Total and Visceral Adiposity Are Associated With Prevalent Vertebral Fracture in Women but Not Men at Age 62 Years: The Newcastle Thousand Families Study

Low body weight is an established risk factor for osteoporosis and fracture, but the skeletal risks of higher adiposity are unclear and appear sex‐specific and site‐dependent. The aim of this study was to investigate associations of total fat mass (TFM), visceral adipose tissue (VAT), and C‐reactive protein (CRP) with bone mineral density (BMD) and prevalent vertebral fracture (VF) in men and women aged 62 years. A total of 352 men and women aged 62.5 ± 0.5 years from the Newcastle Thousand Families Study cohort received dual‐energy X‐ray absorptiometry (DXA) evaluations of femoral neck and lumbar spine BMD, of the lateral spine for vertebral fracture assessment, and of the whole body for TFM and VAT (GE Lunar CoreScan, Madison, WI, USA). Plasma CRP, FRAX scores, falls in the last 12 months, and occupation at age 50 years were also included in the analysis. Vertebral fractures were less prevalent in women than in men (odds ratio [OR] = 0.33, p < 0.001) and BMD or FRAX scores did not differ between participants with and without VF. Women with VF were heavier and had higher TFM, VAT, and CRP than women without (p < 0.001). In women, greater (+1 SD) TFM and VAT increased the odds of any grade VF (TFM: OR = 1.06, p = 0.001; VAT: OR = 2.50, p = 0.002), and greater VAT mass increased the odds of prevalent mild VF (OR = 2.60, p = 0.002). In contrast, there were no associations in men. In both sexes, after controlling for body weight, neither VAT nor CRP were associated with BMD. In conclusion, irrespective of BMD, total and visceral adiposity were associated with prevalent VF in women but not in men. High fat mass, particularly if visceral, should be considered when assessing VF risk in women. Risk factors for VF in men require further investigation, particularly given their high prevalence. © 2017 American Society for Bone and Mineral Research.     

Unusual case of left iliac vein compression secondary to May-Thurner syndrome and crossed fused renal ectopia

External compression of the left iliac vein against the fifth lumbar vertebra by the right iliac artery May and Thurner syndrome is a well-known anatomic variant. We identified a rare case of May-Thurner syndrome associated with crossed fused renal ectopia on the left side. The patient presented with complete thrombosis of the left common iliac vein down to the popliteal vein. He was treated with catheter directed thrombolysis followed by anticoagulant therapy.     

Toll-like receptor 4 ligand can differentially modulate the release of cytokines by human platelets

Blood platelets link the processes of haemostasis and inflammation. This study examined the immunomodulatory factors released by platelets after Toll-Like Receptor 4 (TLR4) engagement on their surfaces. Monoclonal anti-human FcγRII Ab (IV.3)-treated human platelets were cultured with TLR4 ligands in the presence or absence of blocking monoclonal antibody to human TLR4. The release of sCD62p, epidermal growth factor (EGF), transforming growth factor β (TGFβ), interleukin (IL)-8, platelet activating factor 4 (PAF4), platelet-derived growth factor, α, β polypeptide (PDGF-AB), Angiogenin, RANTES (regulated upon activation, normal T-cell expressed, and presumably secreted) and sCD40L were measured by specific enzyme-linked immunosorbent assay. TLR4 ligand [ Escherichia coli lipopolysaccharide (LPS)] bound platelet TLR4, which differentially modulates the release of cytokines by platelets. It was noted that (i) sCD62p, IL-8, EGF and TGFβ release were each independent of platelet activation after TLR4 engagement; (ii) RANTES, Angiogenin and PDGF-AB concentration were weaker in platelet supernatant after TLR4 engagement; (iii) sCD40L and PAF4 are present in large concentration in the releaseate of platelets stimulated by TLR4 ligand. The effects of LPS from E. coli on the modulation of secretory factors were attenuated by preincubation of platelets with an anti-TLR4 monoclonal antibody, consistent with the immunomodulation being specifically mediated by the TLR4 receptor. We propose that platelets adapt the subsequent responses, with polarized cytokine secretion, after TLR4 involvement.     

Monitoring of neoadjuvant chemotherapy using multiparametric, <Superscript>23</Superscript>Na sodium MR,and multimodality (PET/CT/MRI) imaging in locally advanced breast cancer

We prospectively investigated using advanced magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) to identify radiological biomarkers for treatment response in patients receiving preoperative systemic therapy (PST) for locally advanced breast cancer. Patients with a stage II or III breast cancer receiving PST were selected and underwent positron emission tomography (PET), magnetic resonance imaging (MRI), and breast biopsies at baseline and after the first cycle of PST (days 7–8) during the full course of treatment. PET/CT was acquired after injection of 2-deoxy-2-[18F]-fluoro-d-glucose (¹⁸FDG, 0.22 mCi/kg) and quantified with standardized uptake value assessment (SUV). Diagnostic breast MRI and sodium (²³Na) was acquired at 1.5 T. Total tissue sodium concentration (TSC), response criteria in solid tumors (RECIST), and volumes were quantified. Treatment response was determined by pathological assessment at surgery. Immunohistochemistry values of the proliferative index (Ki-67) were performed on biopsy specimens. Six of nineteen eligible women (43 ± 11 years) who received PST underwent radiological imaging of ¹⁸FDG-PET/CT and MRI for at least two cycles of treatment. Five patients had a pathological partial response (pPR) and one had pathological non-response (pNR). TSC decreased 21% in responders with increases in the non-responder (P = 0.03). Greater reduction in SUV was observed in responders (38%) compared to the non-responder (22%; P = 0.03). MRI volumes decreased after cycle 1 by 42% (responders) and 35% (non-responder; P = 0.11). Proliferation index Ki-67 declined in responders in the first cycle (median = 47%, range = 29–20%), but increased (4%) in the non-responder. Significant decreases in TSC, SUV, and Ki-67 were observed in responders with increases in TSC and Ki-67 in non-responders. Our results demonstrate the feasibility of using multi-modality proton, ²³Na MRI, and PET/CT metrics as radiological biomarkers for monitoring response to PST in patients with operable breast cancer.     

Hyper‐CVAD plus nelarabine in newly diagnosed adult T‐cell acute lymphoblastic leukemia and T‐lymphoblastic lymphoma

Nelarabine, a water soluble prodrug of 9‐β‐D‐arabinofuranosylguanine (ara‐G), is a T‐cell specific purine nucleoside analogue. Given its activity in relapsed and refractory T acute lymphoblastic leukemia (T‐ALL) and T lymphoblastic lymphoma (T‐LBL), we sought to define its role in the frontline treatment of adult patients. Therefore, we conducted a single arm phase 2 study to determine the safety and efficacy of nelarabine in combination with hyper‐CVAD in newly diagnosed patients. For induction/consolidation, patients received eight cycles of hyper‐CVAD alternating with high‐dose methotrexate and cytarabine plus two cycles of nelarabine given at a dose of 650 mg/m² intravenously daily for 5 days. This was followed by thirty months of POMP maintenance chemotherapy with two additional cycles of nelarabine given instead of cycles 6 and 7 of POMP maintenance. Sixty‐seven patients, including 40 with T‐ALL and 26 with T‐LBL, were enrolled. Complete response rates in both T‐ALL and T‐LBL were 87% and 100% respectively. Grade 3 to 4 neurotoxic adverse events were reported in 5 patients. There were 21 relapses (31%) including 2 after allogeneic stem cell transplantation. Median duration of follow‐up was 42.5 months. The 3‐year complete remission duration (CRD) and overall survival (OS) rates were 66% and 65%, respectively. Compared to our historic hyper‐CVAD data, there was no survival benefit with the addition of nelarabine. In conclusion, hyper‐CVAD plus nelarabine was well tolerated and active in the frontline treatment of adult T‐ALL/LBL patients.