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ObjectivesTo evaluate the diagnostic performance of a deep learning algorithm for automated detection of small 18F-FDG-avid pulmonary nodules in PET scans, and to assess whether novel block sequential regularized expectation maximization (BSREM) reconstruction affects detection accuracy as compared to ordered subset expectation maximization (OSEM) reconstruction.MethodsFifty-seven patients with 92 18F-FDG-avid pulmonary nodules (all ≤ 2 cm) undergoing PET/CT for oncological (re-)staging were retrospectively included and a total of 8824 PET images of the lungs were extracted using OSEM and BSREM reconstruction. Per-slice and per-nodule sensitivity of a deep learning algorithm was assessed, with an expert readout by a radiologist/nuclear medicine physician serving as standard of reference. Receiver-operator characteristic (ROC) curve of OSEM and BSREM were assessed and the areas under the ROC curve (AUC) were compared. A maximum standardized uptake value (SUVmax)–based sensitivity analysis and a size-based sensitivity analysis with subgroups defined by nodule size was performed.ResultsThe AUC of the deep learning algorithm for nodule detection using OSEM reconstruction was 0.796 (CI 95%; 0.772–0.869), and 0.848 (CI 95%; 0.828–0.869) using BSREM reconstruction. The AUC was significantly higher for BSREM compared to OSEM (p = 0.001). On a per-slice analysis, sensitivity and specificity were 66.7% and 79.0% for OSEM, and 69.2% and 84.5% for BSREM. On a per-nodule analysis, the overall sensitivity of OSEM was 81.5% compared to 87.0% for BSREM.ConclusionsOur results suggest that machine learning algorithms may aid detection of small 18F-FDG-avid pulmonary nodules in clinical PET/CT. AI performed significantly better on images with BSREM than OSEM.Key Points• The diagnostic value of deep learning for detecting small lung nodules (≤ 2 cm) in PET images using BSREM and OSEM reconstruction was assessed.• BSREM yields higher SUVmaxof small pulmonary nodules as compared to OSEM reconstruction.• The use of BSREM translates into a higher detectability of small pulmonary nodules in PET images as assessed with artificial intelligence.

Breast tumors lacking expression of human epidermal growth factor receptor 2 (HER2) and the estrogen and the progesterone receptors (triple negative; TNBC) are more aggressive than other disease subtypes, and no molecular targeted agents are currently available for their treatment. Because TNBC commonly displays EGF receptor (EGFR) expression, and combinations of monoclonal antibodies to EGFR effectively inhibit other tumor models, we addressed the relevance of this strategy to treatment of TNBC. Unlike a combination of the clinically approved monoclonal antibodies, cetuximab and panitumumab, which displaced each other and displayed no cooperative effects, several other combinations resulted in enhanced inhibition of TNBC’s cell growth both in vitro and in animals. The ability of certain antibody mixtures to remove EGFR from the cell surface and to promote its intracellular degradation correlated with the inhibitory potential. However, unlike EGF-induced sorting of EGFR to lysosomal degradation, the antibody-induced pathway displayed independence from the intrinsic kinase activity and dimer formation ability of EGFR, and it largely avoided the recycling route. In conclusion, although TNBC clinical trials testing EGFR inhibitors reported lack of benefit, our results offer an alternative strategy that combines noncompetitive antibodies to achieve robust degradation of EGFR and tumor inhibition.

PurposeThe fast-increasing use of positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) ligand for the imaging of prostate cancer (PCA) biochemical recurrence has led to a rapid change in treatment concepts. Since the superiority of 68Ga-PSMA-11 PET in detecting recurrent PCA is well established, the aim of our study was to assess its effect on management and outcome in all patients imaged during the first year after its introduction into clinical routine.MethodsOf 327 patients imaged, 223 were referred for recurrent PCA and gave written informed consent for further analysis of their data for this retrospective consecutive cohort analysis. Twenty patients were lost to further follow-up. The rate of detection of recurrence by 68Ga-PSMA-11 PET was based on the clinical reports. Management before the availability of PET diagnostic information was assessed according to guidelines (therapy option without 68Ga-PSMA-11 PET). In the 203 patients with follow-up 6 months after 68Ga-PSMA-11 PET, the therapies effectively implemented as well as follow-up PSA levels were evaluated, with a PSA value of <0.2 ng/ml representing a complete response and a decrease in PSA value of at least 50% from baseline representing a partial response.Results68Ga-PSMA-11 PET was positive and identified recurrence in 166 of the 223 patients (74%), with a detection rate of 50% for recurrent disease at low PSA values of <0.5 ng/ml. 68Ga-PSMA-11 PET led to a change in management in 122 of the 203 patients (60%). A substantial increase in the use of metastasis-targeted treatment and a reduction in the use of systemic treatment were observed, with 59 of the 203 patients (29%) undergoing targeted radiotherapy (RTXa) only, and 20 patients (10%) undergoing RTXa with hormonal therapy as the two most frequently selected therapy options. The proportion of patients in whom systemic therapy was selected decreased from 60% (133 of 223 patients) to 34% (70 of 203 patients) on the basis of the information provided by the 68Ga-PSMA-11 PET scan. PSMA PET-directed metastasis-targeted treatment led to a complete response after 6 months in 45% of patients.ConclusionThe high rate of recurrence detection by PSMA PET was confirmed and PSMA PET led to a change in management in 60% of patients. Focal therapy for PSMA-positive lesions is a promising approach with complete responses in 45% of patients.

Background: Investigation of the clinical feasibility of dynamic whole-body (WB) [18F]FDG PET, including standardized uptake value (SUV), rate of irreversible uptake (Ki), and apparent distribution volume (Vd) in physiologic tissues, and comparison between inflammatory/infectious and cancer lesions. Methods: Twenty-four patients were prospectively included to undergo dynamic WB [18F]FDG PET/CT for clinically indicated re-/staging of oncological diseases. Parametric maps of Ki and Vd were generated using Patlak analysis alongside SUV images. Maximum parameter values (SUVmax, Kimax, and Vdmax) were measured in liver parenchyma and in malignant or inflammatory/infectious lesions. Lesion-to-background ratios (LBRs) were calculated by dividing the measurements by their respective mean in the liver tissue. Results: Seventy-seven clinical target lesions were identified, 60 malignant and 17 inflammatory/infectious. Kimax was significantly higher in cancer than in inflammatory/infections lesions (3.0 vs. 2.0, p = 0.002) while LBRs of SUVmax, Kimax, and Vdmax did not differ significantly between the etiologies: LBR (SUVmax) 3.3 vs. 2.9, p = 0.06; LBR (Kimax) 5.0 vs. 4.4, p = 0.05, LBR (Vdmax) 1.1 vs. 1.0, p = 0.18). LBR of inflammatory/infectious and cancer lesions was higher in Kimax than in SUVmax (4.5 vs. 3.2, p < 0.001). LBRs of Kimax and SUVmax showed a strong correlation (Spearman’s rho = 0.83, p < 0.001). Conclusions: Dynamic WB [18F]FDG PET/CT is feasible in a clinical setting. LBRs of Kimax were higher than SUVmax. Kimax was higher in malignant than in inflammatory/infectious lesions but demonstrated a large overlap between the etiologies.

Background The tumour microenvironment is a critical regulator of malignant cancer progression. While endothelial cells have been widely studied in the context of tumour angiogenesis, their role as modulators of cancer cell invasion and migration is poorly understood. Methods We have investigated the influence of endothelial cells on the invasive and migratory behaviour of human cancer cells in vitro. Results Upon exposure to culture supernatants of endothelial cells, distinct cancer cells, such as SK-BR-3 cells, showed significantly increased invasion and cell migration concomitant with changes in cell morphology and gene expression reminiscent of an epithelial-mesenchymal transition (EMT). Interestingly, the pro-migratory effect on SK-BR-3 cells was significantly enhanced by supernatants obtained from subconfluent, proliferative endothelial cells rather than from confluent, quiescent endothelial cells. Systematically comparing the supernatants of subconfluent and confluent endothelial cells by quantitative MS proteomics revealed eight candidate proteins that were secreted at significantly higher levels by confluent endothelial cells representing potential inhibitors of cancer cell migration. Among these proteins, nidogen-1 was exclusively expressed in confluent endothelial cells and was found to be necessary and sufficient for the inhibition of SK-BR-3 cell migration. Indeed, SK-BR-3 cells exposed to nidogen-1-depleted endothelial supernatants showed increased promigratory STAT3 phosphorylation along with increased cell migration. This reflects the situation of enhanced SK-BR-3 migration upon stimulation with conditioned medium from subconfluent endothelial cells with inherent absence of nidogen-1 expression. Conclusion The identification of nidogen-1 as an endothelial-derived inhibitor of migration of distinct cancer cell types reveals a novel mechanism of endothelial control over cancer progression.

ObjectivesPSMA PET/MRI showed the potential to increase the sensitivity for extraprostatic disease (EPD) assessment over mpMRI; however, the interreader variability for EPD is still high. Therefore, we aimed to assess whether quantitative PSMA and mpMRI imaging parameters could yield a more robust EPD prediction.MethodsWe retrospectively evaluated PCa patients who underwent staging mpMRI and [68Ga]PSMA-PET, followed by radical prostatectomy at our institution between 01.02.2016 and 31.07.2019. Fifty-eight cases with PET/MRI and 15 cases with PET/CT were identified. EPD was determined on histopathology and correlated with quantitative PSMA and mpMRI parameters assessed by two readers: ADC (mm2/1000 s), longest capsular contact (LCC, mm), tumor volume (cm3), PSMA-SUVmax and volume-based parameters using a fixed threshold at SUV > 4 to delineate PSMAtotal (g/ml) and PSMAvol (cm3). The t test was used to compare means, Pearson’s test for categorical correlation, and ROC curve to determine the best cutoff. Interclass correlation (ICC) was performed for interreader agreement (95% CI).ResultsSeventy-three patients were included (64.5 ± 6.0 years; PSA 14.4 ± 17.1 ng/ml), and 31 had EPD (42.5%). From mpMRI, only LCC reached significance (p = 0.005), while both volume-based PET parameters PSMAtotal and PSMAvol were significantly associated with EPD (p = 0.008 and p = 0.004, respectively). On ROC analysis, LCC, PSMAtotal, and PSMAvol reached an AUC of 0.712 (p = 0.002), 0.709 (p = 0.002), and 0.718 (p = 0.002), respectively. ICC was moderate–good for LCC 0.727 (0.565–0.828) and excellent for PSMAtotal and PSMAvol with 0.944 (0.990–0.996) and 0.985 (0.976–0.991), respectively.ConclusionsQuantitative PSMA parameters have a similar potential as mpMRI LCC to predict EPD of PCa, with a significantly higher interreader agreement.

PurposeProstate-specific membrane antigen (PSMA) targeted positron emission tomography (PET) imaging significantly improved the detection of recurrent prostate cancer (PCa). However, the value of PSMA PET imaging in patients with advanced hormone-sensitive or hormone-resistant PCa is still largely unknown. The aim of this study was to analyze the detection rate and distribution of lesions using PSMA PET imaging in patients with advanced PCa and ongoing androgen deprivation therapy (ADT).MethodsA total of 84 patients diagnosed with hormone-sensitive or hormone-resistant PCa who underwent 68Ga-PSMA-11 PET/magnetic resonance imaging (MRI) or computer tomography (CT) under ongoing ADT were retrospectively analyzed. We assessed the detection of PSMA-positive lesions overall and for three PSA subgroups (0 to < 1 ng/mL, 1 to < 20 ng/mL and > 20 ng/mL). In addition, PSMA-positive findings were stratified by localization (prostatic fossa, pelvic, para-aortic, mediastinal/supraclavicular and axillary lymph nodes, bone lesions and visceral lesions) and hormone status (hormone-sensitive vs. hormone-resistant). Furthermore, we assessed how many patients would be classified as having oligometastatic disease (≤ 3 lesions) and theoretically qualify for metastasis-directed radiotherapy (MDRT) in a personalized patient management.ResultsWe detected PSMA-positive lesions in 94.0% (79 of 84) of all patients. In the three PSA subgroups detection rates of 85.2% (0 to < 1 ng/mL, n = 27), 97.3% (1 to < 20 ng/mL, n = 37) and 100% (> 20 ng/mL, n = 20) were observed, respectively. PSMA-positive visceral metastases were observed only in patients with a PSA > 1 ng/mL. Detection of PSMA-positive lesions did not significantly differ between patients with hormone-sensitive and hormone-resistant PCa. Oligometastatic PCa was detected in 19 of 84 patients (22.6%). Almost all patients, 94.7% (n = 18) would have been eligible for MDRT.ConclusionsIn this study, we observed an overall very high detection rate of 94% using PSMA PET imaging in patients with advanced PCa and ongoing ADT. Even in a majority of patients with very low PSA values < 1 ng/ml PSMA-positive lesions were found.

Introduction: The role of positron-emission tomography/computed-tomography (PET/CT) in the management of sarcomas and as a prognostic tool has been studied. However, it remains unclear which metric is the most useful. We aimed to investigate if volume-based PET metrics (Tumor volume (TV) and total lesions glycolysis (TLG)) are superior to maximal standardized uptake value (SUVmax) and other metrics in predicting survival of patients with soft tissue and bone sarcomas. Materials and Methods: In this retrospective cohort study, we screened over 52′000 PET/CT scans to identify patients diagnosed with either soft tissue, bone or Ewing sarcoma and had a staging scan at our institution before initial therapy. We used a Wilcoxon signed-rank to assess which PET/CT metric was associated with survival in different patient subgroups. Receiver-Operating-Characteristic curve analysis was used to calculate cutoff values. Results: We identified a total of 88 patients with soft tissue (51), bone (26) or Ewing (11) sarcoma. Median age at presentation was 40 years (Range: 9–86 years). High SUVmax was most significantly associated with short survival (defined as <24 months) in soft tissue sarcoma (with a median and range of SUVmax 12.5 (8.8–16.0) in short (n = 18) and 5.5 (3.3–7.2) in long survival (≥24 months) (n = 31), with (p = 0.001). Similar results were seen in Ewing sarcoma (with a median and range of SUVmax 12.1 (7.6–14.7) in short (n = 6) and 3.7 (3.5–5.5) in long survival (n = 5), with (p = 0.017). However, no PET-specific metric but tumor-volume was significantly associated (p = 0.035) with survival in primary bone sarcomas (with a median and range of 217 cm3 (186–349) in short survival (n = 4) and 60 cm3 (22–104) in long survival (n = 19), with (p = 0.035). TLG was significantly inversely associated with long survival only in Ewing sarcoma (p = 0.03). Discussion: Our analysis shows that the outcome of soft tissue, bone and Ewing sarcomas is associated with different PET/CT metrics. We could not confirm the previously suggested superiority of volume-based metrics in soft tissue sarcomas, for which we found SUVmax to remain the best prognostic factor. However, bone sarcomas should probably be evaluated with tumor volume rather than FDG PET activity.

PurposeProstate-specific membrane antigen (PSMA-) PET has become a promising tool in staging and restaging of prostate carcinoma (PCa). However, specific primary tumour features might impact accuracy of PSMA-PET for PCa detection. We investigated histopathological parameters and immunohistochemical PSMA expression patterns on radical prostatectomy (RPE) specimens and correlated them to the corresponding 68Ga-PSMA-11-PET examinations.MethodsRPE specimens of 62 patients with preoperative 68Ga-PSMA-11-PET between 2016 and 2018 were analysed. WHO/ISUP grade groups, growth pattern (expansive vs. infiltrative), tumour area and diameter as well as immunohistochemical PSMA heterogeneity, intensity and negative tumour area (PSMA%neg) were correlated with spatially corresponding SUVmax on 68Ga-PSMA-11-PET in a multidisciplinary analysis.ResultsAll tumours showed medium to strong membranous (2–3 +) and weak to strong cytoplasmic (1–3 +) PSMA expression. Heterogeneously expressed PSMA was found in 38 cases (61%). Twenty-five cases (40%) showed at least 5% and up to 80% PSMA%neg. PSMA%neg, infiltrative growth pattern, smaller tumour area and diameter and WHO/ISUP grade group 2 significantly correlated with lower SUVmax values. A ROC curve analysis revealed 20% PSMA%neg as an optimal cutoff with the highest sensitivity and specificity (89% and 86%, AUC 0.923) for a negative PSMA-PET scan. A multiple logistic regression model revealed tumoural PSMA%neg (p < 0.01, OR = 9.629) and growth pattern (p = 0.0497, OR = 306.537) as significant predictors for a negative PSMA-PET scan.ConclusionsWe describe PSMA%neg, infiltrative growth pattern, smaller tumour size and WHO/ISUP grade group 2 as parameters associated with a lower 68Ga-PSMA-11 uptake in prostate cancer. These findings can serve as fundament for future biopsy-based biomarker development to enable an individualized, tumour-adapted imaging approach.