Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, ...suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.
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•ATRTs are comprised of three epigenetically distinct subgroups: TYR, SHH, and MYC•H3K27Ac enhancer landscapes reveal ATRT subgroup-specific regulatory networks•Regulatory networks lead to identification of potential therapeutic targets•Epigenetic profiles point at distinct cellular origins of ATRT subgroups
SMARCB1 is the sole highly recurrently mutated gene in atypical teratoid/rhabdoid tumors (ATRTs). Johann et al. show that ATRTs are composed of three epigenetic subgroups that have different clinical characteristics, and identify subgroup-specific regulatory networks that suggest potential therapeutic targets.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pancreatic ductal carcinoma (PDAC) is a highly lethal cancer, and early detection and accurate staging are critical to prolonging survival. PDAC typically has a prominent stroma including ...cancer-associated fibroblasts that express fibroblast activation protein (FAP). FAP is a new target molecule for PET imaging of various tumors. In this retrospective study, we describe the clinical impact of PET/CT imaging using 68Ga-labeled FAP-inhibitors (68Ga-FAPI PET/CT) in 19 patients with PDAC (7 primary, 12 progressive/recurrent). Methods: All patients underwent contrast-enhanced CT (ceCT) for TNM staging before 68Ga-FAPI PET/CT imaging. PET scans were acquired 60 min after administration of 150–250 MBq of 68Ga-labeled FAP-specific tracers. To characterize 68Ga-FAPI uptake over time, additional scans after 10 or 180 min were acquired in 6 patients. SUVmax and SUVmean values of PDAC manifestations and healthy organs were analyzed. The tumor burden according to 68Ga-FAPI PET/CT was compared with TNM staging based on ceCT and changes in oncologic management were recorded. Results: Compared with ceCT, 68Ga-FAPI PET/CT results led to changes in TNM staging in 10 of 19 patients. Eight of 12 patients with recurrent/progressive disease were upstaged, 1 was downstaged, and 3 had no change. In newly diagnosed PDAC, 1 of 7 patients was upstaged, and the staging of 6 patients did not change. Changes in oncologic management occurred in 7 patients. Markedly elevated uptake of 68Ga-FAPI in PDAC manifestations after 1 h was seen in most cases. Differentiation from pancreatitis based on static imaging 1 h after injection was challenging. With respect to imaging after multiple time points, PDAC and pancreatitis showed a trend for differential uptake kinetics. Conclusion: 68Ga-FAPI PET/CT led to restaging in half of the patients with PDAC and most patients with recurrent disease compared with standard of care imaging. The clinical value of 68Ga-FAPI PET/CT should be further investigated.
Purpose
FAPI ligands (fibroblast activation protein inhibitor), a novel class of radiotracers for PET/CT imaging, demonstrated in previous studies rapid and high tumor uptake. The purpose of this ...study is the head-to-head intra-individual comparison of
68
Ga-FAPI versus standard-of-care
18
F-FDG in PET/CT in organ biodistribution and tumor uptake in patients with various cancers.
Material and Methods
This international retrospective multicenter analysis included PET/CT data from 71 patients from 6 centers who underwent both
68
Ga-FAPI and
18
F-FDG PET/CT within a median time interval of 10 days (range 1–89 days). Volumes of interest (VOIs) were manually drawn in normal organs and tumor lesions to quantify tracer uptake by SUVmax and SUVmean. Furthermore, tumor-to-background ratios (TBR) were generated (SUVmax tumor/ SUVmax organ).
Results
A total of 71 patients were studied of, which 28 were female and 43 male (median age 60). In 41 of 71 patients, the primary tumor was present. Forty-three of 71 patients exhibited 162 metastatic lesions.
68
Ga-FAPI uptake in primary tumors and metastases was comparable to
18
F-FDG in most cases. The SUVmax was significantly lower for
68
Ga-FAPI than
18
F-FDG in background tissues such as the brain, oral mucosa, myocardium, blood pool, liver, pancreas, and colon. Thus,
68
Ga-FAPI TBRs were significantly higher than
18
F-FDG TBRs in some sites, including liver and bone metastases.
Conclusion
Quantitative tumor uptake is comparable between
68
Ga-FAPI and
18
F-FDG, but lower background uptake in most normal organs results in equal or higher TBRs for
68
Ga-FAPI. Thus,
68
Ga-FAPI PET/CT may yield improved diagnostic information in various cancers and especially in tumor locations with high physiological
18
F-FDG uptake.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
For oncologic management or radiotherapy planning, reliable staging tools are essential. The recent development of quinoline-based ligands targeting cancer-associated fibroblasts demonstrated ...promising preclinical and clinical results. The current study aimed to evaluate the role of fibroblast activation protein inhibitor (FAPI) PET/CT as a first clinical analysis for primary malignancies within the lower gastrointestinal tract (LGT). Methods: 68Ga-FAPI PET/CT was performed on a cohort of 22 patients with LGT tumors, including 15 patients with metastatic disease, 1 patient with suspected local relapse, and 6 treatment-naïve patients. Uptake of 68Ga-FAPI-04 and 68Ga-FAPI-46 was quantified by SUVmax and SUVmean. After comparison with standard imaging, changes in tumor stage or localization and in oncologic or radiooncologic management were recorded. Results: The highest uptake of FAPI tracer was observed in liver metastases and anal cancer, with an SUVmax of 9.1 and 13.9, respectively. Because of low background activity in normal tissue, there was a high tumor-to-background ratio of more than 3 in most lesions. In treatment-naïve patients, TNM was changed in 50%, whereas in patients with metastases, new findings occurred in 47%. In total, FAPI imaging caused a high, medium, and low change in oncologic or radiooncologic management in 19%, 33%, and 29%, respectively. For almost every patient undergoing irradiation, target volume delineation was improved by 68Ga-FAPI PET/CT. Conclusion: The present study demonstrated that both primary and metastatic LGT tumors were reliably detected by 68Ga-FAPI PET/CT, leading to relevant changes in TNM status and oncologic or radiooncologic management. 68Ga-FAPI PET/CT seems to be a highly promising imaging agent for the diagnosis and management of LGT tumors, potentially opening new applications for tumor staging or restaging.
Purpose
68
Ga-FAPI (fibroblast activation protein inhibitor) is a novel and highly promising radiotracer for PET/CT imaging. The aim of this retrospective analysis is to explore the potential of ...FAPI-PET/CT in gynecological malignancies. We assessed biodistribution, tumor uptake, and the influence of pre- or postmenopausal status on tracer accumulation in hormone-sensitive organs. Furthermore, a comparison with the current standard oncological tracer
18
F-FDG was performed in selected cases.
Patients and methods
A total of 31 patients (median age 59.5) from two centers with several gynecological tumors (breast cancer; ovarian cancer; cervical cancer; endometrial cancer; leiomyosarcoma of the uterus; tubal cancer) underwent
68
Ga-FAPI-PET/CT. Out of 31 patients, 10 received an additional
18
F-FDG scan within a median time interval of 12.5 days (range 1–76). Tracer uptake was quantified by standardized uptake values (SUV)max and (SUV)mean, and tumor-to-background ratio (TBR) was calculated (SUVmax tumor/ SUVmean organ). Moreover, a second cohort of 167 female patients with different malignancies was analyzed regarding their FAPI uptake in normal hormone-responsive organs: endometrium (
n
= 128), ovary (
n
= 64), and breast (
n
= 147). These patients were categorized by age as premenopausal (<35 years;
n
= 12), postmenopausal (>65 years;
n
= 68), and unknown menstrual status (35–65 years;
n
= 87), followed by an analysis of FAPI uptake of the pre- and postmenopausal group.
Results
In 8 out of 31 patients, the primary tumor was present, and all 31 patients showed lesions suspicious for metastasis (
n
= 81) demonstrating a high mean SUVmax in both the primary (SUVmax 11.6) and metastatic lesions (SUVmax 9.7). TBR was significantly higher in
68
Ga-FAPI compared to
18
F-FDG for distant metastases (13.0 vs. 5.7;
p
= 0.047) and by trend for regional lymph node metastases (31.9 vs 27.3;
p
= 0.6). Biodistribution of
68
Ga-FAPI-PET/CT presented significantly lower uptake or no significant differences in 15 out of 16 organs, compared to
18
F-FDG-PET/CT. The highest uptake of all primary lesions was obtained in endometrial carcinomas (mean SUVmax 18.4), followed by cervical carcinomas (mean SUVmax 15.22). In the second cohort, uptake in premenopausal patients differed significantly from postmenopausal patients in endometrium (11.7 vs 3.9;
p
< 0.0001) and breast (1.8 vs 1.0;
p
= 0.004), whereas no significant difference concerning ovaries (2.8 vs 1.6;
p
= 0.141) was observed.
Conclusion
Due to high tracer uptake resulting in sharp contrasts in primary and metastatic lesions and higher TBRs than
18
F-FDG-PET/CT,
68
Ga-FAPI-PET/CT presents a promising imaging method for staging and follow-up of gynecological tumors. The presence or absence of the menstrual cycle seems to correlate with FAPI accumulation in the normal endometrium and breast. This first investigation of FAP ligands in gynecological tumor entities supports clinical application and further research in this field.
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Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
A growing family of 68Ga-fibroblast activation protein inhibitor (FAPI) PET probes has shown promise in imaging a variety of medical conditions. 68Ga-FAPI-46, in particular, has emerged as unique for ...both its diagnostic and its theranostic applications; however, the optimal timing of PET remains unclear. Therefore, we evaluated uptake at 3 time points after 68Ga-FAPI-46 administration in a spectrum of tumor types. Methods: The cohort consisted of 43 patients with diverse cancer diagnoses undergoing 68Ga-FAPI-46 PET/CT at 3 time points (10 min, 1 h, and 3 h). We determined the tracer uptake based on SUVmean and SUVmax and on tumor-to-background-ratios (TBRs) (SUVmax/SUVmean). Results: There were 171 lesions in the 43 patients. Comparing all lesions at different time points, the mean SUVmax was maximal at 10 min (8.2) and declined slightly at 1 h (8.15) and 3 h (7.6) after tracer administration. Similarly, the mean SUVmax log still had a similar pattern in primary lesions at 10 min, 1 h, and 3 h (n = 30; 0.98, 1.01, and 0.98, respectively), lymph node metastases (n = 37; 0.82, 0.84, and 0.81, respectively), and distant metastases (n = 104; 0.81, 0.79, and 0.74, respectively). TBR also showed nonsignificant differences at the 3 times. Conclusion: 68Ga-FAPI-46 PET/CT imaging revealed remarkably stable tumor and background uptake as determined by SUV metrics and maintained high TBRs within 3 h of injection. Thus, it may be possible to scan with 68Ga-FAPI-46 within 10–20 min of injection, improving workflow and decreasing patient wait times. Confirmation of these findings in a larger cohort is under way.
68Ga-fibroblast activation protein inhibitors (FAPIs) 2, 4, and 46 have already been proposed as promising PET tracers. However, the short half-life of 68Ga (68 min) creates problems with manufacture ...and delivery. 18F (half-life, 110 min) labeling would result in a more practical large-scale production, and a cold-kit formulation would improve the spontaneous availability. The NOTA chelator ligand FAPI-74 can be labeled with both 18F-AlF and 68Ga. Here, we describe the in vivo evaluation of 18F-FAPI-74 and a proof of mechanism for 68Ga-FAPI-74 labeled at ambient temperature. Methods: In 10 patients with lung cancer, PET scans were acquired at 10 min, 1 h, and 3 h after administration of 259 ± 26 MBq of 18F-FAPI-74. Physiologic biodistribution and tumor uptake were semiquantitatively evaluated on the basis of SUV at each time point. Absorbed doses were evaluated using OLINDA/EXM, version 1.1, and QDOSE dosimetry software with the dose calculator IDAC-Dose, version 2.1. Identical methods were used to evaluate one examination after injection of 263 MBq of 68Ga-FAPI-74. Results: The highest contrast was achieved in primary tumors, lymph nodes, and distant metastases at 1 h after injection, with an SUVmax of more than 10. The effective dose per a 100-MBq administered activity of 18F-FAPI-74 was 1.4 ± 0.2 mSv, and for 68Ga-FAPI-74 it was 1.6 mSv. Thus, the radiation burden of a diagnostic 18F-FAPI-74 PET scan is even lower than that of PET scans with 18F-FDG and other 18F tracers; 68Ga-FAPI-74 is comparable to other 68Ga ligands. FAPI PET/CT supported target volume definition for guiding radiotherapy. Conclusion: The high contrast and low radiation burden of FAPI-74 PET/CT favor multiple clinical applications. Centralized large-scale production of 18F-FAPI-74 or decentralized cold-kit labeling of 68Ga-FAPI-74 allows flexible routine use.
A growing family of
Ga-fibroblast activation protein inhibitor (FAPI) PET probes has shown promise in imaging a variety of medical conditions.
Ga-FAPI-46, in particular, has emerged as unique for ...both its diagnostic and its theranostic applications; however, the optimal timing of PET remains unclear. Therefore, we evaluated uptake at 3 time points after
Ga-FAPI-46 administration in a spectrum of tumor types.
The cohort consisted of 43 patients with diverse cancer diagnoses undergoing
Ga-FAPI-46 PET/CT at 3 time points (10 min, 1 h, and 3 h). We determined the tracer uptake based on SUV
and SUV
and on tumor-to-background-ratios (TBRs) (SUV
/SUV
).
There were 171 lesions in the 43 patients. Comparing all lesions at different time points, the mean SUV
was maximal at 10 min (8.2) and declined slightly at 1 h (8.15) and 3 h (7.6) after tracer administration. Similarly, the mean SUV
log still had a similar pattern in primary lesions at 10 min, 1 h, and 3 h (
= 30; 0.98, 1.01, and 0.98, respectively), lymph node metastases (
= 37; 0.82, 0.84, and 0.81, respectively), and distant metastases (
= 104; 0.81, 0.79, and 0.74, respectively). TBR also showed nonsignificant differences at the 3 times.
Ga-FAPI-46 PET/CT imaging revealed remarkably stable tumor and background uptake as determined by SUV metrics and maintained high TBRs within 3 h of injection. Thus, it may be possible to scan with
Ga-FAPI-46 within 10-20 min of injection, improving workflow and decreasing patient wait times. Confirmation of these findings in a larger cohort is under way.
Pancreatic ductal carcinoma (PDAC) is a highly lethal cancer, and early detection and accurate staging are critical to prolonging survival. PDAC typically has a prominent stroma including ...cancer-associated fibroblasts that express fibroblast activation protein (FAP). FAP is a new target molecule for PET imaging of various tumors. In this retrospective study, we describe the clinical impact of PET/CT imaging using
Ga-labeled FAP-inhibitors (
Ga-FAPI PET/CT) in 19 patients with PDAC (7 primary, 12 progressive/recurrent).
All patients underwent contrast-enhanced CT (ceCT) for TNM staging before
Ga-FAPI PET/CT imaging. PET scans were acquired 60 min after administration of 150-250 MBq of
Ga-labeled FAP-specific tracers. To characterize
Ga-FAPI uptake over time, additional scans after 10 or 180 min were acquired in 6 patients. SUV
and SUV
values of PDAC manifestations and healthy organs were analyzed. The tumor burden according to
Ga-FAPI PET/CT was compared with TNM staging based on ceCT and changes in oncologic management were recorded.
Compared with ceCT,
Ga-FAPI PET/CT results led to changes in TNM staging in 10 of 19 patients. Eight of 12 patients with recurrent/progressive disease were upstaged, 1 was downstaged, and 3 had no change. In newly diagnosed PDAC, 1 of 7 patients was upstaged, and the staging of 6 patients did not change. Changes in oncologic management occurred in 7 patients. Markedly elevated uptake of
Ga-FAPI in PDAC manifestations after 1 h was seen in most cases. Differentiation from pancreatitis based on static imaging 1 h after injection was challenging. With respect to imaging after multiple time points, PDAC and pancreatitis showed a trend for differential uptake kinetics.
Ga-FAPI PET/CT led to restaging in half of the patients with PDAC and most patients with recurrent disease compared with standard of care imaging. The clinical value of
Ga-FAPI PET/CT should be further investigated.
Ga-fibroblast activation protein inhibitors (FAPIs) 2, 4, and 46 have already been proposed as promising PET tracers. However, the short half-life of
Ga (68 min) creates problems with manufacture and ...delivery.
F (half-life, 110 min) labeling would result in a more practical large-scale production, and a cold-kit formulation would improve the spontaneous availability. The NOTA chelator ligand FAPI-74 can be labeled with both
F-AlF and
Ga. Here, we describe the in vivo evaluation of
F-FAPI-74 and a proof of mechanism for
Ga-FAPI-74 labeled at ambient temperature.
In 10 patients with lung cancer, PET scans were acquired at 10 min, 1 h, and 3 h after administration of 259 ± 26 MBq of
F-FAPI-74. Physiologic biodistribution and tumor uptake were semiquantitatively evaluated on the basis of SUV at each time point. Absorbed doses were evaluated using OLINDA/EXM, version 1.1, and QDOSE dosimetry software with the dose calculator IDAC-Dose, version 2.1. Identical methods were used to evaluate one examination after injection of 263 MBq of
Ga-FAPI-74.
The highest contrast was achieved in primary tumors, lymph nodes, and distant metastases at 1 h after injection, with an SUV
of more than 10. The effective dose per a 100-MBq administered activity of
F-FAPI-74 was 1.4 ± 0.2 mSv, and for
Ga-FAPI-74 it was 1.6 mSv. Thus, the radiation burden of a diagnostic
F-FAPI-74 PET scan is even lower than that of PET scans with
F-FDG and other
F tracers;
Ga-FAPI-74 is comparable to other
Ga ligands. FAPI PET/CT supported target volume definition for guiding radiotherapy.
The high contrast and low radiation burden of FAPI-74 PET/CT favor multiple clinical applications. Centralized large-scale production of
F-FAPI-74 or decentralized cold-kit labeling of
Ga-FAPI-74 allows flexible routine use.
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