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In patients with locally advanced adenocarcinoma of the oesophagogastric junction (AEG), early metabolic response defined by 18-fluorodeoxyglucose-PET ([ 18F]FDG-PET) during neoadjuvant chemotherapy is predictive of histopathological response and survival. We aimed to assess the feasibility of a PET-response-guided treatment algorithm and its potential effect on prognosis. Between May 27, 2002, and Aug 4, 2005, 119 patients with locally advanced adenocarcinoma of AEG type 1 (distal oesophageal adenocarcinoma) or type 2 (gastric cardia adenocarcinoma) were recruited into this prospective, single-centre study. All patients were assigned to 2 weeks of platinum and fluorouracil-based induction chemotherapy (evaluation period). Those with decreases in tumour glucose standard uptake values (SUVs), predefined as decreases of 35% or more at the end of the evaluation period and measured by PET, were defined as metabolic responders. Responders continued to receive neoadjuvant chemotherapy of folinic acid and fluorouracil plus cisplatin, or folinic acid and fluorouracil plus cisplatin and paclitaxel, or folinic acid and fluorouracil plus oxaliplatin for 12 weeks and then proceeded to surgery. Metabolic non-responders discontinued chemotherapy after the 2-week evaluation period and proceeded to surgery. The primary endpoint was median overall survival of metabolic responders and non-responders. Secondary endpoints were median event-free survival, postoperative complications and mortality, number of residual tumour-free (R0) resections, and histopathological responses. This study has been registered in the European Clinical Trials Database (EudraCT) as trial 2007-003356-11. 110 patients were evaluable for metabolic responses. 54 of these patients had metabolic responses (ie, decrease of 35% or more in tumour glucose SUV) after 2 weeks of induction chemotherapy, corresponding to a response of 49% (95% CI 39–59). 104 patients had tumour resection (50 in the responder group and 54 in the non-responder group). After a median follow-up of 2·3 years (IQR 1·7–3·0), median overall survival was not reached in metabolic responders, whereas median overall survival was 25·8 months (19·4–32·2) in non-responders (HR 2·13 [1·14–3·99, p=0·015). Median event-free survival was 29·7 months (95% CI 23·6–35·7) in metabolic responders and 14·1 months (7·5–20·6) in non-responders (hazard ratio [HR] 2·18 [1·32–3·62], p=0·002). Major histological remissions (<10% residual tumour) were noted in 29 of 50 metabolic responders (58% [95% CI 48–67]), but no histological response was noted in metabolic non-responders. This study confirmed prospectively the usefulness of early metabolic response evaluation, and shows the feasibility of a PET-guided treatment algorithm. These findings might enable tailoring of multimodal treatment in accordance with individual tumour biology in future randomised trials.

The precise definition of the post-operative resection status in high-grade gliomas (HGG) is crucial for further management. We aimed to assess the feasibility of assessment of the resection status with early post-operative positron emission tomography (PET) using [18F]O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET). 25 patients with the suspicion of primary HGG were enrolled. All patients underwent pre-operative [18F]FET-PET and magnetic resonance imaging (MRI). Intra-operatively, resection status was assessed using 5-aminolevulinic acid (5-ALA). Imaging was repeated within 72 h after neurosurgery. Post-operative [18F]FET-PET was compared with MRI, intra-operative assessment and clinical follow-up. [18F]FET-PET, MRI and intra-operative assessment consistently revealed complete resection in 12/25 (48%) patients and incomplete resection in 6/25 cases (24%). In 7 patients, PET revealed discordant findings. One patient was re-resected. 3/7 experienced tumor recurrence, 3/7 died shortly after brain surgery. Early assessment of the resection status in HGG with [18F]FET-PET seems to be feasible.

Aims: Stem cell-based regenerative therapies for the treatment of ischemic myocardium are currently a subject of intensive investigation. A variety of cell populations have been demonstrated to be safe and to exert some positive effects in human Phase I and II clinical trials, however conclusive evidence of efficacy is still lacking. While the relevance of animal models for appropriate pre-clinical safety and efficacy testing with regard to application in Phase III studies continues to increase, concerns have been expressed regarding the validity of the mouse model to predict clinical results. Against the background that hundreds of preclinical studies have assessed the efficacy of numerous kinds of cell preparations - including pluripotent stem cells - for cardiac repair, we undertook a systematic re-evaluation of data from the mouse model, which initially paved the way for the first clinical trials in this field. Methods and Results: A systematic literature screen was performed to identify publications reporting results of cardiac stem cell therapies for the treatment of myocardial ischemia in the mouse model. Only peer-reviewed and placebo-controlled studies using magnet resonance imaging (MRI) for left ventricular ejection fraction (LVEF) assessment were included. Experimental data from 21 studies involving 583 animals demonstrate a significant improvement in LVEF of 8.59%+/- 2.36; p=.012 (95% CI, 3.7–13.8) compared with control animals. Conclusion: The mouse is a valid model to evaluate the efficacy of cell-based advanced therapies for the treatment of ischemic myocardial damage. Further studies are required to understand the mechanisms underlying stem cell based improvement of cardiac function after ischemia.

PurposeBesides PSMA, prostate cancer cells also express gastrin-releasing peptide receptor (GRPr) which is therefore a promising target for theranostic approaches. The high affinity GRPr antagonist RM2 can be labeled with beta-emitting radiometals for therapeutic purposes. The aim of this study was to calculate absorbed doses for critical organs and tumor lesions for [177Lu]Lu-RM2 therapy administered in a group of metastatic castration-resistant prostate cancer (mCRPC) patients who had insufficient PSMA expression or showed lower PSMA accumulation after previous cycles of [177Lu]Lu-PSMA-617 therapy.MethodsThirty-five patients suffering from mCRPC without further treatment options for approved therapies were examined with [68Ga]Ga-RM2-PET/CT. Out of these, 4 patients (mean age 68 years) were treated with [177Lu]Lu-RM2; two of these also received a 2nd therapy cycle. Mean activity was 4.5 ± 0.9 GBq. For dosimetry, patients underwent planar WB-scintigraphy and SPECT/CT imaging of the upper and lower abdomen at approximately 1, 24, 48, and 72 h p.i. along with blood sampling. Absorbed doses for kidneys, pancreas, liver, spleen, gallbladder wall, and tumor lesions were derived based on quantitative SPECT/CT according to RADAR dosimetry scheme; individual organ masses were extracted from CT. Absorbed dose to bone marrow was calculated based on serial whole-body images and blood sampling according to the EANM guideline.ResultsTherapy was well tolerated by all patients and no side effects were observed. An increased uptake in tumor lesions and the pancreas was seen within the first 1 h. Mean absorbed organ doses were 1.08 ± 0.44 Gy/GBq in the pancreas, 0.35 ± 0.14 Gy/GBq in the kidneys, 0.05 ± 0.02 Gy/GBq in the liver, 0.07 ± 0.02 Gy/GBq in the gallbladder wall, 0.10 ± 0.06 Gy/GBq in the spleen, and 0.02 ± 0.01 Gy/GBq for the red bone marrow. The mean dose for tumor lesions was 6.20 ± 3.00 Gy/GBq.ConclusionsApplication of GRPr antagonist [177Lu]Lu-RM2 is suitable for targeted radiotherapy of mCRPC as it shows high tumor uptake and rapid clearance from normal organs. Absorbed doses in tumor lesions are therapeutically relevant. The critical organ receiving the highest absorbed dose was the pancreas. Results suggest that the activity administered for each cycle could be increased to maximize the absorbed dose of tumors and metastases.

Epileptic seizures are frequent in patients with glioblastoma, and anticonvulsive treatment is often necessary. While clinical guidelines recommend all approved anticonvulsants, so far it is still unclear which of the available drugs is the best therapeutic option for treating glioma-associated seizures, also in view of possible anti-tumorigenic effects. In our study, we employed four patient-derived low-passage cell lines of glioblastoma and three cell lines of brain metastases, and challenged these cultures with four anticonvulsants with different mechanisms of action: levetiracetam, valproic acid, carbamazepine and perampanel. Cell proliferation was determined by bromodeoxyuridine incorporation. To further analyze the effects of perampanel, apoptosis induction was measured by caspase 3/7 activation. Glutamate release was quantified and glucose uptake was determined using 18 F-fluorodeoxyglucose. Real-time polymerase chain reaction was employed to assess the expression of genes associated with glutamate release and uptake in brain tumor cells. Of the four anticonvulsants, only perampanel showed systematic inhibitory effects on cell proliferation, whereas all other anticonvulsants failed to inhibit glioma and metastasis cell growth in vitro . Metastasis cells were much more resistant to perampanel than glioblastoma cell lines. Glucose uptake was attenuated in all glioblastoma cells after perampanel exposure, whereas cell death via apoptosis was not induced. Extracellular glutamate levels were found to be significantly higher in glioblastoma cell lines as compared to metastasis cell lines, but could be reduced by perampanel exposure. Incubation with perampanel up-regulated glutamine synthetase expression in glioblastoma cells, whereas treatment with valproic acid and levetiracetam downregulated excitatory amino acid transporter-2 expression. Overall, our data suggest that perampanel acts as an anticonvulsive drug and additionally mediated anti-tumorigenic effects.

A clinical implementation of cell-based bone regeneration in combination with scaffold materials requires the development of efficient, controlled and reproducible seeding procedures and a tailor-made bioreactor design. A perfusion system for efficient, homogeneous, and rapid seeding with human adipogenic stem cells in bone substitute scaffolds was designed. Variants concerning medium inlet and outlet port geometry, i.e. cylindrical or conical diffuser, cell concentration, perfusion mode and perfusion rates were simulated in silico. Cell distribution during perfusion was monitored by dynamic [ 18 F]FDG micro-PET/CT and validated by laser scanning microscopy with three-dimensional image reconstruction. By iterative feedback of the in silico and in vitro experiments, the homogeneity of cell distribution throughout the scaffold was optimized with adjustment of flow rates, cell density and perfusion properties. Finally, a bioreactor with a conical diffusor geometry was developed, that allows a homogeneous cell seeding (hoover coefficient: 0.24) in less than 60 min with an oscillating perfusion mode. During this short period of time, the cells initially adhere within the entire scaffold and stay viable. After two weeks, the formation of several cell layers was observed, which was associated with an osteogenic differentiation process. This newly designed bioreactor may be considered as a prototype for chairside application.

O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET has a higher specificity than contrast-enhanced T1-weighted MRI (CE-T1MRI) in diagnosing recurrent glioblastoma. We aimed to evaluate whether a FET-PET-based target volume delineation, compared with CE-T1MRI, improves outcomes in patients with recurrent glioblastoma scheduled for re-irradiation. GLIAA was a multicentre, open-label, parallel randomised study done in 15 radiation oncology centres in Germany. Patients aged 18 years or older with a Karnofsky performance score greater than 60% and a macroscopic WHO grade IV recurrent glioblastoma (1–6 cm) were randomly assigned (1:1) to receive either FET-PET-based or CE-T1MRI-based target volume delineation followed by re-irradiation with 39 Gy in 13 fractions. Randomisation was performed centrally, using a minimisation technique with a random element and a computer-assisted randomisation tool, stratified by time since first radiotherapy, previous chemotherapy, tumour diameter, MGMT status, and planned chemotherapy. The primary endpoint was progression-free survival from randomisation, assessed in the per-protocol population (patients who initiated treatment per their assigned group). Adverse events were systematically assessed in all patients who commenced therapy. The trial was registered with ClinicalTrials.gov (NCT01252459), German Clinical Trials Registry (DRKS00000634), and European Clinical Trials Database (EudraCT 2012–001121–27), and is completed. Between Nov 22, 2013, and Aug 18, 2021, 271 patients were recruited and screened for eligibility, 200 of whom were randomly assigned to re-irradiation based on FET-PET (n=100) or CE-T1MRI (n=100). 85 (43%) participants were female and 115 (58%) were male. 98 patients in the FET-PET group and 97 in the CE-T1MRI group were treated per protocol. Median follow-up for censored patients was 12·2 months (IQR 6·6-20·7). Median progression-free survival was 4·0 months (95% CI 3·7–5·2) in the FET-PET group and 4·9 months (3·7–6·0) in the CE-T1MRI group (one-sided stratified log-rank p=0·98; adjusted hazard ratio 1·14 [95% CI 0·85–1·52]; p=0·39; median follow-up for six censored patients 4·1 months [IQR 2·3–6·6]). The most common grade 3–4 adverse event was radionecrosis (eight [8%] of 99 in the FET-PET group vs seven [7%] of 99 in the CE-T1MRI group). Acute and subacute serious adverse events occurred in 15 (15%) of 99 patients in each group; possibly re-irradiation-related late serious adverse events occurred in ten (10%) of 97 patients in the FET-PET group and 18 (19%) of 96 in the CE-T1MRI group. There were no treatment-related deaths. FET-PET-based target volume delineation for re-irradiation did not lead to a significant clinical benefit compared with CE-T1MRI-based treatment in patients with recurrent glioblastoma. Thus, CE-T1MRI remains the preferred delineation method in this setting. Deutsche Krebshilfe.

Perioperative chemotherapy in stage II and stage III gastric cancer is now accepted as a standard of care in the Western world. Two randomized phase III studies have shown improved survival for patients with induction chemotherapy followed by surgery compared with surgery alone. It is generally accepted that patients who respond to induction therapy have a significantly improved survival compared with that in nonresponding patients. Unfortunately no prospectively tested markers predicting response and/or prognosis are available for clinical practice. In adenocarcinomas of the esophagogastric junction (AEG), fluorodeoxyglucose-positron emission tomography (FDG-PET) prospectively was established as a surrogate predicting response and prognosis. The MUNICON (Metabolic response evalUatioN for Individualisation of neoadjuvant Chemotherapy in oesOphageal and oesophagogastric adeNocarcinoma) I study confirmed prospectively the usefulness of early metabolic response evaluation and showed the feasibility of a PET-guided treatment algorithm. These findings are an important step forward in the tailoring of multimodal treatment in accordance with tumor biology. In gastric cancer, we have analyzed FDG-PET in a prospective study. In gastric cancer the issue is more complicated, because about 30% of gastric cancers cannot be visualized with sufficient contrast for quantification. Insufficient FDG uptake is mostly associated with diffuse-type gastric cancer with signet ring cells and mucinous content. In FDG-avid patients, FDG-PET can be used for response evaluation, comparable to that in AEG. The prognosis of FDG-nonavid patients is similar to that in metabolic nonresponders. The addition of new tracers such as fluorothymidine may increase the sensitivity of PET in the future. Treatment concepts such as immediate resection after only 2 weeks of induction therapy with or without adjuvant treatment could be considered in metabolic nonresponders, or modified chemotherapy regimens, possibly including biologically targeted drugs, could be considered in those with FDG-nonavid tumors.

Background The initial idea of functional tissue replacement has shifted to the concept that injected cells positively modulate myocardial healing by a non-specific immune response of the transplanted cells within the target tissue. This alleged local modification of the scar requires assessment of regional properties of the left ventricular wall in addition to commonly applied measures of global morphological and functional parameters. Hence, we aimed at investigating the effect of cardiac cell therapy with cardiovascular progenitor cells, so-called cardiac induced cells, on both global and regional properties of the left ventricle by a multimodal imaging approach in a mouse model. Methods Myocardial infarction was induced in mice by ligation of the left anterior descending artery, the therapy group received an intramyocardial injection of 1 × 10 6 cardiac induced cells suspended in matrigel, the control group received matrigel only. [ 18 F]FDG positron emission tomography imaging was performed after 17 days, to assess regional glucose metabolism. Three weeks after myocardial infarction, cardiac magnetic resonance imaging was performed for morphological and functional assessment of the left ventricle. Following these measurements, hearts were excised for histological examinations. Results Cell therapy had no significant effect on global morphological parameters. Similarly, there was no difference in scar size and capillary density between therapy and control group. However, there was a significant improvement in contractile function of the left ventricle – left ventricular ejection fraction, stroke volume and cardiac output. Regional analysis of the left ventricle identified changes of wall properties in the scar area as the putative mechanism. Cell therapy reduced the thinning of the scar and significantly improved its radial contractility. Furthermore, the metabolic defect, assessed by [ 18 F]FDG, was significantly reduced by the cell therapy. Conclusion Our data support the relevance of extending the assessment of global left ventricular parameters by a structured regional wall analysis for the evaluation of therapies targeting at modulation of healing myocardium. This approach will enable a deeper understanding of mechanisms underlying the effect of experimental regenerative therapies, thus paving the way for a successful translation into clinical application.

Prostate cancer is one of the most common cancers in men, leading to substantial morbidity and mortality. After definitive therapy with surgery or radiation, many patients have biochemical relapse of disease—ie, an increase in their prostate-specific antigen level—which often precedes clinically apparent disease by months or even years. Therefore, imaging of the site and extent of tumour recurrence (local, regional, distant, or a combination) is of great interest. Conventional morphological imaging methods showed limited accuracy for assessment of recurrent prostate cancer; however, in recent years, functional and molecular imaging have offered the possibility of imaging molecular or cellular processes of individual tumours, often with more accuracy than morphological imaging. Hybrid imaging modalities (PET–CT, and single-photon emission CT [SPECT]–CT) have been introduced that combine functional and morphological data and allow whole-body imaging. Here, we review the contribution of radionuclide imaging and hybrid imaging for assessment of recurrent prostate cancer (local vs regional vs distant disease). We discuss available data on PET–CT and SPECT–CT, and provide an overview of experimental tracers and their preclinical and clinical development. Finally, we present a perspective on the potential of future hybrid magnetic resonance–PET imaging.