Drug utilisation in children and adolescents before and after the start of the COVID-19 pandemic: Interrupted time-series analyses in three European countries.

BACKGROUND: The COVID-19 pandemic has affected children and adolescents in several ways, including worsened mental health, improvement of asthma, and increases in diabetes ketoacidosis. Less is known about how medication use in children and adolescents has been affected by the pandemic. OBJECTIVES: To explore how the COVID-19 pandemic affected drug utilisation in children and adolescents in Norway, Sweden, and Italy, by child age. METHODS: We conducted a longitudinal drug utilisation study among all children and adolescents (<18 years old) in Norway and Sweden and a nationwide paediatric database covering 3% of the paediatric population in Italy. We conducted an interrupted time-series analysis from January 2018 to December 2021, with March 2020 as the interruption point. Dispensing or prescription rates of antidepressants, anxiolytics, sleep medications, attention-deficit/hyperactivity disorder (ADHD) medications, insulin, and asthma medications were examined. RESULTS: The study population in January 2018 consisted of 3,455,521 children and adolescents (136,188 from Italy, 1,160,431 from Norway, and 2,158,902 from Sweden). For sleep medications and insulin, there were only minor changes in level or trend in some age groups after March 2020. For asthma medications, the pandemic was associated with an immediate decrease in dispensing in Norway and Sweden (range of change in level: -19.2 to -3.7 dispensings per 1000 person-months), and an increasing trend in all countries afterward (range of change in trend: 0.3-6.4 dispensings per 1000 person-months), especially for the youngest age groups. Among adolescents, the pandemic was associated with an increased trend for ADHD medications, antidepressants, and anxiolytics in Norway and Sweden, but not in Italy. CONCLUSIONS: The increasing trend of psychotropic medication dispensing, especially among adolescents after the start of the pandemic, is concerning and should be investigated further. Aside from a temporary effect on asthma medication dispensing, the pandemic did not greatly affect the dispensing of the medications investigated.

Multiple primary dermatofibrosarcoma protuberans tumors in a single patient with chromosomal microarray analysis: A case report and review.

Dermatofibrosarcoma protuberans (DFSP) is a cutaneous sarcoma with a high propensity for local invasion and recurrence. Although it is a rare event, the occurrence of multiple tumors in a single patient raises a diagnostic dilemma, as metastatic disease should be differentiated from multiple primary malignant events. In more than 90% of DFSP, a pathogenic t(17;22) translocation leads to the expression of COL1A1::PDGFB fusion transcripts. Karyotype analysis, fluorescence in situ hybridization, and RT-PCR can be useful ancillary studies in detecting this characteristic rearrangement, and sequencing of the fusion transcript can be used to support a clonal origin in metastatic and multifocal disease. However, previous reports have demonstrated variable sensitivity of these assays, in part due to the high sequence variability of the COL1A1::PDGFB fusion. Here, we report a patient who developed two distinct DFSP tumors over the course of 7 years. Chromosomal microarray analysis identified distinctive genomic alterations in the two tumors, supporting the occurrence of multiple primary malignant events.

Medication adherence among persons with coronary heart disease and associations with blood pressure and low-density-lipoprotein-cholesterol.

PURPOSE: To describe medication adherence to lipid-lowering drugs (LLDs), antihypertensive drugs, and acetylsalicylic acid (ASA) among persons with coronary heart disease (CHD) and explore its association with low-density-lipoprotein (LDL)-cholesterol, and systolic and diastolic blood pressure. METHODS: Based on record linkage between the seventh wave of the Tromsø Study and the Norwegian Prescription Database, medication adherence was calculated as the proportion of days covered (PDC) for persistent prevalent users in the period of 365 days before the attendance date. Multivariable linear regression models were used to assess the association between systolic and diastolic blood pressure and medication nonadherence to antihypertensive drugs, age, sex, lifestyle, body mass index (BMI), current and previous diabetes, and between LDL-cholesterol and medication nonadherence to LLDs, age, sex, lifestyle, BMI, and current and previous diabetes. RESULTS: Mean PDC was 0.94 for LLDs and antihypertensive drugs and 0.97 for ASA. Among persons with PDC ≥ 0.80 for LLDs, 12.0% had an LDL-cholesterol < 1.8 mmol/L. Blood pressure < 140/90 mmHg (< 140/80 mmHg if diabetes patient) was reached by 55.1% of those with a PDC ≥ 0.80 for antihypertensive drugs. Adherence to LLDs was associated with lower LDL-cholesterol, while neither systolic nor diastolic blood pressure was associated with adherence to antihypertensive drugs. CONCLUSION: Adherence to antihypertensive drugs, LLDs, and ASA among persons with CHD were high despite low achievement of treatment goals for blood pressure and LDL-cholesterol. There was a statistically significant association between adherence to LLDs and LDL-cholesterol, but not between adherence to antihypertensive drugs and blood pressure.

Adherence to prescription guidelines and achievement of treatment goals among persons with coronary heart disease in Tromsø 7.

BACKGROUND: Adherence to clinical practice guidelines for coronary heart disease (CHD) reduces morbidity, mortality and treatment costs. We aimed to describe and compare adherence to prescription guidelines for persons with CHD, and explore its association with treatment goal achievement. METHOD: We included all participants reporting myocardial infarction, angina, percutaneous coronary intervention and/or coronary artery bypass surgery in the seventh wave of the Tromsø Study (2015-2016, n = 1483). Medication use and treatment goal measures (blood pressure, low-density lipoprotein (LDL)-cholesterol and HbA1c) were compared to clinical practice guidelines on secondary CHD prevention. Propensity score matched logistic regression was used to assess the association between the use of antihypertensive drugs and achievement of treatment goal for blood pressure, and the use of lipid-lowering drugs (LLDs) and achievement of treatment goal for LDL-cholesterol. RESULTS: The prevalence of pharmacological CHD treatment was 76% for LLDs, 72% for antihypertensive drugs and 66% for acetylsalicylic acid. The blood pressure goal (< 140/90 mmHg, < 140/80 mmHg if diabetic) was achieved by 58% and the LDL-cholesterol goal (< 1.8 mmol/l or < 70 mg/dL) by 9%. There was a strong association between using LLDs and achieving the treatment goal for LDL-cholesterol (OR 14.0, 95% CI 3.6-54.7), but not between using antihypertensive drugs and blood pressure goal achievement (OR 1.4, 95% CI 0.7-2.7). CONCLUSION: Treatment goal achievement of LDL-cholesterol and blood pressure was low, despite the relatively high use of LLDs and antihypertensive drugs. Further research is needed to find the proper actions to increase achievement of the treatment goals.

The Ewing Sarcoma Secretome and Its Response to Activation of Wnt/beta-catenin Signaling.

Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta-catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells up-regulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.

High intensity exercise for 3 months reduces disease activity in axial spondyloarthritis (axSpA): a multicentre randomised trial of 100 patients.

BACKGROUND: Exercise is considered important in the management of patients with rheumatic diseases, but the effect of high intensity exercises on disease activity is unknown. OBJECTIVE: To investigate the effectiveness of high intensity exercises on disease activity in patients with axial spondyloarthritis (axSpA). METHOD: Assessor blinded multicentre randomised controlled trial. 100 patients (aged from their 20s to their 60s) with axSpA were randomly assigned to an exercise group or to a no-intervention control group. The exercise group performed cardiorespiratory and muscular strength exercises at high intensity over 3 months. The control group received standard care and was instructed to maintain their usual physical activity level. Primary outcome was disease activity measured with the Ankylosing Spondylitis (AS) Disease Activity Scale (ASDAS, higher score=worst) and the Bath AS Disease Activity Index (BASDAI, 0-10, 10=worst). Secondary outcomes were inflammatory markers, physical function and cardiovascular (CV)-health. There was patient involvement in the design and reporting of this study. RESULTS: 97 of the 100 (97%) randomised patients completed the measurements after the intervention. There was a significant treatment effect of the intervention on the primary outcome (ASDAS: -0.6 [-0.8 to -0.3], p<0.001 and BASDAI: -1.2 [-1.8 to -0.7], p<0.001). Significant treatment effects were also seen for inflammation, physical function and CV-health. CONCLUSION: High intensity exercises reduced disease symptoms (pain, fatigue, stiffness) and also inflammation in patients with axSpA. It improves patients' function and CV health. This debunks concerns that high intensity exercise might exacerbate disease activity in patients with axSpA. TRIAL REGISTRATION NUMBER: NCT02356874.

An 82-year-old man with recurrent angioedema.

Angioedema is a potentially life-threatening swelling condition that can occur either in isolation or in the context of other syndromes, e.g., anaphylaxis. Angioedema is typically asymmetric, lasts for hours to days, is not gravity dependent, and is often nonpitting. Recurrent angioedema is typically associated with histaminergic and bradykinin-mediated causes, some of which can indicate underlying etiologies with high morbidity or mortality. The differential diagnosis for acute angioedema can include anaphylaxis, chronic urticaria with angioedema, medications such as angiotensin-converting-enzyme inhibitors, hereditary C1 esterase inhibitor defects, and acquired defects; however, the cause is often idiopathic, and effective therapy can be elusive. In this article, we described a unique etiology of a case of isolated recurrent angioedema that improved when the possible underlying cause was successfully treated.

Mental states and activities in Danish narratives: children with autism and children with language impairment.

This study focuses on the relationship between content elements and mental-state language in narratives from twenty-seven children with autism (ASD), twelve children with language impairment (LI), and thirty typically developing children (TD). The groups did not differ on chronological age (10;6-14;0) and non-verbal cognitive skills, and the groups with ASD and TD did not differ on language measures. The children with ASD and LI had fewer content elements of the storyline than the TD children. Compared with the TD children, the children with ASD used fewer subordinate clauses about the characters' thoughts, and preferred talking about mental states as reported speech, especially in the form of direct speech. The children with LI did not differ from the TD children on these measures. The results are discussed in the context of difficulties with socio-cognition in children with ASD and of language difficulties in children with LI.

Context predicts word order processing in Broca's region.

The function of the left inferior frontal gyrus (L-IFG) is highly disputed. A number of language processing studies have linked the region to the processing of syntactical structure. Still, there is little agreement when it comes to defining why linguistic structures differ in their effects on the L-IFG. In a number of languages, the processing of object-initial sentences affects the L-IFG more than the processing of subject-initial ones, but frequency and distribution differences may act as confounding variables. Syntactically complex structures (like the object-initial construction in Danish) are often less frequent and only viable in certain contexts. With this confound in mind, the L-IFG activation may be sensitive to other variables than a syntax manipulation on its own. The present fMRI study investigates the effect of a pragmatically appropriate context on the processing of subject-initial and object-initial clauses with the IFG as our ROI. We find that Danish object-initial clauses yield a higher BOLD response in L-IFG, but we also find an interaction between appropriateness of context and word order. This interaction overlaps with traditional syntax areas in the IFG. For object-initial clauses, the effect of an appropriate context is bigger than for subject-initial clauses. This result is supported by an acceptability study that shows that, given appropriate contexts, object-initial clauses are considered more appropriate than subject-initial clauses. The increased L-IFG activation for processing object-initial clauses without a supportive context may be interpreted as reflecting either reinterpretation or the recipients' failure to correctly predict word order from contextual cues.

Context improves comprehension of fronted objects.

Object-initial clauses (OCs) are associated with more processing difficulties than subject-initial clauses (SCs) in a number of languages (e.g. English, German and Finnish), but a supportive context can reduce or neutralize the difference between SCs and OCs with respect to reading times. Still, it is unresolved how context can affect the comprehension of OCs. In the present self-paced reading study of Danish, we therefore investigated both reading times, comprehension accuracy and response times for OCs and SCs. In line with previous studies on word order processing, OCs in an unsupportive context showed longer reading times than SCs, longer response times and a comprehension accuracy as poor as chance level. A manipulation of context showed no effect of reading time, but a supportive context had a stronger facilitating effect on comprehension (response accuracy and response time) for OCs than for SCs.

Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study.

Several studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of 'cold' cognition (including inhibition, cognitive flexibility, memory) and 'hot cognition' including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive either 20 mg of escitalopram (n = 32) or placebo (n = 34), balanced for age, sex and intelligence quotient (IQ) for at least 21 days. Questionnaires, neuropsychological tests and serum escitalopram measures were taken. We analysed group differences on the cognitive measures using linear regression models as well as innovative hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task. The novel and important finding was that escitalopram reduced reinforcement sensitivity compared to placebo on both the Sequential Model-Based/Model-Free task and the PRL task. We found no other significant group differences on 'cold' or 'hot' cognition. These findings demonstrate that serotonin reuptake inhibition is involved in reinforcement learning in healthy individuals. Lower reinforcement sensitivity in response to chronic SSRI administration may reflect the 'blunting' effect often reported by patients with MDD treated with SSRIs. Trial Registration: NCT04239339 .

Self-reported medication use among coronary heart disease patients showed high validity compared with dispensing data.

OBJECTIVE: To validate self-reported use of medications for secondary prevention of coronary heart disease (CHD) in a population-based health study by comparing self-report with pharmacy dispensing data, and explore different methods for defining medication use in prescription databases. STUDY DESIGN AND SETTING: Self-reported medication use among participants with CHD (n = 1483) from the seventh wave of the Tromsø Study was linked with the Norwegian Prescription Database (NorPD). Cohen's kappa, sensitivity, specificity, and positive and negative predictive values were calculated, using NorPD as the reference standard. Medication use in NorPD was defined in three ways; fixed-time window of 180 days, and legend-time method assuming a daily dose of one dosage unit or one defined daily dose (DDD). RESULTS: Kappa-values for antihypertensive drugs, lipid-lowering drugs and acetylsalicylic acid all showed substantial agreement (kappa ≥0.61). Validity varied depending on the method used for defining medication use in NorPD. Applying a fixed-time window gave higher agreement, positive predictive values and specificity compared with the legend-time methods. CONCLUSION: Self-reported use of medication for secondary prevention of CHD shows high validity when compared with pharmacy dispensing data. For CHD medications, fixed-time window appears to be the most appropriate method for defining medication use in prescription databases.

High-Intensity Exercise Improves Fatigue, Sleep, and Mood in Patients With Axial Spondyloarthritis: Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVE: Although exercise is recommended in the treatment of axial spondyloarthritis (axSpa), the focus has been on flexibility, and the effect of high-intensity exercises is unknown. The purpose of this study was to investigate the effect of high-intensity exercises on fatigue, sleep, and mood in patients with axSpA. METHODS: In this secondary analysis of a randomized controlled trial, participants were recruited from outpatient clinics at 4 hospitals in Scandinavia. A total of 100 patients with axSpA were randomized to either an exercise group (n = 50) or a control group (n = 50). High-intensity exercise was provided 3 times per week for 3 months and supervised by a physical therapist. The controls received no intervention. Measurements were self-reported at baseline, 3 months, and 12 months: fatigue, using the Fatigue Severity Scale (range = 0-7, 7 = worst, ≥5 = severe); vitality, using the RAND 36-item short-form health survey (SF-36, range = 0-100, 100 = best); sleep, using the Pittsburgh Sleep Quality Index (range = 0-21, 21 = worst, >5 = poor quality); mood, using the General Health Questionnaire 12 (range = 0-36, 36 = worst); and general health, using the EUROQoL (range = 0-100, 100 = best). RESULTS: A total of 38 participants (76%) in the exercise group followed ≥80% of the exercise protocol. At 3 months, there was a significant beneficial effect on fatigue (mean group differences = -0.4, 95% CI = -0.7 to -0.1), vitality (5.0, 95% CI = 1.1 to 10.5), mood (-2, 95% CI = -3.7 to -0.04), and general health (9.0, 95% CI = 3.3 to 14.7) but no effect on sleep (-1.1, 95% CI = -2.1 to 0.2). Compared with the control group, the exercise group had a reduced rate of severe fatigue and poor sleep. No differences were seen between the groups at 12 months. CONCLUSIONS: A 3-month exercise program had a beneficial effect on fatigue, sleep, mood, and general health in patients with axSpA at the end of the intervention; however, no long-term effects were seen. IMPACT: High-intensity cardiorespiratory and strength exercises should be considered as important in exercise programs for patients with axSpA.

Responsiveness and Interpretability of 2 Measures of Physical Function in Patients With Spondyloarthritis.

BACKGROUND: Maintenance or improvement of physical function is an important treatment target in the management of patients with axial spondyloarthritis (axSpA); measurement tools that can detect changes in physical function are therefore important. OBJECTIVES: The objective of this study was to compare responsiveness and interpretability of the patient-reported Bath Ankylosing Spondylitis Functional Index (BASFI) and the Ankylosing Spondylitis Performed-Based Improvement (ASPI) in measuring change in physical function after exercise in patients with axSpA. DESIGN: This was a sub-study of 58 patients nested within a randomized controlled trial comparing the effect of 12 weeks of exercise with usual care. METHODS: Responsiveness and interpretability were assessed according to the Consensus-based Standards for the selection of health status Measurement Instrument. Responsiveness was assessed by testing 8 predefined hypotheses for ASPI and BASFI. Interpretability was assessed by: (1) using patients' reported change as an anchor ("a little better" = minimal important change) and (2) by categorizing patients with a 20% improvement as responders. RESULTS: For ASPI and BASFI, 5 of 8 (63%) versus 2 of 8 (25%) of the predefined hypotheses for responsiveness were confirmed. The minimal important change values for improvement in physical function were 3.7 seconds in ASPI and 0.8 points (on a scale from 0 to 10) for BASFI. In the intervention group, 21 of 30 (70%) and 13 of 30 (43%) of the patients were categorized as responders measured with ASPI and BASFI, respectively. There was a tendency towards a floor effect in BASFI, as 8 of 58 (14%) patients scored the lowest value at baseline. LIMITATIONS: This study was limited by its moderate sample size. CONCLUSIONS: Our findings suggest that ASPI is preferable over BASFI when evaluating physical function after exercise interventions in patients with axSpA.

Longterm Effect on Leisure Time Physical Activity Level in Individuals with Axial Spondyloarthritis: Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVE: To explore the longterm effect of a 3-month exercise program on leisure time physical activity level in individuals with axial spondyloarthritis (axSpA). METHODS: A secondary analysis was performed on data from 100 individuals with axSpA who were included in a randomized controlled trial. The exercise group (EG) participated in a 3-month exercise program while the control group (CG) received no intervention. Physical activity during leisure time was measured with a questionnaire (physically active: ≥ 1 h/week with moderate/vigorous intensity physical activity). Disease activity was measured with the Ankylosing Spondylitis Disease Activity Scale (ASDAS; higher score = worst). Statistical analyses were performed on an intention-to-treat basis using chi-square tests, logistic regression, and mixed models. RESULTS: At the 12-month followup, significantly more individuals in the EG than in the CG were physically active [29 (67%) vs 13 (30%), p < 0.001] and exercised 2-3 times/week [25 (58%) vs 15 (34%), p = 0.02], and fewer exercised at light intensity [3 (8%) vs 14 (44%), p = 0.002]. "Participation in the EG" (OR 6.7, 95% CI 2.4-18.6, p < 0.001) and "being physically active at baseline" (OR 4.7, 95% CI 1.4-15.8, p = 0.01) were the factors most associated with being physically active. There were no differences between the groups in ASDAS (p = 0.79). CONCLUSION: A 3-month exercise program had a beneficial longterm effect on leisure time physical activity in individuals with axSpA, thus indicating a more beneficial health profile. Still, few individuals continued the intensive program, and there was no difference between the groups in disease activity after 12 months. (ClinicalTrials.gov: NCT02356874).

Wnt/ß-catenin-activated Ewing sarcoma cells promote the angiogenic switch.

Wnt/ß-catenin signaling is active in small subpopulations of Ewing sarcoma cells, and these cells display a more metastatic phenotype, in part due to antagonism of EWS-FLI1-dependent transcriptional activity. Importantly, these ß-catenin-activated Ewing sarcoma cells also alter secretion of extracellular matrix (ECM) proteins. We thus hypothesized that, in addition to cell-autonomous mechanisms, Wnt/ß-catenin-active tumor cells might contribute to disease progression by altering the tumor microenvironment (TME). Analysis of transcriptomic data from primary patient biopsies and from ß-catenin-active versus -nonactive tumor cells identified angiogenic switch genes as being highly and reproducibly upregulated in the context of ß-catenin activation. In addition, in silico and in vitro analyses, along with chorioallantoic membrane assays, demonstrated that ß-catenin-activated Ewing cells secreted factors that promote angiogenesis. In particular, activation of canonical Wnt signaling leads Ewing sarcoma cells to upregulate expression and secretion of proangiogenic ECM proteins, collectively termed the angiomatrix. Significantly, our data show that induction of the angiomatrix by Wnt-responsive tumor cells is indirect and is mediated by TGF-ß. Mechanistically, Wnt/ß-catenin signaling antagonizes EWS-FLI1-dependent repression of TGF-ß receptor type 2, thereby sensitizing tumor cells to TGF-ß ligands. Together, these findings suggest that Wnt/ß-catenin-active tumor cells can contribute to Ewing sarcoma progression by promoting angiogenesis in the local TME.

Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer.

One of the most life-threatening complications of prostate cancer is skeletal metastasis. In order to develop treatment for metastasis, it is important to understand its molecular mechanisms. Our work in this field has drawn parallels between hematopoietic stem cell and prostate cancer homing to the marrow. Our recent work demonstrated that annexin II expressed by osteoblasts and endothelial cells plays a critical role in niche selection. In this study, we demonstrate that annexin II and its receptor play a crucial role in establishing metastasis of prostate cancer. Prostate cancer cell lines migrate toward annexin II and the adhesion of prostate cancer to osteoblasts and endothelial cells was inhibited by annexin II. By blocking annexin II or its receptor in animal models, short-term and long-term localization of prostate cancers are limited. Annexin II may also facilitate the growth of prostate cancer in vitro and in vivo by the MAPK pathway. These data strongly suggest that annexin II and its receptor axis plays a central role in prostate cancer metastasis, and that prostate cancer utilize the hematopoietic stem cell homing mechanisms to gain access to the niche.

CD26/dipeptidyl peptidase IV regulates prostate cancer metastasis by degrading SDF-1/CXCL12.

Stromal derived factor-1 (SDF-1 or CXCL12) expressed by osteoblasts and endothelial cells, and its receptors CXCR4 and CXCR7/RDC1 are key molecular determinants in prostate cancer (PCa) metastasis. What drives PCa cells into the extravascular marrow space(s) once they make contact with the blood vessel endothelium, however remains unclear. Here, we evaluated whether degradation of CXCL12 facilitates PCa cell entry into the marrow cavity by locally lowering CXCL12 levels intravascularly. To explore this possibility, co-cultured conditioned media from PCa cells and endothelial cells were evaluated for their ability to degrade biotinylated CXCL12 (bCXCL12). Co-culture of PCa cells/endothelial cells resulted in greater digestion of CXCL12 than was achieved by either cell type alone, and this activity regulated invasion in vitro. The ability to degrade CXCL12 was not however observed in PCa and osteoblasts co-cultures. Fractionation and inhibitor studies suggested that the activity was CD26/dipeptidyl peptidase IV (DPPIV) and possibly other cysteine/serine proteases. By inhibiting CD26/DPPIV, invasion and metastasis of PCa cell lines were enhanced in in vitro and in vivo metastasis assays. Together, these data suggest that the degradation of CXCL12 by CD26/DPPIV may be involved in the metastatic cascades of PCa, and suggests that inhibition of CD26/DPPIV may be a trigger of PCa metastasis.