Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening

Centralization of lung cancer surgery in the Netherlands: differences in care and survival of patients with stage I non-small cell lung cancer between hospitals with and without in-house lung cancer surgery

Stem cells & developmental biolog

Association of tumour and stroma PD-1, PD-L1, CD3, CD4 and CD8 expression with DCB and OS to nivolumab treatment in NSCLC patients pre-treated with chemotherapy

Background: Immune checkpoint inhibitors are most beneficial in patients with high tumour PD-L1 expression. However, the use of PD-L1 expression is not straightforward. We investigated PD-L1 expression and immune cell (IC) infiltrates in non-small-cell lung cancer (NSCLC) patients treated with nivolumab. Methods: Tumour tissue specimens of 139 NSCLC patients were scored for tumour/stromal PD-L1 and various IC expression markers, and associated with durable clinical benefit (DCB) and overall survival (OS). Results: Median OS was higher for patients with high stromal infiltration of CD8+ ICs (9.0 months) compared with patients with low and intermediate infiltration (both 5.0 months, p = 0.035) and for patients with high infiltration of stromal CD4+ ICs (9.0 months) compared with patients with low and intermediate infiltration (both 5.0 months, p = 0.010) and this was confirmed in the validation cohort. Post hoc analyses showed that biopsies taken after the last line of chemotherapy (ACT) were predictive for DCB and OS, whereas samples obtained before the last line of chemotherapy (BCT) were not. Conclusions: Stromal infiltration of ICs can predict response to PD-1-directed immunotherapy in NSCLC patients. Interestingly, we found differences in the predictive value of IC markers between the ACT and BCT biopsies, suggesting that chemotherapy might influence the immune microenvironment

Effects of Tracer Uptake Time in Non-Small Cell Lung Cancer 18F-FDG PET Radiomics

Positron emission tomography (PET) radiomics applied to oncology allows the measurement of intra-tumoral heterogeneity. This quantification can be affected by image protocols hence there is an increased interest in understanding how radiomic expression on PET images is affected by different imaging conditions. To address that, this study explores how radiomic features are affected by changes in 18F-FDG uptake time, image reconstruction, lesion delineation, and radiomics binning settings. Methods: Ten non-small cell lung cancer (NSCLC) patients underwent 18F-FDG PET scans on two consecutive days. On each day, scans were obtained at 60min and 90min post-injection and reconstructed following EARL version 1 (EARL1) and with point-spread-function resolution modelling (PSF-EARL2). Lesions were delineated using thresholds at SUV=4.0, 40% of SUVmax, and with a contrast-based isocontour. PET image intensity was discretized with both fixed bin width (FBW) and fixed bin number (FBN) before the calculation of the radiomic features. Repeatability of features was measured with intraclass correlation (ICC), and the change in feature value over time was calculated as a function of its repeatability. Features were then classified on use-case scenarios based on their repeatability and susceptibility to tracer uptake time. Results: With PSFEARL2 reconstruction, 40% of SUVmax lesion delineation, and FBW intensity discretization, most features (94%) were repeatable at both uptake times (ICC>0.9), 39% being classified for dual-time-point use-case for being sensitive to changes in uptake time, 39% were classified for cross-sectional studies with unclear dependency on time, 20% classified for cross-sectional use while being robust to tracer uptake time changes, and 6% were discarded for poor repeatability. EARL1 images had one less repeatable feature than PSF-EARL2 (Neighborhood Gray-Level Different Matrix Coarseness), the contrast-based delineation had the poorest repeatability of the delineation methods with 45% features being discarded, and FBN resulted in lower repeatability than FBW (45% and 6% features were discarded, respectively). Conclusion: Repeatability was maximized with PSF-EARL2 reconstruction, lesion delineation at 40% of SUVmax, and FBW intensity discretization. Based on their susceptibility to tracer uptake time, radiomic features were classified into specific NSCLC PET radiomics use-cases

High PD-1 expression on regulatory and effector T-cells in lung cancer draining lymph nodes

The treatment of advanced nonsmall cell lung cancer (NSCLC) with PD-1/PD-L1 immune checkpoint inhibitors has improved clinical outcome for a proportion of patients. The current challenge is to find better biomarkers than PD-L1 immunohistochemistry (IHC) that will identify patients likely to benefit from this therapy. In this exploratory study we assessed the differences in T-cell subsets and PD-1 expression levels on T-cells in tumour-draining lymph nodes (TDLNs) and peripheral blood mononuclear cells (PBMCs). To evaluate this, flow cytometric analyses were performed on endobronchial ultrasound-guided (EBUS) fine-needle aspirates (FNA) from TDLNs of patients with NSCLC, and the results were compared to paired PBMC samples. For a select number of patients, we were also able to obtain cells from a non-TDLN (NTDLN) sample. Our data show that the frequency of PD-1+ CD4+ and CD8+ T-cells, as well as the PD-1 expression level on activated regulatory T (aTreg) and CD4+ and CD8+ T-cells, are higher in TDLNs than in PBMCs and, in a small sub-analysis, NTDLNs. These elevated PD-1 expression levels in TDLNs may reflect tumour-specific T-cell priming and conditioning, and may serve as a predictive or early-response biomarker during PD-1 checkpoint blockade

Accuracy and Precision of Partial-Volume Correction in Oncological PET/CT Studies

Accurate quantification of tracer uptake in small tumors using PET is hampered by the partial-volume effect as well as by the method of volume-of-interest (VOI) delineation. This study aimed to investigate the effect of partial-volume correction (PVC) combined with several VOI methods on the accuracy and precision of quantitative PET. Methods: Four image-based PVC methods and resolution modeling (applied as PVC) were used in combination with several common VOI methods. Performance was evaluated using simulations, phantom experiments, and clinical repeatability studies. Simulations were based on a whole-body F-18-FDG PET scan in which differently sized spheres were placed in lung and mediastinum. A National Electrical Manufacturers Association NU2 quality phantom was used for the experiments. Repeatability data consisted of an F-18-FDG PET/CT study on 11 patients with advanced non-small cell lung cancer and an F-18-fluoromethylcholine PET/CT study on 12 patients with metastatic prostate cancer. Results: Phantom data demonstrated that most PVC methods were strongly affected by the applied resolution kernel, with accuracy differing by about 20%-50% between full-width-at half-maximum settings of 5.0 and 7.5 mm. For all PVC methods, large differences in accuracy were seen among all VOI methods. Additionally, the image-based PVC methods were observed to have variable sensitivity to the accuracy of the VOI methods. For most PVC methods, accuracy was strongly affected by more than a 2.5-mm misalignment of true (simulated) VOI. When the optimal VOI method for each PVC method was used, high accuracy could be achieved. For example, resolution modeling for mediastinal lesions and iterative deconvolution for lung lesions were 99% +/- 1.5% and 99% +/- 0.9% accurate, respectively, for spheres 15-40 mm in diameter. Precision worsened slightly for resolution modeling and to a larger extent for some image-based PVC methods. Uncertainties in delineation propagated into uncertainties in PVC performance, as confirmed by the clinical data. Conclusion: The accuracy and precision of the tested PVC methods depended strongly on VOI method, resolution settings, contrast, and spatial alignment of the VOI. PVC has the potential to substantially improve the accuracy of tracer uptake assessment, provided that robust and accurate VOI methods become available. Commonly used delineation methods may not be adequate for this purpose

Monitoring Response to Antiangiogenic Therapy in Non-Small Cell Lung Cancer Using Imaging Markers Derived from PET and Dynamic Contrast-Enhanced MRI

With antiangiogenic agents, tumor shrinkage may be absent, despite survival benefit. The present study assessed the predictive value of molecular imaging for the identification of survival benefit during antiangiogenic treatment with bevacizumab and erlotinib in patients with advanced non-small cell lung cancer. Methods: Patients were evaluated using an imaging protocol including CT, F-18-FDG PET, H-2 O-15 PET, and dynamic contrast-enhanced MRI to derive measurements on tumor size, glucose metabolism, perfusion, and microvascular permeability. The percentage change in imaging parameters after 3 wk of treatment as compared with baseline was calculated and correlated with progression-free survival (PFS). Results: Forty-four patients were included, and 40 underwent CT and F-18-FDG PET at both time points. Complete datasets, containing all imaging modalities, were available for 14 patients. Bevacizumab and erlotinib treatment resulted in decreased metabolism, perfusion, and tumor size. A decrease in standardized uptake value or tumor perfusion of more than 20% at week 3 was associated with longer PFS (9.7 vs. 2.8 mo, P = 0.01, and 12.5 vs. 2.9 mo, P = 0.009, respectively). Whole-tumor K-trans (the endothelial transfer constant) was not associated with PFS, but patients with an increase of more than 15% in the SD of tumor K-trans values-that is, an increase in regions with low or high K-trans values-after 3 wk had shorter PFS (2.3 vs. 7.0 mo, P = 0.008). A partial response, according to the response evaluation criteria in solid tumors (RECIST), at week 3 was also associated with prolonged PFS (4.6 vs. 2.9 mo, P = 0.017). However, 40% of patients with a partial response as their best RECIST response still had stable disease at week 3. In these cases tumor perfusion was already decreased and K-trans heterogeneity showed no increase, indicating that the latter parameters seem to be more discriminative than RECIST at the 3-wk time point. Conclusion: PET and dynamic contrast-enhanced MRI were able to identify patients who benefit from bevacizumab and erlotinib treatment. Molecular imaging seems to allow earlier response evaluation than CT