Body mass index, triglyceride-glucose index, and prostate cancer death: a mediation analysis in eight European cohorts.

BACKGROUND: Insulin resistance is a hypothesised biological mechanism linking obesity with prostate cancer (PCa) death. Data in support of this hypothesis is limited. METHODS: We included 259,884 men from eight European cohorts, with 11,760 incident PCa's and 1784 PCa deaths during follow-up. We used the triglyceride-glucose (TyG) index as indicator of insulin resistance. We analysed PCa cases with follow-up from PCa diagnosis, and the full cohort with follow-up from the baseline cancer-free state, thus incorporating both PCa incidence and death. We calculated hazard ratios (HR) and the proportion of the total effect of body mass index (BMI) on PCa death mediated through TyG index. RESULTS: In the PCa-case-only analysis, baseline TyG index was positively associated with PCa death (HR per 1-standard deviation: 1.11, 95% confidence interval (CI); 1.01-1.22), and mediated a substantial proportion of the baseline BMI effect on PCa death (HRtotal effect per 5-kg/m2 BMI: 1.24; 1.14-1.35, of which 28%; 4%-52%, mediated). In contrast, in the full cohort, the TyG index was not associated with PCa death (HR: 1.03; 0.94-1.13), hence did not substantially mediate the effect of BMI on PCa death. CONCLUSIONS: Insulin resistance could be an important pathway through which obesity accelerates PCa progression to death.

Aetiology, ejection fraction and mortality in chronic heart failure: a mediation analysis.

OBJECTIVE: Clinical decision making in chronic heart failure (CHF) is based primarily on left ventricular ejection fraction (LVEF), and only secondarily on aetiology of the underlying disease. Our aim was to investigate the mediating role of LVEF in the relationship between aetiology and mortality. METHODS: Using data of 2056 Austrian patients with CHF (mean age 57.2 years; mean follow-up 8.8 years), effects of aetiology on LVEF and overall mortality were estimated using multivariable-adjusted linear and Cox regression models. In causal mediation analyses, we decomposed the total effect of aetiology on mortality into direct and indirect (mediated through LVEF) effects. RESULTS: For the analysed aetiologies (dilated (DCM, n=1009) and hypertrophic (HCM, n=89) cardiomyopathy; ischaemic (IHD, n=529) and hypertensive (HHD, n=320) heart disease; cardiac amyloidosis (CA, n=109)), the effect of LVEF on mortality was similar (HR5%-points lower LVEF=1.07, 95% CI 1.04 to 1.10; pinteraction=0.718). HCM and CA were associated with significantly higher, and IHD and DCM with significantly lower LVEF compared with other aetiologies. Compared with respective other aetiologies, the corresponding total effect HRs for mortality were 0.77 (95% CI 0.67 to 0.89), 0.47 (95% CI 0.25 to 0.88), 1.40 (95% CI 1.21 to 1.62), 0.79 (95% CI 0.67 to 0.95) and 2.36 (95% CI 1.81 to 3.08) for DCM, HCM, IHD, HHD and CA, respectively. CA had the highest mortality despite a HRindirect effect of 0.74 (95% CI 0.65 to 0.83). For all other aetiologies, <20% of the total mortality effects were mediated through LVEF. CONCLUSIONS: The direct effect of aetiology on mortality dominates the indirect effect through LVEF. Therefore, clarification of aetiology is as important as measurement of LVEF.

Prediagnostic markers of insulin resistance and prostate cancer risk and death: A pooled study.

BACKGROUND: Insulin resistance has been shown to be related to a higher risk of several cancers, but the association with prostate cancer (PCa) has been inconsistent. METHODS: We investigated prediagnostic markers of insulin resistance in men in four cohorts in Sweden, in relation to PCa risk (total, non-aggressive and aggressive) and PCa death using multivariable-adjusted Cox regression. The number of men, PCa cases and PCa deaths was up to 66,668, 3940 and 473 for plasma glucose and the triglyceride-glucose (TyG) index, and up to 3898, 586 and 102 for plasma insulin, glycated haemoglobin (HbA1c) and leptin. RESULTS: Higher HbA1c was related to a lower risk of non-aggressive PCa but no significant associations were found for insulin resistance markers with the risk of aggressive or total PCa. In PCa cases, higher glucose and TyG index were related to a higher risk of PCa death (hazard ratio [HR] per higher standard deviation, 1.22, 95% CI 1.00-1.49 and 1.24, 95% CI 1.00-1.55), which further increased when restricting the analyses to glucose and TyG index measures taken <10 years before the PCa diagnosis (HR, 1.70, 95% CI 1.09-2.70 and 1.66, 95% CI 1.12-2.51). No associations were observed for other markers in relation to PCa death. CONCLUSIONS: The results of this study showed no associations of insulin resistance markers with the risk of clinically relevant PCa, but higher glucose and TyG index were associated with poorer survival from PCa. The lack of association for other insulin resistance markers may be due to their smaller sample size.

Metabolically (un)healthy obesity and risk of obesity-related cancers: a pooled study.

BACKGROUND: Studies of obesity with or without metabolic aberrations, commonly termed metabolically unhealthy or healthy obesity, in relation to cancer risk are scarce. METHODS: We investigated body mass index (normal weight, overweight, obesity) jointly and in interaction with metabolic health status in relation to obesity-related cancer risk (n = 23 630) among 797 193 European individuals. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to define metabolically healthy and unhealthy status. Hazard ratios (HRs) and multiplicative interactions were assessed using Cox regression, and additive interactions were assessed using the relative excess risk for interaction. All statistical tests were 2-sided. RESULTS: Metabolically unhealthy obesity, with a baseline prevalence of 7%, was, compared with metabolically healthy normal weight, associated with an increased relative risk of any obesity-related cancer and of colon, rectal, pancreas, endometrial, liver, gallbladder, and renal cell cancer (P < .05), with the highest risk estimates for endometrial, liver, and renal cell cancer (HR = 2.55-3.00). Metabolically healthy obesity showed a higher relative risk for any obesity-related cancer and colon (in men), endometrial, renal cell, liver, and gallbladder cancer, though the risk relationships were weaker. There were no multiplicative interactions, but there were additive, positive interactions between body mass index and metabolic health status on obesity-related and rectal cancer among men and on endometrial cancer (P < .05). CONCLUSIONS: This study highlights that the type of metabolic obesity phenotype is important when assessing obesity-related cancer risk. In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.

Smoking and Risk of Prostate Cancer and Prostate Cancer Death: A Pooled Study.

BACKGROUND: Prospective and detailed investigations of smoking and prostate cancer (PCa) risk and death are lacking. OBJECTIVE: To investigate prediagnosis smoking habit (status, intensity, duration, and cessation) as a risk factor, on its own and combined with body mass index (BMI), for PCa incidence and death. DESIGN, SETTING, AND PARTICIPANTS: We included 351448 men with smoking information from five Swedish cohorts. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used Cox regression to calculate hazard ratios (HRs) and confidence intervals (CIs) for PCa incidence (n = 24731) and death (n = 4322). RESULTS AND LIMITATIONS: Smoking was associated with a lower risk of any PCa (HR 0.89, 95% CI 0.86-0.92), which was most pronounced for low-risk PCa (HR 0.74, 95% CI 0.69-0.79) and was restricted to PCa cases diagnosed in the prostate-specific antigen (PSA) era. Smoking was associated with a higher risk of PCa death in the full cohort (HR 1.10, 95% CI 1.02-1.18) and in case-only analysis adjusted for clinical characteristics (HR 1.20, 95% CI 1.11-1.31), which was a consistent finding across case groups (p = 0.8 for heterogeneity). Associations by smoking intensity and, to lesser degree, smoking duration and cessation, supported the associations for smoking status. Smoking in combination with obesity (BMI ≥30 kg/m2) further decreased the risk of low-risk PCa incidence (HR 0.40, 95% CI 0.30-0.53 compared to never smokers with BMI <25 kg/m2) and further increased the risk of PCa death (HR 1.49, 95% CI 1.21-1.84). A limitation of the study is that only a subgroup of men had information on smoking habit around the time of their PCa diagnosis. CONCLUSIONS: The lower PCa risk for smokers in the PSA era, particularly for low-risk PCa, can probably be attributed to low uptake of PSA testing by smokers. Poor survival for smokers, particularly obese smokers, requires further study to clarify the underlying causes and the preventive potential of smoking intervention for PCa death. PATIENT SUMMARY: Smokers have a higher risk of dying from prostate cancer, which further increases with obesity.

Real-world comparison of Docetaxel versus new hormonal agents in combination with androgen-deprivation therapy in metastatic hormone-sensitive prostate cancer descrying PSA Nadir ≤ 0.05 ng/ml as marker for treatment response.

PROPOSE: Using Docetaxel chemotherapy or new hormonal agents (NHT) to intensify upfront systemic therapy resulted in improved survival rates compared to androgen deprivation monotherapy (ADT). Hence, combination therapies have become the new standard of care (SOC) in metastatic hormone-sensitive prostate cancer (mHSPC). However, head-to-head trails comparing different therapies as well as treatment-guiding biomarkers are still lacking. Thus, the aim of the present study was to compare clinical outcomes of Docetaxel versus NHT therapy in the real-world setting as well as to elaborate biomarkers predicting clinical outcome. METHODS: We retrospectively assessed overall-survival (OS), progression-free survival 1 and 2 (PFS1/2) and time to progression (TTP) in 42 patients treated by either ADT + NHT or ADT + Docetaxel. In addition, we investigated clinical prognostic biomarkers. RESULTS: Our survival analysis revealed 3-year OS of 89.4% in the NHT group compared to 82.4% in the Docetaxel group. 3-year PFS1 was 59.6% in the NHT group compared to 32.2% in the Docetaxel group and the TTP was 53.8% vs 32.2% (pOS = 0.189; pPFS1 = 0.082; pTTP = 0.055). In addition, castration-resistance occurred more often in the Docetaxel group (78.6% vs 25%, p = 0.004). Interestingly, a PSA-Nadir ≤ 0.05 ng/ml during therapy was associated with increased survival rates (p < 0.001) while PSA levels at primary diagnosis had no influence on therapy outcome. Furthermore, a thyroid-stimulating hormone (TSH) increase during therapy was associated with improved clinical outcome (p = 0.06). CONCLUSION: We observed a trend towards a higher benefit of NHT as first-line treatment compared to Docetaxel in men with mHSPC. Of note, a PSA-Nadir ≤ 0.05 ng/ml or a TSH-increase during therapy were predictors for therapy response.

Do we need repeated CT imaging in uncomplicated blunt renal injuries? Experiences of a high-volume urological trauma centre.

BACKGROUND: Current guidelines recommend repeat computed tomography (CT) imaging in high-grade blunt renal injury within 48-96 h, yet diagnostic value and clinical significance remain controversial. The aim of this work was to determine the possible gain of CT re-imaging in uncomplicated patients with blunt renal trauma at 48 h after injury, presenting one of the largest case series. METHODS: A retrospective database of patients admitted to our centre with isolated blunt renal trauma due to sporting injuries was analysed for a period of 20 years (2000-2020). We included only patients who underwent repeat imaging at 48 h after trauma irrespective of AAST renal injury grading (grade 1-5) and initial management. The primary outcome was intervention rates after CT imaging at 48 h in uncomplicated patients versus CT scan at the time of clinical symptoms. RESULTS: A total of 280 patients (mean age: 37.8 years; 244 (87.1%) male) with repeat CT after 48 h were included. 150 (53.6%) patients were classified as low-grade (grade 1-3) and 130 (46.4%) as high-grade (grade 4-5) trauma. Immediate intervention at trauma was necessary in 59 (21.1%) patients with high-grade injuries: minimally invasive therapy in 48 (81.4%) and open surgery in 11 (18.6%) patients, respectively. In only 16 (5.7%) cases, intervention was performed based on CT re-imaging at 48 h (low-grade vs. high-grade: 3.3% vs. 8.5%; p = 0.075). On the contrary, intervention rate due to clinical symptoms was 12.5% (n = 35). Onset of clinical progress was on average (range) 5.3 (1-17) days post trauma. High-grade trauma (odds ratio [OR]grade 4 vs. grade 3, 14.62; p < 0.001; ORgrade 5 vs. grade 3, 22.88, p = 0.004) and intervention performed at the day of trauma (OR 3.22; p = 0.014) were powerful predictors of occurrence of clinical progress. CONCLUSION: Our data suggest that routine CT imaging 48 h post trauma can be safely omitted for patients with low- and high-grade blunt renal injury as long as they remain clinically stable. Patients with high-grade renal injury have the highest risk for clinical progress; thus, close surveillance should be considered especially in this group.

Nephrotoxicity and hematotoxicity one year after four cycles of peptide receptor radionuclide therapy (PRRT) and its impact on future treatment planning - A retrospective analysis.

PURPOSE: Nephro- and hematotoxicity after peptide receptor radionuclide therapy (PRRT) have been described in multiple studies with heterogeneous cumulative activities, number of cycles or radiolabelled peptides. Though highly differentiated metastasized neuroendocrine tumours (NET) have long progression free survival, they may progress. We analysed long-term side effects in a homogenous treatment schedule in PRRT-patients and their impact on future oncologic treatment in case of progression. METHODS: From our database 89/384 patients receiving the same PRRT (Lu-177-DOTATATE or Y-90-DOTATOC) 4 times every 10-12 weeks and a follow-up at 12 months were analysed. One patient had three and 11 patients had two times four PRRT-cycles resulting in 102 cases. eGFR, Hb, WBC and platelets before the first and one year after the fourth therapy cycle were compared. eGFR-Grading was done according to chronic kidney disease classification (CKD) and grading of hematotoxicity according to CTCAE. Impact of age, gender, cumulative activity, type of PRRT on long-term-toxicity was also assessed. RESULTS: eGFR grade 1-2 dropped from 87/102 at the baseline to 71 cases at follow-up (p < 0.001). Before treatment grade 3a was found in 13, grade 3b in 2 cases, and at follow-up grade 3a in 25, grade 3b in 5, and grade 4 in 1 case. Anaemia prior to PRRT and at follow-up was grade 0 in 63 versus 48 (p < 0.001), grade 1 in 36 versus 48, and grade 2 in three versus six cases. In white blood cell count and platelets, there were no significant changes in grading occurring. Subgroup analysis revealed that only in the age group 65 and older was there a higher incidence for anaemia (p = 0.006). CONCLUSION: In roughly 20% of cases an increase in grading of nephro- or hematotoxicity is observed. In those patients, except in one, toxicity findings were mild or moderate one year after completion of four cycles of PRRT with either Y-90- or Lu-177-SST-analogues. In terms of safety, PRRT has no critical impact on further oncologic treatment options in the case of disease progression.

Seasonal Variations in the Diagnosis of Testicular Germ Cell Tumors: A National Cancer Registry Study in Austria.

We conducted a retrospective National Cancer Registry study in Austria to assess a possible seasonal variation in the clinical diagnosis of testicular germ cell tumors (TGCT). In total, 3615 testicular cancer diagnoses were identified during an 11-year period from 2008 to 2018. Rate ratios for the monthly number of TGCT diagnoses, as well as of seasons and half-years, were assessed using a quasi-Poisson model. We identified, for the first time, a statistically significant seasonal trend (p < 0.001) in the frequency of monthly newly diagnosed cases of TGCT. In detail, clear seasonal variations with a reduction in the tumor incidence during the summer months (Apr-Sep) and an increase during the winter months (Oct-Mar) were observed (p < 0.001). Focusing on seasonality, the incidence during the months of Oct-Dec (p = 0.008) and Jan-Mar (p < 0.001) was significantly higher compared to the months of Jul-Sep, respectively. Regarding histopathological features, there is a predominating incidence in the winter months compared to summer months, mainly concerning pure seminomas (p < 0.001), but not the non-seminoma or mixed TGCT groups. In conclusion, the incidence of TGCT diagnoses in Austria has a strong seasonal pattern, with the highest rate during the winter months. These findings may be explained by a delay of self-referral during the summer months. However, the hypothetical influence of vitamin D3 in testicular carcinogenesis underlying seasonal changes in TGCT diagnosis should be the focus of further research.

Comparison of Early Imaging and Imaging 60 min Post-Injection after Forced Diuresis with Furosemide in the Assessment of Local Recurrence in Prostate Cancer Patients with Biochemical Recurrence Referred for 68Ga-PSMA-11 PET/CT.

BACKGROUND: 68Ga-PSMA-11 PET/CT is a promising method for the assessment of local recurrence (LR) in prostate cancer (PCa) patients. The aim of this study was to evaluate the diagnostic performance of early 68Ga-PSMA-11 PET imaging in comparison to 68Ga-PSMA-11 PET imaging 60 min post-injection (p.i.) in the detection of LR in patients with biochemical recurrence (BR) of prostate carcinoma. MATERIALS AND METHODS: 190 image sets of patients with BR in PCa who underwent 68Ga-PSMA-11 PET/CT were assessed retrospectively (median prostate specific antigen (PSA) value, 0.70 ng/mL (range, 0.1-105.6 ng/mL)). Patients received an early static scan of the pelvic area (median, 248 s p.i. (range, 56-923 s)) and a whole-body scan 60 min p.i. (median, 64 min p.i. (range, 45-100 min)) with intravenous administration of 20 mg furosemide i.v. at the time of tracer application, followed by intravenous hydration with 500 mL of sodium chloride (NaCl 0.9%). Assessment was based on visual analysis and calculation of the maximum standardized uptake value (SUVmax) of the pathologic lesions present in the prostate fossa found in the early PET imaging and 60 min PET scans. The scans were characterized as negative, positive, or equivocal. The results were compared, and the combination of early and 60 min p.i. imaging was evaluated. RESULTS: Image assessment resulted in 30 (15.8%) positive, 17 (8.9%) equivocal, and 143 (75.3%) negative findings in early scans, and 28 (14.7%) positive, 25 (13.2%) equivocal, and 137 (72.1%) negative findings of LR in 60 min p.i. images. For combined image analysis, 33 (17.4%) cases were positive and 20 (10.5%) were equivocal. There was no statistical significance between the number of positive (p = 0.815), negative (p = 0.327), and equivocal (p = 0.152) findings. Furthermore, the combination of both scans showed no statistically significant differences for the positive and negative findings (p = 0.063). The median SUVmax was 4.9 (range, 2.0-55.2) for positive lesions in the early scans and 8.0 (range, 2.1-139.9) in the scans 60 min p.i. The median SUVmax for bladder activity was 2.5 (range, 0.9-12.2) in the early scans and 8.2 (range, 1.8-27.6) in the scans 60 min p.i. CONCLUSION: Early static imaging additional to 68Ga-PSMA-11 PET images acquired 60 min p.i. has limited value in patients prepared with furosemide and hydration, and showed no statistically significant change in the detection rate (DR) of LR and the number of equivocal findings. Based on our results, in departments following a protocol with forced diuresis, including furosemide, additional early static imaging cannot be routinely recommended for the assessment of BR in PCa patients.

Administration of fibrinogen concentrate combined with prothrombin complex maintains hemostasis in children undergoing congenital heart repair (a long-term propensity score-matched study).

BACKGROUND: Bleeding is a common problem in children with congenital heart disease undergoing major cardiac surgery requiring cardiopulmonary bypass (CPB). Little is known about optimal management with blood products. OBJECTIVE: To investigate clinical outcome and hemostatic effects of fibrinogen concentrate (FC) in combination with prothrombin complex concentrate (PCC) versus standard treatment with fresh frozen plasma (FFP) in children undergoing cardiac surgery. METHODS: For this single-institution cohort study, data on 525 children were analyzed. Propensity score matching in 210 children was applied to reduce the impact of various baseline characteristics. RESULTS: Three children treated with FC/PCC developed surgical site bleeding requiring surgical revision. One child developed central venous line-related thrombosis. Blood loss through chest tube drainage was independent of FC/PCC. Coagulation abnormalities were not present in any of these children. Time to extubation and ICU stay did not differ. In the FC/PCC group, children received (median, Q1, Q3) 52 mg/kg (32, 83) FC and 28IU/kg (13, 44) PCC. Fibrinogen concentration was comparable at baseline. On admission to the ICU, fibrinogen was higher in children receiving FC/PCC, namely, 232 mg/dL (196, 280), than in children receiving FFP (186 mg/dL, 149, 224; P < .001). On discharge from the ICU, values did not differ ((FC/PCC 416 mg/dL (288, 501)), non-FC/PCC 418 mg/dL (272, 585; P = 1.000)). CONCLUSION: FC/PCC was well tolerated and permitted hemostasis to be maintained, even in the very young. We were not able to detect a signal for inferiority of this treatment. We conclude that FC/PCC can safely replace FFP.

The "COVID-19 Pandemic Gap" and Its Influence on Oncologic Outcomes of Bladder Cancer.

Coronavirus-19 (COVID-19)-induced effects on deferred diagnosis and treatment of bladder cancer (BC) patients are currently not clarified. The aim of this study was to evaluate outcomes of the COVID-19 pandemic by considering its effects on tumor stage and grade, and to create feasible clinical triage decisions. A retrospective single-center analysis of all patients who underwent diagnostic and surgical procedures due to BC, during January 2019 and December 2020, was performed. Due to COVID-19 lockdowns, significantly fewer (diagnostic and therapeutic) endoscopic procedures were performed in the first 6 months of 2020 compared to 2019 (p = 0.002). In patients with a primary diagnosis of BC, a significant increase of high-grade tumors (p < 0.001), as well as advanced tumor stages (p = 0.014), were noticed during 2020 in comparison to 2019. On the contrary, patients with recurrent BC undergoing risk-adapted surveillance, depending on previous tumor histology, showed no adverse outcomes regarding tumor stage and grade when comparing the pre COVID-19 era with 2020. Thus, more awareness in clinical urologic practice is mandatory to avoid adverse consequences, with increased rates of advanced and aggressive tumors in patients with primary BC. In recurrent BC, an individual risk stratification in order to avoid worse outcomes during the COVID-19 pandemic seems to be justified.

Cardiac output and cerebral blood flow during carotid surgery in regional versus general anesthesia: A prospective randomized controlled study.

OBJECTIVE: Carotid endarterectomy (CEA) is a preventive procedure aimed at decreasing the subsequent risk of fatal or disabling stroke in patients with significant carotid stenosis. It is well-known that carotid surgery under ultrasound-guided regional anesthesia (US-RA) causes a significant increase in blood pressure, heart rate and stress hormone levels owing to increased sympathetic activity. However, little is known about the effects on cardiac output (CO), cardiac index (CI), and cerebral blood flow (CBF) under US-RA as compared with general anesthesia (GA). METHODS: Patients scheduled for CEA were randomized prospectively to receive US-RA (n = 37) or GA (n = 41). The primary end point was the change in CI after induction of anesthesia and the change from baseline over time at four different times during the entire procedure in the respective randomized US-RA and GA groups. In addition to systolic blood pressure and heart rate, we also recorded peak systolic velocity, end-diastolic velocity, and minimum diastolic velocity as seen from transcranial Doppler ultrasound examination, as well as regional cerebral oxygenation (rSO2) as seen from near-infrared refracted spectroscopy to evaluate cerebral blood flow. RESULTS: In the US-RA group, the CI increased after induction of anesthesia (3.7 ± 0.8 L/min/m2) and remained constant until the end of the procedure. In the GA group CI was significantly lower (2.4 ± 0.6 L/min/m2; P < .001). After induction of anesthesia, the rSO2 remained constant in the GA group on both the ipsilateral (63 ± 9 rSO2) and the contralateral (65 ± 7 rSO2) sides; in contrast, it significantly increased in the US-RA group (ipsilateral 72 ± 8 rSO2; P < .001; contralateral 72 ± 6 rSO2; P < .001). The transcranial Doppler ultrasound parameters (peak systolic velocity, end-diastolic velocity, and minimum diastolic velocity) did not differ between the US-RA and the GA group. The clinical outcome was similarly favorable for both groups. CONCLUSIONS: CI was maintained near baseline values throughout the procedure during US-RA, whereas a significant decrease in CI values was observed during CEA under GA. Near-infrared refracted spectroscopy values, reflecting blood flow in small vessels, were higher in US-RA patients than in those with GA. These differences did not influence clinical outcome.

Early Injection of Furosemide Increases Detection Rate of Local Recurrence in Prostate Cancer Patients with Biochemical Recurrence Referred for 68Ga-PSMA-11 PET/CT.

The aim of this study was twofold. First, we aimed to assess the impact of forced diuresis with early furosemide injection on the detection rate of local recurrence in prostate cancer patients with biochemical recurrence referred for 68Ga-labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC (68Ga-PSMA-11) PET/CT. Second, we determined whether intravenous administration of furosemide shortly after tracer injection increases renal washout of 68Ga-PSMA-11 before it binds to the PSMA receptor with possible influence on biodistribution and intensity of tracer uptake in organs with physiologic tracer accumulation. Methods: In a retrospective analysis, 2 different groups with 220 prostate cancer patients each, referred for 68Ga-PSMA-11 PET/CT because of biochemical recurrence after primary therapy, were compared: patients in group 1 (median prostate-specific antigen, 1.30 ng/mL) received no preparation before imaging, whereas patients in group 2 (median prostate-specific antigen, 0.82 ng/mL) were injected with 20 mg of furosemide and 500 mL of sodium chloride (NaCl 0.9%) immediately after tracer injection. The presence of local recurrence was assessed visually. In addition, the intensity of tracer accumulation in organs with physiologic tracer uptake was evaluated. Results: The detection rate of lesions judged positive for local recurrence was significantly higher in patients receiving furosemide than in patients without preparation: 56 cases (25.5%) versus 38 cases (17.3%), respectively (P = 0.048). Median maximum SUVs (SUVmax) of organs with physiologic uptake of 68Ga-PSMA-11 in groups 1 and 2 were urinary bladder (63.0 vs. 8.9), kidney (55.6 vs. 54.5), liver (9.9 vs. 9.4), spleen (11.2 vs. 11.9), small bowel (16.2 vs. 17.1), parotid gland (19.2 vs. 19.6), lacrimal gland (8.9 vs. 10.9), blood-pool activity (2.2 vs. 2.3), muscle (1.0 vs. 1.1), and bone (1.6 vs. 1.6). Apart from bladder activity, no significant reduction of tracer accumulation was found in the patient group receiving furosemide. Conclusion: Injection of 20 mg of furosemide at the time point of radiotracer administration significantly increases the detection rate of local recurrence in prostate cancer patients with biochemical recurrence referred for 68Ga-PSMA-11 PET/CT. As intensity of 68Ga-PSMA-11 uptake in organs with physiologic uptake is not significantly reduced, a negative impact of early furosemide injection on targeting properties and biodistribution of 68Ga-PSMA-11 seems unlikely.

Impact of forced diuresis with furosemide and hydration on the halo artefact and intensity of tracer accumulation in the urinary bladder and kidneys on [68Ga]Ga-PSMA-11-PET/CT in the evaluation of prostate cancer patients.

PURPOSE: to assess the influence of intravenous hydration and forced diuresis with furosemide in two different dosages (20 vs 40 mg) on the intensity of tracer accumulation in the urinary collection system and on the occurrence of halo artefact surrounding the urinary bladder and kidneys in [68Ga]Ga-PSMA-11-PET/CT scans. MATERIALS AND METHODS: Comparison of four groups with 50 patients each, receiving different preparation prior to [68Ga]Ga-PSMA-11-PET/CT. Group one, no preparation. Group two, 500 ml sodium chloride administered immediately after tracer injection. Group three, 500 ml sodium chloride and injection of 20 mg furosemide immediately after tracer administration. Group four, 500 ml sodium chloride and injection of 40 mg furosemide immediately after tracer injection. Images were judged visually whether halo artefact was present; semiquantitative measurements were performed with standardised uptake value (SUV). RESULTS: Halo artefact of the urinary bladder was present in twelve patients without preparation, in eight patients receiving only sodium chloride, in one patient injected with 20 mg furosemide/sodium chloride and in two patients receiving 40 mg furosemide/sodium chloride, showing a median SUVmean in the bladder of 45.8, 14.4, 4.6 and 5.8, respectively. Differences between patient group without preparation and the two groups with furosemide/sodium chloride were statistically significant. Patient groups receiving 20 mg furosemide and 40 mg furosemide did not differ significantly. Renal halo artefacts were observed in 15 patients of group one, in ten patients of group two, in 14 patients of group three and in 14 patients of group four, with corresponding median SUVmean values of 33.9, 32.0, 37.8 and 30.4 (no statistically significant differences). CONCLUSION: Performing [68Ga]Ga-PSMA-11-PET/CT, intravenous injection of 20-mg furosemide and 500-ml sodium chloride significantly reduces the number of bladder halo artefacts and intensity of tracer accumulation in the urinary bladder. A total of 40 mg furosemide does not further improve results.

Benefits of risk-adapted and mould-specific antifungal prophylaxis in childhood leukaemia.

Fluconazole is one of the most commonly used drugs for antifungal prophylaxis in childhood leukaemia. However, its interaction with vincristine may induce neuropathy and the emergence of antifungal drug resistance contributes to substantial mortality caused by invasive fungal infections (IFIs). In a retrospective single-centre study, we compared tolerability and outcome of different antifungal prophylaxis strategies in 198 children with acute leukaemia (median age 5·3 years). Until 2010, antifungal prophylaxis with fluconazole was offered to most of the patients and thereafter was replaced by liposomal amphotericin-B (L-AMB) and restricted to high-risk patients only. Vincristine-induced neurotoxicity was significantly reduced under L-AMB, as the percentage of patients with severe constipation decreased (15·4% vs. 3·7%, before vs. after 31 December·2010, P = 0·01) and stool frequency increased by up to 38% in polyene-treated patients (P = 0·005). Before 2011, 10 patients developed confirmed IFIs, most of them were infected with Aspergillus species. After risk adaption in 2011, IFIs were completely prevented (P = 0·007). L-AMB prophylaxis is beneficial in childhood leukaemia patients, as it offers effective antifungal activity with improved tolerability as compared to fluconazole. The potential impact of our risk-adapted antifungal treatment should be included in current prophylaxis guidelines for childhood leukaemia.

The triglyceride-glucose index as a measure of insulin resistance and risk of obesity-related cancers.

BACKGROUND: The role of insulin resistance as a mediator in the association of body mass index (BMI) with site-specific cancer risk has, to our knowledge, never been systematically quantified. METHODS: Altogether 510 471 individuals from six European cohorts, with a mean age of 43.1 years, were included. We used the triglyceride glucose product (TyG index) as a surrogate measure for insulin resistance. We fitted Cox models, adjusted for relevant confounders, to investigate associations of TyG index with 10 common obesity-related cancers, and quantified the proportion of the effect of BMI mediated through TyG index on the log-transformed hazard ratio (HR) scale. RESULTS: During a median follow-up of 17.2 years, 16 052 individuals developed obesity-related cancers. TyG index was associated with the risk of cancers of the kidney HR per one standard deviation increase 1.13, 95% confidence interval: 1.07 to 1.20], liver (1.13, 1.04 to 1.23), pancreas (1.12, 1.06 to 1.19), colon (1.07, 1.03 to 1.10) and rectum (1.09, 1.04 to 1.14). Substantial proportions of the effect of BMI were mediated by TyG index for cancers of the pancreas (42%), rectum (34%) and colon (20%); smaller proportions for kidney (15%) and liver (11%). Little or no mediation was observed for breast (postmenopausal), endometrial and ovarian cancer. Results were similar for males and females, except for pancreatic cancer where the proportions mediated were 20% and 91%, respectively. CONCLUSIONS: The TyG index was associated with increased risk of cancers of the digestive system and substantially mediated the effect of BMI, suggesting that insulin resistance plays a promoting role in the pathogenesis of gastrointestinal cancers.

Positive family history of cardiovascular disease and long-term outcomes after coronary artery bypass grafting: a genetic paradox?

OBJECTIVES: Parental cardiovascular disease (CVD) is a known risk factor for premature CVD. It is unknown whether a positive family history (PFH) affects outcomes after coronary artery bypass grafting (CABG). METHODS: Data come from a retrospective longitudinal study of CABG patients consecutively recruited from 2001 to 2018 (n = 5389). From this study, 2535 patients with premature CVD undergoing CABG under the age of 60 years and information on parental CVD were identified. The Framingham offspring study criteria were used to identify PFH of CVD. Multivariable Cox proportional hazards regression models were used to assess the effect of PFH on overall and major adverse cardiovascular and cerebrovascular event-free survival. RESULTS: A total of 273 deaths and 428 major adverse cardiovascular and cerebrovascular events occurred during follow-up. PFH of CVD was found in 54.2% of patients (n = 1375). Within these patients, 66.1% had a father who experienced a premature cardiovascular event (n = 909), 27.8% a mother (n = 382) and 6.1% both a mother and a father (n = 84). In the majority of cases, the patient's parent had experienced a cardiac event (85.9%, n = 1181) and 14.1% of patients with PFH reported parental stroke (n = 194). Following CABG, PFH was associated with improved overall [adjusted hazards ratio (HR) 0.67, 95% confidence interval (CI) 0.50-0.90; P = 0.008] and major adverse cardiovascular and cerebrovascular event-free survival (adjusted HR 0.73, 95% CI 0.68-0.89; P = 0.01). Among the covariates adjusted for age, diabetes, renal insufficiency, peripheral arterial disease, ejection fraction, previous cerebrovascular events and previous mediastinal radiation were all associated with poorer outcomes. CONCLUSIONS: Although it is well established that a PFH increases the risk of requiring CABG at younger ages, this study shows that, paradoxically, PFH is also protective regarding long-term outcomes. REGISTRATION NUMBER LOCAL IRB: UN4232 297/4.3 (retrospective study).

Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study.

BACKGROUND & AIMS: Little is known about outcomes of liver transplantation for patients with non-alcoholic steatohepatitis (NASH). We aimed to determine the frequency and outcomes of liver transplantation for patients with NASH in Europe and identify prognostic factors. METHODS: We analysed data from patients transplanted for end-stage liver disease between January 2002 and December 2016 using the European Liver Transplant Registry database. We compared data between patients with NASH versus other aetiologies. The principle endpoints were patient and overall allograft survival. RESULTS: Among 68,950 adults undergoing first liver transplantation, 4.0% were transplanted for NASH - an increase from 1.2% in 2002 to 8.4% in 2016. A greater proportion of patients transplanted for NASH (39.1%) had hepatocellular carcinoma (HCC) than non-NASH patients (28.9%, p <0.001). NASH was not significantly associated with survival of patients (hazard ratio [HR] 1.02, p = 0.713) or grafts (HR 0.99; p = 0.815) after accounting for available recipient and donor variables. Infection (24.0%) and cardio/cerebrovascular complications (5.3%) were the commonest causes of death in patients with NASH without HCC. Increasing recipient age (61-65 years: HR 2.07, p <0.001; >65: HR 1.72, p = 0.017), elevated model for end-stage liver disease score (>23: HR 1.48, p = 0.048) and low (<18.5 kg/m2: HR 4.29, p = 0.048) or high (>40 kg/m2: HR 1.96, p = 0.012) recipient body mass index independently predicted death in patients transplanted for NASH without HCC. Data must be interpreted in the context of absent recognised confounders, such as pre-morbid metabolic risk factors. CONCLUSIONS: The number and proportion of liver transplants performed for NASH in Europe has increased from 2002 through 2016. HCC was more common in patients transplanted with NASH. Survival of patients and grafts in patients with NASH is comparable to that of other disease indications. LAY SUMMARY: The prevalence of non-alcoholic fatty liver disease has increased dramatically in parallel with the worldwide increase in obesity and diabetes. Its progressive form, non-alcoholic steatohepatitis, is a growing indication for liver transplantation in Europe, with good overall outcomes reported. However, careful risk factor assessment is required to maintain favourable post-transplant outcomes in patients with non-alcoholic steatohepatitis.

Intrathecal Baclofen Trial Before Device Implantation: 12-Year Experience With Continuous Administration.

OBJECTIVE: To report our experience using continuous intrathecal baclofen (ITB) administration prior to a possible ITB device implantation. DESIGN: Retrospective open label study. Mean duration of follow-up 64 months. SETTING: Primary-care and referral center, ambulatory and hospitalized care. PARTICIPANTS: Patients (N=116) undergoing continuous ITB trials between 2006 and 2017. INTERVENTIONS: Continuous application of baclofen via a temporary intrathecal catheter connected to an external pump. MAIN OUTCOME MEASURES: Assessment of the modified Ashworth Scale and range of movement prior versus end of ITB trial. According to the Barthel Index, definition of high-level patients (60-100 scoring points) and low-level patients (0-55 scoring points). Calculation of the Rivermead Mobility Index in high-level patients prior versus end of ITB trial. Evaluation of occurring adverse events. RESULTS: A total of 119 ITB trials were performed in 116 patients (78 men, mean age 41±16), 113 patients completed the trials (31 of 113 high level, 82 of 113 low level). The median modified Ashworth scale improved from 4 (interquartile range [IQR] 3-4) to 2 (IQR 1-2; P≤.001), the range of movement from 2 (IQR 1-3) to 3 (IQR 3-3; P≤.001). The Rivermead Mobility Index increased from 9 (IQR 6-12) to 10 (IQR 7-12.5; P=.004) in high-level patients. Eighty-eight out of 113 patients (78%) were appropriate candidates for ITB device surgery, 75 of 88 (85%) proceeded to an implantation. A total of 69 adverse events occurred in 57 of 119 trials (48%), 37 of 69 (54%) were drug related, 32 of 69 (46%) were procedure related, and 42 of 69 (61%) were minor. The ITB device was implanted in 69 of 75 patients (92%) at last follow-up. CONCLUSIONS: Continuous administration of ITB is an effective and useful alternative to ITB bolus application during ITB screening period. Half of the patients experienced adverse events; the majority were minor events.