Current treatment of N1M0 prostate cancer (PCa) with locoregional external beam radiotherapy (EBRT) and long-term androgen deprivation therapy (ADT) has suboptimal five-year recurrence-free rates. Adding [177Lu]Lu-PSMA-617 may improve tumour control and reduce reliance on long-term ADT. This phase-1 dose-escalation study explores the safety and tolerability of adding concurrent [177Lu]Lu-PSMA-617 with EBRT and ADT. In the multi-centre phase-1 dose-escalation study (PROQURE-I), treatment-naïve cT1-4N1M0 PCa patients received standard locoregional EBRT (25–35 fractions) and 2–3 years ADT with concurrent [177Lu]Lu-PSMA-617 to determine its maximum tolerated dose (MTD). Dose levels included one cycle (3, 6 or 9 GBq in week 2 of EBRT) or two cycles (2 × 7.4 GBq in week 2 and 4). Grade ≥ 3 toxicity (CTCAE v5.0) was dose-limiting. Tumour and organ dosimetry was performed with SPECT/CT and planar imaging at 4, 24 and 168 h post-injection. Fourteen patients were included. No dose-limiting toxicity was observed and the MTD was not reached. Reported grade 1–2 toxicities were related to EBRT. Median absorbed dose to the primary tumour of 0.71 Gy/GBq (interquartile range (IQR) 0.5–2.9) at the 9 GBq; 0.91 Gy/GBq (IQR 0.6-1.0) at 7.4 GBq cycle 1; and 0.47 Gy/GBq (0.3–0.5) at cycle 2. Concurrent [177Lu]Lu-PSMA-617 with EBRT and ADT is safe and well tolerated in treatment-naïve N1M0 PCa. Clinical efficacy should be evaluated in a subsequent phase 2 study.

PURPOSE:The phase I Hybrid trial assessed the safety of combining simultaneous stereotactic body radiotherapy (SBRT) to the primary tumor and fractionated radiotherapy to the lymph nodes with concurrent cisplatin. MATERIALS AND METHODS:15 patients with stage III non-small cell lung cancer (NSCLC) with a peripheral primary tumor <5 cm were prospectively included and treated with concurrent daily low-dose chemoradiation using a hybrid fractionation schedule of simultaneous 24 fractions conventionally fractionated radiotherapy and 3 fractions SBRT. The allowed mean lung dose (MLD) was escalated by adapting the SBRT fraction dose between 14 and 18 Gy per fraction using the time-to-event continual reassessment method (TITE-CRM). RESULTS:All patients were able to be planned and treated per protocol. No dose-limiting toxicity was observed with a maximum treated MLD of 19.1 Gy. The most common Grade 1-2 toxicities consisted of radiation pneumonitis (N = 7) or rib fractures (N = 6). No G3+ pulmonary or mediastinal toxicities were observed. Although local and regional control were excellent (both 93%), 11 patients (73%) eventually developed progressive disease at distant sites at a median of 11 months. CONCLUSION:Simultaneous SBRT to the primary tumor and fractionated radiotherapy to the lymph nodes is feasible and safe with concurrent daily dose cisplatin with high loco-regional control rates.

Introduction Colorectal cancer patients with peritoneal metastases have a very poor prognosis. A minority of these patients is eligible for curative cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The peritoneal cancer index (PCI) is an important criterion to select patients for CRS-HIPEC. Due to challenges in peritoneal metastasis detection by imaging, the PCI is currently routinely assessed by invasive diagnostic laparoscopy in addition to CT and/or MRI. Yet, open-close procedures and early disease recurrence following CRS-HIPEC are common, indicating the need for better patient selection tools. Fibroblast activation protein (FAP)-targeted imaging has recently emerged as a promising strategy for visualising peritoneal disease. The aim of this study is to assess the potential value of FAP inhibitor positron emission tomography/CT (FAPI-PET/CT) as an alternative non-invasive tool for quantitative PCI assessment. Methods and analysis TROMPET is a prospective observational proof-of-concept study. A total of 25 colorectal cancer patients with suspected or verified peritoneal metastases who are eligible for CRS-HIPEC based on MRI will be included in this study. Patients younger than 18, pregnant and/or breastfeeding, with any contraindication(s) for MRI, PET, CT and/or CRS-HIPEC, and/or with a known additional malignancy within the past five years are excluded. Participants will receive [ 18 F]AlF-FAPI-74 PET/CT prior to surgery. The primary objective is to determine the correlation between PCI scores determined by FAPI-PET/CT and ‘true’ PCI scores determined by histopathological analysis of all resected lesions. The secondary objectives include the correlations between PCI scores determined by FAPI-PET/CT, by MRI and during surgery, the potential of FAPI-PET/CT to detect extraperitoneal metastases, and molecular and immunohistochemical analysis of resected tissue to provide insight into the nature of FAPI-PET-positive lesions. The primary endpoint is all PCI scores determined by FAPI-PET and histopathology and their correlation on patient level. If this study shows that the PCI score can be accurately determined preoperatively by FAPI-PET/CT, it will form the basis for further developing FAPI-PET/CT as a quantitative, standardised, non-invasive diagnostic tool for selecting patients for CRS-HIPEC. Moreover, the ‘radiology-pathology’ setup of the study will allow us to characterise FAPI-PET-positive and PET-negative lesions in detail, providing further insight into the strengths and potential pitfalls of FAPI-PET/CT in the detection of peritoneal metastases from colorectal cancer. Ethics and dissemination This study is approved by the assigned Medical-Research-Ethics-Committee (METC NedMec) on 19-08-2024. All participants will provide written informed consent. Study results will be disseminated through (inter)national meetings and peer-reviewed publications. Trial registration number 2024-512301-16-01

BACKGROUND AND OBJECTIVE:Up to 25% of bladder cancer cases harbour histological subtypes (HSs) distinct from conventional urothelial carcinoma (UC), often with more aggressive behaviour and variable treatment response. Accurate staging is essential, but the optimal approach for HSs remains unclear. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) may improve staging in invasive bladder cancer (IBC), though its value in HSs is unestablished. This study evaluates the diagnostic performance and utility of [18F]FDG-PET/CT in staging HSs. METHODS:We included 112 patients with histologically confirmed IBC containing ≥75% HS content, treated at a national comprehensive cancer centre (2012-2024). An expert pathological review was performed. All patients underwent standard staging with contrast-enhanced CT (CECT) and [18F]FDG-PET/CT. The primary endpoint was visualisation of the primary tumour. The secondary endpoints included incremental diagnostic value (change in nodal or metastatic stage compared with CECT), exploratory comparison with a matched UC cohort, and pathological correlation assessment. KEY FINDINGS AND LIMITATIONS:The predominant HSs were neuroendocrine carcinoma (40%), squamous cell carcinoma (34%), adenocarcinoma (11%), and sarcomatoid carcinoma (11%). The primary tumour was FDG-avid in 87%, and FDG-negative in 5%. In 20%, [18F]FDG-PET/CT modified staging, mainly through upstaging. Differences in FDG avidity and staging impact across HSs and between pure (≥95%) and mixed (75-94%) content were small. A matched UC cohort showed similar rates of [18F]FDG-PET/CT-induced stage modification. Pathological confirmation was limited to a small selected subgroup, restricting the assessment of diagnostic accuracy. CONCLUSIONS AND CLINICAL IMPLICATIONS:The use of [18F]FDG-PET/CT demonstrated high visualisation rates for primary tumour detection and altered staging in one of five patients, supporting its consideration as a complementary modality in HS staging.

This study aimed to evaluate the image quality-dose trade-off in pregnant patients imaged with long-axial field-of-view [18F]FDG PET/CT and to identify the most predictive body composition metric for image quality to develop a pregnancy-tailored dosage model. Patients imaged with [18F]FDG PET/CT according to local pregnancy protocols were included in this study. Using raw PET data, images of various degrees of image quality were reconstructed. Acceptable image quality was identified using signal-to-noise ratio (SNR) in the liver and Likert scores. The minimum required scan statistics was modelled based on SNR and patient body composition. F-tests were used to find the best-fitting model parameter out of weight, weight-to-height-ratio, body-mass-index, and body surface area (BSA). Foetal dose was estimated with PET conversion factors and size-specific CT dose index values. Eleven patients were included in image quality analysis and dosage model optimization. SNR strongly correlated with Likert scores (R² = 0.80), with 10.72 SNR indicating acceptable image quality. BSA best predicted image quality (R² = 0.85), outperforming weight (R² = 0.78), weight-to-height ratio (R² = 0.63), and body mass index (R² = 0.38). The proposed dosage model reduces activity by 41–96

[¹⁸F]FDG‑PET/CT is increasingly used to stage invasive bladder cancer (IBC), resulting in growing demand at tertiary centres for time‑intensive second‑opinion reading of externally acquired scans. However, the incremental clinical value of routine reinterpretation is unclear. We evaluated the clinical impact of second‑opinion [¹⁸F]FDG‑PET/CT reading in a centralised referral network in the Netherlands. In this multicentre retrospective diagnostic cohort study, consecutive patients with histologically confirmed high-grade IBC who underwent externally acquired [¹⁸F]FDG‑PET/CT followed by expert second‑opinion reading at two tertiary centres were evaluated. Initial staging reports were compared with second-opinion staging assessments. Clinically meaningful discrepancies were defined as changes in nodal status (cN0 vs. cN+) or distant metastatic status (cM0 vs. cM1 or cM1a vs. cM1b). Treatment recommendation changes directly attributable to second-opinion reading were recorded. Six hundred patients were included. Agreement between initial and second‑opinion reading was high for both nodal and metastatic staging (κ = 0.89 and κ = 0.87, respectively). Clinically meaningful discrepancies occurred in 33 patients (5.5

Radiolabeled [195mPt]cisplatin has been developed as a tool to determine the biodistribution of cisplatin in vivo through SPECT imaging and possibly aid in patient-selection. This feasibility study aimed to evaluate the (radiation) safety, biodistribution, and image quality of [195mPt]cisplatin SPECT/CT in patients with non-small cell lung cancer (NSCLC). [195mPt]Cisplatin was produced under GMP standards. Six patients received 100 MBq [195mPt]cisplatin in their second or third week of chemoradiation therapy. Planar and SPECT/CT imaging were acquired at 1.5, 48, 120 and 168 h post-administration. Segmentation on SPECT for biodistribution and dosimetry was achieved using TotalSegmentator in 3DSlicer, and organ specific time-activity curves were generated through a mono-exponential curve fit. Effective and absorbed doses were obtained with S-values from IDAC-Dose 2.1. Toxicity was assessed using CTCAE criteria. Six NSCLC patients received 100.9 ± 3.3 MBq [195mPt]cisplatin at a radioactivity concentration of 11.1 ± 4.9 MBq/mL. No adverse events above grade 2 were observed. [195mPt]Cisplatin had a long retention time with an effective half-life of 74.8 h. Uptake was highest in the liver and kidneys, which also resulted in the highest absorbed dose at 48.6 ± 7.9 mGy and 38.4 ± 7.3 mGy, respectively. Tumor uptake was similar to blood, with a ratio of 1.0 ± 0.05. [195mPt]Cisplatin is safe to use for imaging in patients with NSCLC when injecting 100 MBq, reaching a mean effective dose of 14.6 ± 1.5 mSv. The image quality of [195mPt]cisplatin was suitable for SPECT imaging and quantification. Tumor uptake was similar to blood. CCMO, NL74272.031.21. Registered 28 January 2022, https://www.onderzoekmetmensen.nl/nl/trial/55147 .

Background: F-18-FLT PET/CT visualizes cellular proliferation and may correlate more directly with tumor aggressiveness and treatment response than F-18-FDG PET/CT in melanoma patients treated with BRAF/MEK inhibitors. We aimed to assess whether F-18-FLT PET/CT can predict early resistance to BRAF/MEK inhibitors in addition to current clinical tools in patients with BRAF-mutated metastatic melanoma. Patients and Methods:This explorative side study of the phase II multicenter REPOSIT trial included 19 patients with stage IV BRAF V600E/K-mutated cutaneous melanoma who underwent optional F-18-FLT PET/CT. F-18-FLT PET/CT was performed at baseline and after 2 weeks of treatment to evaluate baseline uptake and early changes in metabolic activity. F-18-FDG PET/CT was performed at baseline for comparison. Ki67 expression was assessed in metastatic tissue samples. Analyses included: (1) visual comparison of baseline 18F-FLT and F-18-FDG uptake, (2) correlation of 18F-FLT uptake with Ki-67, (3) semiquantitative analysis of baseline F-18-FLT uptake, and (4) evaluation of percentage change in 18F-FLT uptake after 2 weeks. Results:Patients with consistently lower F-18-FLT than F-18-FDG uptake in metastases had longer progression-free survival (PFS; median 9.6 months, range: 3.4 to 32.3) compared with those with equal/higher or heterogeneous F-18-FLT uptake (3.5 to 5.3 mo). Baseline F-18-FLT SULpeak did not correlate with Ki67 expression (P = 0.601), nor was Ki67 associated with PFS (P = 0.39). No significant PFS difference was observed between patients with baseline F-18-FLT SULpeak below or above the median (P = 0.601). However, a greater percentage decrease in F-18-FLT uptake at 2 weeks was associated with longer PFS (median: 13.9 vs 4.3 mo, P = 0.005). Conclusions:Baseline F-18-FLT uptake patterns relative to F-18-FDG, and early changes in F-18-FLT uptake, were associated with PFS in patients treated with BRAF/MEK inhibitors. These explorative findings suggest that F-18-FLT PET/CT may have predictive value, warranting confirmation in larger prospective studies.

PURPOSE:The majority of patients with HNSCC primarily treated with (chemo)radiation receive bilateral elective nodal irradiation(B-ENI). However, this concept has shown to result in a considerable toxicity and deterioration of quality-of-life. We report on the technical feasibility of a SPECT/CT-based sentinel node procedure (SNP) approach to select patients for unilateral ENI (U-ENI). PATIENTS AND METHODS:The primary tumor of 90 patients with lateralized T1-4N0-3 (N2c excluded) carcinoma of oropharynx, larynx and hypopharynx were injected under local anesthesia with indocyanine green (ICG)-99mTechnetium(Tc)-nanocolloid, 3-4 h later SPECT/CT was done for lymph drainage mapping (LDM). Patients without contralateral drainage (CLD) received U-ENI and those with CLD received SNP. Patients with negative SN still received U-ENI while those with positive SN received B-ENI. ENDPOINTS:contralateral regional failure and toxicity. RESULTS:Of the entire group, 82% had oropharyngeal cancer, 83% T1-2, and 77% Node-positive disease. LDM was successful in all patients. Flexible laryngoscope with working channel was used for the peri-tumoral injection in 53% of patients. Only 6 patients experienced the procedure as uncomfortable/painful. CLD was seen in 41 patients (45.5%), mainly in level II (63.4%). All of them received SNP and only 8 patients had positive SLN (19.5%), 7 of which in level II. These patients received B-ENI and the other 82 patients (91%) U-ENI. There was only one minor surgical complication (postoperative bleeding). CONCLUSIONS:The SPECT/CT-based SNP to guide U-ENI is feasible, safe and has resulted in significant increase in proportion of patients treated by U-ENI. The results of oncologic outcome and toxicity need to be awaited.

18F-FLT PET/CT visualizes cellular proliferation and may correlate more directly with tumor aggressiveness and treatment response than 18F-FDG PET/CT in melanoma patients treated with BRAF/MEK inhibitors. We aimed to assess whether 18F-FLT PET/CT can predict early resistance to BRAF/MEK inhibitors in addition to current clinical tools in patients with BRAF-mutated metastatic melanoma. This explorative side study of the phase II multicenter REPOSIT trial included 19 patients with stage IV BRAF V600E/K-mutated cutaneous melanoma who underwent optional 18F-FLT PET/CT. 18F-FLT PET/CT was performed at baseline and after 2 weeks of treatment to evaluate baseline uptake and early changes in metabolic activity. 18F-FDG PET/CT was performed at baseline for comparison. Ki67 expression was assessed in metastatic tissue samples. Analyses included: (1) visual comparison of baseline 18F-FLT and 18F-FDG uptake, (2) correlation of 18F-FLT uptake with Ki-67, (3) semiquantitative analysis of baseline 18F-FLT uptake, and (4) evaluation of percentage change in 18F-FLT uptake after 2 weeks. Patients with consistently lower 18F-FLT than 18F-FDG uptake in metastases had longer progression-free survival (PFS; median 9.6 months, range: 3.4 to 32.3) compared with those with equal/higher or heterogeneous 18F-FLT uptake (3.5 to 5.3 mo). Baseline 18F-FLT SULpeak did not correlate with Ki67 expression (P = 0.601), nor was Ki67 associated with PFS (P = 0.39). No significant PFS difference was observed between patients with baseline 18F-FLT SULpeak below or above the median (P = 0.601). However, a greater percentage decrease in 18F-FLT uptake at 2 weeks was associated with longer PFS (median: 13.9 vs 4.3 mo, P = 0.005). Baseline 18F-FLT uptake patterns relative to 18F-FDG, and early changes in 18F-FLT uptake, were associated with PFS in patients treated with BRAF/MEK inhibitors. These explorative findings suggest that 18F-FLT PET/CT may have predictive value, warranting confirmation in larger prospective studies.

Patients with cutaneous squamous cell carcinoma (CSCC) frequently require mutilating surgery and adjuvant radiotherapy (RT). CSCC has been demonstrated to be highly responsive to neoadjuvant anti-PD-1 immune-checkpoint blockade (ICB). However, efficacy and safety of neoadjuvant anti-PD-1 combined with anti-CTLA-4 are lacking. In the MATISSE trial, the primary objective was met to investigate the pathological response rate on neoadjuvant nivolumab (NIVO) and nivolumab plus ipilimumab (NIVO + IPI) at the time of standard of care (SOC: surgery ± RT), defined as the proportion of remaining viable tumor cells in the surgical specimen. Fifty patients with stage I-IVa resectable CSCC were treated with NIVO (weeks 0 and 2) or NIVO (weeks 0 and 2) plus low-dose IPI (week 0) before SOC in week 4. The median follow-up was 31 months. Forty patients underwent SOC; 9 of 20 (45%) patients who received NIVO and 10 of 20 (50%) patients who received NIVO + IPI reached a major pathological response (MPR) and 2 of 20 (10%) patients with NIVO and 6 of 20 (30%) with NIVO + IPI reached a partial pathological response (PPR), resulting in pathological response rates of 55% and 80%, respectively. MPR or PPR was accompanied by 2-year disease-specific survival (DSS) of 100%. ICB was safe with 12% (NIVO) and 8% (NIVO + IPI), grade 3, immune-related toxicity without surgical delays. Ten patients opted to decline surgery and RT, of whom nine reached durable organ preservation and a clinical complete remission on two ICB infusions alone, accompanied by a 2-year DSS of 100% and favorable health-related quality of life. Early changes in [18F]fluorodeoxyglucose positron emission tomography/computed tomography's total lesion glycolysis can safely select patients for response-guided treatment de-escalation in future trials. The ClinicalTrials.gov identifier is: NCT04620200 .

BACKGROUND:Thyroid incidentalomas (TIs) are incidental thyroid lesions detected on fluorodeoxy- d -glucose ( 18 F-FDG) PET/computed tomography (PET/CT) scans. This study aims to investigate the role of noninvasive PET/CT-derived radiomic features in characterizing 18 F-FDG PET/CT TIs and distinguishing benign from malignant thyroid lesions in oncological patients. MATERIALS AND METHODS:We included 46 patients with PET/CT TIs who underwent thyroid ultrasound and thyroid surgery at our oncological referral hospital. Radiomic features extracted from regions of interest (ROI) in both PET and CT images and analyzed for their association with thyroid cancer and their predictive ability. The TIs were graded using the ultrasound TIRADS classification, and histopathological results served as the reference standard. Univariate and multivariate analyses were performed using features from each modality individually and combined. The performance of radiomic features was compared to the TIRADS classification. RESULTS:Among the 46 included patients, 36 patients (78%) had malignant thyroid lesions, while 10 patients (22%) had benign lesions. The combined run length nonuniformity radiomic feature from PET and CT cubical ROIs demonstrated the highest area under the curve (AUC) of 0.88 ( P < 0.05), with a negative correlation with malignancy. This performance was comparable to the TIRADS classification (AUC: 0.84, P < 0.05), which showed a positive correlation with thyroid cancer. Multivariate analysis showed higher predictive performance using CT-derived radiomics (AUC: 0.86 ± 0.13) compared to TIRADS (AUC: 0.80 ± 0.08). CONCLUSION:This study highlights the potential of 18 F-FDG PET/CT-derived radiomics to distinguish benign from malignant thyroid lesions. Further studies with larger cohorts and deep learning-based methods could obtain more robust results.

Background and purpose:A recent study investigated the use of PSMA-PET in monitoring loss of secretory cells in salivary glands of head and neck cancer (HNC) patients. Previously, a dose-effect relation has been formulated to the PSMA-PET uptake in salivary glands. The aim of this study was to derive a proton RBE model from the PSMA-PET uptake in salivary glands after proton therapy of HNC patients. Materials and methods:Six patients treated with proton therapy were included. These patients received a PET-CT scan using 68Ga (N = 1) or 18F (N = 5) PSMA before treatment (baseline) and one month after the last fraction (follow-up). Physical dose (D), D·LETd and the follow-up PSMA-PET scan were deformed to the baseline PET-CT using deformable image registration. Parotid and submandibular gland delineations were adjusted to include voxels which had an uptake of ≥ 5 g/ml in the baseline PSMA-PET scan. Results:The average RBE-LET slope was 0.075 [0.009; 0.125] (keV/μm)-1 (mean [95 %CI]) for parotid and submandibular glands combined. When analyzing parotid or submandibular glands separately the RBE-LET curve slope varies with two and five patients showing a positive RBE-LET slope when only analyzing parotid or submandibular glands respectively. Conclusion:Our study did not find clear evidence of an increased RBE in parotid and submandibular glands with increasing LETd. On average an LETd effect was observed, however our sample size was too small to clearly define an RBE-LET relation. A larger cohort scanned at later time intervals could shed more light on this issue.

OBJECTIVES:To evaluate the evolution and current diagnostic capabilities of medical imaging in cancer of unknown primary (CUP) and explore promising technologies for enhancing diagnostic precision. METHODS:A comprehensive literature search was conducted across MEDLINE, Embase, and Scopus in March 2023 (updated in August 2024) to identify original articles focusing on CUP imaging. Two reviewers independently selected articles and extracted data. Quality assessment was performed using QUADAS-2 and Radiomics Quality Score. Given the variability in study designs, imaging techniques, and reported outcomes, a narrative synthesis was performed. Subgroup analyses compared detection rates across modalities. RESULTS:From 4760 de-duplicated search results, 140 original articles were included. Early CUP imaging relied on 2D modalities with notable diagnostic limitations. Modern 3D modalities have risen in prominence, though mammography and ultrasound remain in CUP guidelines. Implementing CT and MRI significantly improved primary tumour detection and disease characterization. CT is fundamental for CUP evaluation, and MRI offers superior soft tissue resolution, effective for detecting occult breast cancer, head and neck primaries, and suspected abdominopelvic neoplasms. FDG-PET/CT showed varying primary detection capabilities, adding value in identifying lesions/metastases missed by other modalities, essential for confirming locoregional treatment strategies. Emerging technologies for CUP imaging include whole-body MRI, FAPI-PET/CT, and AI/radiomics. CONCLUSIONS:Advancements in imaging have improved the diagnostic workup for CUP. Innovative approaches show potential for further improvement in diagnostic accuracy. ADVANCES IN KNOWLEDGE:This study provides a comprehensive overview of CUP imaging and introduces emerging modalities that could boost diagnostic accuracy. PROSPERO REGISTRATION:CRD42023453393.

Ultra-short immunotherapy may spare cutaneous squamous cell carcinoma (CSCC) patients from mutilating surgery, but early identification of (non-)response is needed to safely guide treatment adaptation. This study evaluated the feasibility of sequential [18F]FDG-PET/CT (FDG-PET) as a response biomarker in resectable CSCC patients. In the MATISSE, a randomized phase-II trial, 50 CSCC patients received two courses of neoadjuvant nivolumab (weeks 0 and 2) with or without low-dose ipilimumab (week 0) before surgery (week 4). FDG-PET scans were obtained pre-treatment and shortly prior to surgery to assess the change (Δ) in maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) at the primary tumour and largest (= index) lymph node metastasis (ILN). ΔMTV50 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-001074-30

OBJECTIVES:Diagnostic pathways for cancer of unknown primary (CUP) are often underdeveloped. At our tertiary referral centre for CUP, we recently introduced a new diagnostic workflow that includes digital discussion of CUP patients by a dedicated multidisciplinary team (MDT), centralized second opinion reviews, and an MDT-guided approach to further diagnostic steps. This study retrospectively assesses the outcomes of this optimized workflow on efficiency, diagnostic yield, and healthcare professional satisfaction. METHODS:We retrospectively compared outcomes for 39 patients from period A (May 2021-April 2022) to 41 patients from period B (Dec 2022-Nov 2023) following workflow optimization. Outcomes included time-to-diagnosis, diagnostic yield, impact of second opinion imaging reviews, and satisfaction levels among involved MDT members. RESULTS:After workflow implementation, median time to diagnosis/treatment decreased from 36 to 28 days (P = .07). Second opinion imaging reviews led to the detection of new tumour lesions in 10% of cases. A primary tumour diagnosis was established 49% patients from period A versus 61% from period B (P = .37). Satisfaction among MDT members notably improved, especially regarding interdisciplinary communication and workflow efficiency. CONCLUSION:Our optimized CUP workflow with digital MDT-discussions and routine second opinion reviews of imaging data, improved diagnostic efficiency and satisfaction among physicians. These results highlight the value of a multidisciplinary, patient-centred approach focused on effective patient management in CUP. ADVANCES IN KNOWLEDGE:Integrating digital MDT discussions and centralized second-opinion reviews in CUP care improves diagnostic efficiency and may enhance primary tumour detection rates. Radiologists and other diagnosticians play a key role in this multidisciplinary approach.