Maximal Systolic Acceleration and Near-Infrared Fluorescence Imaging With Indocyanine Green as Predictors for Successful Lower Extremity Revascularization.

BACKGROUND: Patients with lower extremity arterial disease (LEAD) frequently require revascularization procedures. Currently used diagnostic methods are insufficient in predicting successful outcomes and focus on macrovascular rather than microvascular state. Several promising modalities to increase diagnostic accuracy are emerging, including maximal systolic acceleration (ACCmax), measured by duplex ultrasound (DUS). For the assessment of tissue perfusion, near-infrared fluorescence (NIR) imaging using indocyanine green (ICG) demonstrates promising results. This study aims to identify the usefulness of combining these two methods for macrovascular and microvascular perfusion assessment to predict successful clinical outcomes. METHODS: A retrospective study was performed collecting preinterventional and postinterventional DUS and ICG NIR fluorescence imaging measurements from LEAD patients undergoing revascularization. The correlation between the preinterventional and postinterventional perfusion parameters, described as the delta (Δ) ACCmax and ΔICG NIR fluorescence parameters, were analyzed. Improvements in perfusion parameters were compared to clinical outcomes, defined as improvement in pain-free walking distance, freedom from rest pain, or tendency toward wound and ulcer healing. RESULTS: A total of 38 patients (42 limbs) were included. ACCmax and ICG NIR fluorescence perfusion parameters improved significantly after revascularization (p<0.001). Patients with a poor clinical outcome had a significantly lower improvement of both parameters after revascularization (p<0.001-0.016). Lack of correlation was found between the delta of ACCmax and ICG NIR fluorescence imaging. Multiple non-congruent improvements of macrovascular parameters (ACCmax) and perfusion (ICG NIR fluorescence) were seen within patients. However, for all patients with a successful clinical outcome, at least one parameter improved. CONCLUSION: Combining ACCmax and ICG NIR fluorescence imaging revealed improvement in at least one parameter within all patients with a successful clinical outcome. This study highlights the potential of assessing both the macrovascular state and tissue perfusion following lower extremity revascularization, as both appear to reflect different aspects of vascularization. CLINICAL IMPACT: Numerous techniques have been developed to assess tissue perfusion to predict clinical outcomes following revascularization in patients with peripheral artery disease. However, none are widely implemented in clinical practice. This study emphasized the importance of employing multiple modalities from different perspectives for more accurate prediction. By focusing on both the macrovascular state and tissue perfusion, clinicians can better guide themselves in their treatment strategies.

Role of Antiplatelet Therapy in Patients Managed for Complex Aortic Aneurysms using Fenestrated or Branched Endovascular Repair.

OBJECTIVE: Despite the increasing number of fenestrated/branched endovascular aortic repair (f/bEVAR) procedures, evidence on post-operative antiplatelet therapy is lacking. This study aimed to investigate the role of single antiplatelet therapy (SAPT) vs. double antiplatelet therapy (DAPT) after f/bEVAR on 30 day and follow up outcomes. METHODS: A multicentre retrospective analysis was conducted, including f/bEVAR patients managed from 1 January 2018 to 31 December 2022. Comparative outcomes were assessed according to post-operative antiplatelet therapy. The cohort was divided into the SAPT group (acetylsalicylic acid [ASA] or clopidogrel) and DAPT group (ASA and clopidogrel). The duration of SAPT or DAPT was one to six months. Primary outcomes were 30 day death, and cardiovascular ischaemic and major haemorrhagic events. Secondary outcomes were survival and target vessel (TV) patency during follow up. RESULTS: A total of 1 430 patients were included: 955 under SAPT and 475 under DAPT. The 30 day mortality was similar (SAPT 2.1% vs. DAPT 1.5%; p = .42). Cardiovascular ischaemic events were lower in the DAPT group (SAPT 11.9% vs. DAPT 8.2%; p = .040), with DAPT being an independent protector for acute mesenteric (p = .009) and lower limb ischaemia (p = .020). No difference was found in 30 day major haemorrhagic events (SAPT 7.5% vs. DAPT 6.3%; p = .40). The mean follow up was 21.8 ± 2.9 months. Cox regression showed no cofounders on survival, with similar rates between groups (log rank p = .71). DAPT patients presented higher TV patency (SAPT 93.4%, standard error [SE] 0.7% vs. DAPT 96.6%, SE 0.7%; log rank p = .007) at thirty six months. Cox regression revealed bEVAR as a predictor of worse TV patency (hazard ratio 2.03, 95% confidence interval 1.36 - 3.03; p < .001). DAPT was related to higher patency within bEVAR patients (SAPT 87.2%, SE 2.1% vs. DAPT 94.9%, SE 1.9%; p < .001). CONCLUSIONS: DAPT after f/bEVAR was associated with lower risk of cardiovascular ischaemic events and higher TV patency, especially in bEVAR cases. No difference in major haemorrhagic events was observed at 30 days.

Learning Curve Analysis of Complex Endovascular Aortic Repair.

BACKGROUND: When introducing new techniques, attention must be paid to learning curve. Besides quantitative outcomes, qualitative factors of influence should be taken into consideration. This retrospective cohort study describes the quantitative learning curve of complex endovascular aortic repair (EVAR) in a nonhigh-volume academic center and provides qualitative factors that were perceived as contributors to this learning curve. With these factors, we aim to aid in future implementation of new techniques. METHODS: All patients undergoing complex EVAR in the Leiden University Medical Center (LUMC) between July 2013 and April 2021 were included (n = 90). Quantitative outcomes were as follows: operating time, blood loss, volume of contrast, hospital stay, major adverse events (MAE), 30-day mortality, and complexity. Patients were divided into 3 temporal groups (n = 30) for dichotomous outcomes. Regression plots were used for continuous outcomes. In 2017, the treatment team was interviewed by an external researcher. These interviews were reanalyzed for factors that contributed to successful implementation. RESULTS: Length of hospital stay (P = 0.008) and operating time (P = 0.010) decreased significantly over time. Fewer cardiac complications occurred in the third group (3: 0% vs. 2: 17% vs. 1: 17%, P = 0.042). There was a trend of increasing complexity (P = 0.076) and number of fenestrations (P = 0.060). No significant changes occurred in MAE and 30-day mortality. Qualitative factors that, according to the interviewees, positively influenced the learning curve were as follows: communication, mutual trust, a shared sense of responsibility and collective goals, clear authoritative structures, mutual learning, and team capabilities. CONCLUSIONS: In addition to factors previously identified in the literature, new learning curve factors were found (mutual learning and shared goals in the operating room (OR)) that should be taken into account when implementing new techniques.

Functional Performance After Complex Endovascular Aortic Repair: A Single-Center Retrospective Cohort Study.

PURPOSE: Complex endovascular aortic repair (EVAR) procedures provide a treatment option for patients with aortic aneurysms involving visceral branches. Good technical results and short-term outcomes have been reported. Whether complex EVAR provides acceptable functional outcomes is not clear. The current study aims to describe postoperative functional outcomes in complex EVAR patients-an older and relatively frail patient group. MATERIALS AND METHODS: A single-center retrospective cohort study was performed, using data from a computerized database of consecutive patients who underwent complex EVAR in the Leiden University Medical Center (LUMC, The Netherlands) between July 2013 and September 2020. As of May 2017, patients scheduled for complex EVAR were referred to a geriatric care pathway to determine (Instrumental) Activities of Daily Living ((I)ADL) scores at baseline and, if informed consent was given, after 12 months. For the total patient group, adverse functional performance outcomes were: discharge to a nursing home and 12-month mortality. For the patients included in geriatric follow-up, the additional outcome was the incidence of functional decline (defined by a ≥2 point increase in (I)ADL-score) at 12-month follow-up. RESULTS: Eighty-two patients underwent complex EVAR, of which 68 (82.9%) were male. Mean age was 73.3 years (SD=6.3). Within 30 days postsurgery, 6 patients (7.3%) died. Mortality within 12 months for the total patient group was 14.6% (n=12). After surgery, no patients had to be discharged to a nursing home. Fifteen patients (18.3%) were discharged to a rehabilitation center. Twenty-three patients gave informed consent and were included in geriatric follow-up. Five patients (21.7%) presented functional decline 12 months postsurgery and 4 patients had died (17.4%) by that time. This means that 39.1% of the patients in the care pathway suffered an adverse outcome. CONCLUSION: To our knowledge, this is the only study that examined functional performance after complex EVAR, using a prospectively maintained database. No patients were newly discharged to a nursing home and functional performance results at 12 months are promising. Future multidisciplinary research should focus on determining which patients are most prone to deterioration of function, so that efforts can be directed toward preventing postoperative functional decline.

Efficacy of Sclerotherapy With Polidocanol (Ethoxysclerol) in Primary Aneurysmal Bone Cysts in Children and Adolescents.

BACKGROUND: Aneurysmal bone cysts (ABC) are rare benign osseous lesions that can be locally aggressive. Traditionally, curettage with or without bone grafting is the treatment of choice. Recent data suggest that percutaneous sclerotherapy is a safe alternative to surgery. We present our experience with percutaneous sclerotherapy. Primary study aims were success rate, risk factors for treatment failure, and complications. METHODS: In this single-center retrospective study (January 2003 to June 2019), 70 patients were treated with percutaneous sclerotherapy for primary ABC at various skeletal sites. Median age was 11 years (range: 3 to 17 y). Median follow-up was 40 months (range 18 to 144 mo). Clinical and radiologic assessments were performed until cyst healing. RESULTS: Successful healing was seen in 58 of 70 patients (83%) after 1 or more injections with polidocanol. In 12 patients (17%), definitive curettage was performed after previous sclerotherapy, which was considered failure of primary sclerotherapy treatment. Trends toward increased risk for >3 treatments or treatment failure included age younger than 5, epiphyseal plate involvement, and lower leg lesions. The only complication was anaphylaxis in 1 patient shortly after injection of polidocanol/contrast agent and ropivacaine, with full recovery after short resuscitation. CONCLUSIONS: Our results show that percutaneous sclerotherapy with polidocanol has high efficacy in the treatment of primary ABC, with a low complication rate. Our only complication may have been an immediate allergic reaction to polidocanol/contrast agent or ropivacaine. Trends toward increased risk for treatment failure were age younger than 5, epiphyseal plate involvement, and lower leg lesions. LEVEL OF EVIDENCE: Level IV-therapeutic study.

European multicentre study on technical success and long-term clinical outcome of radiofrequency ablation for the treatment of spinal osteoid osteomas and osteoblastomas.

PURPOSE: To evaluate technical success and long-term outcome of CT-guided radiofrequency ablation (RFA) of spinal osteoid osteomas (OO) and osteoblastomas (OB) in six different European centres. METHODS: Eighty-seven patients with spinal OO (77) or OB (10) were treated with CT-guided RFA, after three-dimensional CT-guided access planning. Patient's long-term outcome was assessed by clinical examination and questionnaire-based evaluation including 10-point visual analogue scales (VAS) regarding the effect of RFA on severity of pain and limitations of daily activities. Clinical success was defined as a reduction of > 30% in the VAS score and patient's satisfaction. RESULTS: Overall, RFA was technically successful in 82/87 cases (94.3%) with no major complications; clinical success was achieved in 78/87 cases (89.7%). The OO/OB were localized in the cervical (n = 9/3), the thoracic (n = 27/1), the lumbar (n = 29/4), and the sacral spine (n = 12/2). A decrease in severity of pain after RFA was observed in 86/87 patients (98.9%) with a persistent mean reduction of overall pain score from 8.04 ± 0.96 to 1.46 ± 1.95 (p < 0.001) after a median follow-up time of 29.35 ± 35.59 months. VAS scores significantly decreased for limitations of both daily (5.70 ± 2.73 to 0.67 ± 1.61, p < 0.001) and sports activities (6.40 ± 2.58 to 0.67 ± 1.61, p < 0.001). CONCLUSION: In a multicentric setting, this trial proves RFA to be a safe and efficient method to treat spinal OO/OB and should be regarded as first-line therapy after interdisciplinary case discussion.

Correction to: European multicentre study on technical success and long-term clinical outcome of radiofrequency ablation for the treatment of spinal osteoid osteomas and osteoblastomas.

The original version of this paper contained an error: the Acknowledgements were dropped during early manuscript editing.

Adherence to Guidelines for Adult (Non-GIST) Soft Tissue Sarcoma in the Netherlands: A Plea for Dedicated Sarcoma Centers.

INTRODUCTION: Optimal management of soft tissue sarcoma (STS) remains a challenge. A nationwide survey assessed the quality of STS care in the Netherlands, thereby aiming to identify potentialities for improvement through more centralized disease management. METHODS: From the Netherlands Cancer Registry (NCR), data were obtained on 3317 adult STS patients (excluding gastrointestinal stromal tumor, GIST) diagnosed in 2006-2011. Logistic regression models were employed to compare outcomes on selected clinical indicators reflecting prevailing STS guidelines between high-volume (≥10 resections annually) and low-volume (<10 resections) hospitals, between academic and general hospitals, and between sarcoma research centers and other hospitals, adjusted for case mix. Analyses were performed on imputed datasets (m = 50), generated through multiple imputations by chained equations. RESULTS: Overall, 89% of patients underwent surgical resection. Resection status remained unknown in 24% (excluding those with metastasized disease), and grade was not documented for one-third of tumors. Microscopic residual disease was detected in 20% with an increased risk for older patients, larger and deeply located tumors, and those located in the (retro)peritoneum or upper extremity. Almost half of patients with an R1 resection received adjuvant radiotherapy. Following adjustment for case mix factors, patients treated in high-volume hospitals less often had macroscopic residual disease (R2 resection; adjusted odds ratio: 0.54). A strongly skewed distribution of surgical volumes was observed. CONCLUSIONS: These survey results indicate a potential for improving Dutch STS care. More centralized sarcoma management should improve definitive pathology reporting on tumor characteristics, adherence to treatment guidelines and overall disease outcome.

Soft Tissue Tumors in Adults: ESSR-Approved Guidelines for Diagnostic Imaging.

Soft tissue sarcomas are rare, but early, accurate diagnosis with subsequent appropriate treatment is crucial for the clinical outcome. The ESSR guidelines are intended to help radiologists in their decision-making and support discussion among clinicians who deal with patients with suspected or proven soft tissue tumors. Potentially malignant lesions recognized by ultrasound should be referred for magnetic resonance imaging (MRI), which also serves as a preoperative local staging modality, with specific technical requirements and mandatory radiological report elements. Radiography may add information about matrix calcification and osseous involvement. Indeterminate lesions, or lesions in which therapy is dependent on histology results, should be biopsied. For biopsy, we strongly recommend referral to a specialist sarcoma center, where an interdisciplinary tumor group, with a specialized pathologist, radiologist, and the surgeon are involved. In sarcoma, a CT scan of the chest is mandatory. Additional staging modalities are entity-specific. There are no evidence-based recommendations for routine follow-up in surgically treated sarcomas. However, we would recommend regular follow-up with intervals dependent on tumor grade, for 10 years after the initial diagnosis.

The clinical approach toward giant cell tumor of bone.

We provide an overview of imaging, histopathology, genetics, and multidisciplinary treatment of giant cell tumor of bone (GCTB), an intermediate, locally aggressive but rarely metastasizing tumor. Overexpression of receptor activator of nuclear factor κB ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated giant cells. Conventional radiographs show a typical eccentric lytic lesion, mostly located in the meta-epiphyseal area of long bones. GCTB may also arise in the axial skeleton and very occasionally in the small bones of hands and feet. Magnetic resonance imaging is necessary to evaluate the extent of GCTB within bone and surrounding soft tissues to plan a surgical approach. Curettage with local adjuvants is the preferred treatment. Recurrence rates after curettage with phenol and polymethylmethacrylate (PMMA; 8%-27%) or cryosurgery and PMMA (0%-20%) are comparable. Resection is indicated when joint salvage is not feasible (e.g., intra-articular fracture with soft tissue component). Denosumab (RANKL inhibitor) blocks and bisphosphonates inhibit GCTB-derived osteoclast resorption. With bisphosphonates, stabilization of local and metastatic disease has been reported, although level of evidence was low. Denosumab has been studied to a larger extent and seems to be effective in facilitating intralesional surgery after therapy. Denosumab was recently registered for unresectable disease. Moderate-dose radiotherapy (40-55 Gy) is restricted to rare cases in which surgery would lead to unacceptable morbidity and RANKL inhibitors are contraindicated or unavailable.

Comparison of dixon and T1-weighted MR methods to assess the degree of fat infiltration in duchenne muscular dystrophy patients.

PURPOSE: To compare different lipid multipeak spectral models to the single-peak model in Dixon-based fat-water separation and to evaluate differences between visually scored magnetic resonance (MR) images and quantitatively assessed fat fractions in muscle of Duchenne muscular dystrophy patients. MATERIALS AND METHODS: T1-weighted and 3-point Dixon imaging of the upper and lower leg was performed in 13 Duchenne patients and six healthy controls. Three-, four-, and five-peak lipid spectrum models were compared to a single-peak model and to each other. T1-weighted images were visually scored by two radiologists and quantitative fat fractions were obtained from Dixon images. RESULTS: Differences between the multipeak spectral models were minimal. The three-peak model was used for subsequent comparisons. Although there was high correlation between quantitative and visual scores, visual scores were consistently higher than quantitative values of the same muscles. CONCLUSION: There are minor differences between the various lipid spectral models in terms of quantifying fat fraction in a large number of skeletal muscles in the legs of Duchenne patients and healthy controls. Quantitative 3-point Dixon MRI is more precise and reliable than visual radiological methods for evaluation of fat fractions for potential longitudinal follow-up or therapy evaluation of Duchenne patients.

A multidisciplinary approach to giant cell tumors of tendon sheath and synovium--a critical appraisal of literature and treatment proposal.

Giant cell tumors deriving from synovium are classified into a localized (GCT of tendon sheath; GCT-TS) and diffuse form (diffuse-type GCT, Dt-GCT). We propose a multidisciplinary management based upon a systematic review and authors' opinion. Open excision for GCT-TS and open synovectomy (plus excision) for Dt-GCT is advised to reduce the relatively high recurrence risk. External beam radiotherapy should be considered in severe cases, as Dt-GCT commonly extends extra-articular.

Therapeutic management of in-stent thrombosis after thoracic endovascular aortic repair for blunt thoracic aortic injury in a coronavirus disease 2019 patient.

A 27-year-old man underwent thoracic endovascular aortic repair for blunt thoracic aortic injury. Fourteen months later, he presented with intermittent paraplegia, congestive heart failure, and a decline of kidney function as a result of high-grade aortic stenosis caused by in-stent thrombosis. He had a concurrent infection with coronavirus disease 2019. The patient was successfully treated using axillofemoral bypass, followed by stent relining 2 weeks later. The possible risk factors and the optimal therapeutic approach for in-stent thrombosis remain unknown, because only a limited number of cases describing this rare complication have been reported.

Increased Aortic Exclusion in Endovascular Treatment of Complex Aortic Aneurysms.

PURPOSE: Perioperative risk assessments for complex aneurysms are based on the anatomical extent of the aneurysm and do not take the length of the aortic exclusion into account, as it was developed for open repair. Nevertheless, in the endovascular repair (ER) of complex aortic aneurysms, additional segments of healthy aorta are excluded compared with open repair (OR). The aim of this study was to assess differences in aortic exclusion between the ER and OR of complex aortic aneurysms, to subsequently assess the current classification for complex aneurysm repair. METHODS: This retrospective observational study included patients that underwent complex endovascular aortic aneurysm repair by means of fenestrated endovascular aneurysm repair (FEVAR), fenestrated and branched EVAR (FBEVAR), or branched EVAR (BEVAR). The length of aortic exclusion and the number of patent segmental arteries were determined and compared per case in ER and hypothetical OR, using a Wilcoxon signed-rank test. RESULTS: A total of 71 patients were included, who were treated with FEVAR (n = 44), FBEVAR (n = 8), or BEVAR (n = 19) for Crawford types I (n = 5), II (n = 7), III (n = 6), IV (n = 7), and V (n = 2) thoracoabdominal or juxtarenal (n = 44) aneurysms. There was a significant increase in the median exclusion of types I, II, III, IV, and juxtarenal aneurysms (p < 0.05) in ER, compared with hypothetical OR. The number of patent segmental arteries in the ER of type I-IV and juxtarenal aneurysms was significantly lower than in hypothetical OR (p < 0.05). CONCLUSION: There are significant differences in the length of aortic exclusion between ER and hypothetical OR, with the increased exclusion in ER resulting in a lower number of patent segmental arteries. The ER and OR of complex aortic aneurysms should be regarded as distinct modalities, and as each approach deserves a particular risk assessment, future efforts should focus on reporting on the extent of exclusion per treatment modality, to allow for appropriate comparison.

The association between sarcopenia and adverse outcomes after complex endovascular aortic repair.

BACKGROUND: Sarcopenia is identified as a predictive factor for adverse outcomes after complex endovascular aortic repair (complex EVAR). Consensus on preferred parameters for sarcopenia is not yet reached. The current study compares three CT-assessed parameters on their association with adverse outcomes after complex EVAR. METHODS: This was a single-center retrospective cohort study. Psoas Muscle Index (PMI), Skeletal Muscle Index (SMI), and lean psoas muscle area (LPMA) were examined by CT-segmentation. PMI, SMI, and LPMA were analyzed as continuous variables. In addition, cut-off values from previous research were used to diagnose patients as sarcopenic or non-sarcopenic. Outcomes were: all-cause mortality, major adverse events (MAE), length of hospital stay, and non-home discharge. A sub-analysis was made for severe sarcopenia; sarcopenia combined with low physical performance (gait speed, Time Up and Go test, Metabolic Equivalent of Task-score). RESULTS: We included 101 patients. A higher PMI (HR=0.590, CI: 0.374-0.930, P=0.023), SMI (HR=0.453, CI: 0.267-0.768, P=0.003), and LPMA (HR=0.559, CI: 0.333-0.944, P=0.029) were associated with a lower risk of mortality. Sarcopenia based on cut-off values for PMI and LPMA was not significantly associated with survival. Sarcopenia based on SMI did present a higher mortality risk (P=0.017). A sub-analysis showed that severely sarcopenic patients were at even higher risk of mortality (P=0.036). None of the parameters were significantly associated with the other outcomes. CONCLUSIONS: SMI had a slightly stronger association with mortality compared to PMI and LPMA. High-risk patients were selected by adding physical performance scores. Future research could focus on complex EVAR-specific PMI and LPMA cut-off values.

Three new chondrosarcoma cell lines: one grade III conventional central chondrosarcoma and two dedifferentiated chondrosarcomas of bone.

BACKGROUND: Chondrosarcoma is the second most common primary sarcoma of bone. High-grade conventional chondrosarcoma and dedifferentiated chondrosarcoma have a poor outcome. In pre-clinical research aiming at the identification of novel treatment targets, the need for representative cell lines and model systems is high, but availability is scarce. METHODS: We developed and characterized three cell lines, derived from conventional grade III chondrosarcoma (L835), and dedifferentiated chondrosarcoma (L2975 and L3252) of bone. Proliferation and migration were studied and we used COBRA-FISH and array-CGH for karyotyping and genotyping. Immunohistochemistry for p16 and p53 was performed as well as TP53 and IDH mutation analysis. Cells were injected into nude mice to establish their tumorigenic potential. RESULTS: We show that the three cell lines have distinct migrative properties, L2975 had the highest migration rate and showed tumorigenic potential in mice. All cell lines showed chromosomal rearrangements with complex karyotypes and genotypic aberrations were conserved throughout late passaging of the cell lines. All cell lines showed loss of CDKN2A, while TP53 was wild type for exons 5-8. L835 has an IDH1 R132C mutation, L2975 an IDH2 R172W mutation and L3252 is IDH wild type. CONCLUSIONS: Based on the stable culturing properties of these cell lines and their genotypic profile resembling the original tumors, these cell lines should provide useful functional models to further characterize chondrosarcoma and to evaluate new treatment strategies.

Study Protocol: Adjuvant Holmium-166 Radioembolization After Radiofrequency Ablation in Early-Stage Hepatocellular Carcinoma Patients-A Dose-Finding Study (HORA EST HCC Trial).

PURPOSE: To investigate the biodistribution of holmium-166 microspheres (166Ho-MS) when administered after radiofrequency ablation (RFA) of early-stage hepatocellular carcinoma (HCC). The aim is to establish a perfused liver administration dose that results in a tumoricidal dose of holmium-166 on the hyperaemic zone around the ablation necrosis (i.e. target volume). MATERIALS AND METHODS: This is a multicentre, prospective, dose-escalation study in HCC patients with a solitary lesion 2-5 cm, or a maximum of 3 lesions of ≤ 3 cm each. The day after RFA patients undergo angiography and cone-beam CT (CBCT) with (super)selective infusion of technetium-99 m labelled microalbumin aggregates (99mTc-MAA). The perfused liver volume is segmented from the CBCT and 166Ho-MS is administered to this treatment volume 5-10 days later. The dose of holmium-166 is escalated in a maximum of 3 patient cohorts (60 Gy, 90 Gy and 120 Gy) until the endpoint is reached. SPECT/CT is used to determine the biodistribution of holmium-166. The endpoint is met when a dose of ≥ 120 Gy has been reached on the target volume in 9/10 patients of a cohort. Secondary endpoints include toxicity, local recurrence, disease-free and overall survival. DISCUSSION: This study aims to find the optimal administration dose of adjuvant radioembolization with 166Ho-MS after RFA. Ultimately, the goal is to bring the efficacy of thermal ablation up to par with surgical resection for early-stage HCC patients. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03437382.

Study Protocol PROMETHEUS: Prospective Multicenter Study to Evaluate the Correlation Between Safety Margin and Local Recurrence After Thermal Ablation Using Image Co-registration in Patients with Hepatocellular Carcinoma.

PURPOSE: The primary objective is to determine the minimal ablation margin required to achieve a local recurrence rate of < 10% in patients with hepatocellular carcinoma undergoing thermal ablation. Secondary objectives are to analyze the correlation between ablation margins and local recurrence and to assess efficacy. MATERIALS AND METHODS: This study is a prospective, multicenter, non-experimental, non-comparative, open-label study. Patients > 18 years with Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma (or B with a maximum of two lesions < 5 cm each) are eligible. Patients will undergo dual-phase contrast-enhanced computed tomography directly before and after ablation. Ablation margins will be quantitatively assessed using co-registration software, blinding assessors (i.e. two experienced radiologists) for outcome. Presence and location of recurrence are evaluated independently on follow-up scans by two other experienced radiologists, blinded for the quantitative margin analysis. A sample size of 189 tumors (~ 145 patients) is required to show with 80% power that the risk of local recurrence is confidently below 10%. A two-sided binomial z-test will be used to test the null hypothesis that the local recurrence rate is ≥ 10% for patients with a minimal ablation margin ≥ 2 mm. Logistic regression will be used to find the relationship between minimal ablation margins and local recurrence. Kaplan-Meier estimates are used to assess local and overall recurrence, disease-free and overall survival. DISCUSSION: It is expected that this study will result in a clear understanding of the correlation between ablation margins and local recurrence. Using co-registration software in future patients undergoing ablation for hepatocellular carcinoma may improve intraprocedural evaluation of technical success. Trial registration The Netherlands Trial Register (NL9713), https://www.trialregister.nl/trial/9713 .