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PurposeThe prognosis of patients with metastatic GIST and imatinib-sensitive primary mutations has significantly improved. However, limited data are available to inform patients about outcomes across different lines of treatment. This retrospective analysis aims to evaluate patient outcomes at a large German GIST referral center over the past 15 years.Patients and methodsOverall survival (OS) and progression-free survival (PFS) were analyzed in patients with metastatic GIST, with diagnosis of metastases between 2008 and 2021, when at least three lines of treatment were available in Germany (n = 174).ResultsThe median overall survival far exceeds historical data for patients with primary exon 11 and exon 9 mutations (median OS in palliative treatment with imatinib: 7.1 years; median OS in second-line palliative treatment with sunitinib: 2.9 years; median OS in third-line palliative treatment with regorafenib: 1.9 years). Among those patients who received palliative imatinib treatment, no significant difference in median OS survival was observed between those who had received perioperative imatinib for localized disease and those who did not. Furthermore, the location of metastases significantly impacted survival, whereas the time between the initial diagnosis and the diagnosis of metastases had no significant effect on survival.ConclusionIn conclusion, this study provides a novel, real-world reference for survival outcomes in patients with metastatic GIST.

The fibroblast activation protein α (FAP)-directed radiotracer [68Ga]Ga-FAPI-46 for PET–CT has shown promising diagnostic accuracy in cancer staging in retrospective studies. We aim to investigate the positive predictive value (PPV) of [68Ga]Ga-FAPI-46 PET for detecting FAP-expressing tumours and the potential association between PET radiotracer uptake intensity and immunohistochemical FAP expression. This single-centre, single-arm, interventional, phase 2 trial was conducted at the University Hospital Essen, Essen, Germany. Adults aged 18 years or older undergoing initial staging or restaging were eligible if they had at least one measurable tumour lesion (>1 cm) and a confirmed or suspected diagnosis of breast cancer, colorectal cancer, endometrial cancer, oesophageal cancer, head and neck cancer, ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), prostate cancer, thyroid cancer, glioma, hepatocellular carcinoma, lymphoma, multiple myeloma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), sarcoma, seminoma, cancer of unknown primary origin, or other tumour types; had a planned or recent surgery or biopsy within 8 weeks before or after enrolment; and an ECOG performance status of 2 or less. Key exclusion criteria were previous external beam radiotherapy to the target lesion and receiving systemic cancer therapy within 1 month before enrolment. PET–CT images were acquired at a median of 11 min (IQR 10–14) after an intravenous injection of a median of 145 Megabecquerel (MBq; 124–154) of [68Ga]Ga-FAPI-46 and analysed by three independent, masked readers. The study concluded on day 30 of follow-up if histopathological confirmation and archived tumour tissue were already available, or on the day of biopsy or surgery within 8 weeks of receiving [68Ga]Ga-FAPI-46 PET–CT. Immunohistochemical FAP expression (score 0–3) was evaluated by an independent masked pathologist. The primary endpoint was the PPV of [68Ga]Ga-FAPI-46 PET for detecting immunohistochemical FAP-positive tumours (histopathologically confirmed) on a per-patient and per-region basis, with a predefined threshold of PPV of at least 75%, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05160051, and is complete. Between Dec 1, 2021, and Feb 6, 2024, 158 eligible participants were enrolled and three were excluded. 98 (63%) of 155 participants who received [68Ga]Ga-FAPI-46 PET–CT were male and 57 (37%) were female. One (1%) participant was African, two (1%) were Asian, and 152 (98%) were White. The median age of participants was 62 years (IQR 55–70). The median follow-up was 29 days (29–30). The patient-based PPV of [68Ga]Ga-FAPI-46 PET for detecting FAP-positive tumours based on immunohistochemical FAP staining was 90% (95% CI 84–95) and region-based PPV was 92% (85–96) in 127 (88%) of 144 participants with histopathological validation. Five (6%) of 90 adverse events were classified as possibly related to [68Ga]Ga-FAPI-46. Seven (8%) adverse events were serious, none related to [68Ga]Ga-FAPI-46. One participant died due to disease progression. These results confirm the safety and potential of [68Ga]Ga-FAPI-46 PET as an imaging biomarker for the detection of FAP-expressing tumours. Further studies are warranted to refine the specificity and define the role of [68Ga]Ga-FAPI-46 PET in clinical practice. SOFIE Biosciences.

Purpose Radiolabelled fibroblast activation protein inhibitors (FAPIs) are becoming increasingly important for imaging various tumour diseases. However, it is essential to be aware of potential pitfalls. Here, we investigate FAP expression in the thyroid gland in autoimmune thyroiditis (AIT). Methods AIT patients with pathological thyroid uptake on [ 68 Ga]Ga-FAPI PET were compared with glucose metabolism on 2-[ 18 F]FDG PET in terms of SUV max /SUV peak /SUV mean /tissue-to-background ratio (TBR), and with a healthy control group. Results Between September 2019 and July 2021, 6 patients presented with a visually increased thyroid uptake and TBR on [ 68 Ga]Ga-FAPI PET. In the retrospective clinical work-up, all patients had known or newly diagnosed AIT. Compared to a matched healthy control group, FAP expression and glucose metabolism were significantly increased ([ 68 Ga]Ga-FAPI (SUV peak ): 7.0 vs. 1.7; p  = 0.004/(TBR bloodpool ): 6.8 vs. 1.7; p  = 0.002; 2-[ 18 F]FDG (SUV peak ): 3.9 vs. 1.4; p  = 0.004/(TBR bloodpool ): 4.0 vs. 1.2; p  = 0.041). However, there was no significant difference in median uptake between [ 68 Ga]Ga-FAPI and 2-[18F]FDG PET (SUV peak : 7.3 vs. 5.6; p  = 0.104). Conclusion Patients with AIT show higher thyroid uptake on [ 68 Ga]Ga-FAPI and 2-[ 18 F]FDG PET. Incidental thyroid uptake is another pitfall in the interpretation of [ 68 Ga]Ga-FAPI PET and should prompt a clinical work-up.

BackgroundSome sarcomas respond to immune checkpoint inhibition, but predictive biomarkers are unknown. We analyzed tumor DNA methylation profiles in relation to immunological parameters and response to anti-programmed cell death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy in patients with sarcoma.Patients and methodsWe retrospectively identified adult patients who had received anti-PD-1 ICI therapy for recurrent sarcoma in two independent centers. We performed (1) blinded radiological response evaluation according to immune response evaluation criteria in solid tumors (iRECIST) ; (2) tumor DNA methylation profiling of >850,000 probes using Infinium MethylationEPIC microarrays; (3) analysis of tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and intratumoral expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) using immunohistochemistry; and (4) evaluation of blood-based systemic inflammation scores (neutrophil-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio). Response to anti-PD-1 ICI therapy was bioinformatically and statistically correlated with DNA methylation profiles and immunological data.Results35 patients (median age of 50 (23–81) years; 18 females, 17 males; 27 soft tissue sarcomas; 8 osteosarcomas) were included in this study. The objective response rate to anti-PD-1 ICI therapy was 22.9% with complete responses in 3 out of 35 and partial responses in 5 out of 35 patients. Adjustment of DNA methylation data for tumor-infiltrating immune cells resulted in identification of methylation differences between responders and non-responders to anti-PD-1 ICI. 2453 differentially methylated CpG sites (DMPs; 2043 with decreased and 410 with increased methylation) were identified. Clustering of sarcoma samples based on these DMPs revealed two main clusters: methylation cluster 1 (MC1) consisted of 73% responders and methylation cluster 2 (MC2) contained only non-responders to anti-PD-1 ICI. Median progression-free survival from anti-PD-1 therapy start of MC1 and MC2 patients was 16.5 and 1.9 months, respectively (p=0.001). Median overall survival of these patients was 34.4 and 8.0 months, respectively (p=0.029). The most prominent DNA methylation differences were found in pathways implicated in Rap1 signaling, focal adhesion, adherens junction Phosphoinositide 3-kinase (PI3K)-Akt signaling and extracellular matrix (ECM)–receptor interaction.ConclusionsOur data demonstrate that tumor DNA methylation profiles may serve as a predictive marker for response to anti-PD-1 ICI therapy in sarcoma.

Purpose In metastatic castration-resistant prostate cancer (mCRPC), some patients show low/absent PSMA expression in tumour lesions on positron emission tomography (PET) scans, indicating heterogeneity and heightened risk of non-response to PSMA-RLT (radioligand therapy). Imaging cancer-associated fibroblasts and glucose uptake may further characterise tumour heterogeneity in mCRPC patients. Here, we aimed to evaluate tumour heterogeneity and its potential implications for management in mCRPC patients assessed for PSMA-RLT using [ 68 Ga]Ga-FAPI-46, 2-[ 18 F]FDG and [ 68 Ga]Ga-/[ 18 F]F-PSMA-11/-1007 PET. Material and Methods Patients with advanced, progressive mCRPC underwent clinical [ 68 Ga]Ga-/[ 18 F]F-PSMA-11/-1007, 2-[ 18 F]FDG and [ 68 Ga]Ga-FAPI-46 PET/CT to evaluate treatment with PSMA-directed RLT. Tumour detection/semiquantitative parameters were compared on a per-lesion/-region basis. Two phenotypes were defined: Criteria for the mixed phenotype were: (a) PSMA-negative findings for lymph node metastases ≥ 2.5 cm, any solid organ metastases ≥ 1.0 cm, or bone metastases with soft tissue component ≥ 1.0 cm, (b) low [ 68 Ga]Ga-/[ 18 F]F-PSMA-11/-1007 uptake and/or (c) balanced tumour uptake of all radioligands. The PSMA-dominant phenotype was assigned if the criteria were not met. Results In ten patients, 472 lesions were detected on all imaging modalities (miTNM regions: M1b: 327 (69.3%), M1a: 95 (20.1%), N1: 26 (5.5%), M1c: 18 (3.8%), T: 5 (1.1%) and Tr: 1 (0.2%). [ 68 Ga]Ga-/[ 18 F]F-PSMA-11/-1007 (n = 453 (96.0%)) demonstrates the highest detection rate, followed by [ 68 Ga]Ga-FAPI-46 (n = 268 (56.8%))/2-[ 18 F]FDG (n = 241 (51.1%)). Semiquantitative uptake was highest for [ 68 Ga]Ga-/[ 18 F]F-PSMA-11/-1007 (mean SUV max (interquartile range): 22.7 (22.5), vs. [ 68 Ga]Ga-FAPI-46 (7.7 (3.7)) and 2-[ 18 F]FDG (6.8 (4.7)). Seven/three patients were retrospectively assigned to the PSMA-dominant/mixed phenotype. Median overall survival was significantly longer for patients who underwent [ 177 Lu]Lu-PSMA-617 RLT and were retrospectively assigned to the PSMA-dominant phenotype (19.7 vs. 9.3 months). Conclusion Through whole-body imaging, we identify considerable inter- and intra-patient heterogeneity of mCRPC and potential imaging phenotypes. Regarding uptake and tumour detection, [ 68 Ga]Ga-/[ 18 F]F-PSMA-11/-1007 was superior to [ 68 Ga]Ga-FAPI-46 and 2-[ 18 F]FDG, while the latter two were comparable. Patients who underwent [ 177 Lu]Lu-PSMA-617 RLT based on clinical-decision making had a longer overall survival and could be assigned to the PSMA-dominant phenotype. Graphical Abstract

In metastatic castration-resistant prostate cancer (mCRPC), some patients show low/absent PSMA expression in tumour lesions on positron emission tomography (PET) scans, indicating heterogeneity and heightened risk of non-response to PSMA-RLT (radioligand therapy). Imaging cancer-associated fibroblasts and glucose uptake may further characterise tumour heterogeneity in mCRPC patients. Here, we aimed to evaluate tumour heterogeneity and its potential implications for management in mCRPC patients assessed for PSMA-RLT using [68Ga]Ga-FAPI-46, 2-[18F]FDG and [68Ga]Ga-/[18F]F-PSMA-11/-1007 PET.PURPOSEIn metastatic castration-resistant prostate cancer (mCRPC), some patients show low/absent PSMA expression in tumour lesions on positron emission tomography (PET) scans, indicating heterogeneity and heightened risk of non-response to PSMA-RLT (radioligand therapy). Imaging cancer-associated fibroblasts and glucose uptake may further characterise tumour heterogeneity in mCRPC patients. Here, we aimed to evaluate tumour heterogeneity and its potential implications for management in mCRPC patients assessed for PSMA-RLT using [68Ga]Ga-FAPI-46, 2-[18F]FDG and [68Ga]Ga-/[18F]F-PSMA-11/-1007 PET.Patients with advanced, progressive mCRPC underwent clinical [68Ga]Ga-/[18F]F-PSMA-11/-1007, 2-[18F]FDG and [68Ga]Ga-FAPI-46 PET/CT to evaluate treatment with PSMA-directed RLT. Tumour detection/semiquantitative parameters were compared on a per-lesion/-region basis. Two phenotypes were defined: Criteria for the mixed phenotype were: (a) PSMA-negative findings for lymph node metastases ≥ 2.5 cm, any solid organ metastases ≥ 1.0 cm, or bone metastases with soft tissue component ≥ 1.0 cm, (b) low [68Ga]Ga-/[18F]F-PSMA-11/-1007 uptake and/or (c) balanced tumour uptake of all radioligands. The PSMA-dominant phenotype was assigned if the criteria were not met.MATERIAL AND METHODSPatients with advanced, progressive mCRPC underwent clinical [68Ga]Ga-/[18F]F-PSMA-11/-1007, 2-[18F]FDG and [68Ga]Ga-FAPI-46 PET/CT to evaluate treatment with PSMA-directed RLT. Tumour detection/semiquantitative parameters were compared on a per-lesion/-region basis. Two phenotypes were defined: Criteria for the mixed phenotype were: (a) PSMA-negative findings for lymph node metastases ≥ 2.5 cm, any solid organ metastases ≥ 1.0 cm, or bone metastases with soft tissue component ≥ 1.0 cm, (b) low [68Ga]Ga-/[18F]F-PSMA-11/-1007 uptake and/or (c) balanced tumour uptake of all radioligands. The PSMA-dominant phenotype was assigned if the criteria were not met.In ten patients, 472 lesions were detected on all imaging modalities (miTNM regions: M1b: 327 (69.3%), M1a: 95 (20.1%), N1: 26 (5.5%), M1c: 18 (3.8%), T: 5 (1.1%) and Tr: 1 (0.2%). [68Ga]Ga-/[18F]F-PSMA-11/-1007 (n = 453 (96.0%)) demonstrates the highest detection rate, followed by [68Ga]Ga-FAPI-46 (n = 268 (56.8%))/2-[18F]FDG (n = 241 (51.1%)). Semiquantitative uptake was highest for [68Ga]Ga-/[18F]F-PSMA-11/-1007 (mean SUVmax (interquartile range): 22.7 (22.5), vs. [68Ga]Ga-FAPI-46 (7.7 (3.7)) and 2-[18F]FDG (6.8 (4.7)). Seven/three patients were retrospectively assigned to the PSMA-dominant/mixed phenotype. Median overall survival was significantly longer for patients who underwent [177Lu]Lu-PSMA-617 RLT and were retrospectively assigned to the PSMA-dominant phenotype (19.7 vs. 9.3 months).RESULTSIn ten patients, 472 lesions were detected on all imaging modalities (miTNM regions: M1b: 327 (69.3%), M1a: 95 (20.1%), N1: 26 (5.5%), M1c: 18 (3.8%), T: 5 (1.1%) and Tr: 1 (0.2%). [68Ga]Ga-/[18F]F-PSMA-11/-1007 (n = 453 (96.0%)) demonstrates the highest detection rate, followed by [68Ga]Ga-FAPI-46 (n = 268 (56.8%))/2-[18F]FDG (n = 241 (51.1%)). Semiquantitative uptake was highest for [68Ga]Ga-/[18F]F-PSMA-11/-1007 (mean SUVmax (interquartile range): 22.7 (22.5), vs. [68Ga]Ga-FAPI-46 (7.7 (3.7)) and 2-[18F]FDG (6.8 (4.7)). Seven/three patients were retrospectively assigned to the PSMA-dominant/mixed phenotype. Median overall survival was significantly longer for patients who underwent [177Lu]Lu-PSMA-617 RLT and were retrospectively assigned to the PSMA-dominant phenotype (19.7 vs. 9.3 months).Through whole-body imaging, we identify considerable inter- and intra-patient heterogeneity of mCRPC and potential imaging phenotypes. Regarding uptake and tumour detection, [68Ga]Ga-/[18F]F-PSMA-11/-1007 was superior to [68Ga]Ga-FAPI-46 and 2-[18F]FDG, while the latter two were comparable. Patients who underwent [177Lu]Lu-PSMA-617 RLT based on clinical-decision making had a longer overall survival and could be assigned to the PSMA-dominant phenotype.CONCLUSIONThrough whole-body imaging, we identify considerable inter- and intra-patient heterogeneity of mCRPC and potential imaging phenotypes. Regarding uptake and tumour detection, [68Ga]Ga-/[18F]F-PSMA-11/-1007 was superior to [68Ga]Ga-FAPI-46 and 2-[18F]FDG, while the latter two were comparable. Patients who underwent [177Lu]Lu-PSMA-617 RLT based on clinical-decision making had a longer overall survival and could be assigned to the PSMA-dominant phenotype.

The benefit of molecularly-informed therapies in cancer of unknown primary (CUP) is unclear. Here, we use comprehensive molecular characterization by whole genome/exome, transcriptome and methylome analysis in 70 CUP patients to reveal substantial mutational heterogeneity with TP53 , MUC16 , KRAS , LRP1B and CSMD3 being the most frequently mutated known cancer-related genes. The most common fusion partner is FGFR2 , the most common focal homozygous deletion affects CDKN2A . 56/70 (80%) patients receive genomics-based treatment recommendations which are applied in 20/56 (36%) cases. Transcriptome and methylome data provide evidence for the underlying entity in 62/70 (89%) cases. Germline analysis reveals five (likely) pathogenic mutations in five patients. Recommended off-label therapies translate into a mean PFS ratio of 3.6 with a median PFS1 of 2.9 months (17 patients) and a median PFS2 of 7.8 months (20 patients). Our data emphasize the clinical value of molecular analysis and underline the need for innovative, mechanism-based clinical trials. The identification of molecular biomarkers in cancer of unknown primary site (CUP) cases may enable the improvement of prognosis in these patients. Here, the authors integrate whole genome/exome, transcriptome and methylome data in 70 CUP patients, recommend therapies based on their analysis and report clinical outcome data.

The fibroblast activation protein α (FAP)-directed radiotracer [68Ga]Ga-FAPI-46 for PET-CT has shown promising diagnostic accuracy in cancer staging in retrospective studies. We aim to investigate the positive predictive value (PPV) of [68Ga]Ga-FAPI-46 PET for detecting FAP-expressing tumours and the potential association between PET radiotracer uptake intensity and immunohistochemical FAP expression.BACKGROUNDThe fibroblast activation protein α (FAP)-directed radiotracer [68Ga]Ga-FAPI-46 for PET-CT has shown promising diagnostic accuracy in cancer staging in retrospective studies. We aim to investigate the positive predictive value (PPV) of [68Ga]Ga-FAPI-46 PET for detecting FAP-expressing tumours and the potential association between PET radiotracer uptake intensity and immunohistochemical FAP expression.This single-centre, single-arm, interventional, phase 2 trial was conducted at the University Hospital Essen, Essen, Germany. Adults aged 18 years or older undergoing initial staging or restaging were eligible if they had at least one measurable tumour lesion (>1 cm) and a confirmed or suspected diagnosis of breast cancer, colorectal cancer, endometrial cancer, oesophageal cancer, head and neck cancer, ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), prostate cancer, thyroid cancer, glioma, hepatocellular carcinoma, lymphoma, multiple myeloma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), sarcoma, seminoma, cancer of unknown primary origin, or other tumour types; had a planned or recent surgery or biopsy within 8 weeks before or after enrolment; and an ECOG performance status of 2 or less. Key exclusion criteria were previous external beam radiotherapy to the target lesion and receiving systemic cancer therapy within 1 month before enrolment. PET-CT images were acquired at a median of 11 min (IQR 10-14) after an intravenous injection of a median of 145 Megabecquerel (MBq; 124-154) of [68Ga]Ga-FAPI-46 and analysed by three independent, masked readers. The study concluded on day 30 of follow-up if histopathological confirmation and archived tumour tissue were already available, or on the day of biopsy or surgery within 8 weeks of receiving [68Ga]Ga-FAPI-46 PET-CT. Immunohistochemical FAP expression (score 0-3) was evaluated by an independent masked pathologist. The primary endpoint was the PPV of [68Ga]Ga-FAPI-46 PET for detecting immunohistochemical FAP-positive tumours (histopathologically confirmed) on a per-patient and per-region basis, with a predefined threshold of PPV of at least 75%, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05160051, and is complete.METHODSThis single-centre, single-arm, interventional, phase 2 trial was conducted at the University Hospital Essen, Essen, Germany. Adults aged 18 years or older undergoing initial staging or restaging were eligible if they had at least one measurable tumour lesion (>1 cm) and a confirmed or suspected diagnosis of breast cancer, colorectal cancer, endometrial cancer, oesophageal cancer, head and neck cancer, ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), prostate cancer, thyroid cancer, glioma, hepatocellular carcinoma, lymphoma, multiple myeloma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), sarcoma, seminoma, cancer of unknown primary origin, or other tumour types; had a planned or recent surgery or biopsy within 8 weeks before or after enrolment; and an ECOG performance status of 2 or less. Key exclusion criteria were previous external beam radiotherapy to the target lesion and receiving systemic cancer therapy within 1 month before enrolment. PET-CT images were acquired at a median of 11 min (IQR 10-14) after an intravenous injection of a median of 145 Megabecquerel (MBq; 124-154) of [68Ga]Ga-FAPI-46 and analysed by three independent, masked readers. The study concluded on day 30 of follow-up if histopathological confirmation and archived tumour tissue were already available, or on the day of biopsy or surgery within 8 weeks of receiving [68Ga]Ga-FAPI-46 PET-CT. Immunohistochemical FAP expression (score 0-3) was evaluated by an independent masked pathologist. The primary endpoint was the PPV of [68Ga]Ga-FAPI-46 PET for detecting immunohistochemical FAP-positive tumours (histopathologically confirmed) on a per-patient and per-region basis, with a predefined threshold of PPV of at least 75%, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05160051, and is complete.Between Dec 1, 2021, and Feb 6, 2024, 158 eligible participants were enrolled and three were excluded. 98 (63%) of 155 participants who received [68Ga]Ga-FAPI-46 PET-CT were male and 57 (37%) were female. One (1%) participant was African, two (1%) were Asian, and 152 (98%) were White. The median age of participants was 62 years (IQR 55-70). The median follow-up was 29 days (29-30). The patient-based PPV of [68Ga]Ga-FAPI-46 PET for detecting FAP-positive tumours based on immunohistochemical FAP staining was 90% (95% CI 84-95) and region-based PPV was 92% (85-96) in 127 (88%) of 144 participants with histopathological validation. Five (6%) of 90 adverse events were classified as possibly related to [68Ga]Ga-FAPI-46. Seven (8%) adverse events were serious, none related to [68Ga]Ga-FAPI-46. One participant died due to disease progression.FINDINGSBetween Dec 1, 2021, and Feb 6, 2024, 158 eligible participants were enrolled and three were excluded. 98 (63%) of 155 participants who received [68Ga]Ga-FAPI-46 PET-CT were male and 57 (37%) were female. One (1%) participant was African, two (1%) were Asian, and 152 (98%) were White. The median age of participants was 62 years (IQR 55-70). The median follow-up was 29 days (29-30). The patient-based PPV of [68Ga]Ga-FAPI-46 PET for detecting FAP-positive tumours based on immunohistochemical FAP staining was 90% (95% CI 84-95) and region-based PPV was 92% (85-96) in 127 (88%) of 144 participants with histopathological validation. Five (6%) of 90 adverse events were classified as possibly related to [68Ga]Ga-FAPI-46. Seven (8%) adverse events were serious, none related to [68Ga]Ga-FAPI-46. One participant died due to disease progression.These results confirm the safety and potential of [68Ga]Ga-FAPI-46 PET as an imaging biomarker for the detection of FAP-expressing tumours. Further studies are warranted to refine the specificity and define the role of [68Ga]Ga-FAPI-46 PET in clinical practice.INTERPRETATIONThese results confirm the safety and potential of [68Ga]Ga-FAPI-46 PET as an imaging biomarker for the detection of FAP-expressing tumours. Further studies are warranted to refine the specificity and define the role of [68Ga]Ga-FAPI-46 PET in clinical practice.SOFIE Biosciences.FUNDINGSOFIE Biosciences.

PurposeClear cell sarcoma (CCS) of tendons and aponeuroses and CCS-like malignant gastrointestinal neuroectodermal tumor/sarcoma (GINET) are characterized by frequent local and distant relapses, alongside with low efficacy of all systemic treatments. We aimed to collect a comprehensive dataset to identify prognostic factors and treatment outcomes.MethodsWe performed a retrospective single center analysis for diagnosed CCS and GINET on demographic, tumor, treatment and survival data.ResultsWe identified 43 patients (w:25, m:18) with a median follow-up of 35mo and a 5y-OS-rate of 42%. At diagnosis the median age was 42yrs. Median tumor size was 3.6 cm (0.3–11.1 cm), and 24/26 (94%) tissues analyzed at our institute were EWSR1::ATF1-translocation-positive. Distant extremities (incl. knee or elbow) were affected in 72.5%. Of note, 79.5% received an excisional biopsy (benign histology suspected in 30.2%) leading to frequent incomplete resection. Final R0 status correlated significantly (p = 0.017) with longer survival rates compared to R + status in localized CCS (N0M0, 5-yr OS 0% vs 64%). Radiation and systemic treatment had limited antitumor effects while isolated limb perfusion was active in some patients. 18.6% of patients showed lymphatic spread and 20.9% distant metastases. Presence of initial M + was associated with a dismal survival of 1.4 years (M +) vs 7.1 years (M0; p < .001).ConclusionWe here present one of the largest clinical cohorts of patients with CCS/GINET. Our data underscores the exceptional risk of metastatic disease even in small tumors. As systemic treatment and radiation showed limited efficacy, complete resection was the most important treatment option.