Histology-Based Radiomics for [18F]FDG PET Identifies Tissue Heterogeneity in Pancreatic Cancer.

Radiomics features can reveal hidden patterns in a tumor but usually lack an underlying biologic rationale. In this work, we aimed to investigate whether there is a correlation between radiomics features extracted from [18F]FDG PET images and histologic expression patterns of a glycolytic marker, monocarboxylate transporter-4 (MCT4), in pancreatic cancer. Methods: A cohort of pancreatic ductal adenocarcinoma patients (n = 29) for whom both tumor cross sections and [18F]FDG PET/CT scans were available was used to develop an [18F]FDG PET radiomics signature. By using immunohistochemistry for MCT4, we computed density maps of MCT4 expression and extracted pathomics features. Cluster analysis identified 2 subgroups with distinct MCT4 expression patterns. From corresponding [18F]FDG PET scans, radiomics features that associate with the predefined MCT4 subgroups were identified. Results: Complex heat map visualization showed that the MCT4-high/heterogeneous subgroup was correlating with a higher MCT4 expression level and local variation. This pattern linked to a specific [18F]FDG PET signature, characterized by a higher SUVmean and SUVmax and second-order radiomics features, correlating with local variation. This MCT4-based [18F]FDG PET signature of 7 radiomics features demonstrated prognostic value in an independent cohort of pancreatic cancer patients (n = 71) and identified patients with worse survival. Conclusion: Our cross-modal pipeline allows the development of PET scan signatures based on immunohistochemical analysis of markers of a particular biologic feature, here demonstrated on pancreatic cancer using intratumoral MCT4 expression levels to select [18F]FDG PET radiomics features. This study demonstrated the potential of radiomics scores to noninvasively capture intratumoral marker heterogeneity and identify a subset of pancreatic ductal adenocarcinoma patients with a poor prognosis.

Comparative Analysis of Morphological and Functional Effects of 225Ac- and 177Lu-PSMA Radioligand Therapies (RLTs) on Salivary Glands.

Most Prostate Specific Membrane Antigens (PSMAs) targeting small molecules accumulate in the salivary glands (SGs), raising concerns about SG toxicity, especially after repeated therapies or therapy with 225Ac-labeled ligands. SG toxicity is assessed clinically by the severity of patient-reported xerostomia, but this parameter can be challenging to objectively quantify. Therefore, we explored the feasibility of using SG volume as a biomarker for toxicity. In 21 patients with late-stage metastatic resistant prostate cancer (mCRPC), the PSMA volume and ligand uptake of SG were analyzed retrospectively before and after two cycles of 177Lu-PSMA (LuPSMA; cohort A) and before and after one cycle of 225Ac-PSMA-617 (AcPSMA, cohort B). Mean Volume-SG in cohort A was 59 ± 13 vs. 54 ± 16 mL (-10%, p = 0.4), and in cohort B, it was 50 ± 13 vs. 40 ± 11 mL (-20%, p = 0.007), respectively. A statistically significant decrease in the activity concentration in the SG was only observed in group B (SUVmean: 9.2 ± 2.8 vs. 5.3 ± 1.8, p < 0.0001; vs. A: SUVmean: 11.2 ± 3.3 vs. 11.1 ± 3.5, p = 0.8). SG volume and PSMA-ligand uptake are promising markers to monitor the SG toxicity after a PSMA RLT.

Artificial Intelligence in Oncological Hybrid Imaging.

BACKGROUND: Artificial intelligence (AI) applications have become increasingly relevant across a broad spectrum of settings in medical imaging. Due to the large amount of imaging data that is generated in oncological hybrid imaging, AI applications are desirable for lesion detection and characterization in primary staging, therapy monitoring, and recurrence detection. Given the rapid developments in machine learning (ML) and deep learning (DL) methods, the role of AI will have significant impact on the imaging workflow and will eventually improve clinical decision making and outcomes. METHODS AND RESULTS: The first part of this narrative review discusses current research with an introduction to artificial intelligence in oncological hybrid imaging and key concepts in data science. The second part reviews relevant examples with a focus on applications in oncology as well as discussion of challenges and current limitations. CONCLUSION: AI applications have the potential to leverage the diagnostic data stream with high efficiency and depth to facilitate automated lesion detection, characterization, and therapy monitoring to ultimately improve quality and efficiency throughout the medical imaging workflow. The goal is to generate reproducible, structured, quantitative diagnostic data for evidence-based therapy guidance in oncology. However, significant challenges remain regarding application development, benchmarking, and clinical implementation. KEY POINTS: · Hybrid imaging generates a large amount of multimodality medical imaging data with high complexity and depth.. · Advanced tools are required to enable fast and cost-efficient processing along the whole radiology value chain.. · AI applications promise to facilitate the assessment of oncological disease in hybrid imaging with high quality and efficiency for lesion detection, characterization, and response assessment. The goal is to generate reproducible, structured, quantitative diagnostic data for evidence-based oncological therapy guidance.. · Selected applications in three oncological entities (lung, prostate, and neuroendocrine tumors) demonstrate how AI algorithms may impact imaging-based tasks in hybrid imaging and potentially guide clinical decision making..

Improved Quality of Life in Metastatic Castration-Resistant Prostate Cancer Patients Receiving Consecutive Cycles of 177Lu-PSMA I&T.

The aim of this retrospective analysis was to evaluate health-related quality of life (HRQoL) for patients with metastatic castration-resistant prostate cancer (mCRPC) receiving consecutive cycles of 177Lu-prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) using the reliable and validated European Organisation for Research and Treatment of Cancer core quality-of-life (QoL) questionnaire. In addition, differences in HRQoL between patients with early discontinuation of treatment because of disease progression and patients who were defined as eligible for treatment continuation were analyzed. Methods: In total, 60 mCRPC patients were included in this analysis. The European Organisation for Research and Treatment of Cancer core QoL questionnaire was completed at baseline, before each treatment cycle up to the sixth treatment cycle, and at the time of PSMA-ligand PET/CT scans after the second and fourth treatment cycles. QoL assessment included global health status, functional scales, and symptom burden during treatment. Results: Global health was significantly improved at the second and fourth cycles of 177Lu-PSMA RLT (P = 0.014 and P = 0.039, respectively). In line with this, role and emotional functioning showed significant improvements at the second and fourth treatment cycles (role functioning, P = 0.045 and P = 0.048, respectively, and emotional functioning, P = 0.035 and P = 0.007, respectively). In addition, compared with baseline, fatigue and pain were significantly alleviated at the second and fourth treatment cycles (pain, P = 0.035 and P = 0.034, respectively, and fatigue, P = 0.042 and P = 0.041, respectively). Other aspects of HRQoL, even if not significantly improved, remained stable over time, except for deterioration of fatigue at the study's end (P = 0.014) and reduction of dyspnea at the second treatment cycle (P = 0.012). Patients with early discontinuation of treatment showed a concordant decline in HRQoL. Conclusion: mCRPC patients showed significant improvement in HRQoL in the course of treatment with 177Lu-PSMA RLT. Furthermore, patients with early discontinuation of treatment showed an analogous decline in HRQoL.

Clinical Translation of Targeted α-Therapy: An Evolution or a Revolution?

The field of radioligand therapy has advanced greatly in recent years, driven largely by ß-emitting therapies targeting somatostatin receptor-expressing tumors and the prostate-specific membrane antigen. Now, more clinical trials are under way to evaluate α-emitting targeted therapies as potential next-generation theranostics with even higher efficacy due to their high linear energy and short range in human tissues. In this review, we summarize the important studies ranging from the first Food and Drug Administration-approved α-therapy, 223Ra-dichloride, for treatment of bone metastases in castration-resistant prostate cancer, including concepts in clinical translation such as targeted α-peptide receptor radiotherapy and 225Ac-PSMA-617 for treatment of prostate cancer, innovative therapeutic models evaluating new targets, and combination therapies. Targeted α-therapy is one of the most promising fields in novel targeted cancer therapy, with several early- and late-stage clinical trials for neuroendocrine tumors and metastatic prostate cancer already in progress, along with significant interest and investment in additional early-phase studies. Together, these studies will help us understand the short- and long-term toxicity of targeted α-therapy and potentially identify suitable therapeutic combination partners.

Prognostic Role of 68Ga-PSMA11 PET-Based Response in Patients with Prostate Cancer Undergoing Taxane-Based Chemotherapy.

This study was performed to assess the prognostic utility of conventional biochemical and imaging response criteria and 68Ga-PSMA11 PET-adapted or -specific systems regarding overall survival (OS) in men with metastatic hormone-sensitive and castration-resistant prostate cancer (PC) treated with taxane-based chemotherapy. Methods: A total of 103 patients (metastatic hormone-sensitive PC, n = 57; castration-resistant PC, n = 46) underwent taxane-based chemotherapy. All patients had a minimum of 2 prostate-specific membrane antigen (PSMA) PET scans (at baseline and up to 3 mo after treatment). PSMA PET response was assessed by RECIST 1.1, adapted Prostate Cancer Working Group Criteria 3 (using PSMA PET instead of bone scan), aPERCIST, and PSMA PET progression (PPP) criteria. Response by each criterion was stratified by either progressive disease (PD) or non-PD. For aPERCIST, stratification by PD, stable disease (SD), and partial/complete remission (PR/CR) was performed. Biochemical response was determined by a prostate-specific antigen decrease of at least 50%. Subgroup analyses were performed by castration status. Univariable Cox proportional hazards regression analyses including Harrell's concordance indices were calculated to investigate the association of PD by response criteria and OS. Kaplan-Meier tests including log-rank statistics were calculated for survival analyses. Results: Twenty-six (25%) patients had unmeasurable disease by RECIST 1.1. PD by any response criterion was associated with an at least 2.5-fold increased risk of death and was highest for PD versus CR/PR by aPERCIST (hazard ratio, 11.4) on univariable regression. Stratified by castration status, a similar pattern was observed. PD by any criterion as associated with significantly shortened OS across overall and subgroup analyses. PR/CR by aPERCIST identified patients with lower risk of death and longer OS compared with patients with PD or SD. Conclusion: PSMA PET-based response criteria (PPP, aPERCIST, adapted Prostate Cancer Working Group Criteria 3) have high prognostic utility in men with metastatic PC undergoing taxane-based chemotherapy. PPP is simple to use, identified most patients with PD, and showed best prognostic utility regarding OS. PR/CR by aPERCIST identifies a subgroup of responders (PR/CR) showing better outcomes than patients with PD or SD. Future studies are warranted to amend the current paradigm relying on mere differentiation of PD versus non-PD in metastatic PC and to identify true treatment responders by imaging criteria.

Artificial Intelligence in Oncological Hybrid Imaging.

BACKGROUND: Artificial intelligence (AI) applications have become increasingly relevant across a broad spectrum of settings in medical imaging. Due to the large amount of imaging data that is generated in oncological hybrid imaging, AI applications are desirable for lesion detection and characterization in primary staging, therapy monitoring, and recurrence detection. Given the rapid developments in machine learning (ML) and deep learning (DL) methods, the role of AI will have significant impact on the imaging workflow and will eventually improve clinical decision making and outcomes. METHODS AND RESULTS: The first part of this narrative review discusses current research with an introduction to artificial intelligence in oncological hybrid imaging and key concepts in data science. The second part reviews relevant examples with a focus on applications in oncology as well as discussion of challenges and current limitations. CONCLUSION: AI applications have the potential to leverage the diagnostic data stream with high efficiency and depth to facilitate automated lesion detection, characterization, and therapy monitoring to ultimately improve quality and efficiency throughout the medical imaging workflow. The goal is to generate reproducible, structured, quantitative diagnostic data for evidence-based therapy guidance in oncology. However, significant challenges remain regarding application development, benchmarking, and clinical implementation. KEY POINTS: · Hybrid imaging generates a large amount of multimodality medical imaging data with high complexity and depth.. · Advanced tools are required to enable fast and cost-efficient processing along the whole radiology value chain.. · AI applications promise to facilitate the assessment of oncological disease in hybrid imaging with high quality and efficiency for lesion detection, characterization, and response assessment. The goal is to generate reproducible, structured, quantitative diagnostic data for evidence-based oncological therapy guidance.. · Selected applications in three oncological entities (lung, prostate, and neuroendocrine tumors) demonstrate how AI algorithms may impact imaging-based tasks in hybrid imaging and potentially guide clinical decision making.. CITATION FORMAT: · Feuerecker B, Heimer M, Geyer T et al. Artificial Intelligence in Oncological Hybrid Imaging. Fortschr Röntgenstr 2023; 195: 105 - 114.

Pneumonitis after Stereotactic Thoracic Radioimmunotherapy with Checkpoint Inhibitors: Exploration of the Dose-Volume-Effect Correlation.

Thoracic stereotactic body radiation therapy (SBRT) is extensively used in combination with immune checkpoint blockade (ICB). While current evidence suggests that the occurrence of pneumonitis as a side effect of both treatments is not enhanced for the combination, the dose-volume correlation remains unclear. We investigate dose-volume-effect correlations for pneumonitis after combined SBRT + ICB. We analyzed patient clinical characteristics and dosimetric data for 42 data sets for thoracic SBRT with ICB treatment (13) and without (29). Dose volumes were converted into 2 Gy equivalent doses (EQD2), allowing for dosimetric comparison of different fractionation regimes. Pneumonitis volumes were delineated and corresponding DVHs were analyzed. We noticed a shift towards lower doses for combined SBRT + ICB treatment, supported by a trend of smaller areas under the curve (AUC) for SBRT+ ICB (median AUC 1337.37 vs. 5799.10, p = 0.317). We present a DVH-based dose-volume-effect correlation method and observed large pneumonitis volumes, even with bilateral extent in the SBRT + ICB group. We conclude that further studies using this method with enhanced statistical power are needed to clarify whether adjustments of the radiation dose constraints are required to better estimate risks of pneumonitis after the combination of SBRT and ICB.

Pretherapeutic Comparative Dosimetry of 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T in Patients with Metastatic Castration-Resistant Prostate Cancer.

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands allow for labeling with 18F and radiometals for endoradiotherapy. rhPSMA-7.3 has been designated as a lead compound with promising preclinical data for 177Lu-rhPSMA-7.3, which has shown higher tumor uptake than 177Lu-PSMA I&T. In this retrospective analysis, we compared pretherapeutic clinical dosimetry data of both PSMA ligands. Methods: Six patients with metastatic castration-resistant prostate cancer underwent both 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T pretherapeutic dosimetry. Whole-body scintigraphy was performed at 1 h, 4 h, 24 h, 48 h, and 7 d after injection. Regions of interest covering the whole body, organs, bone marrow, and tumor lesions were drawn for each patient. Absorbed doses for individual patients and pretherapeutic applications were calculated using OLINDA/EXM. To facilitate the comparison of both ligands, we introduced the therapeutic index (TI), defined as the ratio of mean pretherapeutic doses to tumor lesions over relevant organs at risk. Results: Mean whole-body pretherapeutic effective doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were 0.12 ± 0.07 and 0.05 ± 0.03 Sv/GBq, respectively. Mean absorbed organ doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were, for example, 1.65 ± 0.28 and 0.73 ± 0.18 Gy/GBq for the kidneys, 0.19 ± 0.09 and 0.07 ± 0.03 Gy/GBq for the liver, 2.35 ± 0.78 and 0.80 ± 0.41 Gy/GBq for the parotid gland, and 0.67 ± 0.62 and 0.30 ± 0.27 Gy/GBq for the bone marrow, respectively. Tumor lesions received mean absorbed doses of 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T of 6.44 ± 6.44 and 2.64 ± 2.24 Gy/GBq, respectively. The mean TIs for the kidneys were 3.7 ± 2.2 and 3.6 ± 2.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively, and those for the bone marrow were 15.2 ± 10.2 and 15.1 ± 10.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively. Conclusion: Pretherapeutic clinical dosimetry confirmed preclinical results of mean absorbed doses for tumors that were 2-3 times higher for 177Lu-rhPSMA-7.3 than for 177Lu-PSMA I&T. Absorbed doses to normal organs also tended to be higher for 177Lu-rhPSMA-7.3, resulting overall in similar average TIs for both radiopharmaceuticals with considerable interpatient variability. 177Lu-rhPSMA-7.3 has promise for a therapeutic efficacy similar to that of 177Lu-PSMA I&T at smaller amounts of injected activity, simplifying radiation safety measurements (especially for large patient numbers or dose escalation regimens).

Proof of concept of a multimodal intravital molecular imaging system for tumour transpathology investigation.

BACKGROUND: Transpathology highlights the interpretation of the underlying physiology behind molecular imaging. However, it remains challenging due to the discrepancies between in vivo and in vitro measurements and difficulties of precise co-registration between trans-scaled images. This study aims to develop a multimodal intravital molecular imaging (MIMI) system as a tool for in vivo tumour transpathology investigation. METHODS: The proposed MIMI system integrates high-resolution positron imaging, magnetic resonance imaging (MRI) and microscopic imaging on a dorsal skin window chamber on an athymic nude rat. The window chamber frame was designed to be compatible with multimodal imaging and its fiducial markers were customized for precise physical alignment among modalities. The co-registration accuracy was evaluated based on phantoms with thin catheters. For proof of concept, tumour models of the human colorectal adenocarcinoma cell line HT-29 were imaged. The tissue within the window chamber was sectioned, fixed and haematoxylin-eosin (HE) stained for comparison with multimodal in vivo imaging. RESULTS: The final MIMI system had a maximum field of view (FOV) of 18 mm × 18 mm. Using the fiducial markers and the tubing phantom, the co-registration errors are 0.18 ± 0.27 mm between MRI and positron imaging, 0.19 ± 0.22 mm between positron imaging and microscopic imaging and 0.15 ± 0.27 mm between MRI and microscopic imaging. A pilot test demonstrated that the MIMI system provides an integrative visualization of the tumour anatomy, vasculatures and metabolism of the in vivo tumour microenvironment, which was consistent with ex vivo pathology. CONCLUSIONS: The established multimodal intravital imaging system provided a co-registered in vivo platform for trans-scale and transparent investigation of the underlying pathology behind imaging, which has the potential to enhance the translation of molecular imaging.

Narrative review: prostate-specific membrane antigen-radioligand therapy in metastatic castration-resistant prostate cancer.

Radioactive-labelled ligands targeting the prostate-specific membrane antigen (PSMA), a transmembrane protein overexpressed in prostate cancer (PC), have shown promising activity in treatment of metastatic castration-resistant prostate cancer (mCRPC). PSMA-617 and PSMA-I&T (imaging and therapy), both labeled to the beta-emitter lutetium-177 (Lu177), are most frequently used in clinical routine and have shown a favorable side-effect profile. Common side effects are transient xerostomia. Severe side effects, e.g., treatment-associated myelosuppression, are rare. Currently treatment with Lu177-PSMA outside clinical trials is available for compassionate use for patients who exhausted conventional therapies. Previous retro- and prospective studies reported promising results with ≥50% PSA declines observed in at least one third of patients. Retrospective data suggests worse biochemical response in patients with visceral metastases. Preliminary data from the randomized phase II (TheraP) trial showed an improved biochemical response rate of Lu177-PSMA as compared to cabazitaxel in patients progressing after docetaxel. Following these promising data, the results of the randomized, prospective phase III VISION study are eagerly anticipated. A major challenge remains resistance to radioligand therapy with Lu177-PSMA. As an alternative, a PSMA-ligand labeled to the alpha-emitter Actinium-225 (Ac-225) may be offered to patients, which shows promising activity in patients developing progression under Lu177-PSMA at the cost of higher toxicity. Mostly permanent xerostomia is a relevant side effect resulting in treatment discontinuation in up to a quarter of patients. This review summarizes the literature on activity and toxicity of PSMA-targeted radioligand therapy in mCRPC.

Metabolic Response of Pancreatic Carcinoma Cells under Treatment with Dichloroacetate.

In modern oncology, the analysis and evaluation of treatment response are still challenging. Hence, we used a 13C-guided approach to study the impacts of the small molecule dichloroacetate (DCA) upon the metabolic response of pancreatic cancer cells. Two different oncogenic PI3K-driven pancreatic cancer cell lines, 9580 and 10,158, respectively, were treated with 75 mM DCA for 18 h. In the presence of [U-13C6]glucose, the effects of DCA treatment in the core carbon metabolism were analyzed in these cells using gas chromatography-mass spectrometry (GC/MS). 13C-enrichments and isotopologue profiles of key amino acids revealed considerable effects of the DCA treatment upon glucose metabolism. The DCA treatment of the two pancreatic cell lines resulted in a significantly decreased incorporation of [U-13C6]glucose into the amino acids alanine, aspartate, glutamate, glycine, proline and serine in treated, but not in untreated, cancer cells. For both cell lines, the data indicated some activation of pyruvate dehydrogenase with increased carbon flux via the TCA cycle, but also massive inhibition of glycolytic flux and amino acid biosynthesis presumably by inhibition of the PI3K/Akt/mTORC axis. Together, it appears worthwhile to study the early treatment response in DCA-guided or accompanied cancer therapy in more detail, since it could open new avenues for improved diagnosis and therapeutic protocols of cancer.

Diverse metabolic response of cancer cells treated with a 213Bi-anti-EGFR-immunoconjugate.

Evaluation of treatment response is among the major challenges in modern oncology. We herein used a monoclonal antibody targeting the EGF receptor (EGFR) labelled with the alpha emitter 213Bi (213Bi-anti-EGFR-MAb). EJ28Luc (bladder) and LN18 (glioma) cancer cells, both overexpressing EGFR, were incubated for 3 h with the radioimmunoconjugate. To assess the responses in the core carbon metabolism upon this treatment, these cancer cell lines were subsequently cultivated for 18 h in the presence of [U-13C6]glucose. 13C-enrichment and isotopologue profiles of key amino acids were monitored by gas chromatography-mass spectrometry (GC/MS), in order to monitor the impacts of the radionuclide-treatment upon glucose metabolism. In comparison to untreated controls, treatment of EJ28Luc cells with 213Bi-anti-EGFR-MAb resulted in a significantly decreased incorporation of 13C from [U-13C6]glucose into alanine, aspartate, glutamate, glycine, proline and serine. In sharp contrast, the same amino acids did not display less 13C-enrichments during treatment of the LN18 cells. The data indicate early treatment response of the bladder cancer cells, but not of the glioma cells though cell lines were killed following 213Bi-anti-EGFR-MAb treatment. The pilot study shows that the 13C-labelling approach is a valid tool to assess the responsiveness of cancer cells upon radionuclide-treatment in considerable metabolic detail.

Comparative Preclinical Biodistribution, Dosimetry, and Endoradiotherapy in Metastatic Castration-Resistant Prostate Cancer Using 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T.

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are applicable as radiochemical twins for both diagnostic PET imaging and endoradiotherapy. On the basis of preliminary data as a diagnostic ligand, the isomer rhPSMA-7.3 is a promising candidate for potential endoradiotherapy. The aim of this preclinical evaluation was to assess the biodistribution, dosimetry, and therapeutic efficacy of 19F/177Lu-rhPSMA-7.3 in comparison to the established therapeutic agent 177Lu-PSMA I&T (imaging and therapy). Methods: The biodistribution of 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T was determined in LNCaP tumor-bearing severe combined immunodeficiency (SCID) mice after sacrifice at defined time points up to 7 d (n = 5). Organs and tumors were dissected, percentage injected dose per gram (%ID/g) was determined, and dosimetry was calculated using OLINDA/EXM, version 1.0. The therapeutic efficacy of a single 30-MBq dose of 19F/177Lu-rhPSMA-7.3 (n = 7) was compared with that of 177Lu-PSMA I&T in treatment groups (n = 7) and control groups (n = 6-7) using C4-2 tumor-bearing SCID mice by evaluating tumor growth and survival over 6 wk after treatment. Results: The biodistribution of 19F/177Lu-rhPSMA-7.3 revealed fast blood clearance (0.63 %ID/g at 1 h after injection), and the highest activity uptake was in the spleen and kidneys, particularly in the first hour (33.25 %ID/g and 207.6 %ID/g, respectively, at 1 h after injection), indicating a renal excretion pathway. Compared with 177Lu-PSMA I&T, 19F/177Lu-rhPSMA-7.3 exhibited an initial (1 h) 2.6-fold higher tumor uptake in LNCaP xenografts and a longer retention (4.5 %ID/g vs. 0.9 %ID/g at 168 h). The tumor dose of 19F/177Lu-rhPSMA-7.3 was substantially higher (e.g., 7.47 vs. 1.96 µGy/MBq at 200 mm3) than that of 177Lu-PSMA I&T. In most organs, absorbed doses were higher for 177Lu-PSMA I&T. A significantly greater tumor size reduction was shown for a single dose of 19F/177Lu-rhPSMA-7.3 than for 177Lu-PSMA I&T at the end of the experiment (P = 0.0167). At the predefined termination of the experiment at 6 wk, 7 of 7 and 3 of 7 mice were still alive in the 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T groups, respectively, compared with the respective control groups, with 0 of 7 and 0 of 6 mice. Conclusion: Compared with 177Lu-PSMA I&T, 19F/177Lu-rhPSMA-7.3 can be considered a suitable candidate for clinical translation because it has similar clearance kinetics and a similar radiation dose to healthy organs but superior tumor uptake and retention. Preliminary treatment experiments showed a favorable antitumor response.

Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA.

BACKGROUND: Beta-emitting Lu-177-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new option for metastatic castration-resistant prostate cancer (mCRPC), but its antitumor effect can decrease over time. OBJECTIVE: To report the safety and activity of alpha-emitting Ac-225-PSMA-617 RLT in mCRPC that has progressed after Lu-177-PSMA. DESIGN, SETTING, AND PARTICIPANTS: Twenty-six patients were treated under a compassionate use protocol. The eligibility criteria included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy, progression after Lu-177-PSMA, and positive PSMA-ligand uptake. The median number of previous mCRPC regimens was 6. Ac-225-PSMA-617 was given every 8 wk until progression/intolerable side effects. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS), overall survival (OS), and toxicity were measured. RESULTS AND LIMITATIONS: Sixty-one cycles of Ac-225-PSMA-617 (median number of cycles 2; median activity 9 MBq) were administered. A PSA decline of ≥50% was achieved in 17/26 patients. The median PSA-PFS, cPFS, and OS periods were 3.5 (95% confidence interval [CI] 1.8-11.2), 4.1 (95% CI 3-14.8), and 7.7 (95% CI 4.5-12.1) mo, respectively. Liver metastases were associated with shorter PSA-PFS (median 1.9 vs 4.0 mo; p = 0.02), cPFS (median 1.8 vs 5.2 mo; p = 0.001), and OS (median 4.3 vs 10.4 mo; p = 0.01). Hematological grade 3/4 toxicities were anemia (35%), leucopenia (27%), and thrombocytopenia (19%). All patients experienced grade 1/2 xerostomia. Two and six patients stopped due to hematological toxicity and xerostomia, respectively. A limitation is the retrospective design. CONCLUSIONS: Ac-225-PSMA-617 showed measurable antitumor effect after Lu-177-PSMA failure in late-stage mCRPC. Grade 3/4 hematological side effects were observed in up to one-third of patients, and xerostomia led to treatment halt in a relevant number of patients. PATIENT SUMMARY: Ac-225-labeled prostate-specific membrane antigen (PSMA)-617 therapy showed substantial antitumor effect in late metastatic castration-resistant prostate cancer after Lu-177-PSMA failure. However, dry mouth is a common side effect that caused about a quarter of patients to stop therapy.

Differentiation of acute myeloid leukemia (AML) cells with ATRA reduces 18F-FDG uptake and increases sensitivity towards ABT-737-induced apoptosis.

Acute myeloid leukemia (AML) is a malignant disease of the bone marrow, comprising various subtypes. We have investigated seven different AML cell lines that showed different sensitivities toward the inducer of apoptosis ABT-737, with IC50 concentrations ranging from 9.9 nM to 1.8 µM. Besides, the AML cell lines revealed distinct differences in 18F-FDG uptake ranging from 4.1 to 11.0%. Moreover, the Pearson coefficient (0.363) suggests a moderate correlation between 18F-FDG uptake and the IC50 values of ABT-737. Differentiation of the AML cell lines NB-4 and AML-193 with all-trans-retinoic-acid (ATRA) induced a significant increase in sensitivity towards ABT-737 along with a reduced uptake of 18F-FDG. Therefore, 18F-FDG uptake could be predictive on sensitivity to treatment with ABT-737. Furthermore, because differentiation treatment of AML cells using ATRA reduced 18F-FDG uptake and increased sensitivity towards ABT-737, a combined treatment regimen with ATRA and ABT-737 might be a promising therapeutic option in the future.

Impact of 18F-FDG-PET/CT on the identification of regional lymph node metastases and delineation of the primary tumor in esophageal squamous cell carcinoma patients.

PURPOSE: In patients undergoing chemoradiation for esophageal squamous cell carcinoma (ESCC), the extent of elective nodal irradiation (ENI) is still discussed controversially. This study aimed to analyze patterns of lymph node metastases and their correlation with the primary tumor using 18F­fludeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans. METHODS: 102 ESCC patients with pre-treatment FDG-PET/CT scans were evaluated retrospectively. After exclusion of patients with low FDG uptake and patients without FDG-PET-positive lymph node metastases (LNM), 76 patients were included in the final analysis. All LNM were assigned to 16 pre-defined anatomical regions and classified according to their position relative to the primary tumor (above, at the same height, or below the primary tumor). In addition, the longitudinal distance to the primary tumor was measured for all LNM above or below the primary tumor. The craniocaudal extent (i.e., length) of the primary tumor was measured using FDG-PET imaging (LPET) and also based on all other available clinical and imaging data (endoscopy, computed tomography, biopsy results) except FDG-PET (LCT/EUS). RESULTS: Significantly more LNM were identified with 18F­FDG-PET/CT (177 LNM) compared to CT alone (131 LNM, p < 0.001). The most common sites of LNM were paraesophageal (63% of patients, 37% of LNM) and paratracheal (33% of patients, 20% of LNM), while less than 5% of patients had supraclavicular, subaortic, diaphragmatic, or hilar LNM. With regard to the primary tumor, 51% of LNM were at the same height, while 25% and 24% of lymph node metastases were above and below the primary tumor, respectively. For thirty-three LNM (19%), the distance to the primary tumor was larger than 4 cm. No significant difference was seen between LCT/EUS (median 6 cm) and LPET (median 6 cm, p = 0.846) CONCLUSION: 18F­FDG-PET can help to identify subclinical lymph node metastases which are located outside of recommended radiation fields. PET-based involved-field irradiation might be the ideal compromise between small treatment volumes and decreasing the risk of undertreatment of subclinical metastatic lymph nodes and should be further evaluated.

Assessment of 213Bi-anti-EGFR MAb treatment efficacy in malignant cancer cells with [1-13C]pyruvate and [18F]FDG.

Evaluation of response to therapy is among the key objectives of oncology. A new method to evaluate this response includes magnetic resonance spectroscopy (MRS) with hyperpolarized 13C-labelled metabolites, which holds promise to provide new insights in terms of both therapeutic efficacy and tumor cell metabolism. Human EJ28Luc urothelial carcinoma and LN18 glioma cells were treated with lethal activity concentrations of a 213Bi-anti-EGFR immunoconjugate. Treatment efficacy was controlled via analysis of DNA double-strand breaks (immunofluorescence γH2AX staining) and clonogenic survival of cells. To investigate changes in metabolism of treated cells vs controls we analyzed conversion of hyperpolarized [1-13C]pyruvate to [1-13C]lactate via MRS as well as viability of cells, lactate formation and lactate dehydrogenase activity in the cellular supernatants and [18F]FDG uptake in treated cells vs controls, respectively. Treatment of malignant cancer cells with 213Bi-anti-EGFR-MAb induced intense DNA double-strand breaks, resulting in cell death as monitored via clonogenic survival. Moreover, treatment of EJ28Luc bladder cancer cells resulted in decreased cell viability, [18F]FDG-uptake and an increased lactate export. In both EJ28Luc and LN18 carcinoma cells treatment with 213Bi-anti-EGFR-MAb triggered a significant increase in lactate/pyruvate ratios, as measured with hyperpolarized [1-13C]pyruvate. Treatment with 213Bi-anti-EGFR-MAb resulted in an effective induction of cell death in EJ28Luc and LN18 cells. Lactate/pyruvate ratios of hyperpolarized [1-13C]pyruvate proved to detect early treatment response effects, holding promise for future clinical applications in early therapy monitoring.

Simultaneous characterization of tumor cellularity and the Warburg effect with PET, MRI and hyperpolarized 13C-MRSI.

Modern oncology aims at patient-specific therapy approaches, which triggered the development of biomedical imaging techniques to synergistically address tumor biology at the cellular and molecular level. PET/MR is a new hybrid modality that allows acquisition of high-resolution anatomic images and quantification of functional and metabolic information at the same time. Key steps of the Warburg effect-one of the hallmarks of tumors-can be measured non-invasively with this emerging technique. The aim of this study was to quantify and compare simultaneously imaged augmented glucose uptake and LDH activity in a subcutaneous breast cancer model in rats (MAT-B-III) and to study the effect of varying tumor cellularity on image-derived metabolic information. Methods: For this purpose, we established and validated a multimodal imaging workflow for a clinical PET/MR system including proton magnetic resonance (MR) imaging to acquire accurate morphologic information and diffusion-weighted imaging (DWI) to address tumor cellularity. Metabolic data were measured with dynamic [18F]FDG-PET and hyperpolarized (HP) 13C-pyruvate MR spectroscopic imaging (MRSI). We applied our workflow in a longitudinal study and analyzed the effect of growth dependent variations of cellular density on glycolytic parameters. Results: Tumors of similar cellularity with similar apparent diffusion coefficients (ADC) showed a significant positive correlation of FDG uptake and pyruvate-to-lactate exchange. Longitudinal DWI data indicated a decreasing tumor cellularity with tumor growth, while ADCs exhibited a significant inverse correlation with PET standard uptake values (SUV). Similar but not significant trends were observed with HP-13C-MRSI, but we found that partial volume effects and point spread function artifacts are major confounders for the quantification of 13C-data when the spatial resolution is limited and major blood vessels are close to the tumor. Nevertheless, analysis of longitudinal data with varying tumor cellularity further detected a positive correlation between quantitative PET and 13C-data. Conclusions: Our workflow allows the quantification of simultaneously acquired PET, MRSI and DWI data in rodents on a clinical PET/MR scanner. The correlations and findings suggest that a major portion of consumed glucose is metabolized by aerobic glycolysis in the investigated tumor model. Furthermore, we conclude that variations in cell density affect PET and 13C-data in a similar manner and correlations of longitudinal metabolic data appear to reflect both biochemical processes and tumor cellularity.