Applications of artificial intelligence in prostate cancer histopathology.

The diagnosis of prostate cancer (PCa) depends on the evaluation of core needle biopsies by trained pathologists. Artificial intelligence (AI) derived models have been created to address the challenges posed by pathologists' increasing workload, workforce shortages, and variability in histopathology assessment. These models with histopathological parameters integrated into sophisticated neural networks demonstrate remarkable ability to identify, grade, and predict outcomes for PCa. Though the fully autonomous diagnosis of PCa remains elusive, recently published data suggests that AI has begun to serve as an initial screening tool, an assistant in the form of a real-time interactive interface during histological analysis, and as a second read system to detect false negative diagnoses. Our article aims to describe recent advances and future opportunities for AI in PCa histopathology.

Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial.

Cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC), but it is life-altering. We initiated a phase 2 study in which patients with MIBC received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) could proceed without cystectomy. The co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival in patients forgoing immediate cystectomy or

Health for All: A Report of the 2020 Association of American Medical Colleges Learn Serve Lead Meeting.

Learn Serve Lead (LSL) is the signature annual conference of the Association of American Medical Colleges (AAMC), which focuses on the most pressing issues facing American medical practice and education. Unsurprisingly, the recent AAMC LSL conference at the end of 2020 centered on the multifaceted impacts of the COVID-19 pandemic and racial inequity upon the medical community. At the LSL meeting, national leaders, practicing physicians from diverse specialties, and medical trainees discussed the impact of these challenges and ongoing strategies to overcome them. These efforts paralleled the AAMC mission areas of community collaborations, medical education, clinical care, and research. Additionally, this focus aligns with the ACR's core purpose: to serve patients and society by empowering members to advance the practice, science, and professions of radiological care. ACR is a member of the AAMC Council of Faculty and Academic Society and seeks to collaborate with other medical specialties to promote interdisciplinary collaboration, contribute to medical education, and voice the value of medical imaging for patient care. We summarize the major insights of this interdisciplinary conference and present tailored recommendations for applying these insights specifically within the radiology community. In addition, we review the parallels between the ACR and the AAMC strategic plans.

What's in a Name? Report of the ACR Task Force on General Radiology and Multi-Subspecialization.

The ACR Council passed Resolution 47 at its 2020 annual meeting establishing a representative task force (TF) to explore the concept of the "multispecialty radiologist," previously proposed in 2012. The TF held eight virtual meetings over 8 months, considered data from a 2020 ACR Membership Tracking Survey, conducted a review of current literature, and collected anecdotal experience from TF members and ACR leadership. ACR legal counsel and a cross-section of ACR Commissions and Committees also provided input. The TF concluded that there is scant interest from the radiology community in the multispecialty radiologist title and no agreed-upon definition for the term. Radiologists may identify as diagnostic or subspecialty radiologists; however, the roles they fill in clinical practice include general, multispecialty, and subspecialized radiology. The TF proposes definitions for each of these terms to support radiologist recruitment aligned with optimal patient care in the practice community and to improve the quality of data collection about the field. To reduce ambiguity, the TF proposes adoption of the defined terms by the radiology community, including radiologist recruiters and employers, and suggests ways in which resident training and the ABR board examination can be adapted to support this new structure. Additionally, as part of an exploration of hyperspecialization and trainee preparedness for clinical practice, the TF discussed the challenges faced by community-based practices seeking to provide a full range of high-quality, radiologist-delivered diagnostic and interventional services to their patient populations.

Urothelial carcinoma of the graft kidney with molecular analyses: a rare case report.

BACKGROUND: Malignancy after transplantation is a leading cause of death among kidney transplant recipients. However, donor-derived malignancies are rare. We report a case of a high grade papillary urothelial carcinoma arising in a transplanted kidney. CASE PRESENTATION: A 62-year-old female who received a kidney transplantation more than 30 years ago presented with urinary tract infection, acute renal failure, and hydronephrosis of the transplant kidney. Anterograde nephrostogram showed a large filling defect in the lower pole of the transplant kidney and in the proximal 3-4 cm of the ureter. A biopsy from the renal pelvic mass showed a high grade urothelial carcinoma. She underwent an anterior exenteration, resection of both transplant and native kidneys and bilateral pelvic lymph node dissection. Pathologic examination showed a high grade papillary urothelial carcinoma which appeared to arise in the pelvis of the graft kidney, involve the graft ureter and native urinary bladder. The tumor had metastasized to one left obturator lymph node but spared the two native kidneys and ureters. Short tandem repeat (STR) analysis confirmed the tumor to be of donor origin. Next-generation sequencing identified amplification of TERT and loss of CDKN2A/CDKN2B in the primary tumor. CONCLUSION: While it is known that transplant recipients have an increased risk of urothelial carcinoma compared to the general population, the lack of the well-documented risk factors, such as older age at transplantation, BK polyomavirus infection, and prolonged post-transplantation history and dissemination of the tumor in this case shed light on the de novo tumorigenesis of the graft kidney within the host microenvironment. Amplification of Telomerase reverse transcriptase (TERT) and loss of cyclin dependent kinase inhibitor 2A/2B (CDKN2A/CDKN2B) detected in the tumor by next gene sequencing suggests that they may play an important role in this case.

Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.

Predicted Cost Savings Achieved by the Radiology Support, Communication and Alignment Network from Reducing Medical Imaging Overutilization in the Medicare Population.

OBJECTIVE: The Radiology Support, Communication and Alignment Network (R-SCAN) is a quality improvement program through which patients, referring clinicians, and radiologists collaborate to improve imaging appropriateness based on Choosing Wisely recommendations and ACR Appropriateness Criteria. R-SCAN was shown previously to increase the odds of obtaining an appropriate, higher patient or diagnostic value, imaging study. In the current study, we aimed to estimate the potential imaging cost savings associated with R-SCAN use for the Medicare population. MATERIAL AND METHODS: The R-SCAN data set was used to determine the proportion of appropriate and lesser value imaging studies performed, as well as the percent change in the total number of imaging studies performed, before and after an R-SCAN educational intervention. Using a separate CMS data set, we then identified the total number of relevant imaging studies and associated total costs using a 5% sample of Medicare beneficiaries in 2017. We applied R-SCAN proportions to the CMS data set to estimate the potential impact of the R-SCAN interventions across a broader Medicare population. RESULTS: We observed a substantial reduction in the costs associated with lesser value imaging in the R-SCAN cohort, totaling $260,000 over 3.5 months. When extrapolated to the Medicare population, the potential cost reductions associated with the decrease in lesser value imaging totaled $433 million yearly. CONCLUSION: If expanded broadly, R-SCAN interventions can result in substantial savings to the Medicare program.

Assessment of the Radiology Support, Communication and Alignment Network to Reduce Medical Imaging Overutilization: A Multipractice Cohort Study.

PURPOSE: The aim of this study was to determine whether participation in Radiology Support, Communication and Alignment Network (R-SCAN) results in a reduction of inappropriate imaging in a wide range of real-world clinical environments. METHODS: This quality improvement study used imaging data from 27 US academic and private practices that completed R-SCAN projects between January 25, 2015, and August 8, 2018. Each project consisted of baseline, educational (intervention), and posteducational phases. Baseline and posteducational imaging cases were rated as high, medium, or low value on the basis of validated ACR Appropriateness Criteria®. Four cohorts were generated: a comprehensive cohort that included all eligible practices and three topic-specific cohorts that included practices that completed projects of specific Choosing Wisely topics (pulmonary embolism, adnexal cyst, and low back pain). Changes in the proportion of high-value cases after R-SCAN intervention were assessed for each cohort using generalized estimating equation logistic regression, and changes in the number of low-value cases were analyzed using Poisson regression. RESULTS: Use of R-SCAN in the comprehensive cohort resulted in a greater proportion of high-value imaging cases (from 57% to 79%; odds ratio, 2.69; 95% confidence interval, 1.50-4.86; P = .001) and 345 fewer low-value cases after intervention (incidence rate ratio, 0.45; 95% confidence interval, 0.29-0.70; P < .001). Similar changes in proportion of high-value cases and number of low-value cases were found for the pulmonary embolism, adnexal cyst, and low back pain cohorts. CONCLUSIONS: R-SCAN participation was associated with a reduced likelihood of inappropriate imaging and is thus a promising tool to enhance the quality of patient care and promote wise use of health care resources.

Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer.

PURPOSE: Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. "Switch maintenance" therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons. PATIENTS AND METHODS: Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS). RESULTS: Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival. CONCLUSION: Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

A Secondary Analysis to Identify Patient-Centered Outcomes in the ACR's Appropriateness Criteria.

CONTEXT: There is a growing body of literature indicating imaging testing can affect patients cognitively, socially, behaviorally, and emotionally. The extent to which these patient-centered outcomes (PCOs) are reported in the imaging literature is unclear. Identifying PCOs may facilitate shared decision making around imaging testing. OBJECTIVE: To identify PCOs across a spectrum of clinical topics included in the ACR's Appropriateness Criteria (AC). METHODS: We systematically reviewed AC evidence tables for eligible articles of studies conducted in any clinical setting in high-income countries. Included studies reported PCOs occurring as a direct or indirect result of an imaging test performed for any reason (eg, diagnosis, screening, surveillance, or staging). PCOs and the methods used to measure them were extracted through a secondary analysis and descriptive synthesis. RESULTS: Our search identified 89 articles that reported outcomes of radiation exposure (n = 37), downstream testing (n = 20), complications (n = 19), incidental findings (n = 10), quality of life (n = 7), physical discomfort (n = 5), patient values and experiences (n = 4), patient financial and time costs (n = 4), psychosocial outcomes (n = 4), and test duration (n = 2). These outcomes were rarely reported from the patient perspective and were measured using a range of standardized or validated and nonstandardized methods. CONCLUSIONS: We identified few PCOs incorporated in the AC. Our findings reflect the historical emphasis of diagnostic research on accuracy, clinical utility, and selected outcomes (eg, adverse events). As radiology moves to a more patient-centered approach, it will be important to measure PCOs reported directly from patients.

Bim suppresses the development of SLE by limiting myeloid inflammatory responses.

The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. We demonstrate that Bim acts as a molecular rheostat by controlling macrophage function not only in lymphoid organs but also in end organs, thereby preventing the break in tolerance. Mice lacking Bim in myeloid cells (LysMCreBimfl/fl) develop a systemic lupus erythematosus (SLE)-like disease that mirrors aged Bim-/- mice, including loss of marginal zone macrophages, splenomegaly, lymphadenopathy, autoantibodies (including anti-DNA IgG), and a type I interferon signature. LysMCreBimfl/fl mice exhibit increased mortality attributed to glomerulonephritis (GN). Moreover, the toll-like receptor signaling adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-ß) is essential for GN, but not systemic autoimmunity in LysMCreBimfl/fl mice. Bim-deleted kidney macrophages exhibit a novel transcriptional lupus signature that is conserved within the gene expression profiles from whole kidney biopsies of patients with SLE. Collectively, these data suggest that the Bim may be a novel therapeutic target in the treatment of SLE.

The caspase-8/RIPK3 signaling axis in antigen presenting cells controls the inflammatory arthritic response.

BACKGROUND: Caspase-8 is a well-established initiator of apoptosis and suppressor of necroptosis, but maintains functions beyond cell death that involve suppression of receptor-interacting serine-threonine kinases (RIPKs). A genome-wide association study meta-analysis revealed an SNP associated with risk of rheumatoid arthritis (RA) development within the locus containing the gene encoding for caspase-8. Innate immune cells, like macrophages and dendritic cells, are gaining momentum as facilitators of autoimmune disease pathogenesis, and, in particular, RA. Therefore, we examined the involvement of caspase-8 within these antigen-presenting cell populations in the pathogenesis of an arthritis model that resembles the RA effector phase. METHODS: Cre LysM Casp8 flox/flox and Cre CD11c Casp8 flox/flox mice were bred via a cross between Casp8 flox/flox and Cre LysM or Cre CD11c mice. RIPK3 -/- Cre LysM Casp8 flox/flox and RIPK3 -/- Cre CD11c Casp8 flox/flox mice were generated to assess RIPK3 contribution. Mice were subjected to K/BxN serum-transfer-induced arthritis. Luminex-based assays were used to measure cytokines/chemokines. Histological analyses were utilized to examine joint damage. Mixed bone marrow chimeras were generated to assess synovial cell survival. Flow cytometric analysis was employed to characterize cellular distribution. For arthritis, differences between the groups were assessed using two-way analysis of variance (ANOVA) for repeated measurements. All other data were compared by the Mann-Whitney test. RESULTS: We show that intact caspase-8 signaling maintains opposing roles in lysozyme-M- and CD11c-expressing cells in the joint; namely, caspase-8 is crucial in CD11c-expressing cells to delay arthritis induction, while caspase-8 in lysozyme M-expressing cells hinders arthritis resolution. Caspase-8 is also implicated in the maintenance of synovial tissue-resident macrophages that can limit arthritis. Global loss of RIPK3 in both caspase-8 deletion constructs causes the response to arthritis to revert back to control levels via a mechanism potentially independent of cell death. Mixed bone marrow chimeric mice demonstrate that caspase-8 deficiency does not confer preferential expansion of synovial macrophage and dendritic cell populations, nor do caspase-8-deficient synovial populations succumb to RIPK3-mediated necroptotic death. CONCLUSIONS: These data demonstrate that caspase-8 functions in synovial antigen-presenting cells to regulate the response to inflammatory stimuli by controlling RIPK3 action, and this delicate balance maintains homeostasis within the joint.

Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients. METHODS: We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro. RESULTS: Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity. CONCLUSIONS: These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease.

Association of Increased F4/80high Macrophages With Suppression of Serum-Transfer Arthritis in Mice With Reduced FLIP in Myeloid Cells.

OBJECTIVE: Macrophages are critical in the pathogenesis of rheumatoid arthritis (RA). We recently demonstrated that FLIP is necessary for the differentiation and/or survival of macrophages. We also showed that FLIP is highly expressed in RA synovial macrophages. This study was undertaken to determine if a reduction in FLIP in mouse macrophages reduces synovial tissue macrophages and ameliorates serum-transfer arthritis. METHODS: Mice with Flip deleted in myeloid cells (Flipf/f LysMc/+ mice) and littermate controls were used. Arthritis was induced by intraperitoneal injection of K/BxN serum. Disease severity was evaluated by clinical score and change in ankle thickness, and joints were examined by histology and immunohistochemistry. Cells were isolated from the ankles and bone marrow of the mice and examined by flow cytometry, real-time quantitative reverse transcriptase-polymerase chain reaction, or Western blotting. RESULTS: In contrast to expectations, Flipf/f LysMc/+ mice developed more severe arthritis early in the clinical course, but peak arthritis was attenuated and the resolution phase more complete than in control mice. Prior to the induction of serum-transfer arthritis, the number of tissue-resident macrophages was reduced. On day 9 after arthritis induction, the number of F4/80high macrophages in the joints of the Flipf/f LysMc/+ mice was not decreased, but increased. FLIP was reduced in the F4/80high macrophages in the ankles of the Flipf/f LysMc/+ mice, while F4/80high macrophages expressed an antiinflammatory phenotype in both the Flipf/f LysMc/+ and control mice. CONCLUSION: Our observations suggest that reducing FLIP in macrophages by increasing the number of antiinflammatory macrophages may be an effective therapeutic approach to suppress inflammation, depending on the disease stage.

Lessons Learned From Two Decades of Patient- and Family-Centered Care in Radiology, Part 2: Building a Culture.

As reimbursements are increasingly linked to patient experience, physicians and hospitals will need to find ways to incorporate patient and family input into operational decisions. Rather than starting from the beginning, health systems could learn from practitioners who have been experimenting in this space and are willing to share their experience. The authors share lessons learned from two decades of experience incorporating patient and family advisers into the clinical operation of a radiology department and the resulting culture change. Radiology and radiologists can incorporate principles of patient- and family-centered care into clinical operations without loss of productivity.

Lessons Learned From Two Decades of Patient- and Family-Centered Care in Radiology, Part 1: Getting Started.

Patient- and family-centered care has a long history, but the application of these principles to radiology is limited by infrequent direct patient contact for many radiologists; scarce peer-reviewed data in the radiology literature; and sparse access to implementation strategies, tools, and best practices. In a series of two articles, the authors share two decades of lessons learned from implementing patient- and family-centered care in a radiology department.

Inflammatory properties of inhibitor of DNA binding 1 secreted by synovial fibroblasts in rheumatoid arthritis.

BACKGROUND: Inhibitor of DNA binding 1 (Id1) is a nuclear protein containing a basic helix-loop-helix (bHLH) domain that regulates cell growth by selective binding and prevention of gene transcription. Sources of Id1 production in rheumatoid arthritis synovial tissue (RA ST) and its range of functional effects in RA remain to be clarified. METHODS: We analyzed Id1 produced from synovial fibroblasts and endothelial cells (ECs) with histology and real-time polymerase chain reaction (RT-PCR). Fibroblast supernatants subjected to differential centrifugation to isolate and purify exosomes were measured for Id1 by enzyme-linked immunosorbent assay (ELISA). Western blotting of Id1-stimulated ECs was performed to determine the kinetics of intracellular protein phosphorylation. EC intracellular signaling pathways induced by Id1 were subsequently targeted with silencing RNA (siRNA) for angiogenesis inhibition. RESULTS: By PCR and histologic analysis, we found that the primary source of Id1 in STs is from activated fibroblasts that correlate with inflammatory scores in human RA ST and in joints from K/BxN serum-induced mice. Normal (NL) and RA synovial fibroblasts increase Id1 production with stimulation by transforming growth factor beta (TGF-ß). Most of the Id1 released by RA synovial fibroblasts is contained within exosomes. Endothelial progenitor cells (EPCs) and human dermal microvascular ECs (HMVECs) activate the Jnk signaling pathway in response to Id1, and Jnk siRNA reverses Id1-induced HMVEC vessel formation in Matrigel plugs in vivo. CONCLUSIONS: Id1 is a pleotropic molecule affecting angiogenesis, vasculogenesis, and fibrosis. Our data shows that Id1 is not only an important nuclear protein, but also can be released from fibroblasts via exosomes. The ability of extracellular Id1 to activate signaling pathways expands the role of Id1 in the orchestration of tissue inflammation.

Scleroderma dermal microvascular endothelial cells exhibit defective response to pro-angiogenic chemokines.

OBJECTIVES: Angiogenesis plays a critical role in SSc (scleroderma). The aim of this study was to examine the expression of growth-regulated protein-γ (Gro-γ/CXCL3), granulocyte chemotactic protein 2 (GCP-2/CXCL6) and their receptor CXCR2 in endothelial cells (ECs) isolated from SSc skin and determine whether these cells mount an angiogenic response towards pro-angiogenic chemokines. The downstream signalling pathways as well as the pro-angiogenic transcription factor inhibitor of DNA-binding protein 1 (Id-1) were also examined. METHODS: Skin biopsies were obtained from patients with dcSSc. ECs were isolated via magnetic positive selection. Angiogenesis was measured by EC chemotaxis assay. RESULTS: Gro-γ/CXCL3 and GCP-2/CXCL6 were minimally expressed in both skin types but elevated in SSc serum. Pro-angiogenic chemokine mRNA was greater in SSc ECs than in normal ECs. SSc ECs did not migrate to vascular endothelial growth factor (VEGF), Gro-γ/CXCL3, GCP-2/CXCL6 or CXCL16. The signalling pathways stimulated by these chemokines were also dysregulated. Id-1 mRNA in SSc ECs was lower compared with normal ECs, and overexpression of Id-1 in SSc ECs increased their ability to migrate towards VEGF and CXCL16. CONCLUSION: Our results show that SSc ECs are unable to respond to pro-angiogenic chemokines despite their increased expression in serum and ECs. This might be due to the differences in the signalling pathways activated by these chemokines in normal vs SSc ECs. In addition, the lower expression of Id-1 also decreases the angiogenic response. The inability of pro-angiogenic chemokines to promote EC migration provides an additional mechanism for the impaired angiogenesis that characterizes SSc.