Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5-6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS. METHODS: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early-stage relapsing-remitting MS received ocrelizumab 600 mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration); the durations of the initial infusions (2×300 mg, 14 days apart) were unaffected. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first Randomized Dose. RESULTS: From November 1, 2018, to December 13, 2019, 745 patients were randomized 1:1 to the conventional or shorter infusion group. At the first Randomized Dose, 99/373 patients (26.5%) in the conventional and 107/372 patients (28.8%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild or moderate; >99% of all IRRs resolved without sequelae in both groups (conventional infusion group, 99/99; shorter infusion group, 106/107). No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuations occurred. During the first Randomized Dose, 22/373 (5.9%) and 39/372 (10.5%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. Adverse events were consistent with the known safety profile of ocrelizumab. CONCLUSION: The rates and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shortening the infusion time to 2 hours reduces the total site stay time (including mandatory pre-medication/infusion/observation) from 5.5-6 hours to 4 hours, and may reduce patient and site staff burden. A short video summarizing the key results is provided in supplemental material.

Does Osteoarthritis of the Ipsilateral Hip Develop After Knee Rotationplasty? A Radiologic Study on Patients with Long-term Survival Undergoing Surgery for Bone Tumors.

BACKGROUND: During routine check-ups of long-term surviving knee rotationplasty patients referred to our institute, we noted that the operated limb radiograph showed signs of hip osteoarthritis in some patients, and that one patient reported hip pain. We wondered whether radiographic changes and symptoms are common in patients undergoing rotationplasty due to mechanical or overloading problems during gait. Based on these considerations, we wished to determine how frequently arthrosis or arthritis would arise in the ipsilateral hip to a knee rotationplasty at long-term follow-up. To our knowledge, this issue has not been explored. Clinicians and patients should be aware of any problems that may affect the hip over time that could result in treatment. QUESTIONS/PURPOSES: At a minimum of 10 years after rotationplasty, in a single-center series, we therefore asked: (1) What proportion of patients reported hip pain at rest and with activity? (2) What proportion have radiographically visible arthritic changes in the ipsilateral or contralateral hip? (3) What proportion of patients have changes in the hip morphology (femoral rotation, cervicodiaphyseal angle, acetabular angle, osteopenia)? METHODS: Between 1986 to 2009, 42 patients underwent rotationplasty in our institute. They represent the 16.5% of a series of 254 children (age 3 to 14 years) affected by high-grade bone sarcomas located in the distal half of the femur. Three more patients were adolescents older than 15 years and were treated with rotationplasty because of the tumor volume and extracompartmental involvement. Of these 45 patients, 14 died of disease at a mean of 37 months; 31 patients were survivors at the time the study was done. Three of these long-term survivors were known to be alive but did not come for a clinic visit in the last 5 years. The remaining 28 patients were invited to participate in a research study on the long-term assessment of rotationplasty, and all agreed to participate. Unfortunately, 10 patients living far from our Institute could not come in the 2 days established for the assessment due to family or work constraints. AP plain radiographs of the pelvis were taken in 17 patients with long-term survival after knee rotationplasty. Patients were positioned in a standard weightbearing position, wearing their own prosthesis. Hip osteoarthritis was assessed using the Croft grading system. The presence of hip pain was assessed with the self-reported Numeric Rating Scale (NRS), with scores ranging from 0 to 10, at rest and during daily life activities. Femoral rotation, osteopenia, the cervicodiaphyseal and the acetabular angles were measured on radiographs. The median (range) age at follow-up was 32 years (22 to 45), the median age at the time of the intervention was 9 years (6 to 17), and the median follow-up duration after surgery was 25 years (11 to 30). RESULTS: One of the 17 patients complained of mild pain (NRS score of 2) in the ipsilateral hip during walking. No other patient claimed to have hip pain at rest or during walking or other daily life activities. Eleven of 17 patients had signs of OA according to the Croft grading system: one had Grade 1 OA, seven had Grade 2, and three had Grade 3. Six patients did not show any sign of OA in the ipsilateral hip. Two patients had Grade 1 OA and one had Grade 2 OA of the contralateral hip. Sixteen patients had femoral external rotation. An increased valgus cervicodiaphyseal angle and acetabular angle were present in 10 and 9 patients, respectively. Osteopenia at the ipsilateral hip when compared with the contralateral, was present in all patients but one, with varying degrees of severity. CONCLUSIONS: In this small series, signs of osteoarthritis of the hip ipsilateral to the rotationplasty were present in a high proportion of patients at a minimum follow-up interval of 10 years after surgery, although only one participant reported hip pain. The finding of arthrosis in the hip above a rotationplasty is potentially important because it may be related to gait abnormalities that may modify the hip's morphology over time. It is encouraging that symptomatic hip pain was uncommon in our patients, but this could become more of a clinical problem with longer follow-up and result in therapeutic intervention. Patients (or the parents of patients) undergoing this procedure should be informed that they might develop hip arthritis during young adulthood. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Vascularized fibular autograft as salvage technique in failure of allograft intercalary reconstructions after tumor resections.

Intercalary allografts after diaphyseal resections for bone tumors represent the most frequent option of reconstruction. Main complications are non-unions, fractures and infections. The purpose of the current study was to report our experience with the use of vascularized fibular autograft as rescue technique in failed previous reconstructions after intercalary bone tumor resection of the extremities. Twenty-eight patients were followed over time. Causes of failure were non-union, allograft fracture and infection. Vascularized fibular autograft was used with mechanical support of massive bone allograft in 13 cases. Functional results were excellent in 19 cases, good in 8 and fair in one patient. Among complications we reported 4 non-unions, 2 allograft fractures, 1 non-union with plate breakage, 1 plate breakage, 1 infection, 1 limb shortening and 1 knee varus deformity. The rationale of vascularized fibular autograft is to provide biologic support. The association with massive bone allograft provides mechanical strength and early stability.

SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis.

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.

Biomaterials as bone graft substitutes for spine surgery: from preclinical results to clinical study.

Vertebral fusion is performed in order to stabilize the spine in the presence of degenerative, traumatic or oncological pathologies that alter its stability. The autologous bone, harvested from the patient's iliac crest or from the lamina during surgery, is still considered the "gold standard" for spine fusion due to its osteogenic, osteoinductive and osteoconductive properties. However, several biological and synthetic bone substitutes have been introduced as alternatives for regenerating bone tissue. We have studied in particular the use of ceramic biomaterials prepared from hydroxypatite (HA), starting from in vitro analysis, through an in vivo study on ovine animal model and a post-market surveillance analysis, to finally design and perform a clinical study, which is ongoing in our Department. In the first step, HA-derived biomaterials were tested in vitro in the presence of bone marrow-derived human mesenchymal stem cells (hMSCs) and evaluated for their ability to activate precursor cells. In the second step, the biomimetic bone graft substitute SintLife® putty (MgHA) was evaluated in vivo. A posterolateral fusion procedure was applied on 18 sheep, where a fusion level was treated with MgHA, while the other level was treated with autologous bone. Microtomography and histological/histomorphometric analysis were performed six months of after surgery. In the third step, we reported the results of a post-market surveillance study conducted on 4 independent cohorts of patients (total 115 patients), in which HA-derived biomaterials were used as bone graft substitutes or extenders. Finally, a clinical study has been designed and approved by the Ethics Committee of our Institute and is currently ongoing. This study aims to evaluate the efficacy of the ceramic biomaterial SintLife® putty for bone replacement in patients treated by posterolateral fusion for degenerative spine disorders. HA biomaterials were effective in promoting the in vitro growth of hMSCs and their osteogenic differentiation. In the animal model, SintLife® putty has been effective in generating neo-formed bone tissue with morphological and structural features similar to those of the pre-existing bone. The post-market surveillance analysis has not reported any intra-operative nor early or late post-operative adverse events. Seven patients are currently recruited for the clinical trial designed to evaluate Sintlife efficacy for spine fusion (FU range: 1-7 months). No adverse events have been recorded. The first CT analysis performed at 6 months FU showed a good spine fusion. The study is ongoing. Our results, obtained from in vitro, preclinical and clinical studies, suggest that biomaterials derived from hydroxyapatite could be a valid alternative to autologous bone graft for vertebral fusion. This would potentially avoid or reduce the need of autologous bone harvesting and therefore, the risk of drawback-related side effects.

Sclerosing epithelioid fibrosarcoma of the thigh: report of two cases with synchronous bone metastases.

We report two cases of sclerosing epithelioid fibrosarcoma occurring in the deep soft tissue of the thigh, confirmed by molecular analysis and associated with bone metastases in the lumbar vertebrae and the iliac wing at the time of diagnosis. Synchronous bone metastases of sclerosing epithelioid fibrosarcoma are extremely difficult to diagnose because clinical and radiological features are not specific. In addition, the range of differential diagnoses is very wide, including metastatic carcinoma and osteosarcoma. At present, all but three published cases of sclerosing epithelioid fibrosarcoma with bone metastases showed bone metastases during follow-up. We confirm in our two cases that the distinct pattern of immunohistochemical staining for MUC4, associated with the absence of staining for both SATB2, a marker of osteoblastic differentiation, and pan-cytokeratin, allows differentiating between sclerosing epithelioid fibrosarcoma and metastatic carcinoma or osteosarcoma.

Propagation of magnetic vortices using nanocontacts as tunable attractors.

Magnetic vortices in thin films are in-plane spiral spin configurations with a core in which the magnetization twists out of the film plane. Vortices result from the competition between atomic-scale exchange forces and long-range dipolar interactions. They are often the ground state of magnetic dots, and have applications in medicine, microwave generation and information storage. The compact nature of the vortex core, which is 10-20 nm wide, makes it a suitable probe of magnetism at the nanoscale. However, thus far the positioning of a vortex has been possible only in confined structures, which prevents its transport over large distances. Here we show that vortices can be propagated in an unconstrained system that comprises electrical nanocontacts (NCs). The NCs are used as tunable vortex attractors in a manner that resembles the propelling of space craft with gravitational slingshots. By passing current from the NCs to a ferromagnetic film, circulating magnetic fields are generated, which nucleate the vortex and create a potential well for it. The current becomes spin polarized in the film, and thereby drives the vortex into gyration through spin-transfer torques. The vortex can be guided from one NC to another by tuning attractive strengths of the NCs. We anticipate that NC networks may be used as multiterminal sources of vortices and spin waves (as well as heat, spin and charge flows) to sense the fundamental interactions between physical objects and fluxes of the next-generation spintronic devices.

Mesenchymal stem cells from patients to assay bone graft substitutes.

Bio-engineered scaffolds used in orthopedic clinical applications induce different tissue responses after implantation. In this study, non-stoichiometric Mg(2+) ions and stoichiometric apatites, which are used in orthopedic surgery as bone substitutes, have been assayed in vitro with human adult mesenchymal stem cells (hMSC) to evaluate cytocompatibility and osteoconductivity. hMSCs from the bone marrow aspirates of orthopedic patients were isolated and analyzed by flow cytometry for the surface markers Stro1, CD29, CD44, CD71, CD73, CD90, CD105 (positive) and CD45, CD235 (negative). The hMSC were analyzed for self-renewal capacity and for differentiation potential. The hMSC, which were grown on different biomaterials, were analyzed for (i) cytotoxicity by AlamarBlue metabolic assay, (ii) osteoconductivity by ELISA for activated focal adhesion kinase, (iii) cytoskeleton organization by fluorescence microscopy, and (iv) cell morphology which was investigated by scan electron microscopy (SEM). Results indicate that isolated cell populations agree with minimal criteria for defining hMSC cultures. Non-stoichiometric Mg(2+) and stoichiometric apatites, in granular form, represent a more favorable environment for mesenchymal stem cell adhesion and growth compared to the non-stoichiometric Mg(2+) apatite, in nano-structured paste form. This study indicates that different forms of biomaterials modulate osteoconductivity and cellular growth by differential activation focal adhesion kinase.

Lipid profiles of oil from trout (Oncorhynchus mykiss) heads, spines and viscera: trout by-products as a possible source of omega-3 lipids?

Lipid profiles of fish oil extracted from trout heads, spines and viscera using supercritical carbon dioxide and Randall extraction with hexane were measured. The amount of unsaturated fatty acids (as a percentage of total fatty acids) was within the range of 72.6-75.3% in all the substrates. A significant presence of the most important omega-3 fatty acids was detected. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content in oil from spines, heads and viscera resulted to be 8.7% and 7.3%, 7.9% and 6.3%, and 6.4% and 6.0%, respectively. A low (≈3%), but worth noting, presence of lipids with omega-1 polyunsaturated fatty chains was observed in all the oils. Finally, significant differences were noticed in the relative amounts of triacylglycerides (TAG), diacylglycerides (DAG) and free fatty acids (FFA). Whereas oil from heads and spines was essentially composed of TAG (≈98%), in viscera oil the molar distribution ratio became TAG:DAG:FFA=87:8:5.

Expandable tumor prostheses in children.

Any surgical resection in the lower extremities in children will cause a leg length discrepancy from physeal resection. To avoid the resulting functional deficit, leg length discrepancy must be reconciled with surgical techniques to approximate equal leg lengths at skeletal maturity. Currently there are several manufacturers who offer options for prosthetic reconstruction with expandable implants. These implants can be expanded to a length projected on the basis of three factors: the length of bone resected, the anticipated future growth of the contralateral extremity, and the estimated discrepancy of limb length at skeletal maturity. In this article, we review the basic principles and guidelines for prediction of remaining bone growth and planning lengthening in children, and present the currently available expandable prostheses and the evolution performed over time.

Human mesenchymal stem cells and biomaterials interaction: a promising synergy to improve spine fusion.

PURPOSE: Spine fusion is the gold standard treatment in degenerative and traumatic spine diseases. The bone regenerative medicine needs (i) in vitro functionally active osteoblasts, and/or (ii) the in vivo induction of the tissue. The bone tissue engineering seems to be a very promising approach for the effectiveness of orthopedic surgical procedures, clinical applications are often hampered by the limited availability of bone allograft or substitutes. New biomaterials have been recently developed for the orthopedic applications. The main characteristics of these scaffolds are the ability to induce the bone tissue formation by generating an appropriate environment for (i) the cell growth and (ii) recruiting precursor bone cells for the proliferation and differentiation. A new prototype of biomaterials known as "bioceramics" may own these features. Bioceramics are bone substitutes mainly composed of calcium and phosphate complex salt derivatives. METHODS: In this study, the characteristics bioceramics bone substitutes have been tested with human mesenchymal stem cells obtained from the bone marrow of adult orthopedic patients. RESULTS: These cellular models can be employed to characterize in vitro the behavior of different biomaterials, which are used as bone void fillers or three-dimensional scaffolds. CONCLUSIONS: Human mesenchymal stem cells in combination with biomaterials seem to be good alternative to the autologous or allogenic bone fusion in spine surgery. The cellular model used in our study is a useful tool for investigating cytocompatibility and biological features of HA-derived scaffolds.

Understanding nanoscale temperature gradients in magnetic nanocontacts.

We have determined the temperature profile in magnetic nanocontacts under applied current densities typical of spin-torque oscillators (∼10(8) A/cm2). The study combines experimental measurements of the electrical and magnetic properties of the nanocontacts and full three-dimensional simulations of the heat and current flow in these systems. It is found that the quadratic current-induced increase of the resistance due to Joule heating is independent of the applied temperature from 6 to 300 K. In terms of magnetization dynamics, the measured current-induced vortex nucleation, a thermally activated process, is found to be consistent with local temperatures increases of between 147 and 225 K. Simulations reproduce the experimental findings and show that significant thermal gradients exist out to 450 nm from the nanocontact.

Hospital use of decontaminating mats.

Decontaminating mats made of several layers of adhesive sheets (water-based acrylic 6 g/m2) supplemented with a bactericidal agent (3-1 benzoisothiazolin) at a concentration of 25% were placed in the passages providing access to the operating rooms of an orthopaedic service. Contact plates containing tryptone soy agar were used to assess bacterial concentration at specific points in front of and beyond the mats. For trolley passageways two areas were defined: central and lateral paths, corresponding to the areas walked upon by the personnel pushing the trolleys and to the paths covered by the trolley wheels, respectively. In order to exclude a simple mechanical effect, a comparison of bacterial loads at defined sites beyond the mats was carried out in the presence and in the absence of decontaminating mats. Bacterial colony counts in the presence of decontaminating mats were substantially and statistically significantly reduced compared with the absence of mats. The lower mean number of colony-forming units detected at points located beyond the mats parallels this finding; this difference is also statistically significant. We thus conclude that decontaminating mats are potentially useful in decreasing micro-organism carry-over due to personnel or the passage of trolleys into areas at high risk of infection such as operating rooms.

Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide.

BACKGROUND: Effective adjuvant or neoadjuvant regimens of chemotherapy have dramatically improved the prognosis of patients with high-grade osteosarcoma of the extremity, localized at diagnosis. Currently, little is known about patients with metastatic disease at presentation. PATIENTS AND METHODS: From May 1995 to May 2000, 57 patients with osteosarcoma of the extremity, metastatic at presentation, were treated according to the following scheme: primary chemotherapy, restaging, simultaneous resection of primary tumor and metastatic lesions, and maintenance chemotherapy. RESULTS: Thirty-five patients achieved remission. At a follow-up ranging from 2 to 7 years, seven remained continuously free of disease, one died of chemotherapy-related toxicity and 27 patients relapsed. Twenty-one of the 22 patients who never achieved remission died as a result of the tumor, as well as 20 of the 27 who achieved remission but then relapsed. Of the remaining seven relapsing patients, six are alive with uncontrolled disease, while one is alive and free of disease 24 months after the last post-relapse treatment. Two-year event-free survival (EFS) and overall survival (OS) were 21% and 55%, respectively. These results are significantly poorer than those achieved in 128 contemporary patients with non-metastatic disease at presentation, treated with the same chemotherapy protocol (2-year EFS and OS of 75% and 94%, respectively). CONCLUSIONS: The results of our study confirm that the prognosis of patients with osteosarcoma of the extremity, metastatic at presentation, remains poor, despite the use of aggressive treatments.

Mechanical strength of a femoral reconstruction in paediatric oncology: a finite element study.

In 1997 the proximal femur of a four-year-old child affected by a Ewing sarcoma was reconstructed using a massive bone allograft in conjunction with a vascularized fibula autograft. During the first three years of follow-up the reconstruction underwent important morphological changes. The aim of the present study was to evaluate the risk of fracture of the reconstructed proximal femur, once the physiological loads are restored, associated with a short, slow but unprotected level walk. Subject-specific finite element models of the operated femur, and of the intact contralateral one, were generated from a computed tomography exam, taken for routine clinical monitoring at month 33 of follow-up. The material properties were mapped on to the mesh and a loading condition comprising the hip joint reaction and the abductor muscle force was simulated. The risk of fracture was locally estimated, for the operated and intact femur, using the ratio between the bone tissue strength and the predicted Von Mises equivalent stress, taking into account the different behaviours of the bone tissue in tension or compression. The results showed that although the fibula grew dramatically during follow-up, the reconstructed femur had not recovered the whole mechanical strength of a normal femur. The reconstructed femoral neck seemed to be weaker than the contralateral one and hence at a higher fracture risk. However, no region reached the failure limit, so the model predicted no fracture of the femur if a short, slow but unprotected walk were allowed. The model predictions found an indirect clinical validation when the child was allowed to perform short unprotected walks and did not experience any fracture.

Local and systemic control in Ewing's sarcoma of the femur treated with chemotherapy, and locally by radiotherapy and/or surgery.

The role of radiotherapy and/or surgery in the local treatment of Ewing's sarcoma has still to be determined. The outcome of Ewing's sarcoma may differ according to its location and a selection bias towards surgery limits the ability to compare methods of local treatment. We have carried out a retrospective review of 91 consecutive patients treated for non-metastatic Ewing's sarcoma of the femur. They received chemotherapy according to four different protocols. The primary lesion was treated by surgery alone (54 patients), surgery and radiotherapy (13) and radiotherapy alone (23). One was treated by chemotherapy alone. At a median follow-up of ten years, 48 patients (53%) remain free from disease, 39 (43%) have relapsed, two (2%) have died from chemotherapeutic toxicity and two (2%) have developed a radio-induced second tumour. The probability of survival without local recurrence was significantly (p = 0.01) higher in patients who were treated by surgery with or without radiotherapy (88%) than for patients who received radiotherapy alone (59%). The five- and ten-year overall survival rates were 64% and 57%, respectively. Patients who were treated by surgery, with or without radiotherapy, had a five- and ten-year overall survival of 64%. Patients who received only radiotherapy had a five- and ten-year survival of 57% and 44%, respectively. Our results indicate that in patients with Ewing's sarcoma of the femur, better local control is achieved by surgical treatment (with or without radiotherapy) compared with the use of radiotherapy alone. Further studies are needed to verify the impact of this strategy on overall survival.

The role of vascularized fibula in skeletal reconstruction.

Since March 1988, 144 oncologic bone resections have been surgically treated with vascularized fibula (VF). In 30 patients VF was used after the failure of previous reconstructions, while in 114 cases (79%) VF immediately followed tumor resection. In 14 cases VF was pedicled on its vessel and used to reconstruct the ipsilateral tibia. In 17 young children, the proximal fibula was used to reconstruct with a potential growth the proximal humerus, the distal radius or the proximal femur. In 103 cases VF was combined with bone allografts. In 70 of these the fibula was inserted inside the massive allograft as a viable rod. There were 7 mechanical failures, 9 deep infections, and 10 local recurrences. According to functional evaluation, 69 patients (48%) presented with excellent functional results, 39 patients (27%) had good results while fair of poor results were recorded in 36 cases (25%).