PET imaging in giant cell arteritis (GCA) is crucial for diagnosis. New tracers such as C-X-C motif chemokine receptor 4 (CXCR4) enable to directly visualize inflammatory cells as they are expressed on leukocytes. We aimed to test the value of CXCR4-targeted PET in GCA. Ten treatment-naïve patients with confirmed large-vessel GCA underwent both [18F]FDG and [68Ga]PentixaFor PET/CT scans within a median of two days, without any therapy in between. Thirteen arterial segments per patient were analyzed. Visual interpretation and quantitative target-to-background ratios (TBR; arterial SUVmax divided by superior vena cava SUVmean) were calculated, including per-patient mean TBRs. Five patients without clinical or diagnostic evidence of vasculitis served as Non-GCA controls. Flow cytometry was used to quantify CXCR4 expression on leukocyte subsets, reported as normalized median fluorescence intensity (NMFI). All GCA patients showed positive scan findings on both [18F]FDG and [68Ga]PentixaFor PET/CT. Mean vascular TBRs were 2.43 ± 0.90 for FDG and 1.76 ± 0.76 for PentixaFor (P = 0.07), indicating similar large-vessel uptake. Segment-level analysis showed no significant differences in 10/13 vascular regions, although FDG uptake was higher in selected arteries. PentixaFor TBR was significantly lower in Non-GCA controls (1.15 ± 0.10 vs. 1.76 ± 0.76; P = 0.01), supporting its specificity for inflammation. Blood pool SUVmean did not differ, suggesting minimal signal spill-in. CXCR4 expression was highest on naïve T-helper cells and monocytes. CXCR4-targeted [68Ga]PentixaFor PET/CT provides an imaging pattern comparable to [18F]FDG PET/CT in untreated GCA and reliably differentiates between inflamed and non-inflamed vessels. These findings support CXCR4 PET as a promising, mechanistically grounded imaging approach that merits further evaluation in larger patient cohorts. ClinicalTrials.gov NCT05604482. Registered 3 November 2022.

Acute myocardial infarction (AMI) triggers local inflammation in the injured myocardium, followed by a systemic inflammatory response of lymphatic organs. This prospective trial (NCT05519735) focused on molecular imaging of lymphatic organs (spleen, bone marrow, and heart-draining lymph nodes) and aimed to determine whether uptake in such remote organs identifies individuals predisposed to functional recovery during follow-up after AMI. 41 timely re-perfused ST-elevation AMI patients received baseline C-X-C motif chemokine receptor 4 directed 68Ga-PentixaFor PET, a radiotracer targeting a broad spectrum of leukocytes. To determine left ventricular ejection fraction (LVEF) and infarct size, cardiac magnetic resonance imaging was conducted at baseline and repeated after six (follow-up (FU) 1, available in 38/41) and twelve months (FU 2, available in 36/41). As endpoint, an LVEF increase of ≥ 5

BACKGROUND:Markedly expressed on hematopoietic stem cells, C-X-C motif chemokine receptor 4 (CXCR4)-directed radioligand therapy (RLT) has been used in relapsed/refractory (r/r) MM to prepare for hematopoietic stem cell transplantation (HSCT). We aimed to determine the myeloablative efficacy of CXCR4 RLT in MM patients and assessed the safety profile of this treatment. METHODS:Thirty-eight patients with r/r MM were treated with 40 cycles of CXCR4-targeting [ 90 Y]Y-PentixaTher or [ 177 Lu]Lu-PentixaTher. Myeloablative dynamics were closely monitored by examining hematologic parameters before the application of RLT (day 1), on day 2, and on the start day of conditioning chemotherapy (CON, median day 10). Laboratory parameters evaluating organ toxicity were collected and categorized following the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Cairo-Bishop classification was also applied to identify patients experiencing laboratory tumor lysis syndrome (TLS) caused by RLT. After CON, we determined the rate of patients receiving hematopoietic stem cell transplantation (HSCT) followed by successful neutrophile engraftment. RESULTS:Forty cycles of CXCR4-directed RLT were applied. Myeloablative effects resulted in an 81.8% decline in leukocytes and a 69.4% decrease in neutrophil levels till the day of CON ( P <0.0001, respectively), followed by platelets (63.1%; P <0.0001) and hemoglobin (9%; P =0.002). We observed 58 AE Events (1/58 [1.7%], ≥ grade 3). CON could be applied successfully after 39/40 (97.5%) cycles. After CON, in 39/39 (100%) of the cycles, HSCT was conducted, and successful neutrophil engraftment was reached after 37/39 (94.9%) of these cycles. CONCLUSIONS:CXCR4-directed RLT exerted relevant myeloablative effects. When performing HSCT after applying additional CON, successful neutrophile engraftment was reached in the vast majority of the cases.

Acute myocardial infarction (AMI) triggers local inflammation in the injured myocardium, followed by a systemic inflammatory response of lymphatic organs. This prospective trial investigated whether molecular imaging of lymphatic organs (spleen, bone marrow, and heart-draining lymph nodes (LN)) identifies individuals predisposed to functional recovery during follow-up after AMI. 41 timely re-perfused ST-elevation AMI patients received positron emission tomography (PET) using 68 Ga-PentixaFor, a radiotracer targeting C-X-C motif chemokine receptor 4 (CXCR4) post-AMI. Patients were allocated to an early (2-4 days) or late PET imaging group (5-8 d) based on tracer availability. To determine left ventricular ejection fraction (LVEF) and infarct size, cardiac magnetic resonance imaging was conducted at baseline and repeated after six (follow-up (FU) 1, available in 38/41) and twelve months (FU 2, 36/41). As endpoint, an LVEF increase of ≥5% relative to baseline was then defined as short- (at FU 1) and long-term functional (at FU 2) recovery. We also determined association of 68 Ga-PentixaFor uptake in the infarct territory and lymphatic organs with outcome relative to established clinical and imaging biomarkers. At FU 1, functional recovery was recorded in 21/38 patients. Univariate analysis identified baseline LVEF (Odds Ratio (OR), 0.80, P=0.002) and uptake derived from heart-draining LN (OR, 0.21, P=0.03) as predictor of functional recovery, while only LVEF reached significance at multivariate analysis (OR, 0.72, P=0.007). At FU 2, functional recovery was observed in 21/36 patients and LVEF (OR, 0.84, P=0.005) and splenic PET signal (OR, 2.46, P=0.04) provided prognostic value at univariate analysis. Both parameters remained significant at multivariate outcome analysis (LVEF: OR, 0.73, P=0.01; spleen: OR, 4.17, P=0.04), indicating that low baseline LVEF and high splenic tracer uptake are prognostic for improved long-term functional outcome. Established risk factors of cardiac damage (infarct size) or inflammation (C-reactive protein, white blood cell counts) failed to reach significance for functional recovery at FU 1 and FU 2. Along with baseline EF, imaging of chemokine receptor expression in the spleen provides a complementary in-vivo biomarker for long-term functional recovery. Whole-body PET-based assessment of systemic inflammatory response in lymphatic organs may therefore open avenues for immune modulation strategies in patients after AMI.

Background After C-X-C motif chemokine receptor 4 (CXCR4)–directed radioligand therapy (RLT), lymphoma patients are scheduled for conditioning therapy (CON) followed by hematopoietic stem cell transplantation (HSCT). We aimed to determine whether CXCR4-RLT can achieve bone marrow ablation and direct antilymphoma activity independent from CON/HSCT and also evaluated the safety profile of this theranostic approach in an acute setting. Patients and Methods After CXCR4-directed 68Ga-pentixafor PET/CT, 21 heavily pretreated patients with hematological malignancies underwent CXCR4-directed RLT using 90Y-pentixather. The extent of myeloablative efficacy was determined by investigating hematologic laboratory parameters before RLT (day −1), at the day of RLT (day 0), 2 days after RLT (day 2), and before CON (median day 10). Serving as surrogate marker of antilymphoma activity, lactate dehydrogenase (LDH) levels were also assessed until CON. We also screened for laboratory-defined tumor lysis syndrome after the Cairo-Bishop definition and recorded acute laboratory adverse events using the Common Terminology Criteria for Adverse Events version 5.0. Results After RLT, we observed a significant decline of leukocyte levels by 79.4% ± 18.7% till CON (granulocytes, drop by 70.3% ± 21%; platelets, reduction by 43.1% ± 36%; P ≤ 0.0005 vs day 0, respectively). After RLT, LDH levels already reached a peak at day 2, which was followed by a rapid decline thereafter (peak vs day of CON, P = 0.0006), indicating that 90Y-pentixather exhibits direct antilymphoma activity. At day of CON, LDH levels were also significantly lower when compared with day −1 (P = 0.04), suggestive for durable response mediated by RLT. No patient fulfilled the criteria of tumor lysis syndrome, whereas 25 laboratory adverse events attributable to CXCR4-directed treatment were identified (≥grade 3 in 2/25 [8%]). During further treatment course, all patients (100%) received HSCT. Conclusions CXCR4-directed RLT causes effective myeloablation, which allows for HSCT. In addition, it also exerts direct antilymphoma activity independent of subsequent therapeutic steps, whereas safety profile was acceptable.

C-X-C motif chemokine receptor 4 (CXCR4)-directed molecular imaging provides excellent read-out capabilities in patients with marginal zone lymphoma (MZL). We aimed to determine the interobserver agreement rate of CXCR4-targeted PET/CT among readers with different levels of experience. Methods 50 subjects with MZL underwent CXCR4-targeted PET/CT, which were reviewed by four readers (including two experienced and two less experienced observers). The following 8 parameters were investigated: overall scan result, CXCR4 density in lymphoma tissue, extranodal organ involvement, No. of affected extranodal organs and extranodal organ metastases, lymph node (LN) involvement and No. of affected LN areas and LN metastases. We applied intraclass correlation coefficients (ICC; < 0.4, poor; 0.4-0.59, fair; 0.6-0.74, good and > 0.74 excellent agreement rates). Results Among all readers, fair agreement was recorded for No. of affected extranodal organs (ICC, 0.40; 95% confidence interval [CI], 0.25-0.68), overall scan result (ICC, 0.42; 95%CI, 0.28-0.57), CXCR4 density in lymphoma tissue (ICC, 0.52; 95%CI, 0.38-0.66), and No. of extranodal organ metastases (ICC, 0.55; 95%CI, 0.41-0.61) and LN involvement (ICC, 0.59; 95%CI, 0.46-0.71). Good agreement rates were observed for No. of LN metastases (ICC, 0.71; 95%CI, 0.60-0.81) and No. of LN areas (ICC, 0.73; 95%CI, 0.63-0.82), while extranodal organ involvement (ICC, 0.35; 95%CI, 0.21-0.51) achieved poor concordance. On a reader-by-reader comparison, the experienced readers achieved significantly higher agreement rates in 4/8 (50%) investigated scan items (ICC, range, 0.21-0.90, P < / = 0.04). In the remaining 4/8 (50%), a similar trend with higher ICCs for the experienced readers was recorded (n.s.). Conclusion CXCR4-directed PET/CT mainly provided fair to good agreement rates for scan assessment, while a relevant level of experience seems to be required for an accurate imaging read-out.

We report on an adrenocortical carcinoma (ACC) patient, which has exhausted previous treatment options and was scheduled for prostate-specific membrane antigen (PSMA)- and C-X-C motif chemokine receptor 4 (CXCR4)-targeted PET/CT. We identified PSMA-avid pulmonary metastases exhibiting modest radiotracer accumulation, while chemokine receptor PET/CT provided intense uptake. This dual-tracer molecular imaging approach revealed that chemokine receptor PET appears to be more suitable in patients with advanced ACC, indicating that CXCR4-directed radioligand therapy may be considered in such patients suffering from end-stage disease. Given its dismal prognosis, chemokine receptor-directed theranostics may therefore extend the therapeutic armamentarium as last-line option in advanced ACC.

Parkinson's disease (PD) is the second most prevalent neurodegenerative condition after Alzheimer's disease and it represents one of the fastest emerging neurological diseases worldwide. PD is usually diagnosed after the third decade of life with symptoms like tremors at rest and muscle stiffness. Rapid Eye Movement sleep behavioral disorder (RBD) is another disorder that is caused by a loss of typical muscle relaxation during sleep with a lot of motor activity. Usually, RBD is strongly associated with PD. Recent studies have demonstrated that PD reduces the life expectancy of patients to 10 and 20 years after being diagnosed. In addition, delayed diagnosis and treatment of these neurological disorders have significant socio-economic impacts on patients, their partners and on the general public. Often, it is not clear about PD associated financial burdens both in low and high-income countries. On the other hand, PD triggers neurological variations that affect differences in the dopamine transporter (DAT) and in glucose metabolism. Therefore, positron emission tomography (PET) using specific DAT radiotracers and fluorine-18 labeled desoxyglucose (FDG) has being considered a key imaging technique that could be applied clinically for the very early diagnosis of RBD and in PD. However, a few myths about PET is that it is very expensive. Here, we looked at the cost of treatment of PD and RBD in relation to early PET imaging. Our finding suggests that PET imaging might also be a cost sparing diagnostic option in the management of patients with PD and RBD, not only for first world countries as it is the case now but also for the third world countries. Therefore, PET is a cost-effective imaging technique for very early diagnostic of RBD and PD.

Ziel/Aim Positron emission tomography/computed tomography (PET/CT) with O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is a well-established tool for the non-invasive assessment of adult central nervous system (CNS) tumors. However, data on its diagnostic utility and impact on clinical management in children and adolescents is limited.

BACKGROUNDTreatment with immune checkpoint inhibitors has improved both progression-free survival and overall survival in a subset of patients with tumors. However, the selection of patients who benefit from immune checkpoint inhibitor treatment remains challenging. Positron Emission Tomography (PET) is a non-invasive molecular imaging tool, which offers a promising alternative to the current IHC for detecting the PD-L1 expression in malignant cells in vivo, enabling patient selection and predicting the response to individual patient immunotherapy treatment.OBJECTIVEHerein, we report the development of novel [18F]labeled pyridine-2-carboxamide derivatives [18F]2 and [18F]3 as small-molecule probes for imaging immune checkpoint (PD-1/PD-L1) in cancer using PET.RESULTS[18F]2 and [18F]3 were prepared by an one-step radiofluorination in and 44 ± 5% and 30 ± 4% radiochemical yield and > 98% radiochemical purity for a potential clinical translation. The total synthesis time including HPLC purification was less than 45 min. [18F]2 and [18F]3 showed an excellent stability in injection solution and a significant accumulation and retention in PD-1/PD-L1 expressing MDA-MB-231 breast cancer and in HeLa cervix carcinoma cells (2- 5 cpm/1000 cells). In addition, autoradiographic analysis and inhibition experiments on tumor slices confirm the potential of both compounds as specific imaging probes for the PD-1/PD-L1 axis in tumors.CONCLUSIONThe in vitro evaluation in PD-L1 expressing cells together with results from autoradiographic analysis in PD-L1 positive tumor sections suggest that [18F]2 and [18F]3 could be potential imaging probes for assessing PD-L1 expression in tumors, and warrant further biological evaluations in vivo.

Ziel/Aim Es wurde die diagnostische Performance der CXCR4 PET/CT beim Marginalzonen-Lymphom (MZL) im Vergleich zum Standard (gastrointestinale Endoskopie [GIE], Knochenmarkbiopsie [KMB], Ann-Arbor aus dem CT) ermittelt. Zudem wurde eruiert, ob das PET prognostisch relevant ist und eine CXCR4-gerichtete Endoradiotherapie (ERT) möglich wäre.

Kisspeptins (KPs, KISS1) and their receptor (KISS1R) play a pivotal role as metastasis suppressor for many cancers. Low or lost KP expression is associated with higher tumor grade, increased metastatic potential, and poor prognosis. Therefore, KP expression has prognostic relevance and correlates with invasiveness in cancers. Furthermore, KISS1R represents a very promising target for molecular imaging and therapy for KISS1R-expressing tumors. The goal of this study was to evaluate the developed KISS1-54 derivative, [68Ga]KISS1-54, as a PET-imaging probe for KISS1R-expressing tumors. The NODAGA-KISS1-54 peptide was labeled by Gallium-68, and the stability of the resulting [68Ga]KISS1-54 evaluated in injection solution and human serum, followed by an examination in different KISS1R-expressing tumor cell lines, including HepG2, HeLa, MDA-MB-231, MCF7, LNCap, SK-BR-3, and HCT116. Finally, [68Ga]KISS1-54 was tested in LNCap- and MDA-MB-231-bearing mice, using µ-PET, assessing its potential as an imaging probe for PET. [68Ga]KISS1-54 was obtained in a 77 ± 7% radiochemical yield and at a >99% purity. The [68Ga]KISS1-54 cell uptake amounted to 0.6–4.4% per 100,000 cells. Moreover, the accumulation of [68Ga]KISS1-54 was effectively inhibited by nonradioactive KISS1-54. In [68Ga]KISS1-54-PET, KISS1R-positive LNCap-tumors were clearly visualized as compared to MDA-MB-231-tumor implant with predominantly intracellular KISS1R expression. Our first results suggest that [68Ga]KISS1-54 is a promising candidate for a radiotracer for targeting KISS1R-expressing tumors via PET.

Positron emission tomography (PET) with O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is a well-established tool for non-invasive assessment of adult central nervous system (CNS) tumors. However, data on its diagnostic utility and impact on clinical management in children and adolescents are limited. Twenty-one children and young adults (13 males; mean age, 8.6 ± 5.2 years; range, 1–19 at initial diagnosis) with either newly diagnosed (n = 5) or pretreated (n = 16) CNS tumors were retrospectively analyzed. All patients had previously undergone neuro-oncological work-up including cranial magnetic resonance imaging. In all cases, [18F]FET-PET was indicated in a multidisciplinary team conference. The impact of PET imaging on clinical decision-making was assessed. Histopathology (n = 12) and/or clinical and imaging follow-up (n = 9) served as the standard of reference. The addition of [18F]FET-PET to the available information had an impact on further patient management in 14 out of 21 subjects, with avoidance of invasive surgery or biopsy in four patients, biopsy guidance in four patients, change of further treatment in another five patients, and confirmation of diagnosis in one patient. [18F]FET-PET may provide important additional information for treatment guidance in pediatric and adolescent patients with CNS tumors.

Ziel/Aim Immune checkpoint therapy has improved both progression-free survival and overall survival in a subset of patients with tumors. PET offers a promising alternative to the current immunohistochemical analysis (IHC) for detecting PD-L1 expression in malignant cells in vivo, allowing prediction of response to individual patient immunotherapy and thus patient selection. Herein, we report on the development of two novel F-18 labeled pyridine-2-carboxamide derivatives (F-18-PCA-1 and F-18-PCA-2) as small-molecule probes for assessing the PD-L1 status in tumors using PET.

C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in various solid cancers and can be targeted by CXCR4-directed molecular imaging. We aimed to characterize the in-vivo CXCR4 expression in patients affected with solid tumors, along with a comparison to ex-vivo findings. A total 142 patients with 23 different histologically proven solid tumors were imaged with CXCR4-directed PET/CT using [68 Ga]Ga-pentixafor (total number of scans, 152). A semi-quantitative analysis of the CXCR4-positive tumor burden including maximum standardized uptake values (SUVmax) and target-to-background ratios (TBR) using blood pool was conducted. In addition, we performed histopathological staining to determine the immuno-reactive score (IRS) from patients’ tumor tissue and investigated possible correlations with SUVmax (by providing Spearman’s rho ρ). Based on imaging, we also assessed the eligibility for CXCR4-targeted radioligand therapy or non-radioactive CXCR4 inhibitory treatment (defined as more than five CXCR4-avid target lesions [TL] with SUVmax above 10). One hundred three of 152 (67.8

In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes 90Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as 131I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of 131I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using β-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications.