Prognostic role of nuclear factor/IB and bone remodeling proteins in metastatic giant cell tumor of bone: A retrospective study

Giant cell tumor of bone (GCTb) represents 5% of bone tumors, and although considered benign, 5% metastasize to the lung. The expression of proteins directly or indirectly associated with osteolysis and tumor growth was studied on 163 samples of GCTb. Of these, 33 patients developed lung metastasis during follow‐up. The impact of tumor–host interaction on clinical aspects was evaluated with the aim of finding specific markers for new biological therapies, thus improving clinical management of GCTb. Protein expression was evaluated by immunohistochemical analysis on Tissue Microarray. The majority of GCTb samples from patients with metastatic disease were strongly positive to RANKL and its receptor RANK as well as to CAII and MMP‐2 and to pro‐survival proteins NFIB and c‐Fos. Kaplan–Meier analysis indicated a significant difference in metastasis free survival curves based on protein staining. Interestingly, the statistical correlation established a strong association between all variables studied with a higher τ coefficient for RANK/RANKL, RANK/NFIB, and RANKL/NFIB pairs. At multivariate analysis co‐overexpression of NFIB, RANK and RANKL significantly increased the risk of metastasis with an odds ratio of 13.59 (95%CI 4.12–44.82; p < 0.0005). In conclusion, the interconnection between matrix remodeling and tumor cell activity may identify tumor–host endpoints for new biological treatments. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1205–1211, 2015.     

Cytoskeletal behaviour in spectrin and in band 3 deficient spherocytic red cells: evidence for a differentiated splenic conditioning role

Based on quantitative analysis of red cell membrane proteins, hereditary spherocytosis (HS) can be divided into two main groups including isolated or ankyrin combined spectrin deficiency and band 3 reduction. Protein methyl esterification catalysed by protein carboxyl methyltransferase (PCMT type II; EC 2.1.1.77) is a post-biosynthetic modification which is involved in the metabolism of damaged membrane proteins. We utilized the evaluation of erythrocyte membrane protein methyl esterification as a marker of cytoskeletal disarray in seven HS subjects with spectrin reduction and in seven patients with HS due to band 3 deficiency. Our results support the notion that band 3 deficient erythrocytes are not affected by an extensive cytoskeletal derangement. On the contrary, we found a remarkable increase of membrane methylation in the unsplenectomized, spectrin-deficient, HS patients, suggesting a striking membrane skeleton disarray. This phenomenon was not observed in the spectrin-deficient red cells of splenectomized patients. Therefore in spectrin deficient erythrocytes the induction of cytoskeletal damage, specifically recognized by PCMT type II, could be one of the splenic steps producing conditioned spherocytes.     

Ultrafast transient absorption of eumelanin suspensions: the role of inverse Raman scattering

An ultrafast investigation is carried out on synthetic eumelanin suspended either in water or in DMSO-methanol. Upon photoexcitation by visible femtosecond pulses, the transient absorption (TA) dynamics of the suspensions are probed in a broad visible spectral range, showing clear nonlinearities. The latter arise from pump-probe interactions that induce the inverse Raman scattering (IRS) effect. We show how eumelanin TA dynamics are modified in proximity of the solvent Stokes and anti-Stokes scattering peaks, demonstrating that IRS affects the sign of TA but not the relaxation times. We compare the results obtained in both suspensions, unveiling the role of the surrounding environment. Eventually, the intrinsic response of synthetic eumelanin to ultrafast photoexcitation is evaluated.OCIS codes: (160.1435) Biomaterials, (320.7150) Ultrafast spectroscopy, (300.6240) Spectroscopy, coherent transient, (190.5890) Scattering, stimulated     

Paricalcitol for Secondary Hyperparathyroidism in Renal Transplantation

Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum parathyroid hormone levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, crossover, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/d for 3 months and then uptitrated to 2 µg/d if tolerated) or nonparicalcitol therapy on serum parathyroid hormone levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum parathyroid hormone levels significantly declined on paricalcitol from 115.6 (94.8–152.0) to 63.3 (52.0–79.7) pg/ml (P<0.001) but not on nonparicalcitol therapy. At 6 months, levels significantly differed between treatments (P<0.001 by analysis of covariance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (P<0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (P<0.05). L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (P<0.05 for both densities). Paricalcitol was well tolerated. Overall, 6-month paricalcitol supplementation reduced parathyroid hormone levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. Long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.     

Lack of efficacy of quinapril on vascular damage in limited cutaneous systemic sclerosis

Gliddon et al. conducted a randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy of the angiotensin-converting enzyme inhibitor quinapril for the management of vascular damage in systemic sclerosis (SSc). The trial comprised 213 patients with limited cutaneous SSc or Raynaud's phenomenon (mean age 54 years, 182 females) who were randomly assigned to receive 80 mg/day, or the maximum tolerated dose, of quinapril (n = 105) or placebo (n = 108) for 2-3 years. Patients were assessed every 3 months. The number of new ischemic digital ulcers was recorded as the primary end point, while the frequency of Raynaud's phenomenon episodes, skin score, health status, pulmonary artery pressure and treatments for ischemia were also monitored as secondary end points. There were no detectable differences between patients treated with quinapril and those receiving placebo; however, although no severe adverse effects were observed, patients taking quinapril experienced significantly more adverse effects.     

The role of postoperative radiotherapy for thymomas: a multicentric retrospective evaluation from three Italian centers and review of the literature

BackgroundThymoma is a rare mediastinal neoplasia. Surgery is the backbone of the treatment, but the role of postoperative radiotherapy (PORT) remains controversial. We aimed to obtain data on survival and safety in patients treated with PORT in three different Italian institutions.MethodsWe retrospectively analyzed 183 consecutive patients who underwent surgery from 1981 to 2015. According to the Masaoka-Koga staging system, 39.3%, 32.7%, 18.6% and 9.8% patients were in stage I, II, III and IV of disease, respectively. PORT was indicated in 114 patients (62.3%), while 69 subjects underwent surgery alone. Complete resection was obtained in 68 patients who underwent PORT. Adverse events (AEs) were graded according to CTCAE v4.0. We analyzed the recent literature to describe the current reports on PORT for resected thymoma.ResultsMean follow-up was 130 months (range, 3–417 months). Overall survival (OS) at 1-, 5- and 10-year from surgery was 98.3%, 90.2% and 69.7% respectively. One-, 5- and 10-year disease specific survival (DSS) was 98.9%, 92.3% and 89.8% respectively. Disease free survival (DFS) at 1, 5 and 10 years from surgery was 96.7%, 88.3% and 82.8% respectively. Univariate analysis showed that complete resection, cell histology A-AB-B1 and stages I–II were significant predictors of better DSS and DFS. Multivariate analysis showed that sex, R0 margins and WHO histology was independent prognostic factors. Among patients treated with PORT, a trend towards better OS was evident with Masaoka stage I–II (P=0.09). Patients with R0 margins treated with PORT showed better OS and DSS (P=0.05). No differences in DSS for performance status (P=0.70), WHO histology (P=0.19), paraneoplastic syndrome (P=0.23) and surgical procedure (P=0.53) were evident. Patients treated with PORT had a higher level of acute AEs compared to surgery alone, but none of these was graded ≥3.ConclusionsOur results confirmed that patients with incompletely resected thymoma had the worst OS and DSS. High grade acute toxicity was not different between PORT and surgery alone. Other trials reported a significant benefit in OS, DSS and DFS in stage IIb–IV thymoma treated with PORT.     

Hypothalamitis: a diagnostic and therapeutic challenge

To report an unusual case of biopsy-proven autoimmune hypophysitis with predominant hypothalamic involvement associated with empty sella, panhypopituitarism, visual disturbances and antipituitary antibodies positivity. We present the history, physical findings, hormonal assay results, imaging, surgical findings and pathology at presentation, together with a 2-year follow-up. A literature review on the hypothalamic involvement of autoimmune hypophysitis with empty sella was performed. A 48-year-old woman presented with polyuria, polydipsia, asthenia, diarrhea and vomiting. The magnetic resonance imaging (MRI) revealed a clear suprasellar (hypothalamic) mass, while the pituitary gland appeared atrophic. Hormonal testing showed panhypopituitarism and hyperprolactinemia; visual field examination was normal. Pituitary serum antibodies were positive. Two months later an MRI documented a mild increase of the lesion. The patient underwent biopsy of the lesion via a transsphenoidal approach. Histological diagnosis was lymphocytic “hypothalamitis”. Despite 6 months of corticosteroid therapy, the patient developed bitemporal hemianopia and blurred vision, without radiological evidence of chiasm compression, suggesting autoimmune optic neuritis with uveitis. Immunosuppressive treatment with azathioprine was then instituted. Two months later, an MRI documented a striking reduction of the hypothalamic lesion and visual field examination showed a significant improvement. The lesion is stable at the 2-year follow-up. For the first time we demonstrated that “hypothalamitis” might be the possible evolution of an autoimmune hypophysitis, resulting in pituitary atrophy, secondary empty sella and panhypopituitarism. Although steroid treatment is advisable as a first line therapy, immunosuppressive therapy with azathioprine might be necessary to achieve disease control.     

Which is the best catheter to perform atrial fibrillation ablation? A comparison between standard ThermoCool,SmartTouch, and Surround Flow catheters

Introduction

Catheter ablation (CA) is an established therapy for atrial fibrillation (AF). The SmartTouch catheter (STc) provides information about catheter tip to tissue contact force (CF). The Surround Flow catheter (SFc) provides a uniform cooling of the tip during ablation. We sought to analyze the impact of STc and SFc on CA of paroxysmal AF in terms of feasibility and acute efficacy.

Methods and results

Sixty-three patients (mean age 57.6?±?9.8 years, 53 males) with paroxysmal AF underwent pulmonary veins (PVs) antral isolation, by using standard ThermoCool catheter (TCc) in 21, STc in 21, and SFc in 21. Total procedural, fluoroscopy, and radiofrequency (RF) delivery times; percentage of persistently deconnected PVs after 30 min; and percentage of isolated PVs at the end of the procedure were measured. The use of both STc and SFc obtained a reduction of fluoroscopy time (TCc 34?±?18 min, STc 20?±?10 min, p?<?0.001; SFc 21?±?13 min, p?=?0.02 vs TCc) and RF time (TCc 41?±?13 min, STc 30?±?14 min, p?=?0.013; SFc 30?±?9 min, p?<?0.01 vs TCc). The use of STc resulted in a reduction of procedural time (TCc 181?±?53 min, STc 140?±?53 min, p?<?0.001; SFc 170?±?51 min, p?=?NS vs TCc). The percentage of isolated PVs was comparable between groups (TCc 96 % vs STc 98 % vs SFc 96 %; p?=?NS). The percentage of deconnected PVs at 30 min was lower in TCc (89 %) than in STc (95 %) and in SFc (95 %) group (p?<?0.05).

Conclusions

Both STc and SFc allowed a simplification of CA of paroxysmal AF. In addition, they reduced early PVs reconnection.

Condensed abstract

Sixty-three patients with paroxysmal AF underwent ablation by standard ThermoCool, SmartTouch, or Surround Flow catheter. Both the SmartTouch and the Surround Flow significantly reduced radiofrequency and fluoroscopy times, as well as pulmonary veins reconnection rate at 30 min. Moreover, the SmartTouch reduced overall duration of the procedure.