Psychosocial factors and cancer incidence (PSY-CA):Protocol for individual participant data meta-analyses

OBJECTIVES: Psychosocial factors have been hypothesized to increase the risk of cancer. This study aims (1) to test whether psychosocial factors (depression, anxiety, recent loss events, subjective social support, relationship status, general distress, and neuroticism) are associated with the incidence of any cancer (any, breast, lung, prostate, colorectal, smoking-related, and alcohol-related); (2) to test the interaction between psychosocial factors and factors related to cancer risk (smoking, alcohol use, weight, physical activity, sedentary behavior, sleep, age, sex, education, hormone replacement therapy, and menopausal status) with regard to the incidence of cancer; and (3) to test the mediating role of health behaviors (smoking, alcohol use, weight, physical activity, sedentary behavior, and sleep) in the relationship between psychosocial factors and the incidence of cancer.METHODS: The psychosocial factors and cancer incidence (PSY-CA) consortium was established involving experts in the field of (psycho-)oncology, methodology, and epidemiology. Using data collected in 18 cohorts (N = 617,355), a preplanned two-stage individual participant data (IPD) meta-analysis is proposed. Standardized analyses will be conducted on harmonized datasets for each cohort (stage 1), and meta-analyses will be performed on the risk estimates (stage 2).CONCLUSION: PSY-CA aims to elucidate the relationship between psychosocial factors and cancer risk by addressing several shortcomings of prior meta-analyses.</p

Depression, anxiety, and the risk of cancer: An individual participant data meta-analysis

BACKGROUND: Depression and anxiety have long been hypothesized to be related to an increased cancer risk. Despite the great amount of research that has been conducted, findings are inconclusive. To provide a stronger basis for addressing the associations between depression, anxiety, and the incidence of various cancer types (overall, breast, lung, prostate, colorectal, alcohol-related, and smoking-related cancers), individual participant data (IPD) meta-analyses were performed within the Psychosocial Factors and Cancer Incidence (PSY-CA) consortium. METHODS: The PSY-CA consortium includes data from 18 cohorts with measures of depression or anxiety (up to N = 319,613; cancer incidences, 25,803; person-years of follow-up, 3,254,714). Both symptoms and a diagnosis of depression and anxiety were examined as predictors of future cancer risk. Two-stage IPD meta-analyses were run, first by using Cox regression models in each cohort (stage 1), and then by aggregating the results in random-effects meta-analyses (stage 2). RESULTS: No associations were found between depression or anxiety and overall, breast, prostate, colorectal, and alcohol-related cancers. Depression and anxiety (symptoms and diagnoses) were associated with the incidence of lung cancer and smoking-related cancers (hazard ratios [HRs], 1.06-1.60). However, these associations were substantially attenuated when additionally adjusting for known risk factors including smoking, alcohol use, and body mass index (HRs, 1.04-1.23). CONCLUSIONS: Depression and anxiety are not related to increased risk for most cancer outcomes, except for lung and smoking-related cancers. This study shows that key covariates are likely to explain the relationship between depression, anxiety, and lung and smoking-related cancers. PREREGISTRATION NUMBER: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=157677

Adverse effects of stromal vascular fraction during regenerative treatment of the intervertebral disc: observations in a goat model

Stromal vascular fraction (SVF), an adipose tissue-derived heterogeneous cell mixture containing, among others, multipotent adipose stromal cells (ASCs) and erythrocytes, has proved beneficial for a wide range of applications in regenerative medicine. We sought to establish intervertebral disc (IVD) regeneration by injecting SVF intradiscally during a one-step surgical procedure in an enzymatically (Chondroitinase ABC; cABC) induced goat model of disc degeneration. Unexpectedly, we observed a severe inflammatory response that has not been described before, including massive lymphocyte infiltration, neovascularisation and endplate destruction. A second study investigated two main suspects for these adverse effects: cABC and erythrocytes within SVF. The same destructive response was observed in healthy goat discs injected with SVF, thereby eliminating cABC as a cause. Density gradient removal of erythrocytes and ASCs purified by culturing did not lead to adverse effects. Following these observations, we incorporated an extra washing step in the SVF harvesting protocol. In a third study, we applied this protocol in a one-step procedure to a goat herniation model, in which no adverse responses were observed either. However, upon intradiscal injection of an identically processed SVF mixture into our goat IVD degeneration model during a fourth study, the adverse effects surprisingly occurred again. Despite our quest for the responsible agent, we eventually could not identify the mechanism through which the observed destructive responses occurred. Although we cannot exclude that the adverse effects are species-dependent or model-specific, we advertise caution with the clinical application of autologous SVF injections into the IVD until the responsible agent(s) are identifie

Sterilization and strength of 70/30 polylactide cages: e-beam versus ethylene oxide

In vitro and in vivo studies on the degradation of 70/30 poly(L,DL-lactide) (PLDLLA) cages. To evaluate the effect of e-beam and ethylene oxide sterilization on degradation and strength. e-beam-sterilized PLDLLA cages were shown to maintain mechanical strength for at least 6 months during degradation studies in vitro. Yet failure of the cages was observed after only 3 months in vivo. We hypothesized that degradation characteristics and mechanical strength could be improved by sterilizing the cages through ethylene oxide (EtO) instead of e-beam. PLDLLA cages were sterilized either by e-beam or EtO, and degraded in phosphate-buffered saline. Each month, cages were compressed until failure. Inherent viscosity was determined as a measure of degradation. For the in vivo evaluation, e-beam- or EtO-sterilized cages were implanted at L3-L4 in a standardized goat model. After 3 or 6 months, retrieved segments were scanned by high-resolution magnetic resonance imaging. Also, inherent viscosity of the polymer was measured. e-beam sterilization strongly decreased inherent viscosity of PLDLLA compared with EtO sterilization, but initial strength was only affected marginally. After 6 months, the strength of the e-beam-sterilized cages dropped, while that of EtO-sterilized cages was maintained. Degradation in vivo was slightly faster than in vitro. In both groups, however, mechanical failure occurred at 3 months after implantation. Inherent viscosity decreases with degradation time, but strength only decreases when inherent viscosity is below a certain threshold. Above this threshold, mechanical strength is a property of the polymer and independent of inherent viscosity. e-beam sterilization strongly decreases inherent viscosity and thus advances mechanical degradation. EtO sterilization delays degradation but does not increase initial strength. Early failure of PLDLLA cages in the goat model thus is unrelated to sterilization method and requires further stud

Molecular changes in the degenerated goat intervertebral disc

Study Design. Caprine lumbar intervertebral discs (IVD) were collected from previous studies and categorized as normal, mildly, or severely degenerated. The biochemical composition and the RNA profiles present in both the nucleus pulposus (NP) and the anulus fibrosus (AF) were analyzed. Objective. To determine the molecular changes occurring in a disc degeneration model, evaluating the mechanism through which the degeneration develops in this model. Summary of Background Data. Recently we described an IVD degeneration model in the goat by injecting chondroitinase ABC. This results in mild progressive disc degeneration. Methods. One hundred nine caprine IVDs were assigned to 3 classes: no degeneration, mild, or severe degeneration. Collagen content, collagen cross-links (hydroxylysyl pyridinoline) and the ratio between the glycosaminoglycans (GAGs) and hydroxyprolines (Hyp) (GAG/Hyp ratio) in the NP and AF samples were studied. Furthermore, the gene expression of collagen type I, type II, and aggrecan as well as a desintegrin and metalloproteinase with thrombospondin motifs (ADAMTIS)-2, ADAMTS-14, and matrix metalloproteinases-13 were studied. Results. Collagen content was increased in severely degenerated NPs and decreased in severely degenerated AFs. Collagen cross-links were decreased in the severely degenerated NPs indicating de novo deposition of immature, reducible cross-linked collagens. The GAG/Hyp ratio found in none-degenerate goat discs was comparable to human ratios and decreased in degenerated discs, similar as in humans. The ADAMTS genes were increasingly detectable in the degenerated discs. The matrix metalloproteinases-13 gene increased significantly in degenerated discs. The expression of collagen type I increased in degenerated discs while aggrecan decreased. Conclusion. Changes in the GAG/Hyp ratio of chemically induced degeneration in goat IVD resemble the changes seen in humans. Gene expression profiles match the pattern of degeneration, suggesting that the injection of chondroitinase ABC might mimic the onset of human disc degeneratio

Adjacent segment degeneration: observations in a goat spinal fusion study

The adjacent discs of 13 goats, originally used in a lumbar spinal fusion model study, were analyzed for symptoms of intervertebral disc degeneration by means of magnetic resonance imaging (MRI), macroscopy, and histology. These goats were followed for 6 months and the results were compared with 6 control goats. To evaluate the development of adjacent segment disc degeneration in vivo in a goat lumbar spinal fusion model. There is ongoing debate on whether adjacent segment degeneration (ASD) develops through increased biomechanical load on discs adjacent to fusion sites, or by the natural process of pre-existing degenerative disease. Animal models offer an opportunity to separate these factors by evaluating the development of ASD in nondegenerated animal spines. In a spinal fusion model study 2 segments (L3-L4 and L1-L2) were fixated and followed for 3 months (n = 6) and 6 months (n = 7) in 13 skeletally mature goats. Two adjacent discs (T13-L1 and L4-L5), 1 interjacent disc (L2-L3) and a control disc (L5-L6) were analyzed by means of magnetic resonance imaging, macroscopy, and histology. These results were compared with the discs of 6, nonoperated "normal" goats. No differences were observed in the adjacent and interjacent intervertebral discs after both follow-up periods. However, severe degenerative changes were observed in the L5-L6 level, originally included as controls. Large animal fusion models offer an excellent opportunity to study ASD in vivo, as pre-existing degenerative disc disease is not present and biomechanical effects of the fusion can be studied more isolated. Our results suggest that adjacent disc degeneration does not develop in our spinal goat fusion model. There is, however, an increased risk of disc degeneration in the L5-L6 level through an unclear mechanis

Biomechanical and rheological characterization of mild intervertebral disc degeneration in a large animal model

Biomechanical properties of healthy and degenerated nucleus pulposus (NP) are thought to be important for future regenerative strategies for intervertebral disc (IVD) repair. However, which properties are pivotal as design criteria when developing NP replacement materials is ill understood. Therefore, we determined and compared segmental biomechanics and NP viscoelastic properties in normal and mildly degenerated discs. In eight goats, three lumbar IVDs were chemically degenerated using chondroitinase ABC (CABC), confirmed with radiography and MRI after euthanasia 12 weeks post-operative. Neutral zone (NZ) stiffness and range of motion (ROM) were determined sagitally, laterally, and rotationally for each spinal motion segment (SMS) using a mechanical testing device. NPs were isolated for oscillatory shear experiments; elastic and viscous shear moduli followed from the ratio between shear stress and strain. Water content was quantified by weighing before and after freeze-drying. Disc height on radiographs and signal intensity on MRI decreased (6% and 22%, respectively, p  < 0.01) after CABC treatment, confirming that chemical degeneration provides a good model of disc degeneration. Furthermore, CABC-injected IVDs had significantly lower NZ stiffness and larger ROM in lateral bending (LB) and axial rotation (AR) than controls. Rheometry consistently revealed significantly lower (10-12%) viscoelastic moduli after mild degeneration within goats, though the inter-animal differences were relatively large (complex modulus ∼12 to 41 kPa). Relative water content in the NP was unaffected by CABC, remaining at ∼75%. These observations suggest that viscoelastic properties have a marginal influence on mechanical behavior of the whole SMS. Therefore, when developing replacement materials the focus should be on other design criteria, such as biochemical cues and swelling pressur

MRI T2* mapping correlates with biochemistry and histology in intervertebral disc degeneration in a large animal model

To evaluate intervertebral disc (IVD) degeneration and treatments, an objective diagnostic tool is needed. Recently, T2* relaxation time mapping was proposed as a technique to assess early IVD degeneration, yet the correlation with biochemical content and histological features has not been investigated previously. Our objective was to validate T2* mapping for disc degeneration by correlating this technique with accepted parameters of IVD degeneration. Mildly and severely degenerated lumbar discs were obtained from an in vivo large animal study; two healthy goat spines were acquired as control. In total, 48 IVDs were analysed using T2-weighted MRI, T2* relaxation time mapping, biochemical assays, macroscopic and histological scoring. Correlations between variables were expressed with Spearman's rho (ρ) coefficients. A complete range of degenerative grades were obtained (mean histological grade 2.2, range 0-6). A linear positive correlation was observed between T2* relaxation time and glycosaminoglycan content (ρ = 0.64, p <0.001). T2* relaxation time decreased linearly with increasing degeneration as assessed with Pfirrmann scoring system (ρ = -0.67, p <0.001), macroscopic (ρ = -0.33, p <0.05) and histological (ρ = -0.45, p <0.05) grading. T2* mapping is an MRI technique for IVD evaluation which allows for measurements on a continuous scale thus minimising observer bias compared to grading systems. Although limited by a small sample size, this study showed a relatively good and linear correlation between T2* relaxation time and accepted parameters of disc degeneration. This suggests that T2* mapping is a promising tool to assess disc degeneration in clinical practic