Micro Regional Heterogeneity of ⁶⁴Cu-ATSM and ¹⁸F-FDG Uptake in Canine Soft Tissue Sarcomas: Relation to Cell Proliferation, Hypoxia and Glycolysis

Tumour microenvironment heterogeneity is believed to play a key role in cancer progression and therapy resistance. However, little is known about micro regional distribution of hypoxia, glycolysis and proliferation in spontaneous solid tumours. The overall aim was simultaneous investigation of micro regional heterogeneity of 64Cu-ATSM (hypoxia) and 18F-FDG (glycolysis) uptake and correlation to endogenous markers of hypoxia, glycolysis, proliferation and angiogenesis to better therapeutically target aggressive tumour regions and prognosticate outcome.Exploiting the different half-lives of 64Cu-ATSM (13 h) and 18F-FDG (2 h) enabled simultaneous investigation of micro regional distribution of hypoxia and glycolysis in 145 tumour pieces from four spontaneous canine soft tissue sarcomas. Pairwise measurements of radioactivity and gene expression of endogenous markers of hypoxia (HIF-1α, CAIX), glycolysis (HK2, GLUT1 and GLUT3), proliferation (Ki-67) and angiogenesis (VEGFA and TF) were performed. Dual tracer autoradiography was compared with Ki-67 immunohistochemistry.Micro regional heterogeneity in hypoxia and glycolysis within and between tumour sections of each tumour piece was observed. The spatial distribution of 64Cu-ATSM and 18F-FDG was rather similar within each tumour section as reflected in moderate positive significant correlations between the two tracers (ρ = 0.3920-0.7807; p = 0.0180 -<0.0001) based on pixel-to-pixel comparisons of autoradiographies and gamma counting of tumour pieces. 64Cu-ATSM and 18F-FDG correlated positively with gene expression of GLUT1 and GLUT3, but negatively with HIF-1α and CAIX. Significant positive correlations were seen between Ki-67 gene expression and 64Cu-ATSM (ρ = 0.5578, p = 0.0004) and 18F-FDG (ρ = 0.4629-0.7001, p = 0.0001-0.0151). Ki-67 gene expression more consistently correlated with 18F-FDG than with 64Cu-ATSM.Micro regional heterogeneity of hypoxia and glycolysis was documented in spontaneous canine soft tissue sarcomas. 64Cu-ATSM and 18F-FDG uptakes and distributions showed significant moderate correlations at the micro regional level indicating overlapping, yet different information from the tracers.18F-FDG better reflected cell proliferation as measured by Ki-67 gene expression than 64Cu-ATSM

Simultaneous PET/MRI with 13C magnetic resonance spectroscopic imaging (hyperPET): phantom-based evaluation of PET quantification

BACKGROUND: Integrated PET/MRI with hyperpolarized (13)C magnetic resonance spectroscopic imaging ((13)C-MRSI) offers simultaneous, dual-modality metabolic imaging. A prerequisite for the use of simultaneous imaging is the absence of interference between the two modalities. This has been documented for a clinical whole-body system using simultaneous (1)H-MRI and PET but never for (13)C-MRSI and PET. Here, the feasibility of simultaneous PET and (13)C-MRSI as well as hyperpolarized (13)C-MRSI in an integrated whole-body PET/MRI hybrid scanner is evaluated using phantom experiments. METHODS: Combined PET and (13)C-MRSI phantoms including a NEMA [(18)F]-FDG phantom, (13)C-acetate and (13)C-urea sources, and hyperpolarized (13)C-pyruvate were imaged repeatedly with PET and/or (13)C-MRSI. Measurements evaluated for interference effects included PET activity values in the largest sphere and a background region; total number of PET trues; and (13)C-MRSI signal-to-noise ratio (SNR) for urea and acetate phantoms. Differences between measurement conditions were evaluated using t tests. RESULTS: PET and (13)C-MRSI data acquisition could be performed simultaneously without any discernible artifacts. The average difference in PET activity between acquisitions with and without simultaneous (13)C-MRSI was 0.83 (largest sphere) and −0.76 % (background). The average difference in net trues was −0.01 %. The average difference in (13)C-MRSI SNR between acquisitions with and without simultaneous PET ranged from −2.28 to 1.21 % for all phantoms and measurement conditions. No differences were significant. The system was capable of (13)C-MRSI of hyperpolarized (13)C-pyruvate. CONCLUSIONS: Simultaneous PET and (13)C-MRSI in an integrated whole-body PET/MRI hybrid scanner is feasible. Phantom experiments showed that possible interference effects introduced by acquiring data from the two modalities simultaneously are small and non-significant. Further experiments can now investigate the benefits of simultaneous PET and hyperpolarized (13)C-MRI in vivo studies

Workplace sexual harassment and depressive symptoms:A cross-sectional multilevel analysis comparing harassment from clients or customers to harassment from other employees amongst 7603 Danish employees from 1041 organizations

Abstract Background Previous research has reported that sexual harassment can lead to reduced mental health. Few studies have focused on sexual harassment conducted by clients or customers, which might occur in person-related occupations such as eldercare work, social work or customer service work. This study examined the cross-sectional association between sexual harassment by clients or customers and depressive symptoms. We also examined if this association was different compared to sexual harassment conducted by a colleague, supervisor or subordinate. Further, we investigated if psychosocial workplace initiatives modified the association between sexual harassment by clients or customers and level of depressive symptoms. Methods We used data from the Work Environment and Health in Denmark cohort study (WEHD) and the Work Environment Activities in Danish Workplaces Study (WEADW) collected in 2012. WEHD is based on a random sample of employed individuals aged 18–64. In WEADW, organizational supervisors or employee representatives provided information on workplace characteristics. By combining WEHD and WEADW we included self-reported information on working conditions and health from 7603 employees and supervisors in 1041 organizations within 5 occupations. Data were analyzed using multilevel regression and analyses adjusted for gender, age, occupation and socioeconomic position. Results Exposure to workplace sexual harassment from clients or customers was statistically significantly associated with a higher level of depressive symptoms (2.05; 95% CI: 0.98–3.12) compared to no exposure. Employees harassed by colleagues, supervisors or subordinates had a higher mean level of depressive symptoms (2.45; 95% CI: 0.57–4.34) than employees harassed by clients or customers. We observed no statistically significant interactions between harassment from clients and customers and any of the examined psychosocial workplace initiatives (all p > 0.05). Conclusions The association between sexual harassment and depressive symptoms differed for employees harassed by clients or customers and those harassed by colleagues, supervisors or subordinates. The results underline the importance of investigating sexual harassment from clients or customers and sexual harassment by colleagues, supervisors or subordinates as distinct types of harassment. We found no modification of the association between sexual harassment by clients or customers and depressive symptoms by any of the examined psychosocial workplace initiatives

Simultaneous hyperpolarized 13C-pyruvate MRI and 18F-FDG-PET in cancer (hyperPET):feasibility of a new imaging concept using a clinical PET/MRI scanner

In this paper we demonstrate, for the first time, the feasibility of a new imaging concept - combined hyperpolarized (13)C-pyruvate magnetic resonance spectroscopic imaging (MRSI) and (18)F-FDG-PET imaging. This procedure was performed in a clinical PET/MRI scanner with a canine cancer patient. We have named this concept hyper PET. Intravenous injection of the hyperpolarized (13)C-pyruvate results in an increase of (13)C-lactate, (13)C-alanine and (13)C-CO(2) ((13)C-HCO(3)) resonance peaks relative to the tissue, disease and the metabolic state probed. Accordingly, with dynamic nuclear polarization (DNP) and use of (13)C-pyruvate it is now possible to directly study the Warburg Effect through the rate of conversion of (13)C-pyruvate to (13)C-lactate. In this study, we combined it with (18)F-FDG-PET that studies uptake of glucose in the cells. A canine cancer patient with a histology verified local recurrence of a liposarcoma on the right forepaw was imaged using a combined PET/MR clinical scanner. PET was performed as a single-bed, 10 min acquisition, 107 min post injection of 310 MBq (18)F-FDG. (13)C-chemical shift imaging (CSI) was performed just after FDG-PET and 30 s post injection of 23 mL hyperpolarized (13)C-pyruvate. Peak heights of (13)C-pyruvate and (13)C-lactate were quantified using a general linear model. Anatomic (1)H-MRI included axial and coronal T1 vibe, coronal T2-tse and axial T1-tse with fat saturation following gadolinium injection. In the tumor we found clearly increased (13)C-lactate production, which also corresponded to high (18)F-FDG uptake on PET. This is in agreement with the fact that glycolysis and production of lactate are increased in tumor cells compared to normal cells. Yet, most interestingly, also in the muscle of the forepaw of the dog high (18)F-FDG uptake was observed. This was due to activity in these muscles prior to anesthesia, which was not accompanied by a similarly high (13)C-lactate production. Accordingly, this clearly demonstrates how the Warburg Effect directly can be demonstrated by hyperpolarized (13)C-pyruvate MRSI. This was not possible with (18)F-FDG-PET imaging due to inability to discriminate between causes of increased glucose uptake. We propose that this new concept of simultaneous hyperpolarized (13)C-pyruvate MRSI and PET may be highly valuable for image-based non-invasive phenotyping of tumors. This methods may be useful for treatment planning and therapy monitoring

Changes in Greenland’s peripheral glaciers linked to the North Atlantic Oscillation

Glaciers and ice caps peripheral to the main Greenland Ice Sheet contribute markedly to sea-level rise1,2,3. Their changes and variability, however, have been difficult to quantify on multi-decadal timescales due to an absence of long-term data4. Here, using historical aerial surveys, expedition photographs, spy satellite imagery and new remote-sensing products, we map glacier length fluctuations of approximately 350 peripheral glaciers and ice caps in East and West Greenland since 1890. Peripheral glaciers are found to have recently undergone a widespread and significant retreat at rates of 12.2 m per year and 16.6 m per year in East and West Greenland, respectively; these changes are exceeded in severity only by the early twentieth century post-Little-Ice-Age retreat. Regional changes in ice volume, as reflected by glacier length, are further shown to be related to changes in precipitation associated with the North Atlantic Oscillation (NAO), with a distinct east–west asymmetry; positive phases of the NAO increase accumulation, and thereby glacier growth, in the eastern periphery, whereas opposite effects are observed in the western periphery. Thus, with projected trends towards positive NAO in the future5,6, eastern peripheral glaciers may remain relatively stable, while western peripheral glaciers will continue to diminish