Brushite calcium phosphate cements (bCPCs) are promising synthetic bone substitutes due to their bioactivity, osteoconductivity, and controlled degradation. However, their clinical use is limited by poor handling, low mechanical strength, and insufficient antimicrobial capability. This study explores the incorporation of α-tricalcium phosphate (α-TCP) and silk fibroin (SF) to enhance bCPC performance and enable localized antibiotic delivery using tetracycline (TC). Adding α-TCP improved compressive strength (up to 2.65 MPa), while SF in liquid or fiber form reinforced the matrix. The inclusion of TC and SF extended setting times (4–7 min initial; 7–30 min final) and maintained injectability (up to 50 %). Drug release studies showed a 10 % burst in the first 24 h, with a sustained release of 77 % over 14 days. These multifunctional bCPCs offer injectable, resorbable, and antibacterial properties, making them suitable for non-load-bearing bone repair applications.

To plan optimal management in a patient with breast cancer (BC), accurate baseline staging and early detection and staging of recurrence are necessary.1-3 Representatives from the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) recently published the joint European-American guidelines on the role of 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) in no special type (NST) BC, endorsed by several other imaging and clinical societies: the American College of Radiology (ACR), European Society of Surgical Oncology, European Society for Radiotherapy and Oncology (ESTRO), European Society of Breast Imaging, European Society of Radiology, and European Society of Breast Cancer Specialists (EUSOMA).1 Considering the low [18F]FDG-avidity in invasive lobular carcinoma (ILC), the EANM-SNMMI guidelines focused on NST BC. Guidelines from clinical societies such as the American National Comprehensive Cancer Network (NCCN),4 European Society for Medical Oncology (ESMO),5-7 and Advanced Breast Cancer (ABC) international consensus guidelines8 also evaluate imaging techniques, but they include all histological subtypes of BC. There is a lack of consistency in the optimal utilization of [18F]FDG-PET/CT among published guidelines. This manuscript summarizes available evidence, emphasizes the value of [18F]FDG-PET/CT for staging and restaging of patients with BC, and highlights agreements and discrepancies among international guidelines.

Objective
Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with varying survival outcomes. This study investigated whether baseline PSMA PET/CT parameters are associated with survival and treatment response.

Methods
Sixty mCRPC patients underwent [18F]PSMA-1007 PET/CT before treatment with androgen receptor-targeted agents (ARTAs) or chemotherapy. Intensity-based parameters, volumetric parameters, metastatic sites and DmaxVox (distance between the two outermost voxels) from baseline PSMA PET/CT were collected, as well as age, Gleason score and laboratory parameters. Cox regression analysis evaluated their prognostic value for overall survival (OS). Additionally, a preliminary lesion-level analysis was done (n = 241 lesions) with lesion location and twelve radiomic features selected from previous literature. Logistic regression evaluated their association with PSMA PET/CT-based lesion progression after 3–4 months of treatment.

Results
Total tumour volume (PSMA-TV) (HR = 1.41 per doubling [1.17–1.70]), total lesion uptake (TL-PSMA) (HR = 1.40 per doubling [1.16–1.69]) and DmaxVox (HR = 1.31 per 10 cm increase [1.07–1.62]) were prognostic for OS, each independent of baseline PSA level (HR = 0.82 per doubling [0.68–0.98]), haemoglobin level (HR = 0.68 per mmol/L increase [0.49–0.95]) and line of treatment. On lesion-level, location (prostate vs bone OR = 0.23 [0.06–0.83]) and SUVmean (OR = 1.72 per doubling [1.08–2.75]) were independent prognostic markers for lesion progression, morphological and texture-based radiomic features were not.

Conclusion
Baseline PSMA PET/CT scans have prognostic value in mCRPC patients and can potentially aid in treatment decision-making. DmaxVox can serve as a simpler alternative to PSMA-TV when automated segmentation software is not available. When combined with PSMA-TV, lower PSA levels indicated worse OS, which may be a marker of tumour dedifferentiation. Further research is needed to validate these models in larger patient cohorts.

The appropriate use criteria (AUC) documents are intended to aid medical practitioners in the appropriate use of imaging technology in specific clinical scenarios based on rigorous appraisal of the available published evidence. The purpose of this document is to summarize the appropriate use of PET/CT with ¹⁸F-FDG in the initial staging of malignant disease. A multidisciplinary expert panel convened to appraise an independently performed systematic review and develop the AUC for initial staging of head and neck cancer, lung cancer, breast cancer, esophageal cancer, colorectal cancer, pancreatic cancer, melanoma, lymphoma, myeloma, and sarcoma with an appropriateness score for each clinical scenario established by using a modified Delphi process (Table 1). The full document including the methodology details, discussion of evidence, appendices, and the supplemental material can be accessed at https://snmmi.org/Web/Clinical-Practice/Appropriate-Use-Criteria/Articles/Appropriate_Use_Criteria_for_18F-FDG_PET_CT_for_Initial_Staging_of_Malignant_Disease.

Purpose: This study aims to systematically review and perform a meta-analysis to compare the diagnostic performance of fibroblast activation protein inhibitors (FAPI) radiopharmaceuticals and 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) in gynaecological cancers. Methods: A comprehensive search of PubMed/MEDLINE and EMBASE was conducted and updated to October 25, 2024, to identify clinical studies evaluating FAPI and [¹⁸F]FDG PET/CT or PET/MR in patients with gynaecological cancer. Quality was assessed using the QUADAS-2 tool (Quality Assessment of Diagnostic Accuracy Studies). Per-lesion pooled estimates of sensitivity, specificity, positive predictive value, and negative predictive value were calculated with 95% confidence intervals. Results: Ten studies were included for qualitative assessment and five studies focusing on ovarian cancer were included in the meta-analysis. The detection rates of primary cervical cancer ranged from 96 to 100% for both radiopharmaceuticals. For the primary tumour in ovarian cancer, the pooled sensitivities of ⁶⁸Ga-FAPI and [¹⁸F]FDG were 95% and 92%, and the pooled specificities were 81% for both radiopharmaceuticals. Nodal metastases detection was higher with ⁶⁸Ga-FAPI compared with [¹⁸F]FDG in cervical cancer. Similarly, in ovarian cancer the estimated pooled sensitivities of ⁶⁸Ga-FAPI and [¹⁸F]FDG were 97% and 88%, and the pooled specificities were 83% and 41%, respectively. At peritoneal metastases analysis in ovarian cancer, the pooled sensitivities of ⁶⁸Ga-FAPI and [¹⁸F]FDG were 97% and 70%, and the pooled specificities were 93% and 88%, respectively. At the visual assessment of peritoneal cancer scores, such as peritoneal cancer index, ⁶⁸Ga-FAPI detected a greater tumour burden compared with [¹⁸F]FDG. A comparative analysis of the PET semiquantitative parameters was also performed. Conclusion: Despite limited literature data, radiopharmaceuticals based on FAPIs are a promising alternative to [¹⁸F]FDG for imaging gynaecological cancers, in particular for the detection of nodal metastases in cervical and ovarian cancers, as well as for detecting peritoneal metastases in ovarian cancers. Larger prospective studies are needed to confirm these results and promote the inclusion of FAPI radiopharmaceuticals in clinical practice. Clinical trial number: Not applicable.

Background
The second most common breast cancer subtype is invasive lobular cancer (ILC). Its locoregional staging is challenging, even when using breast MRI. Different non-[18F]FDG PET tracers have been explored in these patients, and promising results were reported with [18F]FACBC. Nevertheless, no publications directly comparing breast MRI and [18F]FACBC PET are available.

Aim
To compare the performance of prone [18F]FACBC PET/CT and breast MRI for assessing disease extent in the breast and for depicting lymph node metastases in patients with locally advanced ILC.

Methods
Retrospective selection of case series of patients with proven locally advanced luminal-like ILC, who underwent both breast MRI and prone [18F]FACBC PET/CT, according to the local clinical standards.

Results
Eight patients were included. [18F]FACBC PET/CT performed similarly to MRI in T-staging and outperformed MRI in N-staging, especially outside axillary level I/II. [18F]FACBC uptake in the index breast lesion was on average 9 times higher than the breast background. Among the 6 patients submitted to surgery, [18F]FACBC provided the correct T&N staging in 5 patients, confirmed by pathology.

Conclusion
This initial descriptive case series suggests that prone [18F]FACBC PET/CT could be a valuable imaging tool for both local and regional staging of low-grade luminal-like ILC. A larger prospective clinical trial is needed to further evaluate this potential application.

Purpose: Nipple discharge is the third most common breast-related complaint. It is recommended to exclude malignancy in pathologic nipple discharge (PND). Mammography and ultrasound are the first-line conventional diagnostic (CD) imaging. Although magnetic resonance is often used as a complementary modality, molecular breast imaging (MBI) with Tc-99m sestamibi may be a suitable alternative. Considering the lack of information on this subject and its clinical importance, this study aimed to evaluate the role of MBI in ruling out malignancy in patients with PND and negative/indeterminate CD. Patients and Methods: Retrospective cohort single-center study including all patients with PND evaluated by CD and MBI between 2012 and 2020. Pathology was considered the gold standard. Follow-up was used when pathology was not available. Results: Of the 96 cases of PND included, 78 were benign, and 18 (20%) corresponded to breast cancer (BC). Although CD and MBI were concordant in the BIRADS classification in 81% (78/96), half of BC were detected by MBI only. BC was located directly behind the nipple in a minority of patients (11%), meaning that MBI could significantly prevent futile central ductal excision. MBI presented higher sensitivity (83% vs. 33%) and negative predictive value (96% vs. 86%) than CD alone, with similar specificity (89% vs. 92%) and positive predictive value (63% vs. 50%). The area under the curve of MBI and CD was 0,86 (P-value<0.001 [95% CI: 0.75-0.97]) and 0.63 (P-value=0.091 [95% CI: 0.47-0.79]), respectively. Conclusions: MBI showed good diagnostic accuracy for detecting BC in patients with PND with negative/indeterminate findings on CD imaging.

Systematic literature reviews (SLRs) are fundamental for aggregating published evidence, identifying knowledge gaps and informing health economic evaluations, especially in the field of novel diagnostics where randomised controlled trials are commonly absent [1]. The global publishing output within the field of novel diagnostics is increasing rapidly owing to increasing efforts towards precision medicine. Simultaneously, the global publishing output within the field of health economics is increasing rapidly owing to increasing efforts towards value-based healthcare and present budget constraints. The number of publications focussing on the health economic impact of diagnostics almost doubled from 86,244 in 2010 to 152,404 in 2025 (PubMed search using MeSH terms ‘Diagnostic Techniques and Procedures’ and ‘Health Care Economics and Organizations’). Consequently, the workload of performing SLRs is increasing as the number of articles that requires screening grows larger. The average time to complete an SLR is over 15 months, while the proportion of truly relevant articles for data extraction may be as low as 1% of the total search results [2]. The high workload may reduce researchers’ willingness to conduct an SLR or may lead to search strategies that are too narrow when prioritising time constraints over review quality. Moreover, it may render an SLR outdated by the time it is published.

Introduction: The ESMO and ECIO-ESOI consensus guidelines vary in their recommendations regarding the use of ¹⁸F-Fluorodeoxyglucose ([¹⁸F]FDG) PET/CT in the follow-up after thermal ablation in patients with colorectal liver metastases. This is partly because studies providing data on long-term benefits of [¹⁸F]FDG PET/CT are lacking. Therefore, a simulation model was developed to examine how follow-up with [¹⁸F]FDG PET/CT impacts treatment planning, health and cost outcomes. Methods: For an illustrative Dutch cohort, lifetime health and cost outcomes were simulated to assess the cost-effectiveness of performing a single additional [¹⁸F]FDG PET/CT. Patients followed a standard surveillance schedule consisting of three-monthly serum CEA and contrast-enhanced CT, plus [¹⁸F]FDG PET/CT 3–4 months after thermal ablation. Therapy could be repeated downstream the care pathway. Quality-of-life and survival estimates were based on disease stage and age. Costs were determined from a healthcare perspective incorporating costs related to diagnostics and treatments. The Consolidated Health Economic Evaluation Reporting Standards were followed. Results: Health benefits of additional [¹⁸F]FDG PET/CT were negligible, incremental QALYs < 0.001, whereas costs increased by €1,277, mainly due to the additional imaging. This lack of health benefits can be explained by the small subset of simulated patients (<5 %) in whom [¹⁸F]FDG PET/CT affected treatment planning. Discussion: Additional [¹⁸F]FDG PET/CT 3–4 months after thermal ablation is unlikely to be cost-effective. More research is needed to determine if using [¹⁸F]FDG PET/CT in subgroups of patients, or at alternative time points, is cost-effective. This requires collecting more (extensive) follow-up data across multiple centres to reflect heterogeneity between hospitals’ clinical practices.

Background: Colorectal cancer is highly prevalent. The stromal tumour microenvironment significantly influences tumour behaviour, and cancer-associated fibroblasts (CAFs), as major component of tumour stroma, are increasingly studied. Specifically, CAF-marker fibroblast activation protein (FAP) is gaining interest as tracer for imaging using radiolabelled FAP-inhibitor (FAPI). We describe patterns of FAP-expression, and associations to intratumoural stroma amount, establishing a biological background and potential future reference to pathology assessment.

Materials and methods: Archival histological material from 125 stage-II/III CRC patients was collected. Haematoxylin-and-eosin staining was performed to determine the tumour-stroma ratio (TSR), indicating stromal percentages in primary tumours, lymph nodes (LNs) and biopsies. On immunohistochemistry stains, FAP-expression was semiquantitatively scored as little-no, heterogeneous, or moderate-high expression. Correlation of TSR and FAP-expression with Chi-square testing was assessed. Other patterns were also described, e.g. tumour epithelial FAP-expression.

Results: In total, 93 patients (40 stage-III colon [CC], 53 stage-II/III RC) were included. Correlation between 41 (44 %) stroma-high CRC (18/40 CC, 45 %; 23/53 RC, 43 %) with high FAP-expression was not significant (P = 0.428 CRC; P = 0.470 CC; P = 0.615 RC). The majority of CRC had any FAP-expression (78 CRC, 84 %), mostly the invasive front, and in most associated LN metastases (87 % CRC tumour-positive LN). However, FAP-expression was often heterogeneous, even staining healthy colon and lymphoid tissue.

Conclusions: CRCs and LN metastases generally express FAP, but levels vary significantly between and within tumours and have no direct correlation with TSR. Care has to be taken translating FAPI-PET/CT results with e.g. disease extent and activity, emphasizing the importance of multidisciplinary approach.

Purpose
The value of integrating clinical variables, radiomics, and tumor-derived cell-free DNA (cfDNA) for the prediction of survival and response to chemoradiation of patients with resectable esophageal adenocarcinoma is not yet known. Our aim was to investigate if radiomics and cfDNA metrics combined with clinical variables can improve personalized predictions.

Methods and Materials
A cohort of 111 patients with resectable esophageal adenocarcinoma from 2 centers treated with neoadjuvant chemoradiation therapy was used for exploratory retrospective analyses. Models combining the clinical variables of the SOURCE survival model with radiomic features and cfDNA were built using elastic net regression and internally validated using 5-fold cross-validation. Model performance for overall survival (OS) and time to progression (TTP) were evaluated with the C-index and the area under the curve for pathologic complete response.

Results
The best-performing baseline models for OS and TTP were based on the combination of SOURCE-cfDNA that reached a C-index of 0.55 and 0.59 compared with 0.44 to 0.45 with SOURCE alone. The addition of restaging positron emission tomography radiomics to SOURCE was the most promising addition for predicting OS (C-index: 0.65) and TTP (C-index: 0.60). Baseline risk stratification was achieved for OS and TTP by combining SOURCE with radiomics or cfDNA, log-rank P < .01. The best-performing combination model for the prediction of pathologic complete response reached an area under the curve of 0.61 compared with 0.47 with SOURCE variables alone.

Conclusions
The addition of radiomics and cfDNA can improve the performance of an established survival model. External validity needs to be further assessed in future studies together with the optimization of radiomic pipelines.

Purpose: This study investigated whether radiomic features extracted from [¹⁸F]FDG-PET scans acquired before and two weeks after neoadjuvant treatment, and their variation, provided prognostic parameters in locally advanced cervical cancer (LACC) patients treated with neoadjuvant chemo-radiotherapy (CRT) followed by radical surgery. Methods: We retrospectively included LACC patients referred to our Institution from 2010 to 2016. [¹⁸F]FDG-PET/CT was performed before neoadjuvant CRT (baseline) and two weeks after the start of treatment (early). Radiomic features were extracted after semi-automatic delineation of the primary tumour, on baseline and early PET images. Delta radiomics were calculated as the relative differences between baseline and early features. We performed 5-fold cross-validation stratified for recurrence and cancer-specific death, integrating dimensionality reduction of the radiomic features and variable hunting with importance within the folds. After supervised feature selection, radiomic models with the best-performing features for each timepoint, as well as clinical models and combined clinico-radiomic models, were built. Model performances are presented as C-indices, for prediction of recurrence/progression (disease-free survival, DFS) and cancer-specific death (overall survival, OS). Results: 95 patients were included. With a median follow-up of 76.0 months (95% CI: 59.5–82.1), 31.6% of patients had recurrence/progression and 20.0% died of disease. None of the models could predict DFS (C-indices ≤ 0.72). Model performances for OS yielded slightly better results, with mean C-indices of 0.75 for both the radiomic and combined model based on early features, 0.79 and 0.78 for the radiomic and combined model derived from delta features, and 0.76 for the clinical models. Conclusion: [¹⁸F]FDG-PET early and delta radiomic features could not predict DFS in patients with LACC treated with neoadjuvant CRT followed by radical surgery. Although slightly improved performances for the radiomic and combined models were observed in the prediction of OS compared to the clinical model, the added value of these parameters and their inclusion in the clinical practice seems to be limited.

Purpose
Prostate-specific membrane antigen (PSMA) expression has been observed in a subset of soft tissue sarcomas, mainly in the neovascular endothelial cells. This feasibility study aimed to evaluate PSMA expression and PSMA PET/CT imaging in metastatic soft tissue sarcoma, providing important insights for potential future exploration of PSMA-targeted radioligand therapy.

Methods
This prospective single-center study included adult patients with metastatic soft tissue sarcoma, with measurable disease (lesion diameter > 1 cm), available biopsy/resection material, ECOG/WHO performance status of 0–2 and either no prior systemic treatment, progressive disease during/after treatment, or stable disease/partial response with the last dose > 8 weeks prior. Immunohistochemical PSMA staining was performed on previously obtained biopsy or resection material. In case of high PSMA expression, a [18F]-JK-PSMA-7 PET/CT scan evaluated tracer uptake, with adequate uptake defined as SUVmax > 8.

Results
Of 25 included patients, 11 (44%) had high PSMA expression: 4/11 leiomyosarcomas, 3/4 dedifferentiated liposarcomas, 2/5 undifferentiated pleomorphic sarcomas, 1/2 myxofibrosarcomas and 1/1 malignant peripheral nerve sheath tumour. Five of 11 patients agreed to a [18F]-JK-PSMA-7 PET/CT, of which 3 had lesions that showed adequate tracer uptake (SUVmax 10.7–16.7). However, uptake across all metastatic lesions was highly heterogeneous (median SUVmax = 3.8; range 0.5–16.7), indicating that these patients are unlikely to benefit sufficiently from PSMA-targeted therapy. The study was therefore terminated prematurely.

Conclusion
PSMA expression and PSMA tracer uptake in metastatic soft tissue sarcoma were highly heterogeneous. A deeper understanding of PSMA biology and improved patient selection criteria are essential for future application of PSMA-targeted radioligand therapy in this disease.

Purpose
Tumor-targeted positron emission tomography (PET) and fluorescence-guided surgery (FGS) could address current challenges in pre- and intraoperative imaging of gastric cancer. Adequate selection of molecular imaging targets remains crucial for successful tumor visualization. This study evaluated the potential of integrin αvβ6, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and human epidermal growth factor receptor-2 (HER2) for molecular imaging of primary gastric cancer, as well as lymph node and distant metastases.

Methods
Expression of αvβ6, CEACAM5, EGFR, EpCAM and HER2 was determined using immunohistochemistry in human tissue specimens of primary gastric adenocarcinoma, healthy surrounding stomach, esophageal and duodenal tissue, tumor-positive and tumor-negative lymph nodes, and distant metastases, followed by quantification using the total immunostaining score (TIS).

Results
Positive biomarker expression in primary gastric tumors was observed in 86% for αvβ6, 72% for CEACAM5, 77% for EGFR, 93% for EpCAM and 71% for HER2. Tumor expression of CEACAM5, EGFR and EpCAM was higher compared to healthy stomach tissue expression, while this was not the case for αvβ6 and HER2. Tumor-positive lymph nodes could be distinguished from tumor-negative lymph nodes, with accuracy ranging from 82 to 93% between biomarkers. CEACAM5, EGFR and EpCAM were abundantly expressed on distant metastases, with expression in 88–95% of tissue specimens.

Conclusion
Our findings show that CEACAM5, EGFR and EpCAM are promising targets for molecular imaging of primary gastric cancer, as well as visualization of both lymph node and distant metastases. Further clinical evaluation of PET and FGS tracers targeting these antigens is warranted.

Introduction: There is much literature about the role of 2-[¹⁸F]FDG PET/CT in patients with breast cancer (BC). However, there exists no international guideline with involvement of the nuclear medicine societies about this subject. Purpose: To provide an organized, international, state-of-the-art, and multidisciplinary guideline, led by experts of two nuclear medicine societies (EANM and SNMMI) and representation of important societies in the field of BC (ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA). Methods: Literature review and expert discussion were performed with the aim of collecting updated information regarding the role of 2-[¹⁸F]FDG PET/CT in patients with no special type (NST) BC and summarizing its indications according to scientific evidence. Recommendations were scored according to the National Institute for Health and Care Excellence (NICE) criteria. Results: Quantitative PET features (SUV, MTV, TLG) are valuable prognostic parameters. In baseline staging, 2-[¹⁸F]FDG PET/CT plays a role from stage IIB through stage IV. When assessing response to therapy, 2-[¹⁸F]FDG PET/CT should be performed on certified scanners, and reported either according to PERCIST, EORTC PET, or EANM immunotherapy response criteria, as appropriate. 2-[¹⁸F]FDG PET/CT may be useful to assess early metabolic response, particularly in non-metastatic triple-negative and HER2+ tumours. 2-[¹⁸F]FDG PET/CT is useful to detect the site and extent of recurrence when conventional imaging methods are equivocal and when there is clinical and/or laboratorial suspicion of relapse. Recent developments are promising. Conclusion: 2-[¹⁸F]FDG PET/CT is extremely useful in BC management, as supported by extensive evidence of its utility compared to other imaging modalities in several clinical scenarios.

Background: In the Netherlands, the COVID-19 pandemic resulted in a temporary halt of population screening for cancer and limited hospital capacity for non-COVID care. We aimed to investigate the impact of the pandemic on the in-hospital diagnostic pathway of breast cancer (BC) and colorectal cancer (CRC). Methods: 71,159 BC and 48,900 CRC patients were selected from the Netherlands Cancer Registry. Patients, diagnosed between January 2020 and July 2021, were divided into six periods and compared to the average of patients diagnosed in the same periods in 2017–2019. Diagnostic procedures performed were analysed using logistic regression. Lead time of the diagnostic pathway was analysed using Cox regression. Analyses were stratified for cancer type and corrected for age, sex (only CRC), stage and region. Results: For BC, less mammograms were performed during the first recovery period in 2020. More PET-CTs were performed during the first peak, first recovery and third peak period. For CRC, less ultrasounds and more CT scans and MRIs were performed during the first peak. Lead time decreased the most during the first peak by 2 days (BC) and 8 days (CRC). Significantly fewer patients, mainly in lower stages, were diagnosed with BC (−47%) and CRC (−36%) during the first peak. Conclusion: Significant impact of the COVID-19 pandemic was found on the diagnostic pathway, mainly during the first peak. In 2021, care returned to the same standards as before the pandemic. Long-term effects on patient outcomes are not known yet and will be the subject of future research.

Purpose: The aim of this study was to investigate the biodistribution of (super-)selective trans-arterial radioembolization (TARE) with holmium-166 microspheres (¹⁶⁶Ho-MS), when administered as adjuvant therapy after RFA of HCC 2–5 cm. The objective was to establish a treatment volume absorbed dose that results in an absorbed dose of ≥ 120 Gy on the hyperemic zone around the ablation necrosis (i.e., target volume). Methods: In this multicenter, prospective dose-escalation study in BCLC early stage HCC patients with lesions 2–5 cm, RFA was followed by (super-)selective infusion of ¹⁶⁶Ho-MS on day 5–10 after RFA. Dose distribution within the treatment volume was based on SPECT-CT. Cohorts of up to 10 patients were treated with an incremental dose (60 Gy, 90 Gy, 120 Gy) of ¹⁶⁶Ho-MS to the treatment volume. The primary endpoint was to obtain a target volume dose of ≥ 120 Gy in 9/10 patients within a cohort. Results: Twelve patients were treated (male 10; median age, 66.5 years (IQR, [64.3–71.7])) with a median tumor diameter of 2.7 cm (IQR, [2.1–4.0]). At a treatment volume absorbed dose of 90 Gy, the primary endpoint was met with a median absorbed target volume dose of 138 Gy (IQR, [127–145]). No local recurrences were found within 1-year follow-up. Conclusion: Adjuvant (super-)selective infusion of ¹⁶⁶Ho-MS after RFA for the treatment of HCC can be administered safely at a dose of 90 Gy to the treatment volume while reaching a dose of ≥ 120 Gy to the target volume and may be a favorable adjuvant therapy for HCC lesions 2–5 cm. Trial registration: Clinicaltrials.gov NCT03437382.