Fibroblast-like synoviocytes (FLS) can augment the inflammatory process observed in synovium of patients with rheumatoid arthritis (RA). A recent transcriptomic study in synovial biopsies revealed ...changes in metabolic pathways before disease onset in absence of synovial tissue inflammation. This raises the question whether alterations in cellular metabolism in tissue resident FLS underlie disease pathogenesis.
To study this, we compared the metabolic profile of FLS isolated from synovial biopsies from individuals with arthralgia who were autoantibody positive but without any evidence of arthritis (RA-risk individuals, n = 6) with FLS from patients with RA (n = 6), osteoarthritis (OA, n = 6) and seronegative controls (n = 6). After synovial digestion, FLS were cultured in vitro and cellular metabolism was assessed using quantitative PCR, flow cytometry, XFe96 Seahorse Analyzer and tritium-labelled oleate oxidation assays.
Real-time metabolic profiling revealed that basal (p < 0.0001) and maximum mitochondrial respiration (p = 0.0024) were significantly lower in RA FLS compared with control FLS. In all donors, basal respiration was largely dependent on fatty acid oxidation while glucose was only highly used by FLS from RA patients. Moreover, we showed that RA-risk and RA FLS are less metabolically flexible. Strikingly, mitochondrial fatty acid β-oxidation was significantly impaired in RA-risk (p = 0.001) and RA FLS (p < 0.0001) compared with control FLS.
Overall, this study showed several metabolic alterations in FLS even in absence of synovial inflammation, suggesting that these alterations already start before clinical manifestation of disease and may drive disease pathogenesis.
•Synovial fibroblasts (FLS) display metabolic alterations before onset of RA.•Lower basal and maximum mitochondrial respiration in RA FLS compared with controls.•Control FLS are more flexible to increase metabolic pathway oxidation.•Fatty acid β-oxidation is significantly impaired in RA-risk and RA FLS.•FLS mitochondria might be attractive drug targets aimed at halting disease progression.
Abstract
Objectives
Earlier retrospective studies have suggested a relation between DISH and cardiovascular disease, including myocardial infarction. The present study assessed the association ...between DISH and incidence of cardiovascular events and mortality in patients with high cardiovascular risk.
Methods
In this prospective cohort study, we included 4624 patients (mean age 58.4 years, 69.6% male) from the Second Manifestations of ARTerial disease cohort. The main end point was major cardiovascular events (MACE: stroke, myocardial infarction and vascular death). Secondary endpoints included all-cause mortality and separate vascular events. Cause-specific proportional hazard models were used to evaluate the risk of DISH on all outcomes, and subdistribution hazard models were used to evaluate the effect of DISH on the cumulative incidence. All models were adjusted for age, sex, body mass index, blood pressure, diabetes, non-HDL cholesterol, packyears, renal function and C-reactive protein.
Results
DISH was present in 435 (9.4%) patients. After a median follow-up of 8.7 (IQR 5.0–12.0) years, 864 patients had died and 728 patients developed a MACE event. DISH was associated with an increased cumulative incidence of ischaemic stroke. After adjustment in cause-specific modelling, DISH remained significantly associated with ischaemic stroke (HR 1.55; 95% CI: 1.01, 2.38), but not with MACE (HR 0.99; 95% CI: 0.79, 1.24), myocardial infarction (HR 0.88; 95% CI: 0.59, 1.31), vascular death (HR 0.94; 95% CI: 0.68, 1.27) or all-cause mortality (HR 0.94; 95% CI: 0.77, 1.16).
Conclusion
The presence of DISH is independently associated with an increased incidence and risk for ischaemic stroke, but not with MACE, myocardial infarction, vascular death or all-cause mortality.
Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to ...investigate clinical outcome, prognostic factors, androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2) expression. SDC patients diagnosed between 1990 and 2014 were identified by the Nationwide Network and Registry of Histo‐ and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease‐free survival (DFS), distant metastasis‐free survival (DMFS) and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent in‐situ hybridization. A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS and DMFS were 51, 23 and 26 months, respectively. In patients presenting without distant metastases, the absolute number of positive lymph nodes was associated with poor OS and DMFS in a multivariable analysis. AR and HER2 were positive in 161/168 (96%) and 44/153 (29%) tumors, respectively, and were not prognostic factors. SDC has a dismal prognosis with primary lymph node involvement in the majority of patients. The absolute number of lymph node metastases was found to be the only prognostic factor for DMFS and OS. AR expression and—to a lesser extent—HER2 expression hold promise for systemic treatment in the metastatic and eventually adjuvant setting.
What's new?
Salivary duct carcinoma (SDC) is a rare and often fatal malignancy. Little is known about associations between its pathological features and clinical outcome. In this study, clinicopathological factors were analyzed for 177 patients diagnosed with SDC in The Netherlands between 1990 and 2014. The data show that median overall survival (OS) and distant metastasis‐free survival (DMFS) were 51 and 26 months, respectively. At diagnosis, 68% of patients presented with lymph node metastases. Lymph node positivity was associated with poor OS and poor DMFS. The absolute number of metastatic lymph nodes was the only significant prognostic factor for survival in a multivariate analysis. Androgen receptor and human epidermal growth factor 2 (HER2) were positive in 96% and 29%, respectively and were not a prognostic factor.
Purpose
Radiation pneumonitis is a serious complication of radioembolization. In holmium-166 (
166
Ho) radioembolization, the lung mean dose (LMD) can be estimated (eLMD) using a scout dose with ...either technetium-99 m-macroaggregated albumin (
99m
TcMAA) or
166
Ho-microspheres. The accuracy of eLMD based on
99m
TcMAA (eLMD
MAA
) was compared to eLMD based on
166
Ho-scout dose (eLMD
Ho-scout
) in two prospective clinical studies.
Materials and Methods
Patients were included if they received both scout doses (
99m
TcMAA and
166
Ho-scout), had a posttreatment
166
Ho-SPECT/CT (gold standard) and were scanned on the same hybrid SPECT/CT system. The correlation between eLMD
MAA
/eLMD
Ho-scout
and LMD
Ho-treatment
was assessed by Spearman’s rank correlation coefficient (
r
). Wilcoxon signed rank test was used to analyze paired data.
Results
Thirty-seven patients with unresectable liver metastases were included. During follow-up, none developed symptoms of radiation pneumonitis. Median eLMD
MAA
(1.53 Gy, range 0.09–21.33 Gy) was significantly higher than median LMD
Ho-treatment
(0.00 Gy, range 0.00–1.20 Gy;
p
< 0.01). Median eLMD
Ho-scout
(median 0.00 Gy, range 0.00–1.21 Gy) was not significantly different compared to LMD
Ho-treatment
(
p
> 0.05). In all cases, eLMD
MAA
was higher than LMD
Ho-treatment
(
p
< 0.01). While a significant correlation was found between eLMD
Ho-scout
and LMD
Ho-treatment
(
r
= 0.43,
p
< 0.01), there was no correlation between eLMD
MAA
and LMD
Ho-treatment
(
r
= 0.02,
p
= 0.90).
Conclusion
166
Ho-scout dose is superior in predicting LMD over
99m
TcMAA, in
166
Ho-radioembolization. Consequently,
166
Ho-scout may limit unnecessary patient exclusions and avoid unnecessary therapeutic activity reductions in patients eligible for radioembolization.
Trail registration
: NCT01031784, registered December 2009. NCT01612325, registered June 2012.
Graphical Abstract
Epithelial ovarian cancer (EOC) is often diagnosed late, with a 5-year relative survival of 30.2% for patients with metastatic disease. Residual disease following cytoreductive surgery is an ...important predictor for poor survival. EOC is characterized by diffuse peritoneal metastases and depositions of small size, challenging a complete resection. Targeted fluorescence imaging is a technique to enhance tumor visualization and can be performed intraoperatively. Folate receptor alpha (FRα) and human epidermal growth factor receptor 2 (HER2) are overexpressed in EOC in 80% and 20% of the cases, respectively, and have been previously studied as a target for intraoperative imaging.
To systematically review the literature on the feasibility of FRα and HER2 targeted fluorescence-guided cytoreductive surgery (FGCS) in women with EOC.
PubMed and Embase were searched for human and animal studies on FGCS targeting either HER2 or FRα in either women with EOC or animal models of EOC. Risk of bias and methodological quality were assessed with the SYRCLE and MINORS tool, respectively.
All animal studies targeting either FRα or HER2 were able to detect tumor deposits using intraoperative fluorescence imaging. One animal study targeting HER2 compared conventional cytoreductive surgery (CCS) to FGCS and concluded that FGCS, either without or following CCS, resulted in statistically significant less residual disease compared to CCS alone. Human studies on FGCS showed an increased detection rate of tumor deposits. True positives ranged between 75%–77% and false positives between 10%–25%. Lymph nodes were the main source of false positive results. Sensitivity was 85.9%, though only reported by one human study.
FGCS targeting either HER2 or FRα appears to be feasible in both EOC animal models and patients with EOC. FGCS is a promising technique, but further research is warranted to validate these results and particularly study the survival benefit.
•Targeted fluorescence-guided cytoreductive surgery is feasible in women with epithelial ovarian cancer positive for FRα.•True positive and false positive values ranged from 75 to 77% and 10–25%, respectively.•FRβ-expressing macrophages in lymph nodes cause a cross-reaction with the FRα-targeted imaging agents.
Imatinib minimal (trough) plasma concentrations after one month of treatment have shown a significant association with clinical benefit in patients with gastrointestinal stromal tumors (GIST). ...Considering that a retrospective pharmacokinetic analysis has also suggested that imatinib clearance increases over time in patients with soft tissue sarcoma and GIST, the primary aim of this study was to assess systemic exposure to imatinib at multiple time points in a long-term prospective population pharmacokinetic study. As imatinib is mainly metabolized in the liver, our secondary aim was to elucidate the potential effects of the volume of liver metastases on exposure to imatinib.
Full pharmacokinetic blood sampling was conducted in 50 patients with GIST on the first day of imatinib treatment, and after one, six, and 12 months. In addition, on day 14, and monthly during imatinib treatment, trough samples were taken. Pharmacokinetic analysis was conducted using a compartmental model. Volume of liver metastases was assessed by computed tomographic (CT) imaging.
After 90 days of treatment, a significant decrease in imatinib systemic exposure of 29.3% compared with baseline was observed (P < 0.01). For every 100 cm(3) increase of metastatic volume, a predicted decrease of 3.8% in imatinib clearance was observed.
This is the first prospective pharmacokinetic study in patients with GIST, showing a significant decrease of approximately 30% in imatinib exposure after long-term treatment. This means that future "trough level - clinical benefit" analyses should be time point specific. GIST liver involvement, however, has a marginal effect on imatinib clearance.
Background
High activities of holmium-166 (
166
Ho)–labeled microspheres are used for therapeutic radioembolization, ideally directly followed by SPECT imaging for dosimetry purposes. The resulting ...high-count rate potentially impacts dead time, affecting the image quality and dosimetric accuracy. This study assesses gamma camera performance and SPECT image quality at high
166
Ho activities of several GBq. To this purpose, the liver compartment, including two tumors, of an anthropomorphic phantom was filled with
166
Ho-chloride, with a tumor to non-tumorous liver activity concentration ratio of 10:1. Multiple SPECT/CT scans were acquired over a range of activities up to 2.7 GBq. Images were reconstructed using a commercially available protocol incorporating attenuation and scatter correction. Dead time effects were assessed from the observed count rate in the photopeak (81 keV, 15% width) and upper scatter (118 keV, 12% width) window. Post reconstruction, each image was scaled with an individual conversion factor to match the known total activity in the phantom at scanning time. The resulting activity concentration was measured in the tumors and non-tumorous liver. The image quality as a function of activity was assessed by a visual check of the absence of artifacts by a nuclear medicine physician. The apparent lung shunt fraction (nonzero due to scatter) was estimated on planar and SPECT images.
Results
A 20% count loss due to dead time was observed around 0.7 GBq in the photopeak window. Independent of the count losses, the measured activity concentration was up to 100% of the real value for non-tumorous liver, when reconstructions were normalized to the known activity at scanning time. However, for tumor spheres, activity concentration recovery was ~80% at the lowest activity, decreasing with increasing activity in the phantom. Measured lung shunt fractions were relatively constant over the considered activity range.
Conclusions
At high
166
Ho count rate, all images, visually assessed, presented no artifacts, even at considerable dead time losses. A quantitative evaluation revealed the possibility of reliable dosimetry within the healthy liver, as long as a post-reconstruction scaling to scanning activity is applied. Reliable tumor dosimetry, instead, remained hampered by the dead time.
We study the density profile and shape of the Galactic halo using deep multicolour images from the MENeaCS and CCCP projects, over 33 fields selected to avoid overlap with the Galactic plane. Using ...multicolour selection and point spread function homogenization techniques we obtain catalogues of F stars (near-main sequence turnoff stars) out to Galactocentric distances up to 60 kpc. Grouping nearby lines of sight, we construct the stellar density profiles through the halo in eight different directions by means of photometric parallaxes. Smooth halo models are then fitted to these profiles. We find clear evidence for a steepening of the density profile power law index around R = 20 kpc, from −2.50 ± 0.04 to −4.85 ± 0.04, and for a flattening of the halo towards the poles with best-fit axis ratio 0.79 ± 0.02. Furthermore, we cannot rule out a mild triaxiality (w ≥ 0.88 ± 0.07). We recover the signatures of well-known substructure and streams that intersect our lines of sight. These results are consistent with those derived from wider but shallower surveys, and augur well for upcoming, wide-field surveys of comparable depth to our pencil beam surveys.
Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, ...cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD.
In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families.
Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas.
We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.
Context. The search for minor bodies in the solar system promises insights into its formation history. Wide imaging surveys offer the opportunity to serendipitously discover and identify these traces ...of planetary formation and evolution. Aim. We aim to present a method to acquire position, photometry, and proper motion measurements of solar system objects (SSOs) in surveys using dithered image sequences. The application of this method on the Kilo-Degree Survey (KiDS) is demonstrated. Methods. Optical images of 346 deg2 fields of the sky are searched in up to four filters using the AstrOmatic software suite to reduce the pixel to catalog data. The SSOs within the acquired sources are selected based on a set of criteria depending on their number of observation, motion, and size. The Virtual Observatory SkyBoT tool is used to identify known objects. Results. We observed 20 221 SSO candidates, with an estimated false-positive content of less than 0.05%. Of these SSO candidates, 53.4% are identified by SkyBoT. KiDS can detect previously unknown SSOs because of its depth and coverage at high ecliptic latitude, including parts of the Southern Hemisphere. Thus we expect the large fraction of the 46.6% of unidentified objects to be truly new SSOs. Conclusions. Our method is applicable to a variety of dithered surveys such as DES, LSST, and Euclid. It offers a quick and easy-to-implement search for SSOs. SkyBoT can then be used to estimate the completeness of the recovered sample.
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