Intra-arterial peptide-receptor radionuclide therapy for neuro-endocrine tumour liver metastases: an in-patient randomised controlled trial (LUTIA).

PURPOSE: Peptide receptor radionuclide therapy (PRRT) using [177Lu]Lu-DOTATATE has been shown to effectively prolong progression free survival in grade 1-2 gastroenteropancreatic neuroendocrine tumours (GEP-NET), but is less efficacious in patients with extensive liver metastases. The aim was to investigate whether tumour uptake in liver metastases can be enhanced by intra-arterial administration of [177Lu]Lu-DOTATATE into the hepatic artery, in order to improve tumour response without increasing toxicity. METHODS: Twenty-seven patients with grade 1-2 GEP-NET, and bi-lobar liver metastases were randomized to receive intra-arterial PRRT in the left or right liver lobe for four consecutive cycles. The contralateral liver lobe and extrahepatic disease were treated via a "second-pass" effect and the contralateral lobe was used as the control lobe. Up to three metastases (> 3 cm) per liver lobe were identified as target lesions at baseline on contrast-enhanced CT. The primary endpoint was the tumour-to-non-tumour (T/N) uptake ratio on the 24 h post-treatment [177Lu]Lu-SPECT/CT after the first cycle. This was calculated for each target lesion in both lobes using the mean uptake. T/N ratios in both lobes were compared using paired-samples t-test. FINDINGS: After the first cycle, a non-significant difference in T/N uptake ratio was observed: T/NIA = 17·4 vs. T/Ncontrol = 16·2 (p = 0·299). The mean increase in T/N was 17% (1·17; 95% CI [1·00; 1·37]). Of all patients, 67% (18/27) showed any increase in T/N ratio after the first cycle. CONCLUSION: Intra-arterial [177Lu]Lu-DOTATATE is safe, but does not lead to a clinically significant increase in tumour uptake.

Propensity score matching demonstrates similar results for radiofrequency ablation compared to surgical resection in colorectal liver metastases.

PURPOSE: Minimally invasive ablative treatments, such as radiofrequency ablation (RFA), are increasingly used in the curative treatment of patients with colorectal liver metastases (CRLM). Selection bias plays an important role in the evaluation of early and late results between RFA and surgery. The purpose of this study was to evaluate recurrences and oncological survival following these two treatment modalities using single pair propensity score matching. METHODS: Between 2000 and 2018, patients curatively treated for CRLM were included in a multicentre database. Patients were excluded when receiving two-staged treatment, synchronous treatment with primary tumor or combination of modalities. Propensity score matching was used to minimize influence of known covariates, i.e., age, ASA, FONG CRS, location and T-stage of the primary tumor. RESULTS: Before matching, the RFA group contained 39 patients and the surgery group 982 patients, after matching both groups contained 36 patients. After matching, mean age was 69 years (53-86) for RFA and 68 (50-86) for surgery, with a mean tumor size of respectively 2.5 cm (0.8-6.5) and 3.4 cm (1-7.5). Both groups showed similar complication rate according to Clavien-Dindo (17vs.33%; p = 0.18), recurrence rate (58vs.64%; p = 0.09) without significant differences in 5-year DFS and OS (RFA compared to surgery respectively 25vs.37%; p = 0.09 and 42vs.53%; p = 0.09). CONCLUSION: After propensity score matching, RFA showed lower complications and similar oncological survival compared to surgical resection. In patients who are suboptimal candidates for surgery, RFA seems to be a good and safe alternative.

Genicular artery embolization as a novel treatment for mild to moderate knee osteoarthritis: protocol design of a randomized sham-controlled clinical trial.

INTRODUCTION: Knee osteoarthritis is a common disease with pain as the most prevalent symptom. Previous cohort studies have shown genicular artery embolization to reduce pain symptoms in patients with mild to moderate knee osteoarthritis. Patients resistant to conservative therapy but not eligible yet for surgical treatment due to young age or comorbidities may profit from an effective and sustained pain reduction treatment. This study is a randomized sham-controlled trial to evaluate the efficacy of genicular artery embolization in patients with knee osteoarthritis. METHODS AND ANALYSIS: Fifty-eight patients with mild-to-moderate knee osteoarthritis will be recruited and randomly allocated to the treatment or control group in a 1:1 ratio. Participants in the treatment group will undergo genicular artery embolization. Patients in the control group will undergo sham treatment. Outcome measurements will be assessed at baseline and after 1, 4, 8, and 12 months with questionnaires, pressure pain threshold testing, and MR imaging. The MR imaging protocol is designed to (semi)quantitatively assess osteoarthritis in the knee joint. The primary outcome is the change from baseline of the Knee injury and Osteoarthritis Outcome Score (KOOS) pain subscale after 4 months. Secondary outcomes include change in osteoarthritis-related questionnaires, pressure pain threshold, and OA-related MRI features, particularly synovitis and bone marrow lesions. ETHICS AND DISSEMINATION: This trial will determine the efficacy of genicular artery embolization compared to a sham treatment. This is of importance to assess before proceeding to larger-scale efficiency studies and, ultimately, implementing this treatment into day to day clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03884049. Registered on 21 March 2019.

Coronary CT angiography for suspected acute coronary syndrome: sex-associated differences.

AIM: The optimal diagnostic test in the work-up of suspected acute coronary syndrome (ACS) may differ between men and women. The aim of this study was to compare sex-associated differences between using a diagnostic strategy including early coronary computed tomography angiography (CCTA) and standard of care (SOC). METHODS: In total, 500 patients who presented with symptoms suggestive of ACS at the emergency department were randomised between a diagnostic strategy supplemented with early CCTA and SOC. RESULTS: Women were generally older than men (mean ± standard deviation 56 ± 10 vs 53 ± 10 years, p < 0.01) and were less often admitted to hospital (33% vs 44%, p = 0.02). Obstructive coronary artery disease on CCTA (> 50% luminal narrowing) was less frequently seen in women (14% vs 26%, p = 0.02), and ACS was diagnosed less often in women (5% vs 10%, p = 0.03). Women underwent less outpatient testing when early CCTA was used in the emergency department evaluation of suspected ACS (p = 0.008). CONCLUSION: Women had a lower incidence of obstructive CAD on CCTA and were less often admitted to hospital than men. They were subjected to less outpatient testing when early CCTA was used in the emergency department evaluation of suspected ACS.

Results after simultaneous surgery and RFA liver ablation for patients with colorectal carcinoma and synchronous liver metastases.

BACKGROUND: Approximately 20% of patients with colorectal cancer present with synchronous liver metastases (sCRLM). These patients can be treated with a "one-step procedure" or staged resection, with or without radiofrequency ablation (RFA). Colorectal surgery in combination with intraoperative RFA leads to concerns regarding postoperative complications and survival. The purpose was to evaluate the one-step procedure with or without RFA in patients with sCRLM. MATERIALS AND METHODS: Between January 2000 and September 2018, patients with sCRLM were selected in two tertiary referral centers and retrospectively analyzed. Postoperative morbidity and survival were analyzed. RESULTS: From a total of 410 patients presenting with sCRLM, 329 patients underwent a staged resection and 81 a one-step procedure. The 3-year overall survival (OS) was respectively 66% and 69% for one-step procedure and staged resection (P = 0.24). A total of 18 patients underwent RFA during the one step procedure. No significant differences were shown in postoperative complications whether intraoperative RFA was used in patients with sCRLM. In the one-step procedure, the 3-year OS was respectively 43% and 72% wheter patients did or did not receive RFA (P = 0.19). CONCLUSION: OS for patients with sCRLM was similar for both one-step procedure and staged resection. Intraoperative RFA for sCRLM is technically safe.

Adjuvant hepatic arterial infusion pump chemotherapy and resection versus resection alone in patients with low-risk resectable colorectal liver metastases - the multicenter randomized controlled PUMP trial.

BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 µg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone. DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival. TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.

[Radiofrequency ablation of a symptomatic benign thyroid nodule]. / Radiofrequente ablatie van symptomatische benigne schildkliernodus.

Radiofrequency ablation (RFA) enables the ablation of selected tissue by means of heat. For the first time in the Netherlands, RFA is being used to treat patients with benign thyroid nodules. RFA is able to reduce the volume of a nodule that may be causing cosmetic complaints or problems due to mass effect. This avoids the need for surgery or treatment with radioactive iodine in this benign condition. The average reduction in size is 80% in the first year, leading to a considerable decrease in both symptomatic and cosmetic complaints. At Erasmus Medical Centre, Rotterdam, the Netherlands, this technique has been introduced in accordance with current guidelines, and it is expected that other centres of excellence will follow in implementing it. It is important that the initial experiences with this technique in the Netherlands in terms of effectiveness, risks and patient satisfaction should be monitored before RFA becomes routine treatment.

Short term and long term results of patients with colorectal liver metastases undergoing surgery with or without radiofrequency ablation.

PURPOSE: The combination of resection and radiofrequency ablation (RFA) may provide an alternative treatment for patients with unresectable colorectal liver metastases (CRLM). Although the results in literature look promising, uncertainty exists with regard to complication risks and survival for this therapy. METHODS: From January 2000 to May 2013, patients were included in a prospective multicenter database when treated for CRLM. Exclusion criteria were: two-staged treatment, synchronous resection of liver metastases and primary tumor, loss to follow-up or extrahepatic metastases. Patients were divided in a resection-only group (ROG) and combination group (CG). Outcome variables were retrospectively analyzed. RESULTS: In CG, 98 patients were included versus 534 patients in ROG. There were no differences in general patient characteristics. Patients in CG had a higher Fong clinical risk score (CRS; P = 0.001), better ASA classification (P = 0.04) and received more neoadjuvant chemotherapy (P = 0.001). There was no difference in postoperative morbidity or 90-day mortality. The 5-year disease-free survival (DFS) for CG and ROG was 25% and 36.1% (P = 0.03), respectively. For the 5-year overall survival (OS) this was respectively 42% and 62.2% (P = 0.001). On multivariate analysis, Fong CRS was a significant predictor for DFS. For OS, Fong CRS, ASA class IV and the combination therapy were significant predictors. CONCLUSION: The combination of hepatic resection and intraoperative RFA is a safe procedure, without increase in postoperative morbidity or mortality. Combining RFA and resection in one session is a valid treatment option for patients who would otherwise be inoperable.

Ventricular function and cardiac reserve in contemporary Fontan patients.

BACKGROUND/OBJECTIVE: Total cavopulmonary connection (TCPC) has been the preferred treatment for patients with univentricular hearts. Current TCPC-techniques are the intra-atrial lateral tunnel (ILT) and the extracardiac conduit (ECC). We aimed to determine ventricular function during rest and stress, and to compare results for both techniques and for left (LV) versus right ventricular (RV) dominance. METHODS: 99 patients, aged 12.5 ± 4.0 years underwent echocardiography and magnetic resonance imaging (MRI), and 69 patients underwent stress MRI. RESULTS: Echocardiography showed impaired systolic and diastolic function. MRI parameters were comparable between ILT and ECC at rest. During dobutamine there was a decrease in end-diastolic volume (EDVi) (91 ± 21 vs. 80 ± 20 ml/m(2) p<0.001). Ejection fraction (EF) and cardiac index (CI) during dobutamine were lower for ILT patients (59 ± 11 (ILT) vs. 64 ± 7% (ECC), p=0.027 and 4.2 ± 1.0 (ILT) vs. 4.9 ± 1.0L/min/m(2) (ECC), p=0.006), whereas other parameters were comparable. TEI-index was higher in ILT-patients (0.72 ± 0.27 (ILT) vs. 0.56 ± 0.22 (ECC), p=0.002). Diastolic function was frequently impaired in patients with a dominant RV (67% (RV) vs. 39% (LV), p=0.011). Patients with dominant LV's had smaller end-systolic volume (ESVi) (40 ± 13 (LV) vs. 47 ± 16 (RV) ml/m(2), p=0.030) and higher EF (55 ± 8 (LV) vs. 49 ± 9 ml/m(2) (RV), p=0.001) and contractility (2.3 ± 0.8 (LV) vs. 1.9 ± 0.7 mmHg/ml/m(2) (RV), p=0.050) during rest and higher EF during dobutamine (63 ± 8 (LV) vs. 58 ± 10 ml/m(2) (RV), p=0.043). CONCLUSION: Ventricular function is relatively well preserved in modern-day Fontan patients. With dobutamine stress there is a decrease in EDVi. ECC patients have higher CI and EF during stress. Patients with a dominant RV have lower systolic, including impaired contractility, and diastolic function.

Percutaneous transhepatic biliary drainage in patients with postsurgical bile leakage and nondilated intrahepatic bile ducts.

OBJECTIVE AND BACKGROUND: Bile leakage is a serious postoperative complication and percutaneous transhepatic biliary drainage (PTBD) may be an option when endoscopic treatment is not feasible. In this retrospective study, we established technical and clinical success rates as well as the complication rates of PTBD in a large group of patients with postoperative bile leakage. METHODS: Data on all patients with nondilated intrahepatic bile ducts who underwent a PTBD procedure for the treatment of bile leakage between January 2000 and August 2012 were retrospectively assessed. Data included type of surgery, site of bile leak, previous attempts of bile leak repair, interval between surgery and PTBD placement. Outcome measures were the technical and clinical success rates, the procedure-related complications, and mortality rate. RESULTS: A total of 63 patients were identified; PTBD placement was technically successful in 90.5% (57/63) after one to three attempts. The clinical success rate was 69.8% (44/63). Four major complications were documented (4/63; 6.3%): liver laceration, pneumothorax, pleural empyema, and prolonged hemobilia. One minor complication involved pain. CONCLUSIONS: PTBD is an effective treatment with low complication rates for the management of postsurgical bile leaks in patients with nondilated bile ducts.

First-line evaluation of coronary artery disease with coronary calcium scanning or exercise electrocardiography.

BACKGROUND: Although conventional (CAG) and computed tomography angiography (CTA) are reliable diagnostic modalities for exclusion of obstructive coronary artery disease (CAD), they are costly and with considerable exposure to radiation and contrast media. We compared the accuracy of coronary calcium scanning (CCS) and exercise electrocardiography (X-ECG) as less expensive and non-invasive means to rule out obstructive CAD. METHODS: In a rapid-access chest pain clinic, 791 consecutive patients with stable chest pain were planned to undergo X-ECG and dual-source CTA with CCS. According to the Duke pre-test probability of CAD patients were classified as low (<30%), intermediate (30-70%) or high risk (>70%). Angiographic obstructive CAD (>50% stenosis by CAG or CTA) was found in 210/791 (27%) patients, CAG overruling any CTA results. RESULTS: Obstructive CAD was found in 12/281 (4%) patients with no coronary calcium and in 73/319 (23%) with a normal X-ECG (p<0.001). No coronary calcium was associated with a substantially lower likelihood ratio compared to X-ECG; 0.11, 0.13 and 0.13 vs. 0.93, 0.55 and 0.46 in the low, intermediate and high risk group. In low risk patients a negative calcium score reduced the likelihood of obstructive CAD to less than 5%, removing the need for further diagnostic work-up. CCS could be performed in 754/756 (100%) patients, while X-ECG was diagnostic in 448/756 (59%) patients (p<0.001). CONCLUSIONS: In real-world patients with stable chest pain CCS is a reliable initial test to rule out obstructive CAD and can be performed in virtually all patients.

Impact of tube current in the quantitative assessment of acute reperfused myocardial infarction with 64-slice delayed-enhancement CT: a porcine model.

PURPOSE: This study evaluated the impact of tube current (mAs) in delayed-enhancement computed tomography (CT) imaging for assessing acute reperfused myocardial infarction in a porcine model. MATERIALS AND METHODS: In five domestic pigs (mean weight 24 kg), the circumflex coronary artery was balloon-occluded for 2 h and then reperfused. After 5 days, CT imaging was performed following administration of iodinated contrast material. A 64-slice CT system was used to perform first-pass coronary angiography with a tube current of 15 mAs/kg [Arterial Phase (ART)] followed by two delayed-enhancement (DE) scans 15 min after contrast material administration, with a tube current of 15 mAs/kg and 37.5 mAs/kg, respectively (DE(1) and DE(2)). The mean heart rate decreased to 51±9 beats/min after administration of zatebradine (10 mg/kg IV). The data set was reconstructed during the end-diastolic phase of the cardiac cycle. Areas with DE, no reflow and remote myocardium [remote left ventricular (LV)] were calculated. CT values expressed in Hounsfield units (HU) were measured using five regions of interest (ROI): DE, no reflow, remote LV, LV cavity (LV lumen) and in air, respectively. Differences, correlations, image quality [signal-to-noise ratio (SNR)] and contrast resolution [contrast-to-noise ratio (CNR)] were calculated. RESULTS: Significant differences were found between attenuation of areas of DE, no reflow and remote LV (p<0.001) within the different scans. There was a fair correlation between DE and no-reflow attenuation (r=0.6; p<0.001). In DE(1) vs. DE(2), areas of DE and no reflow were not significantly different (p>0.05). The SNR and CNR were not significantly different in DE(1) vs. DE(2) (p>0.05). CONCLUSIONS: Tube current does not significantly affect infarction area, image quality or contrast resolution of DE imaging with CT.

Impact of contrast material volume on quantitative assessment of reperfused acute myocardial infarction using delayed-enhancement 64-slice CT: experience in a porcine model.

PURPOSE: Our purpose in this study was to compare the impact of contrast material volume in delayed-enhancement computer tomography (CT) imaging for assessing acute reperfused myocardial infarction. MATERIALS AND METHODS: In five domestic pigs (20-30 kg), the circumflex coronary artery (CX) was balloon-occluded for 2 h followed by reperfusion. After 5 days, CT imaging was performed after intravenous administration of iodinated contrast material (Iomeprol 400 mgI/ml; Bracco, Italy). A 64-slice multidetector CT (MDCT) (Sensation 64, Siemens) scanner was used for imaging, with standard angiography characteristics. Three scans were performed: first, coronary angiography at first pass with 1.25 gI/kg of contrast material (ART); and remaining delayed-enhancement (DE(1)-DE(2)) 15 min after administration of 1.25 (DE(1)) and 15 min after additional administration of 2.50 gI/kg (=total 3.75 gI/kg - DE(2)). Mean heart rate decreased to 51+/-9 bpm after intravenous administration of Zatebradine (10 mg/kg). Data sets were reconstructed during the end-diastolic phase of the cardiac cycle. Areas of infarction-enhanced (DE), no-reflow (no-reflow) and remote myocardial [remote left ventricle (LV)] were manually contoured. CT attenuation values (Hounsfield units) were measured using five regions of interest: DE, no-reflow, remote LV, left ventricular cavity (lumen LV) and in air. Differences, correlations, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. RESULTS: We found significant differences between the attenuation of DE, no-reflow and remote LV (p<0.001). DE and no-reflow size were assessed accurately with DEMDCT. In particular, SNR and CNR showed higher values in DE(2) (approximately 6.0 and 3.5, respectively; r(2)=0.90) vs. DE(1) (approximately 4.0 and 2.2, respectively; r(2)=0.85). CONCLUSIONS: The increase of contrast material volume determines a significant improvement in myocardial infarction image quality with DE-MDCT.

Computed tomography versus exercise electrocardiography in patients with stable chest complaints: real-world experiences from a fast-track chest pain clinic.

OBJECTIVE: To compare the diagnostic performance of CT angiography (CTA) and exercise electrocardiography (XECG) in a symptomatic population with a low-intermediate prevalence of coronary artery disease (CAD). DESIGN: Prospective registry. SETTING: Tertiary university hospital. PATIENTS: 471 consecutive ambulatory patients with stable chest pain complaints, mean (SD) age 56 (10), female 227 (48%), pre-test probability for significant CAD >5%. INTERVENTION: All patients were intended to undergo both 64-slice, dual-source CTA and an XECG. Clinically driven quantitative catheter angiography was performed in 98 patients. MAIN OUTCOME MEASURES: Feasibility and interpretability of, and association between, CTA and XECG, and their diagnostic performance with invasive coronary angiography as reference. RESULTS: CTA and XECG could not be performed in 16 (3.4%) vs 48 (10.2%, p<0.001), and produced non-diagnostic results in 3 (0.7%) vs 140 (33%, p<0.001). CTA showed > or =1 coronary stenosis (> or =50%) in 140 patients (30%), XECG was abnormal in 93 patients (33%). Results by CTA and XECG matched for 185 patients (68%, p = 0.63). Catheter angiography showed obstructive CAD in 57/98 patients (58%). Sensitivity, specificity, positive and negative predictive value of CTA to identify patients with > or =50% stenosis was 96%, 37%, 67% and 88%, respectively; compared with XECG: 71%, 76%, 80% and 66%, respectively. Quantitative CTA slightly overestimated diameter stenosis: 6 (21)% (R = 0.71), compared with QCA. Of the 312 patients (66%) with a negative CTA, 44 (14%) had a positive XECG, but only 2/17 who underwent catheter angiography had significant CAD. CONCLUSION: CTA is feasible and diagnostic in more patients than XECG. For interpretable studies, CTA has a higher sensitivity, but lower specificity for detection of CAD.