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Zusammenfassung Hintergrund Bildgebungsgeräte wie die PET/CT werden angesichts des wachsenden Spektrums an innovativen nuklearmedizinischen Diagnostikverfahren immer wichtiger. Da sowohl die Beschaffung und Inbetriebnahme als auch der laufende Betrieb von Bildgebungsgeräten zu vergleichsweise hohen Kosten führen, ist aus Klinik-/Praxissicht von Interesse, ab welcher Leistungsmenge der (geplante) Gerätebetrieb zu einem Gewinn führt. Im Folgenden stellen wir die Gewinnschwellenanalyse als betriebswirtschaftliche Methode zur Gewinn- und Verlustplanung wie auch ein Kalkulationstool vor, das Anwender in nuklearmedizinischen Kliniken und Praxen grundlegend zur Gewinnschwellenanalyse am Beispiel PET/CT nutzen können. Methodik Bei der Gewinnschwellenanalyse wird der Schnitt- respektive Übergangspunkt ermittelt, ab dem die unternehmens-/bereichs- bzw. gerätespezifischen Erlöse die für den Betrieb anfallenden Gesamtkosten für Personal-, Sachmittel usw. übersteigen. Hierfür gilt es, auf der Kostenseite die fixen und variablen (Plan-)Kostenbestandteile für Gerätebeschaffung und -betrieb sowie auf der Erlösseite die jeweils gerätebezogene (Plan-)Erlösstruktur aufzubereiten. Ergebnisse Die Autoren stellen die Methode der Gewinnschwellenanalyse am Beispiel der geplanten Beschaffung bzw. des fortlaufenden Betriebs eines PET/CT dar. Darüber hinaus wird ein Kalkulationstool vorgestellt, das interessierte Nutzer bei der Erstellung einer einrichtungsspezifischen Gewinnschwellenanalyse unterstützend nutzen können. Hierzu wird auf ausgewählte Kosten- und Leistungs-/Erlösdaten eingegangen, die intern zusammenzutragen und aufzubereiten sowie in vorbereitete Tabellenblätter einzutragen sind. Schlussfolgerung Mittels Gewinnschwellenanalyse lässt sich der Gewinn/Verlust(-punkt) für den (geplanten) Betrieb von Bildgebungsgeräten wie der PET/CT bestimmen. Nutzer aus Bildgebungskliniken/-praxen und Administration können das vorgestellte Kalkulationstool einrichtungsspezifisch anpassen und damit als Basisdokument sowohl für die vorbereitende Beschaffung als auch die fortlaufende Betriebssteuerung von Bildgebungsgeräten im Klinik-/Praxisalltag nutzen.

Since the introduction of PET/CT hybrid imaging about two decades ago the landscape of oncological imaging has fundamentally changed, opening a new era of molecular imaging with emphasis on functional characterization of biological processes such as metabolism, cellular proliferation, hypoxia, apoptosis, angiogenesis and immune response. The most commonly assessed functional hallmark of cancer is the increased metabolism in tumor cells due to well-known Warburg effect, because of which FDG has been the most employed radiotracer, the so-called pan-cancer agent, in oncological imaging. However, several limitations such as low specificity and low sensitivity for several histopathological forms of lung cancer as well as high background uptake in the normal tissue of FDG imaging lead to numerous serious pitfalls. This restricts its utilization and diagnostic value in lung cancer imaging, even though this is currently considered to be the method of choice in pulmonary cancer imaging. Accurate initial tumor staging and therapy response monitoring with respect to the TNM criteria plays a crucial role in therapy planning and management in patients with lung cancer. To this end, many efforts have been made for decades to develop novel PET radiopharmaceuticals with innovative approaches that go beyond the assessment of increased glycolytic activity alone. Radiopharmaceuticals targeting DNA synthesis, amino acid metabolism, angiogenesis, or hypoxia have been extensively studied, leading to the emergence of indications for specific clinical questions or as a complementary imaging tool alongside existing conventional or FDG imaging. Nevertheless, despite some initial encouraging results, these tracers couldn't gain a widespread use and acceptance in clinical routine. However, given its mechanism of action and some initial pilot studies regarding lung cancer imaging, FAPI has emerged as a very promising alternative tool that could provide superior or comparable diagnostic performance to FDG imaging in lung cancer entities. Thus, in this review article, we summarized the current PET radiopharmaceuticals, different imaging approaches and discussed the potential benefits and clinical applications of these agents in lung cancer imaging.

Supplementary Table S1 from Hypermethylation of Tachykinin-1 Is a Potential Biomarker in Human Esophageal Cancer

Purpose: Our aim was to investigate whether and at what stage hypermethylation of the tachykinin-1 (TAC1) gene is associated with human esophageal neoplastic transformation.Experimental Design:TAC1 promoter hypermethylation was examined by real-time methylation-specific PCR in 258 human esophageal specimens and 126 plasma samples from patients or tissues at various stages of neoplastic evolution.Results:TAC1 hypermethylation in tissue samples showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) from normal esophagus (P < 0.0001). Both frequencies and normalized methylation values of TAC1 tissue methylation were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's esophagus, EAC, and ESCC than in normal esophagus (P < 0.01). The frequency of TAC1 hypermethylation increased dramatically and early during neoplastic progression, from 7.5% in normal esophagus to 55.6% in BE from patients with Barrett's metaplasia alone, 57.5% in dysplastic Barrett's esophagus, and 61.2% in EAC. There was a significant relationship between TAC1 hypermethylation and BE segment length, a known clinical risk factor for neoplastic progression. Twelve (50%) of 24 ESCC exhibited TAC1 hypermethylation. Overall patient survival correlated significantly with TAC1 methylation status in ESCC patients (mean survival, 22 versus 110 months; P = 0.0102, log-rank test), but not in EAC patients. Both mean normalized methylation values and frequency of TAC1 hypermethylation in plasma samples were significantly higher in EAC patients than in control subjects. Treatment of KYSE220 ESCC and BIC EAC cells with 5-aza-2′-deoxycytidine reduced TAC1 methylation and increased TAC1 mRNA expression.Conclusions:TAC1 promoter hypermethylation is a common event in both major histologic types of human esophageal carcinoma, occurs early, correlates with other progression risk factors in esophageal adenocarcinogenesis, and is a tissue biomarker of a poor prognosis in ESCC. Circulating methylated TAC1 promoter DNA also offers potential as a biomarker for the diagnosis of EAC.

Supplementary Tables S1 & S2 from Reprimo Methylation Is a Potential Biomarker of Barrett's-Associated Esophageal Neoplastic Progression

Gene silencing through CpG island hypermethylation has been associated with genesis or progression of frequent microsatellite instability (MSI-H) cancers. To identify novel methylation sites unique to MSI-H colon cancers in an unbiased fashion, we conducted a global expression profiling-based methylation target search. We identified 81 genes selectively down-regulated in MSI-H cancers using cDNA microarray analysis of 41 primary colon cancers. Forty six of these 81 genes contained CpG islands overlapping their 5′untranslated regions. Initial screening of six genes in 57 primary colon cancers detected the following gene with MSI-H cancer-specific hypermethylation: RAB32, a ras family member and A-kinase-anchoring protein, was methylated in 14 of 25 (56%) MSI-H cancers but in none of 32 non-MSI-H cancers or 23 normal colonic specimens. RAB32 hypermethylation correlated with RAB32 mRNA down-regulation and with hMLH1 hypermethylation. In addition, the protein-tyrosine phosphatase receptor type Ogene, PTPRO, was frequently methylated in right-sided tumors. This methylation screening strategy should identify additional genes inactivated by epigenetic silencing in colorectal and other cancers.

Supplementary Figure 2 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 1 from Activin Type II Receptor Restoration in ACVR2-Deficient Colon Cancer Cells Induces Transforming Growth Factor-β Response Pathway Genes

Supplementary Table 3 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 1 from Pituitary Tumor-Transforming 1 Increases Cell Motility and Promotes Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma

Supplementary Methods from Activin Type II Receptor Restoration in ACVR2-Deficient Colon Cancer Cells Induces Transforming Growth Factor-β Response Pathway Genes

The activin type II receptor (ACVR2) gene is a putative tumor suppressor gene that is frequently mutated in microsatellite-unstable colon cancers (MSI-H colon cancers). ACVR2 is a member of the transforming growth factor (TGF)-β type II receptor (TGFBR2) family and controls cell growth and differentiation. SMAD proteins are major intracellular effectors shared by ACVR2 and TGFBR2 signaling; however, additional shared effector mechanisms remain to be explored. To discover novel mechanisms transmitting the ACVR2 signal, we restored ACVR2 function by transfecting wild-type ACVR2 (wt-ACVR2) into a MSI-H colon cancer cell line carrying an ACVR2 frameshift mutation. The effect of ACVR2 restoration on cell growth, SMAD phosphorylation, and global molecular phenotype was then evaluated. Decreased cell growth was observed in wt-ACVR2 transfectants relative to ACVR2-deficient vector-transfected controls. Western blotting revealed higher expression of phosphorylated SMAD2 in wt-ACVR2 transfectants versus controls, suggesting cells deficient in ACVR2 had impaired SMAD signaling. Microarray-based differential expression analysis revealed substantial ACVR2-induced overexpression of genes implicated in the control of cell growth and tumorigenesis, including the activator protein (AP)-1 complex genes JUND, JUN, and FOSB, as well as the small GTPase signal transduction family members, RHOB, ARHE, and ARHGDIA. Overexpression of these genes is shared with TGFBR2 activation. This observed similarity between the activin and TGF-β signaling systems suggests that activin may serve as an alternative activator of TGF-β effectors, including SMADs, and that frameshift mutation of ACVR2 may contribute to MSI-H colon tumorigenesis via disruption of alternate TGF-β effector pathways.

Supplementary Table 1 from Identification of Genes Uniquely Involved in Frequent Microsatellite Instability Colon Carcinogenesis by Expression Profiling Combined with Epigenetic Scanning

Supplementary Methods section from Identification of Genes Uniquely Involved in Frequent Microsatellite Instability Colon Carcinogenesis by Expression Profiling Combined with Epigenetic Scanning

Supplementary Table 1 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 4 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 2 from Identification of Genes Uniquely Involved in Frequent Microsatellite Instability Colon Carcinogenesis by Expression Profiling Combined with Epigenetic Scanning

Supplementary Table 2 from Activin Type II Receptor Restoration in ACVR2-Deficient Colon Cancer Cells Induces Transforming Growth Factor-β Response Pathway Genes

Supplementary Figure 1 from Activin Type II Receptor Restoration in ACVR2-Deficient Colon Cancer Cells Induces Transforming Growth Factor-β Response Pathway Genes

Supplementary Figure 1 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Supplementary Table 2 from A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

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Background: Several studies indicate, particularly in the case of [18F]PSMA-1007, a relatively high rate of detection of ganglia in PSMA PET imaging. Ganglia are an integral part of the sympathetic portion of the autonomous nervous system. To date, no studies have directly compared [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 ganglionic uptake intra-individually and analyzed the underlying molecular and physical mechanisms of different detection rates. With this monocentric retrospective study, we sought to evaluate the intra-individual physiological ganglion uptake of these different PSMA ligands in evidence-based imaging for prostate cancer. Methods: Our cohort consists of 19 male patients (median age 72 ± 9 with a range of 56–85) with biochemical recurrence of prostate cancer who underwent both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT in our clinic on the same scanner per standard care between March 2015 and March 2022. Tracer uptake was quantified according to maximum standardized uptake value (SUVmax) for both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT scans. Ganglia-to-background ratios (GBRs) were determined to quantify the image contrast through dividing the SUVmax of the ganglia by the background value (SUVmax of blood pool in the descending aorta, fatty tissue, and skeletal muscle in gluteal region). We used descriptive analyses for demographics and tumor characteristics and performed two-way repeated-measures ANOVA (analysis of variance) for SUV metrics including GBR measurements. Results: In total, we examined 101 ganglia with [18F]PSMA-1007 scanning, localized mostly in pairs as stellate, coeliac, and sacral, of which 76 were also detected with [68Ga]Ga-PSMA-11 PET/CT scanning. There was no statistically significant difference in PSMA uptake in terms of SUVmax between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 (p value: 0.052). In contrast, the comparison of GBRs revealed a higher detectability rate of ganglia with [18F]PSMA-1007 imaging (p < 0.001). Furthermore, a separate comparison of ganglia with respect to their anatomical location also demonstrated statistically significant differences both within and between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 PET/CT scans. Conclusion: Given the impression of more accentuated [18F]PSMA-1007 uptake in ganglia compared with 68Ga-labelled counterparts, our study demonstrated that the better detectability of ganglia is not due to more intense [18F]PSMA-1007 uptake by these small structures but to much more favorable physical properties of the radionuclide 18F. The most relevant limitations of our study are its retrospective design and the small patient cohort.

Background: Radiolabeled fibroblast activation protein (FAP) ligands, a novel class of tracers for PET/CT imaging, have demonstrated very promising results in various oncological, as well as in some benign, diseases with long-term potential to supplant the current pan-cancer agent [18F]FDG in some cancer types. Pancreatic ductal carcinoma (PDAC) belongs to the group of epithelial malignancies with a strong so-called “desmoplastic reaction”, leading to a prominent tumor stroma with cancer-associated fibroblasts that exhibit a marked overexpression of fibroblast activation protein (FAP). The first clinical experiences in PDAC with 68Ga-labeled FAP ligands suggested superior sensitivity to [18F]FDG. However, there is limited data with 18F-labeled FAP derivatives, i.e. [18F]FAPI-74, yet prospective single- and multicenter trials are already ongoing. In this proof-of-concept study, we sought to evaluate the biodistribution, tumor uptake, and lesion detectability in patients with PDAC using [18F]FAPI-74 PET/CT as compared to [18F]FDG PET/CT scans for staging. Methods: This study includes 7 patients (median age 69) who underwent both [18F]FDG PET/CT with contrast-enhancement and [18F]FAPI-74 PET with low-dose CT for primary staging (n = 3) and therapy response control after neoadjuvant (n = 1) or re-staging after palliative therapy (n = 3). The mean interval between PET scans was 11 ± 4 days (range 1–15 days). The [18F]FDG and [18F]FAPI-74 PET/CT scans were acquired at 64 ± 4.1 min (range 61–91 min) and 66.4 ± 6.3 min (range 60–76 min), respectively, after administration of 200 ± 94 MBq (range 79–318 MBq) and 235 ± 88 MBq (range 90–321 MBq), respectively. Quantification of tracer uptake was determined with SUVmax and SUVmean. Furthermore, the tumor-to-background ratio (TBR) was derived by dividing the SUVmax of tumor lesions by the SUVmax of adipose tissue, skeletal muscle, and blood pool. Results: Overall, 32 lesions were detected in 7 patients including primary (n = 7), lung (n = 7), bone (n = 3), lymph node (n = 13), and peritoneal metastases (n = 2). [18F]FAPI-74 detected 22% more lesions compared with [18F]FDG with a better TBR and visual lesion delineation. In one patient the primary lesion could be detected unequivocally with [18F]FAPI-74 but was missed by [18F]FDG imaging. Altogether, most of the lesions demonstrated markedly elevated uptake of [18F]FAPI-74 with a simultaneous lower uptake in the background, providing a very high visual contrast. Conclusion: To the best of our knowledge, this is the first, prospective, intra-individual investigation comparing [18F]FAPI-74 with [18F]FDG imaging in PDAC with encouraging results. These pivotalresults supporta larger, multicentric, prospective study to determine the value of [18F]FAPI-74 in detecting and staging PDAC in comparison with current standard of care imaging.

Fibroblast activation protein (FAP) is ubiquitously present in healthy tissue, and additionally upregulated by cancer associated fibroblasts (CAFs) leading to high levels of FAP. Thus, neoplastic tissue, which is containing CAFs, characterized by a high presence of FAP. Moreover, in more than 90% of all epithelial tumors this phenomenon seems to occur, including many gynecological tumors, providing the foundation for a successful application of FAP-ligands. However, FAP upregulation, can also be initiated by benign conditions such as inflammation, hormonal-influence, and wound healing. Gynecological cancers seem to represent a field of interest for the utilization of FAPI-PET/CT to potentially improve staging, restaging and therapeutic management. First highly promising investigations demand further research in order to validate these preliminary findings.