[Diagnostic imaging of malignant lymphomas]. / Bildgebende Diagnostik von malignen Lymphomen.

BACKROUND: Malignant lymphomas represent approximately 5% of all cancers. Imaging procedures play a crucial role concerning initial staging and assessment of the response to treatment. OBJECTIVE: This article gives an overview of the significance of imaging procedures in the treatment of patients with malignant lymphomas at various times during treatment. These include the initial assessment of the extent of the disease and staging during and after treatment under consideration of the current classification systems. MATERIAL AND METHODS: A selective literature search was carried out with analysis of dedicated original research articles and reviews as well as a discussion of the clinical guidelines. RESULTS: Computed tomography (CT) is the basic diagnostic tool in patients with malignant lymphomas. Particularly important is fluorodeoxyglucose (FDG) positron emission tomography (PET) CT, which enables a more accurate stage definition and a better assessment of the response to treatment in FDG-avid lymphoma subtypes. Using the FDG-PET/CT-based Deauville score persisting disease activity can be identified in residual masses and refractory disease can be distinguished from complete metabolic remission. The use of magnetic resonance imaging (MRI) with diffusion-weighted imaging can represent a future alternative but is, however, not yet sufficiently standardized and validated. CONCLUSION: The standardized analysis and reporting of purely morphological and metabolic imaging procedures is the backbone of treatment decisions in patients with malignant lymphomas.

Initial clinical experience performing sialendoscopy for salivary gland protection in patients undergoing 225Ac-PSMA-617 RLT.

PURPOSE: The main side effect of prostate-specific membrane antigen targeting alpha therapy (PSMA TAT) is dry mouth syndrome. Inflammation of the salivary glands and consequent reduced salivary function have been reported in patients after radioiodine therapy. The beneficial effects of sialendoscopy on radiation-induced inflammation in tissue are well known. Thus sialendoscopy with dilatation, saline irrigation and steroid injections (prednisolone) was performed before and after 225Ac-PSMA-617 TAT to reduce inflammatory effects in the salivary glands and to improve or prevent xerostomia. METHODS: Eleven men with metastatic castration-resistant prostate cancer (mean age 68.5 years, range 58-80 years) underwent sialendoscopy, dilatation, saline irrigation and steroid injection of both submandibular and both parotid glands before or after every cycle of 225Ac-PSMA-617 TAT. Sialendoscopy and steroid injection were performed by a senior ENT physician. Quality of life was evaluated using two health-related quality of life (HRQOL) questionnaires, the Xerostomia Questionnaire (XQ) and the Xerostomia Inventory (XI) before and 3 months after the intervention. RESULTS: In all 11 patients both parotid and both submandibular glands were affected by radiation sialadenitis and sialendoscopy was performed. The patients experienced no complications after sialendoscopy, and showed a significant improvement in HRQOL as measured using the XQ and XI. After sialendoscopy the XQ score decreased significantly from 77.7 ± 13.6 to 42.7 ± 14.8 (p = 0.003) and the XI score decreased from 44.5 ± 6.9 to 25.8 ± 12.8 (p = 0.003). Due to the limited number of patients we only report tendencies. CONCLUSION: Sialendoscopy with dilatation, saline irrigation and steroid injection had beneficial effects on salivary gland function and HRQOL in patients undergoing 225Ac-PSMA-617 RLT. However, even with sialadenoscopic support after multiple cycles of TAT, salivary gland function was reduced and xerostomia was present. Therefore, not only inflammation but also the direct effect of radiation is a putative cause of dry mouth. Further research is necessary to determine the main side effects of PSMA TAT.

IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein-specific PET/CT.

PURPOSE: Targeting fibroblast activation protein (FAP) is a new diagnostic approach allowing the visualization of tumor stroma. Here, we applied FAP-specific PET imaging to gliomas. We analyzed the target affinity and specificity of two FAP ligands (FAPI-02 and FAPI-04) in vitro, and the pharmacokinetics and biodistribution in mice in vivo. Clinically, we used 68Ga-labeled FAPI-02/04 for PET imaging in 18 glioma patients (five IDH-mutant gliomas, 13 IDH-wildtype glioblastomas). METHODS: For binding studies with 177Lu-radiolabeled FAPI-02/04, we used the glioblastoma cell line U87MG, FAP-transfected fibrosarcoma cells, and CD26-transfected human embryonic kidney cells. For pharmacokinetic and biodistribution studies, U87MG-xenografted mice were injected with 68Ga-labeled compounds followed by small-animal PET imaging and 177Lu-labeled FAPI-02/04, respectively. Clinical PET/CT scans were performed 30 min post intravenous administration of 68Ga-FAPI-02/04. PET and MRI scans were co-registrated. Immunohistochemistry was done on 14 gliomas using a FAP-specific antibody. RESULTS: FAPI-02 and FAPI-04 showed high binding specificity to FAP. FAPI-04 demonstrated higher tumor accumulation and delayed elimination compared with FAPI-02 in preclinical studies. IDH-wildtype glioblastomas and grade III/IV, but not grade II, IDH-mutant gliomas showed elevated tracer uptake. In glioblastomas, we observed spots with increased uptake in projection on contrast-enhancing areas. Immunohistochemistry showed FAP-positive cells with mainly elongated cell bodies and perivascular FAP-positive cells in glioblastomas and an anaplastic IDH-mutant astrocytoma. CONCLUSIONS: Using FAP-specific PET imaging, increased tracer uptake in IDH-wildtype glioblastomas and high-grade IDH-mutant astrocytomas, but not in diffuse astrocytomas, may allow non-invasive distinction between low-grade IDH-mutant and high-grade gliomas. Therefore, FAP-specific imaging in gliomas may be useful for follow-up studies although further clinical evaluation is required.

Validating the Xerostomia Inventory in a radiation-induced xerostomia population in German language.

OBJECTIVES: Though xerostomia is a frequent oral symptom, there is no validated disease-specific questionnaire in German. The purpose of this study was to translate and validate versions of the Xerostomia Inventory and the Summated Xerostomia Inventory in a German-speaking population. PARTICIPANTS AND METHODS: Thirty-nine patients including 18 patients suffering from radiation-induced xerostomia enrolled in this study. Both questionnaires were translated into German language according to international accepted guidelines. For validation, we evaluated reliability, validity, and responsiveness using the COSMIN manual for cross-cultural adaptation. RESULTS: Cronbach's α was 0.92 for XI and 0.91 for SXI, showing both high internal consistency. Patients suffering from xerostomia showed significantly higher average scores demonstrating its discriminant validity. Confirmatory factor analysis showed excellent "goodness-of-fit" values for SXI and good to moderate values for XI, confirming the assumed factor structures. The Xerostomia Inventory and its summated version both showed excellent test-retest reliability in the non-xerostomia group (ICC = 0.85 and 0.84). CONCLUSIONS: The XI and SXI in their cross-cultural adapted versions are the first validated self-report assessments for xerostomia in German language. They are characterized by practical design and can be easily interpreted by the treating physician.

Simultaneous whole-body 18F-PSMA-1007-PET/MRI with integrated high-resolution multiparametric imaging of the prostatic fossa for comprehensive oncological staging of patients with prostate cancer: a pilot study.

INTRODUCTION: The aim of the present study was to explore the clinical feasibility and reproducibility of a comprehensive whole-body 18F-PSMA-1007-PET/MRI protocol for imaging prostate cancer (PC) patients. METHODS: Eight patients with high-risk biopsy-proven PC underwent a whole-body PET/MRI (3 h p.i.) including a multi-parametric prostate MRI after 18F-PSMA-1007-PET/CT (1 h p.i.) which served as reference. Seven patients presented with non-treated PC, whereas one patient presented with biochemical recurrence. SUVmean-quantification was performed using a 3D-isocontour volume-of-interest. Imaging data was consulted for TNM-staging and compared with histopathology. PC was confirmed in 4/7 patients additionally by histopathology after surgery. PET-artifacts, co-registration of pelvic PET/MRI and MRI-data were assessed (PI-RADS 2.0). RESULTS: The examinations were well accepted by patients and comprised 1 h. SUVmean-values between PET/CT (1 h p.i.) and PET/MRI (3 h p.i.) were significantly correlated (p < 0.0001, respectively) and similar to literature of 18F-PSMA-1007-PET/CT 1 h vs 3 h p.i. The dominant intraprostatic lesion could be detected in all seven patients in both PET and MRI. T2c, T3a, T3b and T4 features were detected complimentarily by PET and MRI in five patients. PET/MRI demonstrated moderate photopenic PET-artifacts surrounding liver and kidneys representing high-contrast areas, no PET-artifacts were observed for PET/CT. Simultaneous PET-readout during prostate MRI achieved optimal co-registration results. CONCLUSIONS: The presented 18F-PSMA-1007-PET/MRI protocol combines efficient whole-body assessment with high-resolution co-registered PET/MRI of the prostatic fossa for comprehensive oncological staging of patients with PC.

Local recurrence of prostate cancer after radical prostatectomy is at risk to be missed in 68Ga-PSMA-11-PET of PET/CT and PET/MRI: comparison with mpMRI integrated in simultaneous PET/MRI.

PURPOSE: The positron emission tomography (PET) tracer 68Ga-PSMA-11, targeting the prostate-specific membrane antigen (PSMA), is rapidly excreted into the urinary tract. This leads to significant radioactivity in the bladder, which may limit the PET-detection of local recurrence (LR) of prostate cancer (PC) after radical prostatectomy (RP), developing in close proximity to the bladder. Here, we analyze if there is additional value of multi-parametric magnetic resonance imaging (mpMRI) compared to the 68Ga-PSMA-11-PET-component of PET/CT or PET/MRI to detect LR. METHODS: One hundred and nineteen patients with biochemical recurrence after prior RP underwent both hybrid 68Ga-PSMA-11-PET/CTlow-dose (1 h p.i.) and -PET/MRI (2-3 h p.i.) including a mpMRI protocol of the prostatic bed. The comparison of both methods was restricted to the abdomen with focus on LR (McNemar). Bladder-LR distance and recurrence size were measured in axial T2w-TSE. A logistic regression was performed to determine the influence of these variables on detectability in 68Ga-PSMA-11-PET. Standardized-uptake-value (SUVmean) quantification of LR was performed. RESULTS: There were 93/119 patients that had at least one pathologic finding. In addition, 18/119 Patients (15.1%) were diagnosed with a LR in mpMRI of PET/MRI but only nine were PET-positive in PET/CT and PET/MRI. This mismatch was statistically significant (p = 0.004). Detection of LR using the PET-component was significantly influenced by proximity to the bladder (p = 0.028). The PET-pattern of LR-uptake was classified into three types (1): separated from bladder; (2): fuses with bladder, and (3): obliterated by bladder). The size of LRs did not affect PET-detectability (p = 0.84), mean size was 1.7 ± 0.69 cm long axis, 1.2 ± 0.46 cm short-axis. SUVmean in nine men was 8.7 ± 3.7 (PET/CT) and 7.0 ± 4.2 (PET/MRI) but could not be quantified in the remaining nine cases (obliterated by bladder). CONCLUSION: The present study demonstrates additional value of hybrid 68Ga-PSMA-11-PET/MRI by gaining complementary diagnostic information compared to the 68Ga-PSMA-11-PET/CTlow-dose for patients with LR of PC.

Fibroblast Activation Protein-Specific PET/CT Imaging in Fibrotic Interstitial Lung Diseases and Lung Cancer: A Translational Exploratory Study.

Interstitial lung diseases (ILDs) comprise over 200 parenchymal lung disorders. Among them, fibrosing ILDs, especially idiopathic pulmonary fibrosis, are associated with a poor prognosis, whereas some other ILDs, such as sarcoidosis, have a much better prognosis. A high proportion manifests as fibrotic ILD (fILD). Lung cancer (LC) is a frequent complication of fILD. Activated fibroblasts are crucial for fibrotic processes in fILD. The aim of this exploratory study was to evaluate the imaging properties of static and dynamic fibroblast activation protein (FAP) inhibitor (FAPI) PET/CT in various types of fILD and to confirm FAP expression in fILD lesions by FAP immunohistochemistry of human fILD biopsy samples and of lung sections of genetically engineered (Nedd4-2-/- ) mice with an idiopathic pulmonary fibrosislike lung disease. Methods: PET scans of 15 patients with fILD and suspected LC were acquired 10, 60, and 180 min after the administration of 150-250 MBq of a 68Ga-labeled FAPI tracer (FAPI-46). In 3 patients, dynamic scans over 40 min were performed instead of imaging after 10 min. The SUVmax and SUVmean of fibrotic lesions and LC were measured and CT-density-corrected. Target-to-background ratios (TBRs) were calculated. PET imaging was correlated with CT-based fibrosis scores. Time-activity curves derived from dynamic imaging were analyzed. FAP immunohistochemistry of 4 human fILD biopsy samples and of fibrotic lungs of Nedd4-2-/- mice was performed. Results: fILD lesions as well as LC showed markedly elevated 68Ga-FAPI uptake (density-corrected SUVmax and SUVmean 60 min after injection: 11.12 ± 6.71 and 4.29 ± 1.61, respectively, for fILD lesions and 16.69 ± 9.35 and 6.44 ± 3.29, respectively, for LC) and high TBR (TBR of density-corrected SUVmax and SUVmean 60 min after injection: 2.30 ± 1.47 and 1.67 ± 0.79, respectively, for fILD and 3.90 ± 2.36 and 2.37 ± 1.14, respectively, for LC). SUVmax and SUVmean decreased over time, with a stable TBR for fILD and a trend toward an increasing TBR in LC. Dynamic imaging showed differing time-activity curves for fILD and LC. 68Ga-FAPI uptake showed a positive correlation with the CT-based fibrosis index. Immunohistochemistry of human biopsy samples and the lungs of Nedd4-2-/- mice showed a patchy expression of FAP in fibrotic lesions, preferentially in the transition zone to healthy lung parenchyma. Conclusion:68Ga-FAPI PET/CT imaging is a promising new imaging modality for fILD and LC. Its potential clinical value for monitoring and therapy evaluation of fILD should be investigated in future studies.

Trabecular structure analysis using C-arm CT: comparison with MDCT and flat-panel volume CT.

PURPOSE: This paper assesses interscan, interreader, and intrareader variability of C-arm CT and compares it to that of flat-panel volume-CT (fpVCT) and high-definition multi-detector-CT (HD-MDCT). METHODS: Five cadaver knee specimens were imaged using C-arm-CT, fpVCT, and HD-MDCT. Apparent (app.) trabecular bone volume fraction (BV/TV), app. trabecular number (TbN), app. trabecular spacing (TbSp), and app. trabecular thickness (TbTh) of the proximal tibia were measured by three readers. Interreader, intrareader, and interscan variability for C-arm CT was expressed as coefficient of variation (CV), standard deviation (SD), and intraclass correlation coefficient (ICC). RESULTS: With the exception of app.TbSp (CV: 7.05-9.35%, SD: 0.06-0.09, ICC: 0.89-0.94), the variability of C-arm CT was low (CV: 2.41-6.43%, SD: 0.01-0.048, ICC: 0.65-0.98). Its interreader reliability (CV: 2.66-4.55%, SD: 0.01-0.03, ICC: 0.81-0.95) was comparable to that of HD-MDCT (CV: 2.41-4.08%, SD: 0.014-0.016, ICC: 0.95-0.96), and fpVCT (CV: 3.13-5.63%, SD: 0.009-0.036, ICC: 0.64-0.98) for all parameters except app.TbSp. CONCLUSIONS: C-arm CT is a reliable method for assessing trabecular bone architectural parameters with the exception of app.TbSp due to spatial resolution limitation.

FAPI-74 PET/CT Using Either 18F-AlF or Cold-Kit 68Ga Labeling: Biodistribution, Radiation Dosimetry, and Tumor Delineation in Lung Cancer Patients.

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.

FAP-specific PET signaling shows a moderately positive correlation with relative CBV and no correlation with ADC in 13 IDH wildtype glioblastomas.

OBJECTIVES: Targeting Fibroblast Activation Protein (FAP) is a new approach for glioblastoma imaging. In a recent pilot study glioblastomas showed elevated tracer uptake with high intratumoral heterogeneity in projection on the corresponding T2w/FLAIR and contrast enhanced MRI lesions. In this study, we correlated FAP-specific signaling with apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) signals in MRI to further characterize the significance of FAP uptake. METHODS: Clinical PET/CT scans of 13 glioblastoma patients were performed post i. v. administration of 68Ga-labelled-FAP-specific tracer molecules. PET- and corresponding MRI-scans were co-registrated. 3d volumetric segmentations were performed of T2w/FLAIR lesions and contrast enhancing lesions within co-registrated MRI slides. Signal intensity values of FAP-specific PET signaling, ADC and rCBV were analyzed for their pixel wise correlation in each patient. Pooled estimates of the correlation coefficients were calculated by using the Fisher z-transformation. RESULTS: FAP-specific PET signals showed a moderately positive correlation with rCBV values which is more pronounced within the T2w/FLAIR lesion (pooled correlation 0,229) than in the contrast enhancing tumor region (pooled correlation 0.09). FAP-specific PET signals showed no correlation with ADC values. CONCLUSIONS: The moderately positive correlation of FAP-specific signals with rCBV values in MRI indicates that FAP-signaling is not independent from perfusion, but also does not only reflect intratumoral perfusion differences. The missing correlation of FAP-specific signals with ADC indicates that FAP-specific imaging does not reflect cell density, but the spot-like expression of FAP in glioblastomas. The clinical value of FAP-specific imaging needs further investigation.

Response Prediction of 177Lu-PSMA-617 Radioligand Therapy Using Prostate-Specific Antigen, Chromogranin A, and Lactate Dehydrogenase.

Neuroendocrinelike transdifferentiation of prostate cancer adenocarcinomas correlates with serum levels of chromogranin A (CgA) and drives treatment resistance. The aim of this work was to evaluate whether CgA can serve as a response predictor for 177Lu-prostate-specific membrane antigen 617 (PSMA) radioligand therapy (RLT) in comparison with the established tumor markers. Methods: One hundred consecutive patients with metastasized castration-resistant prostate cancer scheduled for PSMA RLT were evaluated for prostate-specific antigen (PSA), lactate dehydrogenase (LDH), and CgA at baseline and in follow-up of PSMA RLT. Tumor uptake of PSMA ligand, a known predictive marker for response, was assessed as a control variable. Results: From the 100 evaluated patients, 35 had partial remission, 16 stable disease, 15 mixed response, and 36 progression of disease. Tumor uptake above salivary gland uptake translated into partial remission, with an odds ratio (OR) of 60.265 (95% confidence interval [CI], 5.038-720.922). Elevated LDH implied a reduced chance for partial remission, with an OR of 0.094 (95% CI, 0.017-0.518), but increased the frequency of progressive disease (OR, 2.717; 95% CI, 1.391-5.304). All patients who achieved partial remission had a normal baseline LDH. Factor-2 elevation of CgA increased the risk for progression, with an OR of 3.089 (95% CI, 1.302-7.332). Baseline PSA had no prognostic value for response prediction. Conclusion: In our cohort, baseline PSA had no prognostic value for response prediction. LDH was the marker with the strongest prognostic value, and elevated LDH increased the risk for progression of disease under PSMA RLT. Elevated CgA demonstrated a moderate impact as a negative prognostic marker in general but was explicitly related to the presence of liver metastases. Well in line with the literature, sufficient tumor uptake is a prerequisite to achieve tumor response.

Dosimetry Estimate and Initial Clinical Experience with 90Y-PSMA-617.

Because of different physical properties, the ß-emitters 177Lu and 90Y offer specific radiologic-biologic advantages in dedicated clinical situations. Our objective was to introduce 90Y-labeled prostate-specific membrane antigen (PSMA)-617 to clinical application, providing additional avenues for personalized medicine. Here, we present our dosimetry estimate for 90Y-PSMA-617, report first clinical experiences, and discuss the advantages and drawbacks of varying the ß-emitter in PSMA-targeting radioligand therapy. Methods: To approximate radiation dosimetry, 4 patients with metastatic castration-resistant prostate cancer underwent serially performed imaging up to 1 wk after 177Lu-PSMA-617 therapy. Time-activity curves were extrapolated to the half-life of 90Y, and OLINDA was used to calculate the dosimetry estimate. In clinical practice, 11 patients with PSMA-positive lymph-nodal bulk disease were stratified to receive 90Y-PSMA-617 radioligand therapy (mean, 3.2 GBq; range, 2.8-3.7 GBq); afterward, safety lab tests, prostate-specific antigen (PSA) response, and clinical findings were thoroughly followed. Results: The projected dosimetry for 90Y-PSMA-617 estimated a mean kidney dose of 3.47 ± 1.40 Gy/GBq, red marrow dose of 0.11 ± 0.04 Gy/GBq, and salivary gland dose of 5.57 ± 1.34 Gy/GBq; randomly chosen metastases were approximated with 22.8 ± 16.10 Gy/GBq. The observed acute hematologic toxicity (5 cases of leukopenia and 2 of thrombocytopenia, all grade 1 or 2) and clinical side effects (2 cases of transient xerostomia and 1 of nausea, all grade 1 or 2), as well as PSA response (any PSA response, 7/11 patients; >50% PSA decline, 5/11 patients), were comparable to 177Lu-PSMA-617 literature data. Conclusion: A factor 3-4 lower treatment activity for 90Y-PSMA-617 translates into a comparable dosimetry estimate and clinical findings similar to those of 177Lu-PSMA-617. However, safety was demonstrated only for patients with oligometastatic disease. Further studies are needed to evaluate its potential in patients with more disseminated bone involvement or visceral metastasis.

68Ga-FAPI PET/CT: Biodistribution and Preliminary Dosimetry Estimate of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various Cancers.

Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts of several tumor entities. The recent development of quinoline-based PET tracers that act as FAP inhibitors (FAPIs) demonstrated promising results preclinically and already in a few clinical cases. Consequently, these tracers are now applied in our hospital to amend the diagnostics of cancer patients facing the limitations of standard examinations. Here, we analyze the tissue biodistribution and preliminary dosimetry of 2 members of this new class of PET radiopharmaceutical. Methods: A preliminary dosimetry estimate for 68Ga-FAPI-2 and 68Ga-FAPI-4 was based on 2 patients examined at 0.2, 1, and 3 h after tracer injection using the QDOSE dosimetry software suit. Further PET/CT scans of tumor patients were acquired 1 h after injection of either 68Ga-FAPI-2 (n = 25) or 68Ga-FAPI-4 (n = 25); for 6 patients an intraindividual related 18F-FDG scan (also acquired 1 h after injection) was available. For the normal tissue of 16 organs, a 2-cm spheric volume of interest was placed in the parenchyma; for tumor lesions, a threshold-segmented volume of interest was used to quantify SUVmean and SUVmaxResults: Similar to literature values for 18F-FDG, 68Ga-DOTATATE, and 68Ga-PSMA-11, an examination with 200 MBq of 68Ga-FAPI-2 or 68Ga-FAPI-4 corresponds to an equivalent dose of approximately 3-4 mSv. After a fast clearance via the kidneys, the normal organs showed a low tracer uptake with only minimal changes between 10 min and 3 h after injection. In 68Ga-FAPI-2, the tumor uptake from 1 to 3 h after injection decreased by 75%, whereas the tumor retention was prolonged with 68Ga-FAPI-4 (25% washout). Regarding tumor-to-background ratios, at 1 h after injection both 68Ga-FAPI tracers performed equally. In comparison to 18F-FDG, the tumor uptake was almost equal (average SUVmax, 7.41 for 18F-FDG and 7.37 for 68Ga-FAPI-2; not statistically significant); the background uptake in brain (11.01 vs. 0.32), liver (2.77 vs. 1.69), and oral/pharyngeal mucosa (4.88 vs. 2.57) was significantly lower with 68Ga-FAPI. Other organs did not relevantly differ between 18F-FDG and 68Ga-FAPI. Conclusion: FAPI PET/CT is a new diagnostic method in imaging cancer patients. In contrast to 18F-FDG, no diet or fasting in preparation for the examination is necessary, and image acquisition can potentially be started a few minutes after tracer application. Tumor-to-background contrast ratios were equal to or even better than those of 18F-FDG.

PET/CT Imaging of NSCLC with a αvß6 Integrin-Targeting Peptide.

PURPOSE: Targeted therapies are regarded as promising approaches to increase 5-year survival rate of non-small cell lung cancer (NSCLC) patients. Here, we investigated the clinical value of the αvß6 integrin-specific peptide SFITGv6 as a diagnostic reagent targeting NSCLC. METHODS: Affinity and binding properties of [125I]SFITGv6 or [177Lu]SFITGv6 for αvß6 integrin-expressing NSCLC cell lines were evaluated in cell culture experiments including competition, kinetic, internalization, and efflux. To confirm αvß6 integrin specificity in vivo small-animal positron emission tomography (PET) imaging using [68Ga]SFITGv6 as radiotracer and biodistribution of [177Lu]SFITGv6 in NCI-H2009 and NCI-H322 tumor-bearing mice was performed. Finally, to distinguish between benign and malignant lesions [68Ga]SFITGv6 was applied as radiotracer for PET/x-ray computed tomography (CT) imaging of NSCLC patients with unclear diagnosis upon routinely performed 2-deoxy-2-[18F]flouro-D-glucose ([18F]FDG)-PET/CT. The biodistribution of the SFITGv6-ligand in different organs and tumor lesions of NSCLC patients was quantified 1 h and 3 h after injection measuring standard uptake values (SUV)max. RESULTS: In vitro experiments revealed a significant time-dependent SFITGv6 binding of up to 33 % to αvß6 integrin-expressing the cell lines NCI-H2009, NCI-H322, NCI-H292, NCI-H358, and high affinity (IC50-mean 3.1 nM) to NCI-H2009 and NCI-H322. Moreover, a fast internalization of approximately 66 % by NCI-H2009 and NCI-H322 cells was observed. Small-animal PET imaging and biodistribution experiments of NCI-H2009 and NCI-H322 xenografts demonstrated an increased tumor-specific accumulation of SFITGv6 40 to 60 min after injection. Finally, PET/CT scans of NSCLC patients after [18F] FDG injection followed by [68Ga]SFITGv6 application revealed correlating images. Comparing the uptake of [68Ga]SFITGv6 and [18F] FDG both PET/CT-examinations presented with significantly increased SUVmax values in histologically proven NSCLC lesions, but a generally higher accumulation of [18F] FDG was noticed. CONCLUSIONS: Even if SFITGv6 demonstrates excellent affinity and specificity for αvß6 integrin-expressing NSCLC cell lines and several NSCLC xenografts [18F]FDG-PET/CT provides an advantage over [68Ga]SFITGv6-PET/CT for the diagnosis of NSCLC patients.

68Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer.

The recent development of quinoline-based PET tracers that act as fibroblast-activation-protein inhibitors (FAPIs) demonstrated promising preclinical and clinical results. FAP is overexpressed by cancer-associated fibroblasts of several tumor entities. Here, we quantify the tumor uptake on 68Ga-FAPI PET/CT of various primary and metastatic tumors to identify the most promising indications for future application. Methods:68Ga-FAPI PET/CT scans were requested by various referring physicians according to individual clinical indications that were considered insufficiently covered by 18F-FDG PET/CT or other imaging modalities. All PET/CT was performed 1 h after injection of 122-312 MBq of 68Ga-FAPI-04. We retrospectively identified 80 patients with histopathologically proven primary tumors or metastases or radiologically unequivocal metastatic lesions of histologically proven primary tumors. Tumor uptake was quantified by SUVmax and SUVmean (60% isocontour). Results: Eighty patients with 28 different tumor entities (54 primary tumors and 229 metastases) were evaluated. The highest average SUVmax (>12) was found in sarcoma, esophageal, breast, cholangiocarcinoma, and lung cancer. The lowest 68Ga-FAPI uptake (average SUVmax < 6) was observed in pheochromocytoma, renal cell, differentiated thyroid, adenoid cystic, and gastric cancer. The average SUVmax of hepatocellular, colorectal, head-neck, ovarian, pancreatic, and prostate cancer was intermediate (SUV 6-12). SUV varied across and within all tumor entities. Because of low background in muscle and blood pool (SUVmax < 2), the tumor-to-background contrast ratios were more than 3-fold in the intermediate and more than 6-fold in the high-intensity uptake group. Conclusion: Several highly prevalent cancers presented with remarkably high uptake and image contrast on 68Ga-FAPI PET/CT. The high and rather selective tumor uptake may open up new applications for noninvasive tumor characterization, staging examinations, or radioligand therapy.

Detection Efficacy of 18F-PSMA-1007 PET/CT in 251 Patients with Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy.

Prostate-specific membrane antigen (PSMA)-targeted PET imaging recently emerged as a new method for the staging and restaging of prostate cancer. Most published studies investigated the diagnostic potential of 68Ga-labeled PSMA agents that are excreted renally. 18F-PSMA-1007 is a novel PSMA ligand that has excellent preclinical characteristics and that is only minimally excreted by the urinary tract, a potential advantage for pelvic imaging. The aim of this study was to investigate the diagnostic efficacy of 18F-PSMA-1007 for biochemical recurrence (BCR) after radical prostatectomy. Methods: From 3 academic centers, 251 patients with BCR after radical prostatectomy were evaluated in a retrospective analysis. Patients who had received second-line androgen deprivation therapy (ADT) or chemotherapy were excluded, but prior first-line ADT exposure was allowed. The median prostate-specific antigen (PSA) level was 1.2 ng/mL (range, 0.2-228 ng/mL). All patients underwent PSMA PET/CT at 92 ± 26 min after injection of 301 ± 46 MBq of 18F-PSMA-1007. The rate of detection of presumed recurrence sites was correlated with the PSA level and original primary Gleason score. A comparison to a subset of patients treated previously with ADT was undertaken. Results: Of the 251 patients, 204 (81.3%) had evidence of recurrence on 18F-PSMA-1007 PET/CT. The detection rates were 94.0% (79/84), 90.9% (50/55), 74.5% (35/47), and 61.5% (40/65) for PSA levels of greater than or equal to 2, 1 to less than 2, 0.5 to less than 1, and 0.2 to less than 0.5 ng/mL, respectively. 18F-PSMA-1007 PET/CT revealed local recurrence in 24.7% of patients (n = 62). Lymph node metastases were present in the pelvis in 40.6% of patients (n = 102), in the retroperitoneum in 19.5% of patients (n = 49), and in supradiaphragmatic locations in 12.0% of patients (n = 30). Bone and visceral metastases were detected in 40.2% of patients (n = 101) and in 3.6% of patients (n = 9), respectively. In tumors with higher Gleason scores (≤7 vs. ≥8), detection efficacy trended higher (76.3% vs. 86.7%) but was not statistically significant (P = 0.32). However, detection efficacy was higher in patients who had received ADT (91.7% vs. 78.0%) within 6 mo before imaging (P = 0.0179). Conclusion:18F-PSMA-1007 PET/CT offers high detection rates for BCR after radical prostatectomy that are comparable to or better than those published for 68Ga-labeled PSMA ligands.

Repeated 177Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq.

Current treatment protocols for 177Lu-labeled PSMA-617 therapies were cautiously derived from dosimetry data, but their practical appropriateness has not yet been proven clinically. We retrospectively report our clinical observations using 4 different treatment activities. Methods: Forty patients with advanced prostate cancer and positive uptake in prostate-specific membrane antigen (PSMA) imaging were treated with 4 GBq of 177Lu activity/80 nmol of precursor, 6 GBq of 177Lu activity/120 nmol of precursor, 7.4 GBq of 177Lu activity/150 nmol of precursor, or 9.3 GBq of 177Lu activity/150 nmol of precursor (10 patients per group) every 2 mo. Safety was checked every 2 wk by laboratory tests, the prostate-specific antigen response was checked every 4 wk, and other effects were assessed by anamnesis. Results: The initial prostate-specific antigen response showed no correlation with treatment activity. However, 2 of 10, 4 of 10, 4 of 10, and 7 of 10 patients receiving doses of 4, 6, 7.4, and 9.3 GBq, respectively, were in partial remission 8 wk after completing all 3 cycles. This finding would be in line with but-because of low patient numbers-would not prove a positive dose-response relationship. Acute hematologic toxicity was also not correlated with treatment activity, and no more than 1 patient per group had grade 3/4 toxicity. Nevertheless, in contrast to the findings for the other groups, the mean platelet count in the 9.3-GBq group decreased chronically over time. Conclusion: If patients with diffuse red marrow infiltration and extensive chemotherapeutic pretreatments are excluded, then treatment activities of up to 3 injections of 9.3 GBq of 177Lu-PSMA-617 every 2 mo are tolerated well. Further dose escalation should be conducted with care, as the highest dose seems to be close to the maximum tolerable dose.

Impact of FDG-PET on the Detection of Patients with Lung Cancer at High Risk for ILD.

BACKGROUND/AIM: Idiopathic pulmonary fibrosis IPF is a type of interstitial lung disease (ILD) with poor prognosis. Lung cancer (LC) is a frequent complication in IPF, where all therapeutic options are potential triggers for acute exacerbation of IPF. PATIENTS AND METHODS: Patients with 2-deoxy-2-fluoro-D-glucose-positron emission tomography/computer tomography (FDG-PET/CT) results before lobectomy for LC with and without (n=10 each) signs of ILD in initial imaging and after-care CT were retrospectively analyzed. FDG uptake was calculated as the maximum standardized uptake value (SUVmax) in the lung periphery divided by the SUVmax of the mediastinal blood pool (rSUVmax). Regional increase of fibrosis and ground-glass features in lobe-based CT analysis was used as standard reference. RESULTS: Patients with LC with ILD presented a significantly higher rSUVmax of 0.57 compared to patients without ILD with rSUVmax 0.47 (p<0.001). CONCLUSION: rSUVmax seems to be a valuable imaging surrogate in predicting patients with LC with increased risk for progressive ILD associated with thoracic surgery.

Impact of sialendoscopy on improving health related quality of life in patients suffering from radioiodineinduced xerostomia.

INTRODUCTION: Xerostomia following radioiodine therapy (RIT) in patients suffering from differentiated thyroid cancer is a common side effect in 2 % to 67 % of patients treated with radioiodine (I-131). In order to evaluate the impact of sialendoscopy on health related quality of life (HRQOL) in patients suffering from therapy induced sialadenitis and xerostomia, we analyzed findings from two dedicated questionnaires (Xerostomy Questionnaire XQ and Xerostomy Inventory XI) in patients before and three months after sialendoscopy. PROCEDURES: In total, 12 patients suffering from differentiated thyroid carcinoma (10 women and 2 men) were evaluated. All patients had experienced conservative management. Patients were offered a sialendoscopy procedure if no major contradictions were present. Patients who denied the procedure formed the control group. Pre- and (three months) postoperative HRQOL was measured with the Patient Reported Outcome Measures (PROM) Xerostomia Questionnaire (XQ) and the Xerostomia Inventory (XI), as well as by a pre- and post-interventional salivary gland scintigram. Patients were graded according to their sialendoscopical findings. RESULTS: Interventional group presented with significant improvements in HRQOL measurements regarding XQ and XI-scores three months postoperatively. Control group showed no significant changes in the XQ or the XI scores. Number of RIT and cumulative activity of I-131 did not correlate with higher disease grade in regards to sialendoscopical findings nor did it correlate with higher XQand XI scores. Pre- and post-interventional salivary gland scintigram stated that parotid glands are more severely damaged than submandibular glands (SMG), but no significant scintigraphically changes could be detected after sialendoscopy. CONCLUSION: Sialendoscopy in patients suffering from therapy induced sialadenitis and xerostomia seems to be beneficial when evaluating the impact on HRQOL. Functional parameters measured by salivary gland scintigram did not show significant changes in post-interventional scintigrams.

Computed tomography and histopathological findings after embolization with inherently radiopaque 40µm-microspheres, standard 40µm-microspheres and iodized oil in a porcine liver model.

PURPOSE: The present study compared standard computed tomography (CT) and histopathological findings after endovascular embolization using a prototype of inherently radiopaque 40µm-microspheres with both standard 40µm-microspheres and iodized oil in a porcine liver model. MATERIALS AND METHODS: Twelve pigs were divided into six study groups, of two pigs each. Four pigs were embolized with iodized oil alone and four with radiopaque microspheres; two animals in each group were sacrificed at 2 hours and two at 7 days. Two pigs were embolized with radiopaque microspheres and heparin and sacrificed at 7 days. Two pigs were embolized with standard microspheres and sacrificed at 2 hours. CT was performed before and after segmental embolization and before sacrifice at 7 days. The distribution of embolic agent, inflammatory response and tissue necrosis were assessed histopathologically. RESULTS: Radiopaque microspheres and iodized oil were visible on standard CT 2 hours and 7 days after embolization, showing qualitatively comparable arterial and parenchymal enhancement. Quantitatively, the enhancement was more intense for iodized oil. Standard microspheres, delivered without contrast, were not visible by imaging. Radiopaque and standard microspheres similarly occluded subsegmental and interlobular arteries and, to a lesser extent, sinusoids. Iodized oil resulted in the deepest penetration into sinusoids. Necrosis was always observed after embolization with microspheres, but never after embolization with iodized oil. The inflammatory response was mild to moderate for microspheres and moderate to severe for iodized oil. CONCLUSION: Radiopaque 40µm-microspheres are visible on standard CT with qualitatively similar but quantitatively less intense enhancement compared to iodized oil, and with a tendency towards less of an inflammatory reaction than iodized oil. These microspheres also result in tissue necrosis, which was not observed after embolization with iodized oil. Both radiopaque and standard 40µm-microspheres are found within subsegmental and interlobar arteries, as well as in hepatic sinusoids.