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Intratumor heterogeneity may contribute to the ambiguous clinical results on PD-L1 status as a predictor for immunotherapy response in patients with HNSCC. This decreases the utility of PD-L1 expression from single tumour biopsies as a predictive biomarker. In this prospective study, intratumor heterogeneity of PD-L1 expression in HNSCC was investigated with both Tumour Proportion Score (TPS) and Combined Positive Score (CPS). Thirty-three whole surgical specimens from 28 patients with HNSCC were included. PD-L1 expression in six random core biopsies from each surgical specimen was used to assess the concordance between multiple biopsies and the negative predictive value of a single negative core biopsy. With 1% cut off, 36% of the specimens were concordant with TPS and 52% with CPS. With a 50% cut-off value the concordance was 70% with TPS and 55% with CPS. Defining a tumour as positive if just a single-one of the biopsies was positive, the negative predictive value (NPV) of a single negative core biopsy was 38.9 and 0% (1% cut off), and 79.9% and 62.8% (50% cut off) for TPS and CPS, respectively. In conclusion, PD-L1 positivity varies markedly within the tumour, both with TPS and CPS, challenging the utility of this biomarker.

The aim of the study was to assess healthy tissue metabolism (HTM) using 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) positron emission tomography/computed tomography (PET/CT) during chemotherapy in Hodgkin lymphoma (HL) and the association of HTM with baseline metabolic tumour volume (MTV), haematological parameters, adverse events (AEs), early response and progression-free survival (PFS). We retrospectively identified 200 patients with advanced HL from the RATHL trial with [ 18 F]FDG-PET/CT before (PET0) and following 2 cycles of chemotherapy (PET2). [ 18 F]FDG-uptake was measured in bone marrow (BM), spleen, liver and mediastinal blood pool (MBP). Deauville score (DS) 1–3 was used to classify responders and DS 4–5, non-responders. [ 18 F]FDG-uptake decreased significantly in BM and spleen and increased in liver and MBP at PET2 (all p  < 0.0001), but was not associated with MTV. Higher BM uptake at PET0 was associated with lower baseline haemoglobin and higher absolute neutrophil counts, platelets, and white blood cells. High BM, spleen, and liver uptake at PET0 was associated with neutropenia after cycles 1–2. BM uptake at PET0 was associated with treatment failure at PET2 and non-responders with higher BM uptake at PET2 had significantly inferior PFS ( p  = 0.023; hazard ratio = 2.31). Based on these results, we concluded that the change in HTM during chemotherapy was most likely a direct impact of chemotherapy rather than a change in MTV. BM uptake has prognostic value in HL.

The overall aim was to investigate the change over time in circulating cell free DNA (cfDNA) in patients with locally advanced non-small cell lung cancer (NSCLC) undergoing concurrent chemo-radiotherapy. Furthermore, to assess the possibility of detecting circulating cell free tumor DNA (ctDNA) using shallow whole genome sequencing (sWGS) and size selection. Ten patients were included in a two-phase study. The first four patients had blood samples taken prior to a radiation therapy (RT) dose fraction and at 30 minutes, 1 hour and 2 hours after RT to estimate the short-term dynamics of cfDNA concentration after irradiation. The remaining six patients had one blood sample taken on six treatment days 30 minutes post treatment to measure cfDNA levels. Presence of ctDNA as indicated by chromosomal aberrations was investigated using sWGS. The sensitivity of this method was further enhanced using in silico size selection. cfDNA concentration from baseline to 120 min after therapy was stable within 95% tolerance limits of +/- 2 ng/ml cfDNA. Changes in cfDNA were observed during therapy with an apparent qualitative difference between adenocarcinoma (average increase of 0.69 ng/ml) and squamous cell carcinoma (average increase of 4.0 ng/ml). Tumor shrinkage on daily cone beam computer tomography scans during radiotherapy did not correlate with changes in concentration of cfDNA. Concentrations of cfDNA remain stable during the first 2 hours after an RT fraction. However, based on the sWGS profiles, ctDNA represented only a minor fraction of cfDNA in this group of patients. The detection sensitivity of genomic alterations in ctDNA strongly increases by applying size selection.

Positron-emission tomography (PET) with 18-fluorodeoxyglucose has a role in the diagnosis and staging of lung cancer, but is also appealing for assessment of prognosis and treatment. A systematic search of the published work shows good evidence that [18F]FDG uptake on PET has independent prognostic value in newly diagnosed nonsmall- cell lung cancer. PET is a sensitive method of measuring the biological effects of anticancer therapy, but until better standardisation and large-scale experience is available, it should only be used for additional assessments of early response in clinical trials. Further studies are needed to define the role of [18F]FDG-PET in restaging after induction therapy in multimodality approaches for locally advanced lung cancer. The assessment of prognosis by [18F]FDG-PET is less substantiated in treated lung cancer than in newly diagnosed patients. Good prospective evidence documents the effectiveness of [18F]FDG-PET over CT in the correct identification of recurrent lung cancer.

High mountain areas above the alpine zone are, despite the low-temperature conditions, inhabited by evolutionary and functionally differing organism groups. We compared the abundance and species richness of vascular plants, oribatid mites, springtails, spiders, and beetles, as well as bacterial and methanogenic archaeal prokaryotes (only abundance), at 100 m vertical intervals from 2,700-3,400 m in the Central Alps. We hypothesized that the less mobile microarthropods and microorganisms are more determined by and respond in similar ways to soil properties as do vascular plants. In contrast, we expected the more mobile surface-dwelling groups to forage also in places devoid of vegetation and thus to show patterns that deviate from that of vascular plants. Surprisingly, the observed patterns were diametrically opposed to our expectations: soil-living oribatid mites and springtails showed high individual numbers at high elevations, even where vascular plants barely occurred. Springtails also showed a rather constant species richness throughout the entire gradient. In contrast, patterns of surface-dwelling organisms and of archaeal prokaryotes did not differ significantly from vascular plants, because of either comparable climate sensitivity or their dependency on vegetated habitats. This study may serve as a baseline to estimate the risks of biodiversity losses in response to climate change across different biotic ecosystem components and to explore the potential and limitations of vascular plants as proxy for other organism groups that are far more challenging to monitor.

BackgroundQuantitative whole-body PET/MRI relies on accurate patient-specific MRI-based attenuation correction (AC) of PET, which is a non-trivial challenge, especially for the anatomically complex head and neck region. We used a deep learning model developed for dose planning in radiation oncology to derive MRI-based attenuation maps of head and neck cancer patients and evaluated its performance on PET AC.MethodsEleven head and neck cancer patients, referred for radiotherapy, underwent CT followed by PET/MRI with acquisition of Dixon MRI. Both scans were performed in radiotherapy position. PET AC was performed with three different patient-specific attenuation maps derived from: (1) Dixon MRI using a deep learning network (PETDeep). (2) Dixon MRI using the vendor-provided atlas-based method (PETAtlas). (3) CT, serving as reference (PETCT). We analyzed the effect of the MRI-based AC methods on PET quantification by assessing the average voxelwise error within the entire body, and the error as a function of distance to bone/air. The error in mean uptake within anatomical regions of interest and the tumor was also assessed.ResultsThe average (± standard deviation) PET voxel error was 0.0 ± 11.4% for PETDeep and −1.3 ± 21.8% for PETAtlas. The error in mean PET uptake in bone/air was much lower for PETDeep (−4%/12%) than for PETAtlas (−15%/84%) and PETDeep also demonstrated a more rapidly decreasing error with distance to bone/air affecting only the immediate surroundings (less than 1 cm). The regions with the largest error in mean uptake were those containing bone (mandible) and air (larynx) for both methods, and the error in tumor mean uptake was −0.6 ± 2.0% for PETDeep and −3.5 ± 4.6% for PETAtlas.ConclusionThe deep learning network for deriving MRI-based attenuation maps of head and neck cancer patients demonstrated accurate AC and exceeded the performance of the vendor-provided atlas-based method both overall, on a lesion-level, and in vicinity of challenging regions such as bone and air.

Since its introduction in 1974, positron emission tomography (PET) has gained widespread use, especially in diagnosis and staging of lung cancer. In this respect, 18 F-fluorodeoxyglucose (FDG) is by far the most used PET tracer exploiting the increased glucose uptake and metabolism in malignant cells. A large number of studies have suggested that addition of FDG-PET to conventional workup can improve diagnosis and staging in patients with non-small cell lung cancer (NSCLC). In meta-analysis, the sensitivity and specificity of PET in diagnosing single pulmonary nodules and masses is found to be 96 and 78%, respectively. In mediastinal staging, the sensitivity and specificity of PET is estimated to be 83 and 92%. In order to achieve high diagnostic values from PET, it is necessary to pay attention to a number of pitfalls, e.g., the uptake of FDG by inflammatory cells causing false-positive results, as well as size and histology of the tumour in order to avoid false-negative results. In 2001, the first integrated PET/computed tomography (CT) was installed, and since then, the use of this modality has expanded steadily, thereby decreasing examination time and overcoming the lack of anatomical details on PET. Recently, PET and PET/CT have become increasingly integrated in therapy planning and evaluation: response evaluation during and after chemotherapy, restaging after neoadjuvant therapy, planning of radiotherapy and detection of recurrent disease are all examples of emerging indications for PET and PET/CT in managing patients with lung cancer.

Purpose New total-body PET scanners with a long axial field of view (LAFOV) allow for higher temporal resolution due to higher sensitivity, which facilitates perfusion estimation by model-free deconvolution. Fundamental tracer kinetic theory predicts that perfusion can be estimated for all tracers despite their different fates given sufficiently high temporal resolution of 1 s or better, bypassing the need for compartment modelling. The aim of this study was to investigate whether brain perfusion could be estimated using model-free Tikhonov generalized deconvolution for five different PET tracers, [ 15 O]H 2 O, [ 11 C]PIB, [ 18 F]FE-PE2I, [ 18 F]FDG and [ 18 F]FET. To our knowledge, this is the first example of a general model-free approach to estimate cerebral blood flow (CBF) from PET data. Methods Twenty-five patients underwent dynamic LAFOV PET scanning (Siemens, Quadra). PET images were reconstructed with an isotropic voxel resolution of 1.65 mm 3 . Time framing was 40 × 1 s during bolus passage followed by increasing framing up to 60 min. AIF was obtained from the descending aorta. Both voxel- and region-based calculations of perfusion in the thalamus were performed using the Tikhonov method. The residue impulse response function was used to estimate the extraction fraction of tracer leakage across the blood–brain barrier. Results CBF ranged from 37 to 69 mL blood min −1  100 mL of tissue −1 in the thalamus. Voxelwise calculation of CBF resulted in CBF maps in the physiologically normal range. The extraction fractions of [ 15 O]H 2 O, [ 18 F]FE-PE2I, [ 11 C]PIB, [ 18 F]FDG and [ 18 F]FET in the thalamus were 0.95, 0.78, 0.62, 0.19 and 0.03, respectively. Conclusion The high temporal resolution and sensitivity associated with LAFOV PET scanners allow for noninvasive perfusion estimation of multiple tracers. The method provides an estimation of the residue impulse response function, from which the fate of the tracer can be studied, including the extraction fraction, influx constant, volume of distribution and transit time distribution, providing detailed physiological insight into normal and pathologic tissue.

Immune checkpoint inhibitor therapy (ICT) is a new treatment strategy developed for the treatment of cancer. ICT inhibits pathways known to downregulate the innate immune response to cancer cells. These drugs have been shown to be effective in the treatment of a variety of cancers, including metastatic melanoma and lung cancer. Challenges in response evaluation of patients in ICT have risen as immune related side effects and immune cell infiltration may be confused with progressive disease. Furthermore, the timing of the evaluation scan may be challenged by relatively slow responses. To overcome this, new response criteria for evaluating these patients with morphologic imaging have been proposed. The aim of this paper is to review and discuss the current evidence for the use of molecular imaging, e.g., PET/CT (Positron Emission Tomography/Computer Tomography) with 18F-Fluorodeoxyglucoes (FDG) as an alternative imaging method for monitoring patients undergoing ICT. Following the currently available evidence, this review will primarily focus on patients with malignant melanoma.

We investigated community structure, trophic ecology (using stable isotope ratios; ¹⁵N/¹⁴N, ¹³C/¹²C) and reproductive mode of oribatid mites (Acari, Oribatida) along an altitudinal gradient (2,050–2,900 m) in the Central Alps (Obergurgl, Austria). We hypothesized that (1) the community structure changes with altitude, (2) oribatid mites span over four trophic levels, (3) the proportion of sexual taxa increases with altitude, and (4) the proportion of sexual taxa increases with trophic level, i.e. is positively correlated with the δ¹⁵N signatures. Oribatid mite community structure changed with altitude indicating that oribatid mites occupy different niches at different altitudes. Oribatid mites spanned over 12 δ¹⁵N units, i.e. about four trophic levels, which is similar to lowland forest ecosystems. The proportion of sexually reproducing taxa increased from 2,050 to 2,900 m suggesting that limited resource availability at high altitudes favors sexual reproduction. Sexual taxa more frequently occurred higher in the food web indicating that the reproductive mode is related to nutrition of oribatid mites. Generally, oribatid mite community structure changed from being decomposer dominated at lower altitude to being dominated by fungal and lichen feeders, and predators at higher altitude. This supports the view that resources from dead organic material become less available with increasing altitude forcing species to feed on living resources such as fungi, lichens and nematodes. Our findings support the hypothesis that limited resource accessibility (at high altitudes) favors sexually reproducing species whereas ample resource supply (at lower altitudes) favors parthenogenetic species.