gallium 68 (68Ga)-labeled Glu-urea-Lys (Ahx)-HBED-CC ligand targeting the prostate-specific membrane antigen (PSMA) (hereafter called 68Ga-PSMA-11) PET/MRI for the detection and localization of primary prostate cancer compared with multiparametric MRI. Purpose To compare the diagnostic accuracy and interrater agreement of multiparametric MRI and 68Ga-PSMA-11 PET/MRI for the detection of extracapsular extension (ECE) and seminal vesicle infiltration (SVI) in patients with prostate cancer. Materials and Methods Retrospective analysis of 40 consecutive men who underwent multiparametric MRI and 68Ga-PSMA-11 PET/MRI within 6 months for suspected prostate cancer followed by radical prostatectomy between April 2016 and July 2018. Four readers blinded to clinical and histopathologic findings rated the probability of ECE and SVI at multiparametric MRI and PET/MRI by using a five-point Likert-type scale. The prostatectomy specimen served as the reference standard. Accuracy was assessed with a multireader multicase analysis and by calculating reader-average areas under the receiver operating characteristics curve (AUCs), sensitivity, and specificity for ordinal and dichotomized data in a region-specific and patient-specific approach. Interrater agreement was assessed with the Fleiss multirater κ. Results For multiparametric MRI versus PET/MRI in ECE detection, respectively, AUC, sensitivity, and specificity in the region-specific analysis were 0.67 and 0.75 (P = .07), 28% (21 of 76) and 47% (36 of 76) (P = .09), and 94% (529 of 564) and 90% (509 of 564) (P = .007). For the patient-specific analysis, AUC, sensitivity, and specificity were 0.66 and 0.73 (P = .19), 46% (22 of 48) and 69% (33 of 48) (P = .04), and 75% (84 of 112) and 67% (75 of 112) (P = .19), respectively. For multiparametric MRI versus PET/MRI in SVI detection, respectively, AUC, sensitivity, and specificity of the region-specific analysis were 0.66 and 0.74 (P = .21), 35% (seven of 20) and 50% (10 of 20) (P = .25), and 98% (295 of 300) and 94% (282 of 300) (P < .001). For the patient-specific analysis, AUC, sensitivity, and specificity were 0.65 and 0.79 (P = .25), 35% (seven of 20) and 55% (11 of 20) (P = .20), and 98% (137 of 140) and 94% (131 of 140) (P = .07), respectively. Interrater reliability for multiparametric MRI versus PET/MRI did not differ for ECE (κ, 0.46 vs 0.40; P = .24) and SVI (κ, 0.23 vs 0.33; P = .39). Conclusion Our results suggest that gallium 68 (68Ga)-labeled Glu-urea-Lys (Ahx)-HBED-CC ligand targeting the prostate-specific membrane antigen (PSMA) (68Ga-PSMA-11) PET/MRI and multiparametric MRI perform similarly for local staging of prostate cancer in patients with intermediate-to-high-risk prostate cancer. The increased sensitivity of 68Ga-PSMA-11 PET/MRI for the detection of extracapsular disease comes at the cost of a slightly reduced specificity. © RSNA, 2019.

8.
Basic Res Cardiol ; 114(5): 33, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31312919

RESUMO

Leukocyte-mediated inflammation is central in atherothrombosis and ST-segment elevation myocardial infarction (STEMI). Neutrophil extracellular traps (NETs) have been shown to enhance atherothrombosis and stimulate fibroblast function. We analyzed the effects of NETs on cardiac remodeling after STEMI. We measured double-stranded (ds)DNA and citrullinated histone H3 (citH3) as NET surrogate markers in human culprit site and femoral blood collected during primary percutaneous coronary intervention (n = 50). Fibrocytes were characterized in whole blood by flow cytometry, and in culprit site thrombi and myocardium by immunofluorescence. To investigate mechanisms of fibrocyte activation, isolated NETs were used to induce fibrocyte responses in vitro. Enzymatic infarct size was assessed using creatine-phosphokinase isoform MB area under the curve. Left ventricular function was measured by transthoracic echocardiography. NET surrogate markers were increased at the culprit site compared to the femoral site and were positively correlated with infarct size and left ventricular dysfunction at follow-up. In vitro, NETs promoted fibrocyte differentiation from monocytes and induced fibrocyte activation. Highly activated fibrocytes accumulated at the culprit site and in the infarct transition zone. Our data suggest that NETs might be important mediators of fibrotic remodeling after STEMI, possibly by stimulating fibrocytes.


Assuntos
Armadilhas Extracelulares , Fibroblastos/patologia , Leucócitos/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Remodelação Ventricular/fisiologia , Adulto , Idoso , Feminino , Fibrose/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-31182537

RESUMO

The triazole drug fluconazole remains one of the most commonly prescribed antifungal drugs, both for prophylaxis in high-risk patients and also as a second-line treatment option for invasive Candida infections. Established susceptibility profiles and clinical interpretive breakpoints are available for fluconazole with Candida albicans, Candida glabrata, Candida tropicalis, and Candida parapsilosis, which account for the majority of infections due to pathogenic yeast species. However, less common species for which only limited susceptibility data are available are increasingly reported in high-risk patients and from breakthrough infections. The UK National Mycology Reference Laboratory performs routine antifungal susceptibility testing of clinical isolates of pathogenic yeast submitted from across the United Kingdom. Between 2002 and 2016, ∼32,000 isolates were referred, encompassing 94 different yeast species. Here, we present fluconazole antifungal susceptibility data generated using a CLSI methodology over this 15-year period for 82 species (2,004 isolates) of less common yeast and yeast-like fungi, and amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, and anidulafungin, with members of the Nakaseomyces clade (C. glabrata, Candida nivariensis, and Candida bracarensis). At least 22 different teleomorph genera, comprising 45 species, exhibited high MICs when tested with fluconazole (>20% of isolates with MICs higher than the clinical breakpoint [≥8 mg/liter] proposed for C. albicans). Since several of these species have been reported anecdotally from breakthrough infections and therapeutic failures in patients receiving fluconazole, the current study underscores the importance of rapid and accurate yeast identification and may aid clinicians dealing with infections with rarer yeasts to decide whether fluconazole would be appropriate.

10.
Int J Cardiol ; 292: 119-125, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31076250

RESUMO

BACKGROUND: Because data on electrical storm (ES) is limited, this study sought to compare the prognosis of patients with ES to those with ventricular tachyarrhythmias on mortality, rehospitalization and major adverse cardiac events (MACE). METHODS: In this retrospective study consecutive implantable cardioverter defibrillator (ICD) recipients presenting with ES were compared to patients surviving ventricular tachyarrhythmias (ventricular tachycardia (VT) or fibrillation (VF); non-ES) on admission from 2002 to 2016. The primary endpoint was all-cause mortality, secondary endpoints were rehospitalization and MACE at 2.5 years of follow-up. RESULTS: 764 consecutive patients with an ICD were included (11% with ES, 89% with VTA). ES was associated with higher rates of all-cause mortality (37% vs. 20%, log-rank p = 0.001; HR 2.084; 95% CI 1.416-3.065, p = 0.001). However, only in secondary preventive ICD recipients, ES remained significantly associated with mortality (39% vs. 20%; log rank p = 0.001; HR 2.235, 95% CI 1.378-3.625, p = 0.001). Furthermore, ES was associated with higher rates of rehospitalization (44% vs. 12%, log-rank p = 0.001; HR 4.763, 95% CI 3.237-7.009, p = 0.001), mainly due to VT (22% vs. 4%, p = 0.001) and acute heart failure (AHF) (17% vs. 4%, p = 0.001) and higher rates of MACE (40% vs. 23%; log rank p = 0.001; HR 1.838; 95% CI 1.273-2.654, p = 0.002). Increasing risks of death and rehospitalization were still observed even after multivariable adjustment. CONCLUSION: ES was associated with increased rates of all-cause mortality, rehospitalization, respectively due to VT and AHF, as well as MACE at 2.5 years compared to patients with ventricular tachyarrhythmias apart from ES.

11.
Scand Cardiovasc J ; 53(2): 71-76, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30958708

RESUMO

OBJECTIVES: The study sought to assess the prognostic impact of recurrences of electrical storm (ES-R) on mortality, rehospitalization and major adverse cardiac events (MACE). BACKGROUND: Data on the prognostic impact of ES-R is rare. METHODS: All consecutive ES patients with an implantable cardioverter defibrillator (ICD) were included retrospectively from 2002 to 2016. Patients with ES-R were compared to patients without ES-R. The primary endpoint was all-cause mortality, secondary endpoints were in-hospital mortality, rehospitalization and MACE. RESULTS: A total of 87 consecutive ES patients with an ICD were included, of which 26% presented with ES-R at 2.5 years of follow-up. ES-R patients revealed lower LVEF compared to non-ES-R patients (91% vs. 61%; p = .081). There was a numerically higher rate of the primary endpoint of all-cause mortality at 2.5 years (50% vs. 32%; log-rank p = .137). Furthermore, ES-R was associated with increasing rates of rehospitalization (64% vs. 37%; p = .031; HR 1.985; 95% CI 1.025-3.845; log-rank p = .042), especially of acute heart failure (32% vs. 12%; p = .001; HR 3.262; 95% CI 1.180-9.023; log rank p = .023). MACE were higher in ES-R patients (55% vs. 35%; p = .113; log rank p = .141). ES patients with LVEF ≤35% were 12.4 times more likely to develop ES-R (HR 12.417; 95% CI 1.329-115.997; p = .027). CONCLUSION: At long-term follow-up of 2.5 years, ES-R was associated with numerically higher rates of long-term all-cause mortality and significantly higher rates of rehospitalization due to acute heart failure. LVEF ≤35% was associated with increased risk of ES-R. Condensed Abstract This study examined retrospectively the impact of recurrences of electrical storm (ES-R) on survival in 87 patients. ES-R was associated with numerically higher long-term all-cause mortality, whereas significantly higher rates of rehospitalization, respectively of acute heart failure were observed. Highlights ES-R is associated with numerically higher rates of all-cause mortality at long-term follow-up. ES-R is associated with significantly higher rates of rehospitalization and numerically higher rates of MACE at long-term follow-up, mainly due to acute heart failure. Patients with LVEF ≤35% were 12.4 times more likely to develop ES-R.


Assuntos
Cardioversão Elétrica , Taquicardia Ventricular/terapia , Fibrilação Ventricular/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Desfibriladores Implantáveis , Cardioversão Elétrica/efeitos adversos , Cardioversão Elétrica/instrumentação , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Recidiva , Retratamento , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taquicardia Ventricular/mortalidade , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Fibrilação Ventricular/mortalidade , Fibrilação Ventricular/fisiopatologia , Função Ventricular Esquerda , Adulto Jovem
12.
J Interv Card Electrophysiol ; 55(3): 307-315, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30762187

RESUMO

OBJECTIVES: The study sought to assess retrospectively the prognostic impact of left ventricular ejection fraction (LVEF) in patients with electrical storm (ES). BACKGROUND: Data regarding the prognostic impact of impaired LVEF in ES patients is rare. METHODS: Consecutive patients presenting with ES from 2002 to 2016 were included retrospectively. Patients with LVEF ≤ 35% were compared to patients with LVEF > 35%. The primary prognostic endpoint was long-term all-cause mortality, and secondary endpoints were rates of in-hospital mortality, rehospitalization, major adverse cardiac events (MACE), and ES recurrences (ES-R) at long-term follow-up. RESULTS: A total of 80 patients with ES were included at 2.5 years of follow-up. 69% of patients suffered from LVEF ≤ 35%. ES patients with LVEF ≤ 35% were associated with higher rates of the primary endpoint of all-cause mortality (53% versus 8%, log-rank p = 0.0001; HR 8.524; 95% CI 2.030-35.793, p = 0.003), as well as the secondary endpoints of MACE (53% versus 20%; log rank p = 0.011; HR 3.213, 95% CI 1.241-8.316, p = 0.016) and ES-R (35% versus 8%; log rank p = 0.019; HR 4.821, 95% CI 1.122-20.706, p = 0.034). Furthermore, ES patients with LVEF ≤ 35% showed higher rates of rehospitalization due to acute heart failure (24% versus 8%, statistical trend p = 0.096). Notably, ES patients with LVEF > 35% were associated with increased rates of rehospitalization due to ventricular tachycardia (36% versus 18%, statistical trend p = 0.083). CONCLUSIONS: ES patients with LVEF ≤ 35% were associated with increased rates of all-cause mortality, MACE, ES-R and heart failure-related rehospitalization at long-term follow-up. This study evaluated retrospectively the prognostic impact of LVEF in patients with ES. LVEF ≤ 35% was associated with increased long-term all-cause mortality (53% versus 8%; HR 8.524; 95% CI 2.030-35.793, p = 0.003), MACE (53% versus 20%; HR 3.213, 95% CI 1.241-8.316, p = 0.016), and ES recurrences (35% versus 8%; HR 4.821, 95% CI 1.122-20.706, p = 0.034), while trends were observed for higher rates of heart-failure related rehospitalization (24% versus 8%, p = 0.096) and MACE (49% versus 28%; p = 0.081).


Assuntos
Arritmias Cardíacas/fisiopatologia , Volume Sistólico , Adulto , Idoso , Idoso de 80 Anos ou mais , Arritmias Cardíacas/mortalidade , Causas de Morte , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/estatística & dados numéricos , Prognóstico , Estudos Retrospectivos
13.
J Nucl Med ; 60(9): 1270-1276, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30737300

RESUMO

The intense accumulation of prostate-specific membrane antigen (PSMA) radioligands in salivary glands is still not well understood. It is of concern for therapeutic applications of PSMA radioligands, because therapeutic radiation will damage these glands. A better understanding of the uptake mechanism is, therefore, crucial to find solutions to reduce toxicity. The aim of this study was to investigate whether the accumulation of PSMA-targeting radioligands in submandibular glands (SMGs) can be explained with PSMA expression levels using autoradiography (ARG) and immunohistochemistry (IHC). Methods: All patients gave written informed consent for further utility of the biologic material. The SMG of 9 patients, pancreatic tissue of 4 patients, and prostate cancer (PCA) lesions of 9 patients were analyzed. Tissue specimens were analyzed by means of PSMA-IHC (using an anti-PSMA-antibody and an immunoreactivity score system [IRS]) and ARG using 177Lu-PSMA-617 (with quantification of the relative signal intensity compared with a PSMA-positive standard). The SUVmax in salivary glands, pancreas, and PCA tissues were quantified in 60 clinical 68Ga-PSMA-11 PET scans for recurrent disease as well as the 9 primary tumors selected for ARG and IHC. Results: PCA tissue samples revealed a wide range of PSMA staining intensity on IHC (IRS = 70-300) as well as in ARG (1.3%-22% of standard). This variability on PCA tissue could also be observed in 68Ga-PSMA-11 PET (SUVmax, 4.4-16) with a significant correlation between ARG and SUVmax (P < 0.001, R 2 = 0.897). On IHC, ARG, and 68Ga-PSMA-11 PET, the pancreatic tissue was negative (IRS = 0, ARG = 0.1% ± 0.05%, SUVmax of 3.1 ± 1.1). The SMG tissue displayed only focal expression of PSMA limited to the intercalated ducts on IHC (IRS = 10-15) and a minimal signal on ARG (1.3% ± 0.9%). In contrast, all SMG showed a high 68Ga-PSMA-11 accumulation on PET scans (SUVmax 23.5 ± 5.2). Conclusion: Our results indicate that the high accumulation of PSMA radioligands in salivary glands does not correspond to high PSMA expression levels determined using ARG and IHC. These findings provide evidence, that the significant accumulation of PSMA radioligands in SMG is not primarily a result of PSMA-mediated uptake.

14.
J Nucl Med ; 60(8): 1118-1123, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30683764

RESUMO

High-intensity focused ultrasound (HIFU) is a promising new modality for the treatment of localized prostate cancer (PCa). Follow-up of patients is recommended with biopsies and multiparametric MRI (mpMRI). However, mpMRI in the postinterventional setting is often false-negative. It was our aim to investigate if the new tracer targeting the prostate-specific membrane antigen (68Ga-PSMA-11) could be used to localize recurrent disease with PET/MR in patients with discrepant findings between mpMRI and template biopsies. Methods: Interim analysis was performed of the first 10 patients scanned between September 2016 and May 2018 with positive template biopsy and negative mpMRI after HIFU from an ongoing clinical trial (NCT02265159). All patients underwent 68Ga-PSMA-11 PET/MRI within 3 mo. Four prostatic quadrants were defined, and for every quadrant suspicion for recurrence was rated on a 5-point Likert scale from definitely no recurrence (1) to highly suspected of recurrence (5), with 4 used as a cutoff for suspected disease based on PET/MRI by a masked reader. 68Ga-PSMA-11 uptake of suspected lesions and background areas was measured with the SUVmax The apparent diffusion coefficient values of lesions and background were given for each segment. PET/MRI scans were compared with the template biopsy results, including corresponding Gleason scores (GS), number of positive cores, and tumor length. Results: The quadrant-based sensitivity, specificity, and positive and negative predictive values for PET/MRI were 55%, 100%, 100%, and 85%, respectively. Patient-based PET/MRI was negative in 4 cases with GS 3 + 4 and a tumor length between 0.1 and 3 mm. All tumor lesions with GS 4 + 3 or higher were detected on PET/MRI. Conclusion: Our preliminary results indicate that 68Ga-PSMA-11-PET/MR has the potential to localize PCa recurrence after HIFU occult on mpMRI.

15.
Pharmacology ; 103(3-4): 179-188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30695778

RESUMO

OBJECTIVE: The study sought to assess the long-term prognostic impact of different pharmacotherapies, including angiotensin-converting enzyme inhibitor-inhibitor/angiotensin receptor blocker (ACEi/ARB), statins, and amiodarone in patients with electrical storm (ES). BACKGROUND: Data regarding the outcome of patients with ES is limited. METHODS: Consecutive patients with ES from 2002 to 2016 were included. Patients on ACEi/ARB were compared to patients without ACEi/ARB, respectively, for statin and amiodarone therapy. The primary prognostic endpoint was all-cause mortality at 4 years. Secondary endpoints comprised ES recurrences, rehospitalization, and major adverse cardiac events (MACE) at 4 years. Kaplan-Meier survival curves and multivariable Cox regression analyses were applied. RESULTS: A total of 84 consecutive patients surviving episodes of ES was included. Beta-blocker was given in 95%, ACEi/ARB in 80%, statin in 60%, and amiodarone in 54%. ACEi/ARB patients were associated with improved all-cause mortality at 4 years (mortality rate 34 vs. 65%, log rank p = 0.018; HR 0.428; 95% CI 0.208-0.881; p = 0.021), as well as improved freedom from MACE. In contrast, statin and amiodarone therapy had no impact on long-term outcomes in ES patients. CONCLUSION: ACEi/ARB therapy is associated with improved survival and MACE in patients with ES, whereas statins and amiodarone therapy had no impact on long-term prognostic endpoints.


Assuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiodarona/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antiarrítmicos/efeitos adversos , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/mortalidade , Arritmias Cardíacas/fisiopatologia , Dispositivos de Terapia de Ressincronização Cardíaca , Desfibriladores Implantáveis , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Recidiva , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
Eur J Nucl Med Mol Imaging ; 46(4): 889-900, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30488099

RESUMO

PURPOSE: The fast-increasing use of positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) ligand for the imaging of prostate cancer (PCA) biochemical recurrence has led to a rapid change in treatment concepts. Since the superiority of 68Ga-PSMA-11 PET in detecting recurrent PCA is well established, the aim of our study was to assess its effect on management and outcome in all patients imaged during the first year after its introduction into clinical routine. METHODS: Of 327 patients imaged, 223 were referred for recurrent PCA and gave written informed consent for further analysis of their data for this retrospective consecutive cohort analysis. Twenty patients were lost to further follow-up. The rate of detection of recurrence by 68Ga-PSMA-11 PET was based on the clinical reports. Management before the availability of PET diagnostic information was assessed according to guidelines (therapy option without 68Ga-PSMA-11 PET). In the 203 patients with follow-up 6 months after 68Ga-PSMA-11 PET, the therapies effectively implemented as well as follow-up PSA levels were evaluated, with a PSA value of <0.2 ng/ml representing a complete response and a decrease in PSA value of at least 50% from baseline representing a partial response. RESULTS: 68Ga-PSMA-11 PET was positive and identified recurrence in 166 of the 223 patients (74%), with a detection rate of 50% for recurrent disease at low PSA values of <0.5 ng/ml. 68Ga-PSMA-11 PET led to a change in management in 122 of the 203 patients (60%). A substantial increase in the use of metastasis-targeted treatment and a reduction in the use of systemic treatment were observed, with 59 of the 203 patients (29%) undergoing targeted radiotherapy (RTXa) only, and 20 patients (10%) undergoing RTXa with hormonal therapy as the two most frequently selected therapy options. The proportion of patients in whom systemic therapy was selected decreased from 60% (133 of 223 patients) to 34% (70 of 203 patients) on the basis of the information provided by the 68Ga-PSMA-11 PET scan. PSMA PET-directed metastasis-targeted treatment led to a complete response after 6 months in 45% of patients. CONCLUSION: The high rate of recurrence detection by PSMA PET was confirmed and PSMA PET led to a change in management in 60% of patients. Focal therapy for PSMA-positive lesions is a promising approach with complete responses in 45% of patients.

17.
Cell Metab ; 29(4): 901-916.e8, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30581121

RESUMO

Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.

18.
Front Physiol ; 9: 1184, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30190681

RESUMO

Objective: Energy expenditure (EE) increases in response to cold exposure, which is called cold induced thermogenesis (CIT). Brown adipose tissue (BAT) has been shown to contribute significantly to CIT in human adults. BAT activity and CIT are acutely influenced by ambient temperature. In the present study, we investigated the long-term effect of seasonal temperature variation on human CIT. Materials and Methods: We measured CIT in 56 healthy volunteers by indirect calorimetry. CIT was determined as difference between EE during warm conditions (EEwarm) and after a defined cold stimulus (EEcold). We recorded skin temperatures at eleven anatomically predefined locations, including the supraclavicular region, which is adjacent to the main human BAT depot. We analyzed the relation of EE, CIT and skin temperatures to the daily minimum, maximum and mean outdoor temperature averaged over 7 or 30 days, respectively, prior to the corresponding study visit by linear regression. Results: We observed a significant inverse correlation between outdoor temperatures and EEcold and CIT, respectively, while EEwarm was not influenced. The daily maximum temperature averaged over 7 days correlated best with EEcold (R2 = 0.123, p = 0.008) and CIT (R2 = 0.200, p = 0.0005). The mean skin temperatures before and after cold exposure were not related to outdoor temperatures. However, the difference between supraclavicular and parasternal skin temperature after cold exposure was inversely related to the average maximum temperature during the preceding 7 days (R2 = 0.07575, p = 0.0221). Conclusion: CIT is significantly related to outdoor temperatures indicating dynamic adaption of thermogenesis and BAT activity to environmental stimuli in adult humans. Clinical Trial Registration: www.ClinicalTrials.gov, Identifier NCT02682706.

19.
EJNMMI Res ; 8(1): 70, 2018 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-30054750

RESUMO

BACKGROUND: In contrast to ordered subset expectation maximization (OSEM), block sequential regularized expectation maximization (BSREM) positron emission tomography (PET) reconstruction algorithms can run until full convergence while controlling image quality and noise. Recent studies with BSREM and 18F-FDG PET reported higher signal-to-noise ratios and higher standardized uptake values (SUV). In this study, we investigate the optimal regularization parameter (ß) for clinical 68Ga-PSMA PET/MR reconstructions in the pelvic region applying time-of-flight (TOF) BSREM in comparison to TOF OSEM. Two-minute emission data from the pelvic region of 25 patients who underwent 68Ga-PSMA PET/MR were retrospectively reconstructed. Reference OSEM reconstructions had 28 subsets and 2 iterations. BSREM reconstructions were performed with 15 ß values between 150 and 1200. Regions of interest (ROIs) were drawn around lesions and in uniform background. Background SUVmean (average) and SUVstd (standard deviation), and lesion SUVmax (average of 5 hottest voxels) were calculated. Differences were analyzed using the Wilcoxon matched pairs signed-rank test. RESULTS: A total of 40 lesions were identified in the pelvic region. Background noise (SUVstd) and lesions SUVmax decreased with increasing ß. Image reconstructions with ß values lower than 400 have higher (p < 0.01) background noise, compared to the reference OSEM reconstructions, and are therefore less useful. Lesions with low activity on images reconstructed with ß values higher than 600 have a lower (p < 0.05) SUVmax compared to the reference. These reconstructions are likely visually appealing due to the lower background noise, but the lower SUVmax could possibly render small low-uptake lesions invisible. CONCLUSIONS: In our study, we showed that PET images reconstructed with TOF BSREM in combination with the 68Ga-PSMA tracer result in lower background noise and higher SUVmax values in lesions compared to TOF OSEM. Our study indicates that a ß value between 400 and 550 might be the optimal compromise between high SUVmax and low background noise.

20.
ACS Appl Mater Interfaces ; 10(21): 18220-18226, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29741090

RESUMO

Au and Pt do not form homogeneous bulk alloys as they are thermodynamically not miscible. However, we show that anodic TiO2 nanotubes (NTs) can in situ be uniformly decorated with homogeneous AuPt alloy nanoparticles (NPs) during their anodic growth. For this, a metallic Ti substrate containing low amounts of dissolved Au (0.1 atom %) and Pt (0.1 atom %) is used for anodizing. The matrix metal (Ti) is converted to oxide, whereas at the oxide/metal interface direct noble metal particle formation and alloying of Au and Pt takes place; continuously these particles are then picked up by the growing nanotube wall. In our experiments, the AuPt alloy NPs have an average size of 4.2 nm, and at the end of the anodic process, these are regularly dispersed over the TiO2 nanotubes. These alloyed AuPt particles act as excellent co-catalyst in photocatalytic H2 generation, with a H2 production rate of 12.04 µL h-1 under solar light. This represents a strongly enhanced activity as compared to TiO2 NTs decorated with monometallic particles of Au (7 µL h-1) or Pt (9.96 µL h-1).

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