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Purpose Globally, spine disorders are the leading cause of disability, affecting more than half a billion individuals. However, less than 50% of G20 countries specifically identify spine health within their public policy priorities. Therefore, it is crucial to raise awareness among policy makers of the disabling effect of spine disorders and their impact on the economic welfare of G20 nations. In 2019, SPINE20 was established as the leading advocacy group to bring global attention to spine disorders. Methods Recommendations were developed through two Delphi methods with international and multi-professional panels. Results In 2022, seven recommendations were delivered to the leaders of G20 countries, urging them to: Develop action plans to provide universal access to evidence-based spine care that incorporates the needs of minorities and vulnerable populations. Invest in the development of sustainable human resource capacity, through multisectoral and inter-professional competency-based education and training to promote evidence-based approaches to spine care, and to build an appropriate healthcare working environment that optimizes the delivery of safe health services. Develop policies using the best available evidence to properly manage spine disorders and to prolong functional healthy life expectancy in the era of an aging population. Create a competent workforce and improve the healthcare infrastructure/facilities including equipment to provide evidence-based inter-professional rehabilitation services to patients with spinal cord injury throughout their continuum of care. Build collaborative and innovative translational research capacity within national, regional, and global healthcare systems for state-of-the-art and cost-effective spine care across the healthcare continuum ensuring equality, diversity, and inclusion of all stakeholders. Develop international consensus statements on patient outcomes and how they can be used to define and develop pathways for value-based care. Recognize that intervening on determinants of health including physical activity, nutrition, physical and psychosocial workplace environment, and smoking-free lifestyle can reduce the burden of spine disabilities and improve the health status and wellness of the population. At the third SPINE20 summit 2022 which took place in Bali, Indonesia, in August 2022, 17 associations endorsed its recommendations. Conclusion SPINE20 advocacy efforts focus on developing public policy recommendations to improve the health, welfare, and wellness of all who suffer from spinal pain and disability. We propose that focusing on facilitating access to systems that prioritize value-based care delivered by a competent healthcare workforce will reduce disability and improve the productivity of the G20 nations.

This article reports the study protocol of a nationwide multicentric study in seven Italian regions aimed at assessing the effectiveness of a digitally supported approach for the early screening of frailty risk factors in community-dwelling older adults. SUNFRAIL+ is a prospective observational cohort study aimed at carrying out a multidimensional assessment of community-dwelling older adults through an IT platform, which allows to connect the items of the SUNFRAIL frailty assessment tool with a cascading multidimensional in-depth assessment of the bio–psycho–social domains of frailty. Seven centers in seven Italian regions will administer the SUNFRAIL questionnaire to 100 older adults. According to the answers provided by older adults, they will be subjected to one or more validated in-depth scale tests in order to perform further diagnostic or dimensional evaluations. The study aims to contribute to the implementation and validation of a multiprofessional and multistakeholder service model for the screening of frailty in community-dwelling older adult population.

Rotator cuff tendinopathy (RCTe) is the most common cause of pain and shoulder dysfunction. Numerous clinical studies have demonstrated the therapeutic capacity of exogenous peritendinous hyaluronic acid (HA), and the effectiveness of extracorporeal shockwaves therapy (ESWT) in reducing pain. The aim of this study was to evaluate the added effects of HA treatment plus ESWT (E-g) or ESWT alone (SC-g), focusing on reduction of self-reported pain and disability of patients with RCTe.Monocentric, randomized open-label clinical trial. Patients' selection, enrollment and interventions were conducted at the Chiparo Physical Medicine and Rehabilitation outpatient facility (Lecce, Italy). Patients with a diagnosis of RCTe, were randomly allocated to the E-g or to the SC-g. Participants were assessed for self-perceived pain, and for disability, at baseline, after 30 and 60 days.Forty adults (mean age 50.8±6.3; 23 woman, 17 men) were enrolled in the study, twenty for each group. During the study, both groups improved their perceived level of disability of the arm (-25.01±2.79; P0.001), and for pain (-3.13±0.50; P0.001). A multiplicative effect was demonstrated in the time × treatment interaction for disability (beta±SE beta: 7.40±1.77; P0.001), and pain (beta±SE beta: 0.95±0.32; P0.001). Moreover, more patients in the E-g reached the MCID in the outcomes-score compared to SC-g. Lastly, number needed to treat were calculated, for disability: NNT=2 (95% CI: 1-3), and for pain-score: NNT=1 (95% CI: 1-2).This study provides preliminary evidence that, compared to ESWT alone, the combining ESWT and peritendinous HA-injections, revert disability and reduces shoulder pain faster in patients with RCTe.

The major histocompatibility complex (MHC) class I expression in cancer cells has a crucial impact on the outcome of T cell-mediated cancer immunotherapy. We now determined the HLA class I allelic variants and their expression in PD-L1-deficient and positive rare sarcoma tissues. Tumor tissues were HLA-I classified based on HLA-A and -B alleles, and for class II, the HLA-DR-B by Taqman genomic PCRs. The HLA-A24*:10-B73*:01 haplotype was the most common. A general down-regulation or deletion of HLA-B mRNA and HLA-A was observed, compared to HLA-DR-B. HLA-I was almost too low to be detectable by immunohistochemistry and 32% of grade III cases were positive to PD-L1. Functional cytotoxic assays co-culturing patient biopsies with autologous T cells were used to assess their ability to kill matched tumor cells. These results establish that deletion of HLA-I loci together with their down-regulation in individual patient restrict the autologous lymphocyte cytotoxic activity, even in the presence of the immune checkpoint blocking antibody, Nivolumab. Additionally, the proposed cytotoxic test suggests a strategy to assess the sensitivity of tumor cells to T cell-mediated attack at the level of the individual patient.

Diabetes mellitus (DM) is a widespread condition, representing a challenging disease to manage. Exercise is being increasingly recommended as part of the therapeutic regimen for DM but the management of different forms of physical activity is difficult for individuals with diabetes, trainers, and physicians. Regular exercise can improve health and well-being, helping individuals to achieve their target lipid profile, body composition, cardio-respiratory fitness, and glycemic goals. People with diabetes tend to be as inactive as the general population, with a large percentage of individuals not achieving the minimum amount of recommended physical activity levels. Indeed, several barriers to exercise exist for persons with diabetes, including sports eligibility, multi-modality management of diabetic athletes, and inadequate knowledge about adequate type and intensity of exercise. The aim of the present review is to provide the current understanding of mechanisms, recommendations, and beneficial effects of different modalities of exercise for the treatment of DM.

Clodronate is a bisphosphonate agent commonly used as anti-osteoporotic drug. Throughout its use, additional anti-inflammatory and analgesic properties have been reported, although the benefits described in the literature could not solely relate to their inhibition of bone resorption. Thus, the purpose of our in vitro study is to investigate whether there are underlying mechanisms explaining the anti-inflammatory effect of clodronate and possibly involving hydrogen sulphide (H2S). Immortalised fibroblast-like synoviocyte cells (K4IM) were cultured and treated with clodronate in presence of TNF-α. Clodronate significantly modulated iNOS expression elicited by TNF-α. Inflammatory markers induced by TNF-α, including IL-1, IL-6, MCP-1 and RANTES, were also suppressed following administration of clodronate. Furthermore, the reduction in enzymatic biosynthesis of CSE-derived H2S, together with the reduction in CSE expression associated with TNF-α treatment, was reverted by clodronate, thus rescuing endogenous H2S pathway activity. Clodronate displays antinflammatory properties through the modulation of H2S pathway and cytokines levels, thus assuring the control of the inflammatory state. Although further investigation is needed to stress out how clodronate exerts its control on H2S pathway, here we showed for the first the involvement of H2S in the additive beneficial effects observed following clodronate therapy.

Purpose The Global Burden of Diseases (GBD) Studies have estimated that low back pain is one of the costliest ailments worldwide. Subsequent to GBD publications, leadership of the four largest global spine societies agreed to form SPINE20. This article introduces the concept of SPINE20, the recommendations, and the future of this global advocacy group linked to G20 annual summits. Methods The founders of SPINE20 advocacy group coordinated with G20 Saudi Arabia to conduct the SPINE20 summit in 2020. The summit was intended to promote evidence-based recommendations to use the most reliable information from high-level research. Eight areas of importance to mitigate spine disorders were identified through a voting process of the participating societies. Twelve recommendations were discussed and vetted. Results The areas of immediate concern were “Aging spine,” “Future of spine care,” “Spinal cord injuries,” “Children and adolescent spine,” “Spine-related disability,” “Spine Educational Standards,” “Patient safety,” and “Burden on economy.” Twelve recommendations were created and endorsed by 31/33 spine societies and 2 journals globally during a vetted process through the SPINE20.org website and during the virtual inaugural meeting November 10–11, 2020 held from the G20 platform. Conclusions This is the first time that international spine societies have joined to support actions to mitigate the burden of spine disorders across the globe. SPINE20 seeks to change awareness and treatment of spine pain by supporting local projects that implement value-based practices with healthcare policies that are culturally sensitive based on scientific evidence.

Muscle injuries are the most common trauma in team and individual sports. The muscles most frequently affected are those of the lower limb, and in particular hamstrings, adductors, rectus femoris and calf muscles. Although several scientific studies have tried to propose different rehabilitation protocols, still too often the real rehabilitation process is not based on scientific knowledge, especially in non-elite athletes. Moreover, the growing use of physical and instrumental therapies has made it increasingly difficult to understand what can be truly effective. Therefore, the aim of the present paper is to review proposed therapeutic algorithms for muscle injuries, proposing a concise and practical summary. Following a three-phase rehabilitation protocol, this review aims to describe the conservative treatment of indirect structural muscle injuries, which are the more routinely found and more challenging type. For each phase, until return to training and return to sport are completed, the functional goal, the most appropriate practitioner, and the best possible treatment according to current evidence are expressed. Finally, the last section is focused on the specific exercise rehabilitation for the four main muscle groups with a structured explanatory timetable.

Several studies suggest that inflammation has a pivotal role during the progression of osteoarthritis (OA) and cytokines have been identified as the main process mediators. This study aimed to explore the ability to modulate the main OA pro‐inflammatory biomarkers of novel gels (H‐HA/BC) based on high molecular weight hyaluronan (H‐HA) and unsulfated biotechnological chondroitin (BC). For the first time, BC was tested also in combination with H‐HA on human primary cells isolated from pathological knee joints. Specifically, the experiments were performed using an OA in vitro model based on human chondrocytes and synoviocytes. To evaluate the anti‐inflammatory effects of H‐HA/BC in comparison with H‐HA and BC single gels, NF‐kB, COMP‐2, MyD88, MMP‐13 and a wide range of cytokines, known to be specific biomarkers in OA (e.g., IL‐6, IL‐8, and TNF‐α), were evaluated. In addition, cell morphology and proliferation occurring in the presence of either H‐HA/BC or single components were assessed using time‐lapse video microscopy. It was shown that synovial fluids and cells isolated from OA suffering patients, presented a cytokine pattern respondent to an ongoing inflammation status. H‐HA and BC significantly reduced the levels of 23 biomarkers associated with cartilage damage. However, H‐HA/BC decreased significantly 24 biological mediators and downregulated 19 of them more efficiently than the single components. In synoviocytes cultures, cytokine analyses proved that H‐HA/BC gels re‐established an extracellular environment more similar to a healthy condition reducing considerably the concentration of 11 analytes. Instead, H‐HA and BC significantly modulated 7 (5 only with a longer treatment) and 8 biological cytokines, respectively. Our results suggest that H‐HA/BC beyond the viscosupplementation effect typical for HA‐based gels, can improve the inflammation status in joints and thus could be introduced as a valid protective and anti‐inflammatory intraarticular device in the field of Class III medical devices for OA treatments., Unsulfated biotechnological chondroitin by itself and complexed to hyaluronic acid counteract inflammation and improve the viability of human primary cells isolated from pathological osteoarthritis joints. Their potential efficacy, especially when combined in novel gels is supported by the modulation of several key biomarkers.

Soccer players are susceptible to repeated trauma that could lead to a precocious development of knee osteoarthritis (OA). Intra-articular hyaluronic acid (IA-HA) injections have been proposed as a valid treatment for knee OA. Objectives: To describe the effects of IA-HA injections and oral collagen supplementation in a female soccer goalkeeper playing in Italian Women’s Serie A with secondary OA in her knee. Design: Case report. Setting: The athlete underwent three IA-HA injections (1 per week for 3 weeks in a row) together with oral collagen supplementation for one month. Treatment outcomes were evaluated using five scoring scales. Results: One week after the first IA-HA injection all the scores improved. One week after the second injection, compared with the first week, two scores improved, two remained the same, and one worsened. One week after the third injection, compared with the second week, all the scores worsened. At one month, compared with the third week, one score remained the same and all the others worsened. From baseline to one month, three scores improved, one remained the same, and one worsened. Conclusions: In our study, IA-HA injections and oral collagen supplementation showed short-term effects on pain and functional impairment for knee OA.

The study of epigenetics reaches its 50th anniversary, however, its clinical application is gradually coming into the clinical setting. Osteoporosis is one of the major and widely diffused bone diseases. Pathogenic mechanisms at the epigenetic level may interfere with bone remodeling occurring during osteoporosis. Preclinical models were used to understand whether such events may interfere with the disease. Besides, observational clinical trials investigated epigenetic-related biomarkers. This effort leads to some epigenetic-related therapies in clinical trials for the treatment of osteoporosis. Bisphosphonates (BPs), target therapy blocking RANK/RANKL pathway, and anti-sclerostin antibody (SOST) are the main therapeutic approaches. However, future large trials will reveal whether epigenetic therapies of osteoporosis will remain a work in progress or data will become more robust in the real-world management of these frailty patients.

The biological activity of chondroitin sulfate (CS) and glucosamine (GlcN) food supplements (FS), sold in USA against osteoarthritis, might depend on the effective CS and GlcN contents and on the CS structural characteristics. In this paper three USA FS were compared to two pharmaceutical products (Ph). Analyses performed by HPAE-PAD, by HPCE and by SEC-TDA revealed that the CS and GlcN titers were up to −68.8% lower than the contents declared on the labels and that CS of mixed animal origin and variable molecular weights was present together with undesired keratan sulfate. Simulated gastric and intestinal digestions were performed in vitro to evaluate the real CS amount that may reach the gut as biopolymer. Chondrocytes and synoviocytes primary cells derived from human pathological joints were used to assess: cell viability, modulation of the NF-κB, quantification of cartilage oligomeric matrix protein (COMP-2), hyaluronate synthase enzyme (HAS-1), pentraxin (PTX-3) and the secreted IL-6 and IL-8 to assess inflammation. Of the three FS tested only one (US FS1) enhanced chondrocytes viability, while all of them supported synoviocytes growth. Although US FS1 proved to be less effective than Ph as it reduced NF-kB, it could not down-regulate COMP-2, HAS-1 was up-regulated but with a lower efficacy. Inflammatory cytokines were markedly reduced by Ph while a slight decrease was only found for US-FS1.

// Flavio Fazioli 1, * , Gianluca Colella 2, * , Roberta Miceli 3 , Mariano Giuseppe Di Salvatore 1 , Michele Gallo 1 , Serena Boccella 4 , Annarosaria De Chiara 5 , Carlo Ruosi 2, * and Filomena de Nigris 6, * 1 Division of Musculoskeletal Oncology Surgery, National Cancer Institute G. Pascale, Naples, Italy 2 Department of Human Health, Federico II University of Naples, Naples, Italy 3 S.C. Cellular Biology and Biotherapy, National Cancer Institute G. Pascale, Naples, Italy 4 Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples Italy 5 Division of Pathology, National Cancer Institute G. Pascale Foundation, Naples, Italy 6 Department of Biochemistry, Biophysics and General Pathology, University of Campania “Luigi Vanvitelli”, Naples Italy * These authors have contributed equally to this work Correspondence to: Filomena de Nigris, email: Filomena.denigris@unina2.it Keywords: recurrences, sarcoma, angiogenesis, stem cells, AKT Received: March 31, 2017 Accepted: May 29, 2017 Published: June 28, 2017 ABSTRACT Giant cell tumors of bone (GCTB) are rare sarcomas with a high rate of unpredictable local relapse. Studies suggest that surgical methods affect recurrence, supporting the idea that local disease develops from re-growth of residual cancer cells. To identify early prognostic markers of individual risk of recurrence, we evaluated the effect of post-surgery fluids from a cohort of GCTB patients on growth of primary and established sarcoma cell lines, and mice xenograph. Post-surgery fluids increased cell growth and enhanced expression of CD44 ++ , the principal receptor for the extracellular matrix component hyaluronan and the mesenchymal stem marker CD117 + . Cancer cells became highly invasive and tumorigenic, acquiring stemness properties, and activated AKT/mTOR pathway. Prolonged stimulation with post-surgery fluids down-regulated the mesenchymal gene TWIST1 and Vimentin protein, and transdifferentiated cells into tubule-like structures positive to the endothelial markers VE-Cadherin and CD31 + . In mice, post-surgery fluids gave rise to larger and more vascularized tumors than control, while in patients AKT/mTOR pathway activation was associated with recurrence by logistic regression (Kaplan-Meier; P

The aim of this study is to understand how many anchor sites are necessary to obtain maximum posterior correction of idiopathic scoliotic curve and if the alloy of instrumentation, stainless steel or titanium, may have a role in the percent of scoliosis correction. We reviewed 143 consecutive patients, affected by AIS (Lenke 1–2), who underwent a posterior spinal fusion with pedicle screw-only instrumentation between 2002 and 2005. According to the implant density and alloy used we divided the cohort in four groups. All 143 patients were reviewed at an average follow-up of 7, 2 years, the overall final main thoracic curve correction averaged 61.4%, whereas the implant density within the major curve averaged 71%. A significant correlation was observed between final% MT correction and preoperative MT flexibility and implant density. When stainless steel instrumentation is used non-segmental pedicle screw constructs seem to be equally effective as segmental instrumentations in obtaining satisfactory results in patients with main thoracic AIS. When the implant alloy used is titanium one, an implant density of ≥60% should be guaranteed to achieve similar results.

Osteogenic differentiation is a complex and still poorly understood biological process regulated by intrinsic cellular signals and extrinsic microenvironmental cues. Following appropriate stimuli, mesenchymal stem cells (MSCs) differentiate into osteoblasts through a tightly regulated multistep process driven by several transcription factors and characterized by the expression of a number of bone-specific proteins. In this study, we describe a novel transcription factor that we named osteoblast inducer (ObI)-1, involved in MSC differentiation toward the osteogenic lineage. ObI-1 encodes for a nuclear protein subjected to proteasomal degradation and expressed during osteoblast differentiation both in a murine multipotent mesenchymal cell line (W20-17) and in primary murine MSCs. RNA interference-mediated knockdown of ObI-1 expression significantly impairs osteoblast differentiation and matrix mineralization with reduced expression of the osteogenic markers, Runt-related transcription factor 2 (Runx2) and osteopontin. Conversely, ObI-1 overexpression enhances osteogenic differentiation and bone-specific markers expression. ObI-1 stimulates bone morphogenetic protein (BMP)-4 expression and the consequent activation of the Smad pathway; treatment with a BMP receptor type I antagonist completely abolishes ObI-1-mediated stimulation of osteogenic differentiation. Collectively, our findings suggest that ObI-1 modulates osteogenic differentiation, at least in part, through the BMP signaling pathway, increasing Runx2 activation and leading to osteoblast commitment and maturation.

To evaluate the efficacy and to underline the right indications of the posterior monosegmental stabilization for the treatment of thoraco-lumbar spine fractures. Twenty patients underwent a monosegmental stabilization at our Institution and were retrospectively reviewed with a minimum follow-up of two years. All the patients had a clinical and radiological assessment before, after the surgery and at final follow-up. All data were evaluated by one independent observer. Data collected were Denis pain and work scale, somatic kyphosis (SK), somatic height (SH), and compression percentage (CP). The mean pre-operative SK angle measured between the upper and lower end plate of the fractured vertebra was 23.6°. The mean SK immediately after surgery was 12.8° and at final follow-up was 13.9°. The mean pre-operative SH was 21.9 mm, the mean value after surgery was 26.5 mm, and at final follow-up was 24.8 mm. The mean pre-operative CP was 66.7%, the mean value after surgery was 80.9%, and at final follow-up was 75.3%. At final follow-up, 75% of the patients had no pain or moderate pain and 95% of the patients returned to a full time work. Monosegmental stabilization with fusion is a safe and effective method to treat well selected thoracolumbar spine fractures. The right indications are type A1, type B2, and type A3 with a load sharing of less than 7 points and some very well selected type C fractures in which there is not lateral and rotatory displacement.

Introduction Oral supplementation of chondroitin sulfate (CS) and glucosamine (GlcN), symptomatic slow-acting molecules, is recommended by European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and Musculoskeletal Diseases (ESCEO) and other European Union (EU) guidelines for the restoration of the articular cartilage surface in patients affected by osteoarthritis (OA). They are commercialized as pharmaceutical grade products and as food supplements in combination with plant extracts hyaluronic acid, methylsulfonylmethane, and other components. Food supplements do not need to undergo the strict regulatory controls of pharmaceutical grade products; thus, composition and contaminants that could be present may not be evidenced before commercialization and these uncertainties may give rise to concerns about the bioactivity of these formulations. Methods In this paper 10 different food supplements (FS) from diverse European countries were analyzed in comparison with two pharmaceutical grade products (Ph) using updated analytical approaches and biochemical cell-based assays. The purity, the titer, and the origin of CS in Ph and FS samples were initially assessed in order to successively compare the biological function. Both food supplements and pharmaceutical formulations were tested in vitro, using the same final CS concentration, on primary chondrocytes and synoviocytes in terms of (i) cell viability, (ii) activation of the NF-κB-mediated inflammation pathway, (iii) cartilage oligomeric matrix protein (COMP-2), IL-6, and IL-8 production. Results All the FS presented a certain insoluble fraction; the CS and the GlcN contents were lower than the declared ones in 9/10 and 8/10 samples, respectively. All FS contained keratan sulfate (KS) at up to 50% of the total glycosaminoglycan amount declared on the label. Primary cells treated with the samples diluted to present the same CS concentration in the medium showed cytotoxicity in 7/10 FS while Ph preserved viability and reduced NF-κB, COMP-2, and secreted inflammatory cytokines. Conclusion Among all samples tested, the pharmaceutical grade products demonstrated effective modulation of biomarkers counteracting the inflammation status and improving viability and the physiological condition of OA human primary chondrocyte and synoviocyte cells. In contrast to that, most FS were cytotoxic at the tested concentrations, and only 3/10 of them showed similarities to Ph sample behavior in vitro. Funding This work was partially supported by PON01_1226 NUTRAFAST, MIUR Ministero dell’Università e della Ricerca Scientifica. Bioteknet financed two short-term grants for graduate technicians. The journal’s Rapid Service and Open Access fees were funded by IBSA CH.

High molecular weight hyaluronan (H-HA) has a pivotal role in the maintenance of normal functions of synovial fluid and structure of the articular joint, but it has been shown that its concentration is reduced in patients affected by degenerative cartilage diseases, such as osteoarthritis (OA). The aim of this study was to investigate the anti-inflammatory effects and properties of hybrid cooperative complexes based on high and low molecular weight hyaluronan (HCC) compared to H-HA on human primary cells derived by pathological joints. In addition, the rheological behavior of HCC was evaluated in order to define their potential as viscosupplement gel in degenerated joints. The experiments were performed using an in vitro model of OA based on human chondrocytes and synoviocytes isolated from degenerated joints of patients hospitalized for surgical replacement. In order to assess the anti-inflammatory effects of HCC, we evaluated NF-kB, COMP-2, IL-6, and IL-8 as specific markers at the transcriptional and/or protein level. Moreover, the proliferative properties of HCC were assessed using time lapse video microscopy. We showed that chondrocytes and synoviocytes clearly presented an altered cytokine profile compatible with a severe ongoing inflammation status. H-HA and, above all, HCC significantly reduced levels of the specific biomarkers evaluated and improved cartilage healing. The rheological profile indicated HCC suitability for intra-articular injection in joint diseases. HCC viscoelastic properties and the protective/anti-inflammatory effect on human chondrocytes and synoviocytes suggest the novel HCC-based gels as a valid support for OA management.

A great interest in the scientific community is focused on the improvement of the cure rate in patients with bone malignancies that have a poor response to the first line of therapies. Novel treatments currently include epigenetic compounds or molecules targeting epigenetic-sensitive pathways. Here, we offer an exhaustive review of such agents in these clinical settings. Carefully designed preclinical studies selected several epigenetic drugs, including inhibitors of DNA methyltransferase (DNMTIs), such as Decitabine, histone deacetylase classes I-II (HDACIs), as Entinostat, Belinostat, lysine-specific histone demethylase (LSD1), as INCB059872 or FT-2102 (Olutasidenib), inhibitors of isocitrate dehydrogenases, and enhancer of zeste homolog 2 (EZH2), such as EPZ6438 (Tazemetostat) To enhance the therapeutic effect, the prevalent approach in phase II trial is the association of these epigenetic drug inhibitors, with targeted therapy or immune checkpoint blockade. Optimization of drug dosing and regimens of Phase II trials may improve the clinical efficiency of such novel therapeutic approaches against these devastating cancers.

Yin Yang 1 (YY1) belongs to the polycomb group (PcG) of proteins that modify chromatin epigeneti-cally during dynamic regulation of their target genes. The predominant feature of YY1 is the zinc finger, an ancient structural motif that mediates protein–protein interactions and is capable of interacting with both DNA and RNA. Evidence reveals that YY1 acts predominantly as an epigenetic modulator, influencing the activity and/or localization of epigenetic modifiers molecules such as DNA methylation transferases, histone deacetylases, or non-coding RNAs. Deregulation of the epigenome is observed frequently in a variety of cancer types and is often correlated directly with advanced metastatic stages and poor prognosis. In this review, we address the current understanding of YY1 as a recruiter of epi-modifier molecules in the mechanism of aberrant regulation of target genes as a part of the metastatic cascade.

Cancer treatment is rapidly evolving toward personalized medicine, which takes into account the individual molecular and genetic variability of tumors. Sophisticated new in vitro disease models, such as three-dimensional cell cultures, may provide a tool for genetic, epigenetic, biomedical, and pharmacological research, and help determine the most promising individual treatment. Sarcomas, malignant neoplasms originating from mesenchymal cells, may have a multitude of genomic aberrations that give rise to more than 70 different histopathological subtypes. Their low incidence and high level of histopathological heterogeneity have greatly limited progress in their treatment, and trials of clinical sarcoma are less frequent than trials of other carcinomas. The main advantage of 3D cultures from tumor cells or biopsy is that they provide patient-specific models of solid tumors, and they overcome some limitations of traditional 2D monolayer cultures by reflecting cell heterogeneity, native histologic architectures, and cell– extracellular matrix interactions. Recent advances promise that these models can help bridge the gap between preclinical and clinical research by providing a relevant in vitro model of human cancer useful for drug testing and studying metastatic and dormancy mechanisms. However, additional improvements of 3D models are expected in the future, specifically the inclusion of tumor vasculature and the immune system, to enhance their full ability to capture the biological features of native tumors in high-throughput screening. Here, we summarize recent advances and future perspectives of spheroid and organoid in vitro models of rare sarcomas that can be used to investigate individual molecular biology and predict clinical responses. We also highlight how spheroid and organoid culture models could facilitate the personalization of sarcoma treatment, provide specific clinical scenarios, and discuss the relative strengths and limitations of these models.

Sacral chordoma is a rare low-to-intermediate grade malignant tumour. The mainstay of treatment is still surgery with en bloc and wide resection margins, which can grant the best chances of a long-term control or cure of this disease. The first aim of this paper is to collect data about survival, time to local recurrence and metastasis among patients affected by sacral chordoma and primarily treated with surgery. The second aim is to analyze the influence of level resection, tumor volume and surgical margins on local recurrence. The study population was composed of 14 patients treated with sacral chordoma resection at the National Tumour Institute of Naples—Pascale (Italy) from January 2000 to June 2013. The median follow-up was 84 months (range 24–132 months). The follow-up was characterized by: standard radiographs, MRI, and a CT scan of the chest annually. Time to recurrence or metastasis was calculated from the date of resection to the date of diagnosis of first recurrence or metastasis. Out of all the patients, six died (42.86 %) during the follow-up; 6 (42.86 %) had local recurrence; 4 (28.57 %) had metastasis. At univariate analysis wide surgical margins (R0) were associated with increased survival up to a local recurrence (OR = 0.0286; 95 % CI = 0.0014–0.5739; P = 0.026); the level of resection (OR = 3.33; 95 % CI = 0.3619–30.7025; P = 0.592) and tumour volume (P = 1) did not show a statistically significant correlation. Based on our experience, we hope all patients to be treated by surgery, the only good standard treatment of this disease. The resection should result in margins as wide as possible. For these reasons, it is essential for this disease to be treated in highly specialized centres because only a complete surgery can offer a chance to care for these patients. Solid survival at long-term follow-up can be achieved by a surgical resection performed with wide margins.

Spondylodiscitis refers to infections of the intervertebral disc and the adjacent vertebral body. Although it is still considered a rare condition, its rate is projected to increase. Mortality rate is considered to be low, but an estimated one third of the survivors experience residual disabilities. Literature shows that uncomplicated spondylodiscitis can be adequately treated by early antibiotic therapy and immobilization. The aim of the study is to evaluate the outcome of conservative treatment in patients with haematogenous spondylodiscitis. All patients with haematogenous spondylodiscitis observed in two orthopaedic centres were retrospectively considered. The medical records, radiologic imaging, bacteriology results, treatment, and complications of all patients were reviewed. Thirty patients (median age 64 years, range 15–77, females 56.7%) were considered in the study, eight (26.7%) showed residual back pain at median follow-up of 117 weeks (range 104–189). A significant difference in SF-36 physical (P

Introduction Obesity and osteoporosis share many features and recent studies have identified many similarities suggesting common pathophysiological mechanisms. Obesity is associated with a higher risk of non-traumatic fractures despite bone mineral density (BMD) being normal or even increased. Materials and methods 54 obese subjects were analyzed (51 ± 16 years, 10 males, 44 females). Spinal deformity index (SDI) is a semi-quantitative method that may be a surrogate index of bone microarchitecture. SDI index was higher in patients than in controls. In 87.5 % of patients and 10 % of controls we found morphometric vertebral fractures, despite a DEXA Tscore not diagnostic of osteoporosis. Conclusion The objective of this study was to assess in obese patients levels of 25OH vitamin D, parathyroid hormone, serum and urinary calcium (Ca) and phosphorus (P), BMD, and SDI. 87.5 % of the obese subjects present nontraumatic vertebral fractures and reduced bone quality as measured by SDI.

Cushing's disease (CD), the chronic endogenous hypercortisolism derived from an ACTH-secreting pituitary adenoma, and multiple osteochondromatosis (MO), a congenital mesoderm dyschondroplasia, represent two distinct rare neoplastic diseases. Clinical appearance of MO usually occurs during the first-second decade of life. In fact, the growth of osteochondromas parallels the patient's growth, then becoming quiescent after the closure of the epiphyses and the achievement of final stature. Here we describe an uncommon case of a patient with a long-term history of childhood-onset CD, who surprisingly developed MO during the third decade of life, after the remission of CD. Indeed, a female patient had been followed for CD from the age of 12 to the age of 24 years, when CD definitively remitted. At the age of 26 the patient complained progressively worsening backache and pain at level of hips and feet. Standard radiography of skeleton showed multiple bone dysmorphisms at level of the four limbs, spine and pelvis consistent with multiple osteochondromas and exostoses. A diagnosis of MO was performed. Total body bone scintigraphy with 99mTc-MDP revealed an increased uptake of the radioligand, suggesting an increased metabolic turnover in correspondence of the majority of the osteochondromas. However, the negativity of the majority of the lesions at 99mTc-DMSA scintigraphy and the histological diagnosis of benign osteochondroma of the only positive lesion at 99mTc-DMSA evidenced that the high metabolic activity of the osteochondromas was not due to malignant transformation. However, the activity of the lesions was highly surprising considering that they usually become quiescent after the achievement of the final stature. In last analysis, the uncommon characteristics of MO and, particularly, its occurrence after stable remission of hypercortisolism, suggests a possible role of glucocorticoids in influencing the clinical course of the skeletal disease. The inhibitory effect of hypercortisolism on bone growth and maturation could explain the block in the proliferation of skeletal lesions during the developmental age, where CD was in the active phase, and the opposite effect of stimulation of the ostochondromas growth during stable normalization of cortisol secretion, after CD remission.

Magnetic resonance imaging (MRI) and ultrasonography (US) are increasingly used in haemophilia A (HA) to detect early joint changes. A total of 40 clinically asymptomatic joints, never involved by bleeding events ["healthy joints" (HJ)], were evaluated by MRI and, in parallel, by US in 20 young subjects with severe HA (22.45 ± 2.72 years old; no history of arthritides, of viral infections or of inhibitors against factor VIII). The same joints were evaluated in 20 matched non-haemophilic (no-HA) subjects (mean age 23.90 ± 2.31 years, P = 0.078 vs. HA subjects). US images were obtained with specific probe positions according to validated procedures. A validated US score and progressive (P-MRI) and additive (A-MRI) MRI scores were employed for data collection and analysis. The US score was higher in HA than in no-HA subjects (3.40 ± 1.72 vs. 0.80 ± 1.10, P < 0.001). Taking into account only moderate/severe alterations, joint effusion was found in 55% of HA and in 5% of no-HA joints (P < 0.001); synovial hypertrophy was found in 20% of HA and in none of the no-HA joints; cartilage erosion was found in 30% of HA and in none of no-HA joints. MRI examinations confirmed these findings and the US score correlated with the A-MRI (r = 0.732, P < 0.001) and with the P-MRI (r = 0.598, P < 0.001) scores. MRI and US data significantly correlated as to effusion (r = 0.819, P = 0.002), synovial hypertrophy (r = 0.633, P = 0.036) and cartilage erosion (r = 0.734, P = 0.010). Despite inherent limitations, joint US examination identified subclinical abnormalities of HJ in young subjects with severe HA.

The use of antithrombotic drugs for the prevention of venous thromboembolism (VTE) in patients undergoing surgery is presently based on solid principles and high-level scientific evidence. This article reviews current strategies of pharmacological thromboprophylaxis. The level of VTE risk following surgery depends on a variety of factors that the surgeon should take into account, including the type of surgery and the presence of additional risk factors, such as elderly age and cancer. In patients undergoing minor general surgery, early mobilization is sufficient as prophylaxis, whereas in those undergoing major general surgery, thromboprophylaxis with low molecular weight heparin (LMWH), low-dose unfractionated heparin, or the pentasaccharide fondaparinux is recommended. Patients undergoing major orthopedic surgery have a particularly high risk of VTE, and routine thromboprophylaxis with LMWH, fondaparinux, or a vitamin K antagonist (international normalized ratio target: 2.0 to 3.0) is the standard of care in this group of patients. Recently, two new oral anticoagulants, rivaroxaban (a factor Xa inhibitor) and dabigatran etexilate (a direct thrombin inhibitor) have been licensed to be used for thromboprophylaxis after orthopedic surgery in Europe. Mechanical methods of thromboprophylaxis (compression stockings, intermittent pneumatic compression, vena cava filters), not discussed in detail in this review, should always be considered in patients at high thrombotic risk, in association with the pharmacological strategies, or in cases of contraindications to anticoagulants, as in patients or procedures at high risk of bleeding.

Because of joint haemorrhages, severe haemophilia subjects often have limitations in their daily activities. Current orthopaedic scores (OJS) in haemophilia miss mild joint impairments and only pick up severe alterations. Twelve young severe haemophiliacs (20.25 ± 1.9 years of age), were evaluated for OJS as well as for indices employed in rheumatoid arthritis [28-joint Disease Activity Score (DAS-28), Ritchie index, Health Assessment Questionnaire (HAQ), visual analogue scale (VAS)], spondyloarthritis [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), HAQ, VAS] and osteoarthritis [Knee injury and Osteoarthritis Outcome Score (KOOS), VAS]. Twenty-four matched apparently healthy subjects and 29 subjects with psoriatic arthritis (PsA) with oligoarticular involvement (one to three swollen joints) served as controls. In addition to the impairment of target joints (elbow, in five of five in those on-demand treatment; three, elbows; four, knee in those on secondary prophylaxis), HAQ (mean 0.71 ± 0.95) and VAS (3.12 ± 2.36) documented a quality of life and a perception of pain in haemophiliacs similar to that of PsA subjects (p = 0.061 and p = 0.063, respectively). Their Ritchie index did not differ from that of subjects with psoriatic arthritis (5.75 ± 8.1 vs 7.73 ± 9.22; p = 0.408), nor did the BASDAI score with respect to psoriatic arthritis patients (p = 0.105). Six of 12 haemophiliacs (50%) had KOOS values from 70 to 50 (significant function joint impairment); 3 of 12 (25%) showed DAS-28 values >3.2 (moderate disease activity), 2 of 12 (16.6%) severe disease activity (>5.1). All these indices significantly correlated with VAS and HAQ in haemophilia subjects. A rheumatologic assessment may help identify early polyarticular disease and subclinical abnormalities involving joints not usually studied (not target joint) in haemophiliacs. These pilot data provide the rationale for testing a systemic involvement in haemophiliacs by means of high-tech imaging and to start early-onset prophylaxis/treatment in this setting.

Objective: Glucocorticoid-induced osteoporosis is the most frequent cause of secondary osteoporosis. Nevertheless, limited data are available on bone status in patients with endogenous cortisol excess. This study is aimed at investigating the role of sex steroids and severity of hypercortisolism on bone mineral density (BMD) and prevalence of vertebral fractures in female patients. Design: Cross-sectional, case–control study. Patients: Seventy-one consecutive women were enrolled: 36 with overt hypercortisolism (26 with ACTH-secreting pituitary adenoma and 10 with cortisol-secreting adrenal tumor) and 35 with subclinical hypercortisolism due to adrenal incidentalomas. They were compared with 71 matched controls. Methods: At diagnosis, we measured serum cortisol, FSH, LH, estradiol, testosterone, androstenedione and DHEAS, and urinary cortisol excretion. BMD was determined by dual energy X-ray absorptiometry at the lumbar spine and femoral neck. Vertebral fractures were investigated by a semiquantitative scoring method. Results: Between women with overt and subclinical hypercortisolism BMD values and prevalence of any vertebral (69 vs 57%, P = 0.56), clinical (28 vs 11.4%, P = 0.22), and multiple vertebral fractures (36 vs 31%, P = 0.92) did not differ. Among patients with subclinical hypercortisolism, amenorrhoic women had a lower BMD (P = 0.035) and more frequent vertebral fractures (80 vs 40%; P = 0.043) when compared with the eumenorrhoic ones. Among women with overt hypercortisolism, there was no difference in lumbar BMD (P = 0.37) and prevalence of fractures (81 vs 60%; P = 0.26) between those amenorrhoic and eumenorrhoic. By logistic regression analysis, lumbar spine BMD values and cortisol-to-DHEAS ratio were the best predictors of vertebral fractures (P < 0.01). Conclusions: Vertebral fractures are very common in women with endogenous cortisol excess, regardless of its severity. The deleterious effects of hypercortisolism on the spine may be partly counterbalanced by DHEAS increase at any degree of cortisol excess, and by preserved menstrual cycles in women with subclinical but not in those with overt hypercortisolism.

Over the past 10 years recombinant activated factor VIIa (rFVIIa) has been successfully used for treatment and prophylaxis of bleeding in patients with platelet defects, including thrombocytopenia and congenital and acquired platelet function abnormalities. Most reported data concern patients with Glanzmann's thrombasthenia and the information available is still limited, especially for surgery. We report on a 15-year-old girl with thrombocytopenia ( approximately 60,000/microl) and platelet dysfunction (bleeding time 30 min, absent platelet aggregation and ATP secretion in response to collagen), related to thrombocytopenia with absent radii syndrome, undergoing two surgical interventions on the upper limbs due to forearm deformities, with prolonged postoperative revisions. In both surgeries rFVIIa was successfully employed as a bolus administration (80 microg/kg every 4 h during the first day, then every 6 h over the following 5 and 3 days, respectively; tranexamic acid was associated from the second day, administered for 2 weeks), avoiding the need for blood products. This report highlights rFVIIa as an attractive, alternative approach to secure hemostasis in patients with platelet defects; on the other hand, the heterogeneity of reported rFVIIa treatment regimens and, in particular, the lack of definite and easily available parameters (or assays) for monitoring rFVIIa efficacy and safety are the main open issues in this setting.

Deep vein thrombosis (DVT), and its most feared complication, pulmonary embolism (PE), still have a high incidence with high risk for patients’ health. Proven prophylactic measures are available but are generally underused, and DVT is still considered the most common cause of preventable death among hospitalized patients. The rationale for prophylaxis of venous thromboembolism is based on the clinically silent nature of the disease, the relatively high prevalence among hospitalized patients and the potentially tragic consequences of a missed diagnosis. During the last 15–20 years, spine surgery has changed radically, developing into a well-defined area of specialist surgery, and some attention is now being given to DVT events in spine surgery. The incidence of DVT during spine surgery is not documented in the literature, because only case reports or retrospective studies are reported. It would therefore be very helpful to initiate a multicenter study in order to understand this problem better and to develop, if possible, some guidelines on prophylactic measures in spine surgery. In doing so, we need to consider each patient’s pattern, any risk factors and every kind of surgical technique related to DVT, in order to improve the outcome of the patient and to reduce any medicolegal problems that could arise from a thrombotic complication or an epidural hematoma, with its high potential for irreversible consequences.