An in vivo tumour organoid model based on the chick embryonic chorioallantoic membrane mimics key characteristics of the patient tissue: a proof-of-concept study.

BACKGROUND: Patient-derived tumour organoids (PDOs) are highly advanced in vitro models for disease modelling, yet they lack vascularisation. To overcome this shortcoming, organoids can be inoculated onto the chorioallantoic membrane (CAM); the highly vascularised, not innervated extraembryonic membrane of fertilised chicken eggs. Therefore, we aimed to (1) establish a CAM patient-derived xenograft (PDX) model based on PDOs generated from the liver metastasis of a colorectal cancer (CRC) patient and (2) to evaluate the translational pipeline (patient - in vitro PDOs - in vivo CAM-PDX) regarding morphology, histopathology, expression of C-X-C chemokine receptor type 4 (CXCR4), and radiotracer uptake patterns. RESULTS: The main liver metastasis of the CRC patient exhibited high 2-[18F]FDG uptake and moderate and focal [68Ga]Ga-Pentixafor accumulation in the peripheral part of the metastasis. Inoculation of PDOs derived from this region onto the CAM resulted in large, highly viable, and extensively vascularised xenografts, as demonstrated immunohistochemically and confirmed by high 2-[18F]FDG uptake. The xenografts showed striking histomorphological similarity to the patient's liver metastasis. The moderate expression of CXCR4 was maintained in ovo and was concordant with the expression levels of the patient's sample and in vitro PDOs. Following in vitro re-culturing of CAM-PDXs, growth, and [68Ga]Ga-Pentixafor uptake were unaltered compared to PDOs before transplantation onto the CAM. Although [68Ga]Ga-Pentixafor was taken up into CAM-PDXs, the uptake in the baseline and blocking group were comparable and there was only a trend towards blocking. CONCLUSIONS: We successfully established an in vivo CAM-PDX model based on CRC PDOs. The histomorphological features and target protein expression of the original patient's tissue were mirrored in the in vitro PDOs, and particularly in the in vivo CAM-PDXs. The [68Ga]Ga-Pentixafor uptake patterns were comparable between in vitro, in ovo and clinical data and 2-[18F]FDG was avidly taken up in the patient's liver metastasis and CAM-PDXs. We thus propose the CAM-PDX model as an alternative in vivo model with promising translational value for CRC patients.

A novel assessment of whole-mount Gleason grading in prostate cancer to identify candidates for radical prostatectomy: a machine learning-based multiomics study.

Purpose: This study aims to assess whole-mount Gleason grading (GG) in prostate cancer (PCa) accurately using a multiomics machine learning (ML) model and to compare its performance with biopsy-proven GG (bxGG) assessment. Materials and Methods: A total of 146 patients with PCa recruited in a pilot study of a prospective clinical trial (NCT02659527) were retrospectively included in the side study, all of whom underwent 68Ga-PSMA-11 integrated positron emission tomography (PET) / magnetic resonance (MR) before radical prostatectomy (RP) between May 2014 and April 2020. To establish a multiomics ML model, we quantified PET radiomics features, pathway-level genomics features from whole exome sequencing, and pathomics features derived from immunohistochemical staining of 11 biomarkers. Based on the multiomics dataset, five ML models were established and validated using 100-fold Monte Carlo cross-validation. Results: Among five ML models, the random forest (RF) model performed best in terms of the area under the curve (AUC). Compared to bxGG assessment alone, the RF model was superior in terms of AUC (0.87 vs 0.75), specificity (0.72 vs 0.61), positive predictive value (0.79 vs 0.75), and accuracy (0.78 vs 0.77) and showed slightly decreased sensitivity (0.83 vs 0.89) and negative predictive value (0.80 vs 0.81). Among the feature categories, bxGG was identified as the most important feature, followed by pathomics, clinical, radiomics and genomics features. The three important individual features were bxGG, PSA staining and one intensity-related radiomics feature. Conclusion: The findings demonstrate a superior assessment of the developed multiomics-based ML model in whole-mount GG compared to the current clinical baseline of bxGG. This enables personalized patient management by identifying high-risk PCa patients for RP.

Multicenter PET image harmonization using generative adversarial networks.

PURPOSE: To improve reproducibility and predictive performance of PET radiomic features in multicentric studies by cycle-consistent generative adversarial network (GAN) harmonization approaches. METHODS: GAN-harmonization was developed to harmonize whole-body PET scans to perform image style and texture translation between different centers and scanners. GAN-harmonization was evaluated by application to two retrospectively collected open datasets and different tasks. First, GAN-harmonization was performed on a dual-center lung cancer cohort (127 female, 138 male) where the reproducibility of radiomic features in healthy liver tissue was evaluated. Second, GAN-harmonization was applied to a head and neck cancer cohort (43 female, 154 male) acquired from three centers. Here, the clinical impact of GAN-harmonization was analyzed by predicting the development of distant metastases using a logistic regression model incorporating first-order statistics and texture features from baseline 18F-FDG PET before and after harmonization. RESULTS: Image quality remained high (structural similarity: left kidney ≥ 0.800, right kidney ≥ 0.806, liver ≥ 0.780, lung ≥ 0.838, spleen ≥ 0.793, whole-body ≥ 0.832) after image harmonization across all utilized datasets. Using GAN-harmonization, inter-site reproducibility of radiomic features in healthy liver tissue increased at least by ≥ 5 ± 14% (first-order), ≥ 16 ± 7% (GLCM), ≥ 19 ± 5% (GLRLM), ≥ 16 ± 8% (GLSZM), ≥ 17 ± 6% (GLDM), and ≥ 23 ± 14% (NGTDM). In the head and neck cancer cohort, the outcome prediction improved from AUC 0.68 (95% CI 0.66-0.71) to AUC 0.73 (0.71-0.75) by application of GAN-harmonization. CONCLUSIONS: GANs are capable of performing image harmonization and increase reproducibility and predictive performance of radiomic features derived from different centers and scanners.

Comparison of discovery rates and prognostic utility of [68Ga]Ga-PSMA-11 PET/CT and circulating tumor DNA in prostate cancer-a cross-sectional study.

BACKGROUND: Circulating-tumor DNA (ctDNA) and prostate-specific membrane antigen (PSMA) ligand positron-emission tomography (PET) enable minimal-invasive prostate cancer (PCa) detection and survival prognostication. The present study aims to compare their tumor discovery abilities and prognostic values. METHODS: One hundred thirty men with confirmed PCa (70.5 ± 8.0 years) who underwent [68Ga]Ga-PSMA-11 PET/CT (184.8 ± 19.7 MBq) imaging and plasma sample collection (March 2019-August 2021) were included. Plasma-extracted cell-free DNA was subjected to whole-genome-based ctDNA analysis. PSMA-positive tumor lesions were delineated and their quantitative parameters extracted. ctDNA and PSMA PET/CT discovery rates were compared, and the prognostic value for overall survival (OS) was evaluated. RESULTS: PSMA PET discovery rates according to castration status and PSA ranges did differ significantly (P = 0.013, P < 0.001), while ctDNA discovery rates did not (P = 0.311, P = 0.123). ctDNA discovery rates differed between localized and metastatic disease (P = 0.013). Correlations between ctDNA concentrations and PSMA-positive tumor volume (PSMA-TV) were significant in all (r = 0.42, P < 0.001) and castration-resistant (r = 0.65, P < 0.001), however not in hormone-sensitive patients (r = 0.15, P = 0.249). PSMA-TV and ctDNA levels were associated with survival outcomes in the Logrank (P < 0.0001, P < 0.0001) and multivariate Cox regression analysis (P = 0.0023, P < 0.0001). CONCLUSION: These findings suggest that PSMA PET imaging outperforms ctDNA analysis in detecting prostate cancer across the whole spectrum of disease, while both modalities are independently highly prognostic for survival outcomes.

Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours.

PURPOSE: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). METHODS: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. RESULTS: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. CONCLUSION: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. TRIAL REGISTRATION: NCT02592707. Registered October 30, 2015.

Diagnosis and prognosis of abnormal cardiac scintigraphy uptake suggestive of cardiac amyloidosis using artificial intelligence: a retrospective, international, multicentre, cross-tracer development and validation study.

BACKGROUND: The diagnosis of cardiac amyloidosis can be established non-invasively by scintigraphy using bone-avid tracers, but visual assessment is subjective and can lead to misdiagnosis. We aimed to develop and validate an artificial intelligence (AI) system for standardised and reliable screening of cardiac amyloidosis-suggestive uptake and assess its prognostic value, using a multinational database of 99mTc-scintigraphy data across multiple tracers and scanners. METHODS: In this retrospective, international, multicentre, cross-tracer development and validation study, 16 241 patients with 19 401 scans were included from nine centres: one hospital in Austria (consecutive recruitment Jan 4, 2010, to Aug 19, 2020), five hospital sites in London, UK (consecutive recruitment Oct 1, 2014, to Sept 29, 2022), two centres in China (selected scans from Jan 1, 2021, to Oct 31, 2022), and one centre in Italy (selected scans from Jan 1, 2011, to May 23, 2023). The dataset included all patients referred to whole-body 99mTc-scintigraphy with an anterior view and all 99mTc-labelled tracers currently used to identify cardiac amyloidosis-suggestive uptake. Exclusion criteria were image acquisition at less than 2 h (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid, 99mTc-hydroxymethylene diphosphonate, and 99mTc-methylene diphosphonate) or less than 1 h (99mTc-pyrophosphate) after tracer injection and if patients' imaging and clinical data could not be linked. Ground truth annotation was derived from centralised core-lab consensus reading of at least three independent experts (CN, TT-W, and JN). An AI system for detection of cardiac amyloidosis-associated high-grade cardiac tracer uptake was developed using data from one centre (Austria) and independently validated in the remaining centres. A multicase, multireader study and a medical algorithmic audit were conducted to assess clinician performance compared with AI and to evaluate and correct failure modes. The system's prognostic value in predicting mortality was tested in the consecutively recruited cohorts using cox proportional hazards models for each cohort individually and for the combined cohorts. FINDINGS: The prevalence of cases positive for cardiac amyloidosis-suggestive uptake was 142 (2%) of 9176 patients in the Austrian, 125 (2%) of 6763 patients in the UK, 63 (62%) of 102 patients in the Chinese, and 103 (52%) of 200 patients in the Italian cohorts. In the Austrian cohort, cross-validation performance showed an area under the curve (AUC) of 1·000 (95% CI 1·000-1·000). Independent validation yielded AUCs of 0·997 (0·993-0·999) for the UK, 0·925 (0·871-0·971) for the Chinese, and 1·000 (0·999-1·000) for the Italian cohorts. In the multicase multireader study, five physicians disagreed in 22 (11%) of 200 cases (Fleiss' kappa 0·89), with a mean AUC of 0·946 (95% CI 0·924-0·967), which was inferior to AI (AUC 0·997 [0·991-1·000], p=0·0040). The medical algorithmic audit demonstrated the system's robustness across demographic factors, tracers, scanners, and centres. The AI's predictions were independently prognostic for overall mortality (adjusted hazard ratio 1·44 [95% CI 1·19-1·74], p<0·0001). INTERPRETATION: AI-based screening of cardiac amyloidosis-suggestive uptake in patients undergoing scintigraphy was reliable, eliminated inter-rater variability, and portended prognostic value, with potential implications for identification, referral, and management pathways. FUNDING: Pfizer.

Value of follow-up diagnostic radioiodine scans in differentiated thyroid cancer.

Background: The most important part of the follow-up of differentiated thyroid carcinoma (DTC) is the measurement of serum thyroglobulin (Tg). An increase of Tg levels indicates likely tumor recurrence. According to the guidelines of the European Society of Medical Oncology (ESMO), the follow-up should consist of serum Tg assays and a neck ultrasound, while the American Thyroid Association (ATA) recommends serum Tg assays, neck ultrasounds, and a diagnostic radioiodine whole-body scan (WBS) if non-stimulated Tg is greater than 10 ng/mL or if Tg is rising. This study questions the necessity of a diagnostic WBS in patients with low stimulated Tg levels during the initial follow-up. Design: This study is a retrospective data analysis. Methods: The data of 185 patients, who were in regular treatment and aftercare between 2015 and 2018 at the Department of Nuclear Medicine in Vienna, as well as the data of 185 patients who were treated in Tbilisi between 2015 and 2019, were analyzed. Results: There was a highly significant relationship between low stimulated Tg levels (<0.5 ng/mL) and the outcome of the diagnostic WBS at the first follow-up (χ 2 = 14.7, P < 0.001). In total, 31 out of 370 patients (8.4%) had positive findings in the diagnostic WBS. Seventy-five of 370 patients (19.74%) had stimulated Tg levels >0.5 ng/mL. Conclusion: Our data suggest that the first follow-up, 4-12 months after the initial therapy of DTC, including the measurement of basal and stimulated Tg levels and Tg antibody levels, does not mandate a diagnostic WBS on all patients. Significance statement: In this study, we examined the still commonly used routine diagnostic radioiodine whole-body scan in the first follow-up of patients with differentiated thyroid carcinoma. We questioned the necessity of the scan in patients with low stimulated thyroglobulin levels. Therefore, we combined retrospective data from the University Hospital in Vienna and in Tbilisi to analyze 370 patients. We were able to demostrate a highly significant relationship between low stimulated thyroglobulin levels (<0.5 ng/mL) and the outcome of the diagnostic scan at the first follow-up (χ = 14.7, P < 0.001).

CXCR4-targeted Theranostics in Hematooncology: Opportunities and Challenges.

C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in a multitude of cancers, including neoplasms of hematopoietic origin. This feature can be leveraged by a theranostic approach, which provides a read-out of the actual CXCR4 expression in vivo, followed by CXCR4-targeted radioligand therapy (RLT) exerting anti-cancer as well as myeloablative efficacy. In a recent meeting of hematooncology and nuclear medicine specialists, statements on the current clinical practice and future perspectives of this innovative concept were proposed and summarized in this opinion article. Experts concluded that i) CXCR4-directed [68Ga]Ga-PentixaFor PET/CT has the potential to improve imaging for patients with marginal zone lymphoma; ii) CXCR4-targeted RLT exerts anti-lymphoma efficacy and myeloablative effects in patients with advanced, treatment-refractory T-cell lymphomas; iii) prospective trials with CXCR4-based imaging and theranostics are warranted.

Alternative schedule of temozolomide/capecitabine in neuroendocrine neoplasms.

The chemotherapy regimen capecitabine/temozolomide (CAPTEM) is routinely used in neuroendocrine tumors (NET), with antitumor activity particularly demonstrated in pancreatic or high-grade neuroendocrine neoplasms (NEN). However, different dosing regimens are used, and the optimal schedule remains to be defined. This single-center retrospective analysis assessed the efficacy and safety of CAPTEM in patients with NEN using a schedule starting both compounds simultaneously (temozolomide on days 1-5 and capecitabine on days 1-14 of a 28-day cycle) rather than sequentially. The primary parameters of interest were response rates, progression-free survival (PFS), and toxicities following this treatment regimen, hereinafter referred to as TEMCAP. The study population comprised 40 patients, half of whom (n = 20) had pancreatic NEN, and 9 patients (22.5%) had pulmonary or thymic NETs. The most common histology was NET G3 (n = 15, 37.5%), and 8 patients (20.0%) had a neuroendocrine carcinoma (NEC). Most patients (77.5%) had at least one prior systemic therapy, and 16 patients (40.0%) prior chemotherapy. The median number of TEMCAP cycles was 6 (range 1-16). Median PFS for the highly heterogeneous population was 13.3 months, while the median overall survival was 31.9 months. In total, 14/36 patients (38.9%) exhibited a partial response, and the disease control rate was 75.0%. The safety profile of TEMCAP (at a below-target mean temozolomide dose of 118.85 mg/m2) in our cohort was remarkably good with no toxicities of grade 3 or 4. Taken together, the results of this analysis further support the use of temozolomide/capecitabine in NEN and prompt further assessment of our modified TEMCAP schedule.

Examining the Relationship and Prognostic Significance of Cell-Free DNA Levels and the PSMA-Positive Tumor Volume in Men with Prostate Cancer: A Retrospective-Prospective [68Ga]Ga-PSMA-11 PET/CT Study.

Functional imaging with prostate-specific membrane antigen (PSMA) ligands has emerged as the standard imaging method for prostate cancer (PCA). In parallel, the analysis of blood-derived, cell-free DNA (cfDNA) has been shown to be a promising quantitative biomarker of PCA aggressiveness and patient outcome. This study aimed to evaluate the relationship and prognostic value of cfDNA concentrations and the PSMA-positive tumor volume (PSMA-TV) in men with PCA undergoing [68Ga]Ga-PSMA-11 PET/CT imaging. Methods: We recruited 148 men with histologically proven PCA (mean age, 70.7 ± 7.7 y) who underwent [68Ga]Ga-PSMA-11 PET/CT (184.9 ± 18.9 MBq) and blood sampling between March 2019 and August 2021. Among these, 74 (50.0%) had hormone-sensitive PCA and 74 (50.0%) had castration-resistant PCA (CRPC). All patients provided written informed consent before blood sample collection and imaging. The cfDNA was extracted and quantified, and PSMA-expressing tumor lesions were delineated to extract the PSMA-TVs. The Spearman coefficient assessed correlations between PSMA-TV and cfDNA concentrations and cfDNA's relation with clinical parameters. The Kruskal-Wallis test examined the mean cfDNA concentration differences based on PSMA-TV quartiles for significantly correlated patient groups. Log-rank and multivariate Cox regression analyses evaluated the prognostic significance of high and low cfDNA and PSMA-TV levels for overall survival. Results: Weak positive correlations were found between cfDNA concentration and PSMA-TV in the overall group (r = 0.16, P = 0.049) and the CRPC group (r = 0.31, P = 0.007) but not in hormone-sensitive PCA patients (r = -0.024, P = 0.837). In the CRPC cohort, cfDNA concentrations significantly differed between PSMA-TV quartiles 4 and 1 (P = 0.002) and between quartiles 4 and 2 (P = 0.016). Survival outcomes were associated with PSMA-TV (P < 0.0001, P = 0.004) but not cfDNA (P = 0.174, P = 0.12), as per the log-rank and Cox regression analysis. Conclusion: These findings suggest that cfDNA might serve as a biomarker of advanced, aggressive CRPC but does not reliably reflect total tumor burden or prognosis. In comparison, [68Ga]Ga-PSMA-11 PET/CT provides a highly granular and prognostic assessment of tumor burden across the spectrum of PCA disease progression.

Metabolic tumor volume and sites of organ involvement predict outcome in NSCLC immune-checkpoint inhibitor therapy.

PURPOSE: The purpose of this study was to assess the ability of pretreatment PET parameters and peripheral blood biomarkers to predict progression-free survival (PFS) and overall survival (OS) in NSCLC patients treated with ICIT. METHODS: We prospectively included 87 patients in this study who underwent pre-treatment [18F]-FDG PET/CT. Organ-specific and total metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured using a semiautomatic software. Sites of organ involvement (SOI) were assessed by PET/CT. The log-rank test and Cox-regression analysis were used to assess associations between clinical, laboratory, and imaging parameters with PFS and OS. Time dependent ROC were calculated and model performance was evaluated in terms of its clinical utility. RESULTS: MTV increased with the number of SOI and was correlated with neutrophil and lymphocyte cell count (Spearman's rho = 0.27 or 0.32; p =.02 or 0.003; respectively). Even after adjustment for known risk factors, such as PD-1 expression and neutrophil cell count, the MTV and the number of SOI were independent risk factors for progression (per 100 cm3; adjusted hazard ratio [aHR]: 1.13; 95% confidence interval [95%CI]: 1.01-1.28; p =.04; single SOI vs. ≥ 4 SOI: aHR: 2.26, 95%CI: 1.04-4.94; p =.04). MTV and the number of SOI were independent risk factors for overall survival (per 100 cm3 aHR: 1.11, 95%CI: 1.01-1.23; p =.03; single SOI vs. ≥ 4 SOI: aHR: 4.54, 95%CI: 1.64-12.58; p =.04). The combination of MTV and the number of SOI improved the risk stratification for PFS and OS (log-rank test p <.001; C-index: 0.64 and 0.67). CONCLUSION: The MTV and the number of SOI are simple imaging markers that provide complementary information to facilitate risk stratification in NSCLC patients scheduled for ICIT.

Deep learning for [18F]fluorodeoxyglucose-PET-CT classification in patients with lymphoma: a dual-centre retrospective analysis.

BACKGROUND: The rising global cancer burden has led to an increasing demand for imaging tests such as [18F]fluorodeoxyglucose ([18F]FDG)-PET-CT. To aid imaging specialists in dealing with high scan volumes, we aimed to train a deep learning artificial intelligence algorithm to classify [18F]FDG-PET-CT scans of patients with lymphoma with or without hypermetabolic tumour sites. METHODS: In this retrospective analysis we collected 16 583 [18F]FDG-PET-CTs of 5072 patients with lymphoma who had undergone PET-CT before or after treatment at the Memorial Sloa Kettering Cancer Center, New York, NY, USA. Using maximum intensity projection (MIP), three dimensional (3D) PET, and 3D CT data, our ResNet34-based deep learning model (Lymphoma Artificial Reader System [LARS]) for [18F]FDG-PET-CT binary classification (Deauville 1-3 vs 4-5), was trained on 80% of the dataset, and tested on 20% of this dataset. For external testing, 1000 [18F]FDG-PET-CTs were obtained from a second centre (Medical University of Vienna, Vienna, Austria). Seven model variants were evaluated, including MIP-based LARS-avg (optimised for accuracy) and LARS-max (optimised for sensitivity), and 3D PET-CT-based LARS-ptct. Following expert curation, areas under the curve (AUCs), accuracies, sensitivities, and specificities were calculated. FINDINGS: In the internal test cohort (3325 PET-CTs, 1012 patients), LARS-avg achieved an AUC of 0·949 (95% CI 0·942-0·956), accuracy of 0·890 (0·879-0·901), sensitivity of 0·868 (0·851-0·885), and specificity of 0·913 (0·899-0·925); LARS-max achieved an AUC of 0·949 (0·942-0·956), accuracy of 0·868 (0·858-0·879), sensitivity of 0·909 (0·896-0·924), and specificity of 0·826 (0·808-0·843); and LARS-ptct achieved an AUC of 0·939 (0·930-0·948), accuracy of 0·875 (0·864-0·887), sensitivity of 0·836 (0·817-0·855), and specificity of 0·915 (0·901-0·927). In the external test cohort (1000 PET-CTs, 503 patients), LARS-avg achieved an AUC of 0·953 (0·938-0·966), accuracy of 0·907 (0·888-0·925), sensitivity of 0·874 (0·843-0·904), and specificity of 0·949 (0·921-0·960); LARS-max achieved an AUC of 0·952 (0·937-0·965), accuracy of 0·898 (0·878-0·916), sensitivity of 0·899 (0·871-0·926), and specificity of 0·897 (0·871-0·922); and LARS-ptct achieved an AUC of 0·932 (0·915-0·948), accuracy of 0·870 (0·850-0·891), sensitivity of 0·827 (0·793-0·863), and specificity of 0·913 (0·889-0·937). INTERPRETATION: Deep learning accurately distinguishes between [18F]FDG-PET-CT scans of lymphoma patients with and without hypermetabolic tumour sites. Deep learning might therefore be potentially useful to rule out the presence of metabolically active disease in such patients, or serve as a second reader or decision support tool. FUNDING: National Institutes of Health-National Cancer Institute Cancer Center Support Grant.

Antihormonal-Treatment Status Affects 68Ga-PSMA-HBED-CC PET Biodistribution in Patients with Prostate Cancer.

Androgen deprivation therapy (ADT) is known to influence the prostate-specific membrane antigen (PSMA) expression of prostate cancer, potentially complicating the interpretation of PSMA ligand PET findings and affecting PSMA radioligand therapy. However, the impact of ADT on PSMA ligand biodistribution in nontumorous organs is not well understood. Methods: Men (n = 112) with histologically proven prostate cancer who underwent 68Ga-PSMA-HBED-CC (68Ga-PSMA-11) PET/CT between November 2015 and July 2021 at the Medical University Vienna with known ADT status were retrospectively recruited. Fifty-six patients were on gonadotropin-releasing hormone-interfering ADT at the time of imaging (ADT group), whereas 56 patients with no history of ADT served as a control group. Physiologically PSMA-expressing organs (salivary glands, kidneys, liver, and spleen) were delineated, and their uptake was compared according to their data distributions. Multivariate regression analysis assessed the relationship between renal, hepatic, splenic, and salivary gland uptake and the explanatory variables metabolic tumor volume, glomerular filtration rate, and ADT status. Results: ADT was associated with lower levels of PSMA uptake in the kidneys (SUVmean: Δ[ADT - control] = -7.89; 95% CI, -10.73 to -5.04; P < 0.001), liver (SUVpeak: Δ[ADT - control] = -2.3; 95% CI, -5.72 to -0.93; P = 0.003), spleen (SUVpeak: Δ[ADT - control] = -1.27; 95% CI, -3.61 to -0.16; P = 0.033), and salivary glands (SUVmean: Δ[ADT - control] = -1.04; 95% CI, -2.48 to -0.13; P = 0.027). In a multivariate analysis, ADT was found to be associated with lower renal (SUVmean: ß = -7.95; 95% CI, -11.06 to -4.84; P < 0.0001), hepatic (SUVpeak: ß = -7.85; 95% CI, -11.78 to -3.91; P < 0.0001), splenic (SUVpeak: ß = -5.83; 95% CI, -9.95 to -1.7; P = 0.006), and salivary gland (SUVmean: ß = -1.47; 95% CI, -2.76 to -0.17; P = 0.027) uptake. A higher glomerular filtration rate was associated with a higher renal SUVmean (ß = 0.16; 95% CI, 0.05 to 0.26; P = 0.0034). Conclusion: These findings suggest that ADT systemically modulates PSMA expression, which may have implications for treatment-optimizing and side-effect-minimizing strategies for PSMA radioligand therapies, particularly those using more potent 225Ac-labeled PSMA conjugates.

Direct Patlak Reconstruction of [68Ga]Ga-PSMA PET for the Evaluation of Primary Prostate Cancer Prior Total Prostatectomy: Results of a Pilot Study.

To investigate the use of kinetic parameters derived from direct Patlak reconstructions of [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) to predict the histological grade of malignancy of the primary tumor of patients with prostate cancer (PCa). Thirteen patients (mean age 66 ± 10 years) with a primary, therapy-naïve PCa (median PSA 9.3 [range: 6.3-130 µg/L]) prior radical prostatectomy, were recruited in this exploratory prospective study. A dynamic whole-body [68Ga]Ga-PSMA-11 PET/CT scan was performed for all patients. Measured quantification parameters included Patlak slope (Ki: absolute rate of tracer consumption) and Patlak intercept (Vb: degree of tracer perfusion in the tumor). Additionally, the mean and maximum standardized uptake values (SUVmean and SUVmax) of the tumor were determined from a static PET 60 min post tracer injection. In every patient, initial PSA (iPSA) values that were also the PSA level at the time of the examination and final histology results with Gleason score (GS) grading were correlated with the quantitative readouts. Collectively, 20 individual malignant prostate lesions were ascertained and histologically graded for GS with ISUP classification. Six lesions were classified as ISUP 5, two as ISUP 4, eight as ISUP 3, and four as ISUP 2. In both static and dynamic PET/CT imaging, the prostate lesions could be visually distinguished from the background. The average values of the SUVmean, slope, and intercept of the background were 2.4 (±0.4), 0.015 1/min (±0.006), and 52% (±12), respectively. These were significantly lower than the corresponding parameters extracted from the prostate lesions (all p < 0.01). No significant differences were found between these values and the various GS and ISUP (all p > 0.05). Spearman correlation coefficient analysis demonstrated a strong correlation between static and dynamic PET/CT parameters (all r ≥ 0.70, p < 0.01). Both GS and ISUP grading revealed only weak correlations with the mean and maximum SUV and tumor-to-background ratio derived from static images and dynamic Patlak slope. The iPSA demonstrated no significant correlation with GS and ISUP grading or with dynamic and static PET parameter values. In this cohort of mainly high-risk PCa, no significant correlation between [68Ga]Ga-PSMA-11 perfusion and consumption and the aggressiveness of the primary tumor was observed. This suggests that the association between SUV values and GS may be more distinctive when distinguishing clinically relevant from clinically non-relevant PCa.

A phase I/II study of the safety and efficacy of [177Lu]Lu-satoreotide tetraxetan in advanced somatostatin receptor-positive neuroendocrine tumours.

PURPOSE: We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [177Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. METHODS: This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [177Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [177Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 µg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. RESULTS: Median cumulative administered activity of [177Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment­related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3-99.4), and overall response rate was 21.1% (95% CI: 9.6-37.3). CONCLUSION: [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.

Does the dose matter? Antiproliferative efficacy and toxicity of everolimus in patients with neuroendocrine tumors - Experiences from a tertiary referral center.

The mTOR-inhibitor everolimus has been approved for the treatment of advanced neuroendocrine tumors (NETs) but is associated with relevant toxicities in clinical practice. Hence, optimal treatment sequencing and the impact of dose reductions have yet to be clarified. This retrospective analysis assessed patients with advanced, well-differentiated NET treated with everolimus at the Medical University of Vienna. The primary objective was to evaluate the efficacy of everolimus in a real-world cohort. A total of 52 patients treated with everolimus for advanced NET grade 1 (G1) or G2 (or typical or atypical carcinoid) 2010-2021 were included in this analysis. The most common sites of origin were pancreas (44%) and lung (29%). The initial dose was decided by the treating physician based on clinical assessment and 25 patients (48%) each were started at 10 mg/day and 5 mg/day. Median progression-free survival (PFS) following everolimus in the overall cohort was 9.8 months (95% CI: 4.3-15.3), with a statistically significant PFS difference (p = .03) between NET G1/typical carcinoids (42.9 months) and NET G2/atypical carcinoids (8.9 months). PFS was numerically but not significantly shorter in patients treated with a reduced dose (7.5 months vs. 12.4 months, p = .359). Even in this mixed full/half dose cohort, 93% developed treatment-related side effects (mostly grade I, no grade IV), 63% had dose reductions or interruptions, and five stopped due to toxicity. Median survival following treatment was 40.9 months (95% CI: 21.5-60.3) and no difference with regard to dosing was observed (p = .517). These data from an unselected patient cohort show long-term outcomes similar to those reported in the pivotal studies. Comparing everolimus starting dose, median PFS did not significantly differ for patients treated at a lower dose. While this finding is limited by the sample size and warrants prospective verification, initiating therapy at a reduced dose might be practicable and safe in a distinct subset of patients.

68Ga-Pentixafor PET/MRI for Treatment Response Assessment in Mantle Cell Lymphoma: Comparison Between Changes in Lesion CXCR4 Expression on PET and Lesion Size and Diffusivity on MRI.

PURPOSE: The aim of this study was to compare CXCR4 imaging with 68Ga-pentixafor PET to MRI for treatment response assessment in patients with mantle cell lymphoma (MCL). PATIENTS AND METHODS: Twenty-two posttreatment 68Ga-pentixafor PET/MRI scans of 16 patients (7 women and 9 men; mean age, 69.9 ± 7.9) with a total of 67 target lesions on baseline PET/MRI were analyzed. Rates of complete remission per lesion and per scan, according to MRI (based on lesion size) and 68Ga-pentixafor PET (based on SUV decrease to lower than liver and blood pool uptake), were compared using McNemar tests. The t tests and Pearson correlation coefficients (r) were used to compare rates of change in lesion diameter products (DPs) on MRI, and standardized uptake values (SUVmax, SUVmean) on PET, relative to baseline. RESULTS: At interim PET/MRI, 18/32 (56.3%) target lesions met CR criteria on 68Ga-pentixafor PET, and 16/32 (50.0%) lesions met size-based MRI criteria for CR (P = 0.63). At end-of-treatment PET/MRI, 40/57 (70.2%) target lesions met 68Ga-pentixafor PET criteria for CR, and 27/57 (47.4%) lesions met size-based MRI criteria for CR (P = 0.021). Complete remission after treatment was observed more frequently on 68Ga-pentixafor PET (11/22 scans, 54.5%) than on MRI (6/22 scans, 27.3%) (P = 0.031). Rates of change did not differ significantly between lesion DP (-69.20% ± 34.62%) and SUVmax (-64.59% ± 50.78%, P = 0.22), or DP and SUVmean (-60.15 ± 64.58, P = 0.064). Correlations were strong between DP and SUVmax (r = 0.71, P < 0.001) and DP and SUVmean (r = 0.73, P < 0.001). CONCLUSIONS: In MCL patients, 68Ga-pentixafor PET may be superior for assessment of complete remission status than anatomic MRI using lesion size criteria, especially at the end of treatment.

A Prognostic Risk Score for Prostate Cancer Based on PSMA PET-derived Organ-specific Tumor Volumes.

Background Prostate-specific membrane antigen (PSMA) PET has high specificity in localizing primary tumors and metastases in patients with prostate cancer, but the individual overall survival probability is still difficult to estimate. Purpose To develop a prognostic risk score using PSMA PET-derived organ-specific total tumor volumes for predicting overall survival in patients with prostate cancer. Materials and Methods Men with prostate cancer who underwent PSMA PET/CT from January 2014 to December 2018 were evaluated retrospectively. All patients from center A were split into training (80%) and internal validation (20%) cohorts. Randomly selected patients from center B were used for external validation. Organ-specific tumor volumes were automatically quantified from PSMA PET scans by a neural network. A prognostic score was selected using multivariable Cox regression guided by the Akaike information criterion (AIC). The final prognostic risk score fitted on the training set was applied to both validation cohorts. Results A total of 1348 men (mean age, 70 years ± 8 [SD]) were included, with 918 patients in the training cohort, 230 in the internal validation cohort, and 200 in the external validation cohort. The median follow-up time was 55.7 months (IQR, 46.7-65.1 months; >4 years; 429 deaths occurred). A body weight-adjusted prognostic risk score integrating total, bone, and visceral tumor volumes obtained high C index values in the internal (0.82) and external (0.74) validation cohorts, as well as in patients with castration-resistant (0.75) and hormone-sensitive (0.68) disease. The fit of the statistical model for the prognostic score was improved compared with a model containing total tumor volume only (AIC, 3324 vs 3351; likelihood ratio test, P < .001). Calibration plots ascertained good model fit. Conclusion The newly developed risk score that included prostate-specific membrane antigen PET-derived organ-specific tumor volumes had good model fit for predicting overall survival in both internal and external validation cohorts. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Civelek in this issue.

Evaluation of Intestinal Fibrosis with 68Ga-FAPI PET/MR Enterography in Crohn Disease.

Background In Crohn disease, differentiation between active intestinal inflammation and fibrosis has implications for treatment, but current imaging modalities are not reliably accurate. Purpose To evaluate the predictive value of gallium 68 (68Ga)-labeled fibroblast activation protein inhibitor (FAPI) PET/MR enterography for the assessment of bowel wall fibrosis in Crohn disease. Materials and Methods In this prospective single-center study, consecutive participants with Crohn disease and obstructive symptoms underwent preoperative 68Ga-FAPI PET/MR enterography from May 2021 to January 2022. Histopathologic analysis of resected bowel segments was performed to grade active inflammation (A0-A2) and fibrosis (F0-F2), which served as the reference standard. The fibroblast activation protein (FAP) expression in bowel wall layers was analyzed immunohistochemically for each layer. 68Ga-FAPI-derived maximum standardized uptake value (SUVmax) was compared with histopathologic results by using mixed-model analysis of variance and Bonferroni-corrected post hoc tests. Results In 14 participants (mean age, 45 years ± 9 [SD]; 10 men), fibrosis was diagnosed histopathologically in 28 of 51 bowel segments (grade F1, n = 14; grade F2, n = 14). Mean SUVmax was higher in segments with fibrosis than without (7.6 vs 2.0; P < .001). In severe fibrosis, mean SUVmax was higher than in mild to moderate fibrosis (8.9 ± 0.9 vs 6.2 ± 0.9; P = .045). Bowel segments with isolated active inflammation had lower mean 68Ga-FAPI uptake than segments with combined active inflammation and fibrosis (SUVmax, 3.2 ± 0.4 vs 8.1 ± 0.1; P = .005). With an SUVmax cutoff value of 3.5, the area under the receiver operating characteristic curve for the prediction of fibrosis was 0.94 (95% CI: 0.9, 1.0), with sensitivity of 26 of 28 segments (93%) and specificity of five of six segments (83%). 68Ga-FAPI-derived SUVmax correlated with FAP expression across all bowel layers (R2 = 0.50, P < .001). Conclusion Higher gallium 68 fibroblast activation protein inhibitor uptake at PET/MR enterography was associated with histopathologically assessed bowel wall fibrosis in participants with Crohn disease, suggesting diagnostic potential for treatment decisions. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by O'Shea in this issue.

Neoadjuvant immune-checkpoint inhibitors in lung cancer - a primer for radiologists.

The introduction of neoadjuvant immune checkpoint inhibitors plus platinum-based chemotherapy has changed treatment regimens of patient's early-stage lung cancer. This treatment combination induces high rates of complete pathologic response and improves clinical endpoints. Imaging plays a fundamental role in assessment of treatment response, monitoring of (immune-related) adverse events and enables both the surgeon and pathologist optimal treatment and diagnostic workup of the resected tumor samples. Knowledge of the strengths and weaknesses of diagnostic imaging in this setting are essential for radiologists to provide valuable input in multidisciplinary team decisions.