Development and Validation of Novel Z-360-Based Macromolecules for the Active Targeting of CCK2-R.

The cholecystokinin type 2 receptor (CCK2-R) represents an ideal target for cancer therapy since it is overexpressed in several tumors and is associated with poor prognosis. Nastorazepide (Z-360), a selective CCK2-R antagonist, has been widely investigated as a CCK2-R ligand for targeted therapy; however, its high hydrophobicity may represent a limit to cell selectivity and optimal in vivo biodistribution. Here, we present three new fluorescent Z-360 derivatives (IP-002G-Rho, IP-002L-Rho, and IP-002M-Rho) in which nastorazepide was linked, through spacers bearing different saccharides (glucose (G), lactose (L), and maltotriose (M)), to sulforhodamine B. A fourth compound (IP-002H-Rho) with no pendant sugar was also synthesized as a control. Through two-dimensional (2D) and three-dimensional (3D) in vitro studies, we evaluated the compound association with and selectivity for CCK2-R-overexpressing cells (A431-CCK2-R+) vs CCK2-R-underexpressing cells (A431 WT). 2D in vitro studies highlighted a progressive increase of IP-002x-Rho association with A431-CCK2-R+ cells according to the linker hydrophilicity, that is, maltotriose > lactose > glucose > hydrogen, with IP-002M-Rho showing a 2.4- and a 1.36-fold higher uptake than IP-002G-Rho and IP-002L-Rho, respectively. Unexpectedly, IP-002H-Rho showed a similar cell association to that of IP-002L-Rho but with no difference between the two tested cell lines. On the contrary, association with A431-CCK2-R+ cells as compared to the A431 WT was found to be 1.08-, 1.14-, and 1.37-fold higher for IP-002G-Rho, IP-002L-Rho, and IP-002M-Rho, respectively, proving IP-002M-Rho to be the best-performing compound, as also confirmed by competition studies. Trafficking studies on A431-CCK2-R+ cells incubated with IP-002M-Rho suggested the coexistence of receptor-mediated endocytosis and simple diffusion. On the contrary, a high and selective uptake of IP-002M-Rho by A431-CCK2-R+ cells only was observed on 3D scaffolds embedded with cells, underlining the importance of 3D models in in vitro preliminary evaluation.

Proximal femoral defect classifications in revision total hip arthroplasty from X-rays imaging to advanced 3D imaging: a narrative review.

Background and Objective: Femoral bone defect in hip arthroplasty revision surgery represents a complex problem, and the treatment is a challenge for orthopedic surgeons called to assess the residual bone stock in an altered anatomy and obtain stability for the new implant. Classification systems available are mostly based on X-rays two-dimensional images and lack of accuracy and reproducibility and comprehensive therapeutic algorithms. However, there is no record of any classification based on computed tomography (CT)-scan images or three-dimensional (3D) modeling modern techniques. We aimed to review the current literature around femoral defect classifications (FDCs) analyzing their different rationale basis, reliability and accuracy, and their benefit in clinical practice. Moreover, we highlighted the role of CT scan-based 3D modeling techniques in the setting of femoral bone defects and revision hip arthroplasty. Methods: A narrative review was conducted. The articles were selected from the PubMed and Scopus medical database updated to March 2023. All Level-I to IV studies in the English language were considered for inclusion. The research was performed using relevant search term items: "femoral defects", "classification", "radiographic", "revision hip arthroplasty", "CT scan" and "3D" and we included only articles that evaluated the accuracy or reliability (or both) of the different femoral bone defects classification system. Key Content and Findings: Our search yielded 408 results, of which 17 were deemed highly relevant. We found seven X-ray-based classification systems which have been attempted to quantify the degree of bone loss with low to good reproducibility. The most used classification system for femoral bone defects were the AAOS and Paprosky classification, which also offers a clinical therapeutic algorithm. In 2021, the FDC interestingly showed a new simple classification system with sub-optimal reproducibility and a practical therapeutic algorithm. Despite the numerous classification system of femoral defects, none of them comprehends the use of CT scan and 3D imaging technologies. Conclusions: Traditional X-rays-based classification system are still widely used event if their intra-observer and inter-observer reliability is sub-optimal. 3D modeling techniques represent an important diagnostic tool that could improve the understanding of bone defects and residual bone supportive structures, allowing to elaborate new, more precise, classification systems.

Biodistribution Assessment of a Novel 68Ga-Labeled Radiopharmaceutical in a Cancer Overexpressing CCK2R Mouse Model: Conventional and Radiomics Methods for Analysis.

The aim of the present study consists of the evaluation of the biodistribution of a novel 68Ga-labeled radiopharmaceutical, [68Ga]Ga-NODAGA-Z360, injected into Balb/c nude mice through histopathological analysis on bioptic samples and radiomics analysis of positron emission tomography/computed tomography (PET/CT) images. The 68Ga-labeled radiopharmaceutical was designed to specifically bind to the cholecystokinin receptor (CCK2R). This receptor, naturally present in healthy tissues such as the stomach, is a biomarker for numerous tumors when overexpressed. In this experiment, Balb/c nude mice were xenografted with a human epidermoid carcinoma A431 cell line (A431 WT) and overexpressing CCK2R (A431 CCK2R+), while controls received a wild-type cell line. PET images were processed, segmented after atlas-based co-registration and, consequently, 112 radiomics features were extracted for each investigated organ / tissue. To confirm the histopathology at the tissue level and correlate it with the degree of PET uptake, the studies were supported by digital pathology. As a result of the analyses, the differences in radiomics features in different body districts confirmed the correct targeting of the radiopharmaceutical. In preclinical imaging, the methodology confirms the importance of a decision-support system based on artificial intelligence algorithms for the assessment of radiopharmaceutical biodistribution.

The anti-SARS-CoV-2 BNT162b2 vaccine suppresses mithramycin-induced erythroid differentiation and expression of embryo-fetal globin genes in human erythroleukemia K562 cells.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causative of the ongoing coronavirus disease 2019 (COVID-19) pandemic. The SARS-CoV-2 Spike protein (S-protein) plays an important role in the early phase of SARS-CoV-2 infection through efficient interaction with ACE2. The S-protein is produced by RNA-based COVID-19 vaccines, that were fundamental for the reduction of the viral spread within the population and the clinical severity of COVID-19. However, the S-protein has been hypothesized to be responsible for damaging cells of several tissues and for some important side effects of RNA-based COVID-19 vaccines. Considering the impact of COVID-19 and SARS-CoV-2 infection on the hematopoietic system, the aim of this study was to verify the effect of the BNT162b2 vaccine on erythroid differentiation of the human K562 cell line, that has been in the past intensively studied as a model system mimicking some steps of erythropoiesis. In this context, we focused on hemoglobin production and induced expression of embryo-fetal globin genes, that are among the most important features of K562 erythroid differentiation. We found that the BNT162b2 vaccine suppresses mithramycin-induced erythroid differentiation of K562 cells. Reverse-transcription-qPCR and Western blotting assays demonstrated that suppression of erythroid differentiation was associated with sharp inhibition of the expression of α-globin and γ-globin mRNA accumulation. Inhibition of accumulation of ζ-globin and ε-globin mRNAs was also observed. In addition, we provide in silico studies suggesting a direct interaction between SARS-CoV-2 Spike protein and Hb Portland, that is the major hemoglobin produced by K562 cells. This study thus provides information suggesting the need of great attention on possible alteration of hematopoietic parameters following SARS-CoV-2 infection and/or COVID-19 vaccination.

Assessing the interaction between hemoglobin and the receptor binding domain of SARS-CoV-2 spike protein through MARTINI coarse-grained molecular dynamics.

The emergence of different coronavirus-related diseases in the 2000's (SARS, MERS, and Covid-19) warrants the need of a complete understanding of the pathological, biological, and biochemical behavior of this class of pathogens. Great attention has been paid to the SARS-CoV-2 Spike protein, and its interaction with the human ACE2 has been thoroughly investigated. Recent findings suggested that the SARS-CoV-2 components may interact with different human proteins, and hemoglobin has very recently been demonstrated as a potential target for the Spike protein. Here we have investigated the interaction between either adult or fetal hemoglobin and the receptor binding domain of the Spike protein at molecular level through advanced molecular dynamics techniques and proposed rational binding modes and energy estimations. Our results agree with biochemical data previously reported in literature. We also demonstrated that co-incubation of pulmonary epithelial cells with hemoglobin strongly reduces the pro-inflammatory effects exerted by the concomitant administration of Spike protein.

Preliminary Discovery of Small Molecule Inhibitors of Epidermal Growth Factor Receptor (EGFR) That Bind to the Extracellular Domain.

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane glycoprotein belonging to the protein kinase superfamily. It is composed of an extracellular domain, a transmembrane anchoring region and a cytoplasmic region endowed with tyrosine kinase activity. Genetic mutations of EGFR kinase cause higher activity thereby stimulating downstream signaling pathways that, in turn, impact transcription and cell cycle progression. Due to the involvement of mutant EGFR in tumors and inflammatory diseases, in the past decade, several EGFR inhibitory strategies have been extensively studied, either targeting the extracellular domain (through monoclonal antibodies) or the intracellular kinase domain (through ATP-mimic small molecules). Monoclonal antibodies impair the binding to growth factor, the receptor dimerization, and its activation, whereas small molecules block the intracellular catalytic activity. Herein, we describe the development of a novel small molecule, called DSF-102, that interacts with the extracellular domain of EGFR. When tested in vitro in KRAS mutant A549 cells, it impairs EGFR activity by exerting (i) dose-dependent toxicity effects; (ii) a negative regulation of ERK, MAPK p38 and AKT; and (iii) a modulation of the intracellular trafficking and lysosomal degradation of EGFR. Interestingly, DSF-102 exerts its EGFR inhibitory activity without showing interaction with the intracellular kinase domain. Taken together, these findings suggest that DSF-102 is a promising hit compound for the development of a novel class of anti-EGFR compounds, i.e., small molecules able to interact with the extracellular domain of EGFR and useful for overcoming the KRAS-driven resistance to TKI treatment.

Chelation of Theranostic Copper Radioisotopes with S-Rich Macrocycles: From Radiolabelling of Copper-64 to In Vivo Investigation.

Copper radioisotopes are generally employed for cancer imaging and therapy when firmly coordinated via a chelating agent coupled to a tumor-seeking vector. However, the biologically triggered Cu2+-Cu+ redox switching may constrain the in vivo integrity of the resulting complex, leading to demetallation processes. This unsought pathway is expected to be hindered by chelators bearing N, O, and S donors which appropriately complements the borderline-hard and soft nature of Cu2+ and Cu+. In this work, the labelling performances of a series of S-rich polyazamacrocyclic chelators with [64Cu]Cu2+ and the stability of the [64Cu]Cu-complexes thereof were evaluated. Among the chelators considered, the best results were obtained with 1,7-bis [2-(methylsulfanyl)ethyl]-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). DO2A2S was labelled at high molar activities in mild reaction conditions, and its [64Cu]Cu2+ complex showed excellent integrity in human serum over 24 h. Biodistribution studies in BALB/c nude mice performed with [64Cu][Cu(DO2A2S)] revealed a behavior similar to other [64Cu]Cu-labelled cyclen derivatives characterized by high liver and kidney uptake, which could either be ascribed to transchelation phenomena or metabolic processing of the intact complex.

Complications and Intraoperative Fractures in Reverse Shoulder Arthroplasty: A Systematic Review.

INTRODUCTION: The reverse shoulder arthroplasty is nowadays a treatment option for a variety of shoulder problems. As its incidence rose, also the number of complications increased, including intraoperative fractures. SIGNIFICANCE: We performed a systematic review and critical analysis of the current literature following the PRISMA guidelines. Our purpose was to: 1) determine incidence, causes, and characteristics of intraoperative fractures; 2) evaluate their current treatment options, possible related complications, reoperation rates, and the patients' outcome; and 3) determine the overall incidence of each complication related to reverse shoulder arthroplasty. The articles were selected from PubMed medical database in April 2020 using a comprehensive search strategy. Rayyan software was used to support the selection process of the records. A descriptive and critical analysis of the results was performed. RESULTS: The study group included a total of 13,513 reverse shoulder arthroplasty procedures. The total number of complications was 1647 (rate 12.1%). The most common complication was dislocation (340 cases, rate 2.5%). Forty-six studies reported a total of 188 intraoperative fractures among the complications (rate 1.4%). The intraoperative fracture rate was 2.9% and 13.6% in primary and revision settings, respectively. There were 136 humeral fractures, 60% of them occurred in revision RSAs, during the removal of the previous implant, and involved the shaft in the majority of cases (39%). Glenoid fractures were 51 and occurred mostly during the reaming of the glenoid. We observed 7 further related complications (rate of 4%) and 3 reoperations (rate of 1.5%). The outcome was satisfactory in the majority of cases. CONCLUSIONS: A comprehensive review on intraoperative fractures in reverse shoulder arthroplasties is presented. Results suggest favorable outcomes for all treatment methods, with a modest further complication rate. This investigation may aid in the treatment decision-making for these complications.

Tyrosine kinase inhibitor prodrug-loaded liposomes for controlled release at tumor microenvironment.

Tyrosine kinase inhibitors (TKIs) represent one of the most advanced class of therapeutics for cancer treatment. Most of them are also cytochrome P450 (CYP) inhibitors and/or substrates thereof. Accordingly, their efficacy and/or toxicity can be affected by CYP-mediated metabolism and by metabolism-derived drug-drug interactions. In order to enhance the therapeutic performance of these drugs, we developed a prodrug (Pro962) of our TKI TK962 specifically designed for liposome loading and pH-controlled release in the tumor. A cholesterol moiety was linked to TK962 through pH-sensitive hydrazone bond for anchoring to the liposome phospholipid bilayer to prevent leakage of the prodrug from the nanocarrier. Bioactivity studies performed on isolated target kinases showed that the prodrug maintains only partial activity against them and the release of TK962 is required. Biopharmaceutical studies carried out with prodrug loaded liposomes showed that the prodrug was firmly associated with the vesicles and the drug release was prevented under blood-mimicking conditions. Conversely, conventional liposome loaded with TK962 readily released the drug. Flow cytometric studies showed that liposomes efficiently provided for intracellular prodrug delivery. The use of the hydrazone linker yielded a pH-controlled drug release, which resulted in about 50% drug release at pH 4 and 5 in 2 h. Prodrug, prodrug loaded liposomes and active lead compound have been tested against cancer cell lines in either 2D or 3D models. The liposome formulation showed higher cytotoxicity than the unformulated lead TK962 in both 2D and 3D models. The stability of prodrug, prodrug loaded liposomes and active lead compound in human serum and against human, mouse, and rat microsomes was also assessed, demonstrating that liposome formulations impair the metabolic reactions and protect the loaded compounds from catabolism. The results suggest that the liposomal formulation of pH releasable TKI prodrugs is a promising strategy to improve the metabolic stability, intracellular cancer cell delivery and release, and in turn the efficacy of this class of anticancer drugs.

Copper Coordination Chemistry of Sulfur Pendant Cyclen Derivatives: An Attempt to Hinder the Reductive-Induced Demetalation in 64/67Cu Radiopharmaceuticals.

The Cu2+ complexes formed by a series of cyclen derivatives bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic and structural points of view to evaluate their potential as chelators for copper radioisotopes. UV-vis spectrophotometric out-of-cell titrations under strongly acidic conditions, direct in-cell UV-vis titrations, potentiometric measurements at pH >4, and spectrophotometric Ag+-Cu2+ competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu2+ complexes. A highly stable 1:1 metal-to-ligand complex (CuL) was found in solution at all pH values for all chelators, and for DO2A2S, protonated species were also detected under acidic conditions. The structures of the Cu2+ complexes in aqueous solution were investigated by UV-vis and electron paramagnetic resonance (EPR), and the results were supported by relativistic density functional theory (DFT) calculations. Isomers were detected that differed from their coordination modes. Crystals of [Cu(DO4S)(NO3)]·NO3 and [Cu(DO2A2S)] suitable for X-ray diffraction were obtained. Cyclic voltammetry (CV) experiments highlighted the remarkable stability of the copper complexes with reference to dissociation upon reduction from Cu2+ to Cu+ on the CV time scale. The Cu+ complexes were generated in situ by electrolysis and examined by NMR spectroscopy. DFT calculations gave further structural insights. These results demonstrate that the investigated sulfur-containing chelators are promising candidates for application in copper-based radiopharmaceuticals. In this connection, the high stability of both Cu2+ and Cu+ complexes can represent a key parameter for avoiding in vivo demetalation after bioinduced reduction to Cu+, often observed for other well-known chelators that can stabilize only Cu2+.

Late onset periprosthetic joint infection of the knee caused by Streptococcus anginosus. Case presentation and literature review.

Periprosthetic joint infection (PJI) is one of the most dramatic complications of joint arthroplasty. Although streptococcal bone and joint infections are less common than staphylococcal cases, their role as causative agents of bone and joint remains significant accounting for at least 10% of PJIs. Streptococcus anginosus group (SAG) bacteria are usually found in the normal flora of the urogenital tract, intestinal tract and oropharynx and could cause pyogenic infections to affect brain, lungs and liver. SAG bacteria are uncommonly reported as a cause of osteomyelitis and the involvement of a joint represent a rare event. S. anginosus has been anecdotical related to implant devices infections such as vascular prosthesis or orthopedic implants, however, PJI of the knee has never been fully reported before. We describe the case of a late onset periprosthetic knee infection due to Streptococcus anginosus successfully treated by a two-stage revision arthroplasty and postoperative parenteral Vancomycin, (2 g per day) and Levofloxacin (750 mg per day) for 4 weeks and then oral Levofloxacin for a further 2 weeks.

Preliminary Study of a 1,5-Benzodiazepine-Derivative Labelled with Indium-111 for CCK-2 Receptor Targeting.

The cholecystokinin-2 receptor (CCK-2R) is overexpressed in several human cancers but displays limited expression in normal tissues. For this reason, it is a suitable target for developing specific radiotracers. In this study, a nastorazepide-based ligand functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator (IP-001) was synthesized and labelled with indium-111. The radiolabeling process yielded >95% with a molar activity of 10 MBq/nmol and a radiochemical purity of >98%. Stability studies have shown a remarkable resistance to degradation (>93%) within 120 h of incubation in human blood. The in vitro uptake of [111In]In-IP-001 was assessed for up to 24 h on a high CCK-2R-expressing tumor cell line (A549) showing maximal accumulation after 4 h of incubation. Biodistribution and single photon emission tomography (SPECT)/CT imaging were evaluated on BALB/c nude mice bearing A549 xenograft tumors. Implanted tumors could be clearly visualized after only 4 h post injection (2.36 ± 0.26% ID/cc), although a high amount of radiotracer was also found in the liver, kidneys, and spleen (8.25 ± 2.21%, 6.99 ± 0.97%, and 3.88 ± 0.36% ID/cc, respectively). Clearance was slow by both hepatobiliary and renal excretion. Tumor retention persisted for up to 24 h, with the tumor to organs ratio increasing over-time and ending with a tumor uptake (1.52 ± 0.71% ID/cc) comparable to liver and kidneys.

Preliminary evaluation of the production of non-carrier added 111Ag as core of a therapeutic radiopharmaceutical in the framework of ISOLPHARM_Ag experiment.

Research in the field of radiopharmaceuticals is increasingly promoted by the widespread and growing interest in applying nuclear medicine procedures in both disease diagnosis and treatment. The production of radionuclides of medical interest is however a challenging issue. Along with the conventional techniques other innovative approaches are being investigated and, among those, the ISOLPHARM project is being developed at INFN-LNL (Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali di Legnaro). Such technique foresees the employment of the SPES ISOL facility to produce isobarically pure Radioactive Ion Beams (RIBs), obtained thanks to electromagnetic mass separation and collected on appropriate substrates. The latter are successively recovered and dissolved, allowing thus the chemical separation and harvesting of the nuclides of interest, free from any isotopic contaminant. Although ISOLPHARM can be potentially employed for most of the routinely used medical radioisotopes, its innovation potential is better expressed considering its capability to provide carrier free unconventional nuclides, difficult to produce with state-of-art techniques, such as 111Ag, a ß- emitter potentially interesting for therapeutic applications. Thus, in the framework of ISOLPHARM, INFN supported a two-years experiment, called ISOLPHARM_Ag, aimed at evaluating the feasibility of the production of a111Ag labelled radiopharmaceutical. The ISOL production yields are estimated by computing intensive Monte Carlo codes, that require an appropriate custom Information Technology infrastructure. The presented work is focused on the first part of the production chain including the capability to extract, ionize, and collect stable Ag beams with SPES technologies. MC calculations were used to estimate the expected 111Ag in-target yields, whereas experiments with stable Ag were performed to test the ionization, transport and collection of Ag beams.

Synthetic Bone Substitutes and Mechanical Devices for the Augmentation of Osteoporotic Proximal Humeral Fractures: A Systematic Review of Clinical Studies.

BACKGROUND: Different augmentation techniques have been described in the literature in addition to the surgical treatment of proximal humeral fractures. The aim of this systematic review was to analyze the use of cements, bone substitutes, and other devices for the augmentation of proximal humeral fractures. METHODS: A systematic review was conducted by using PubMed/MEDLINE, ISI Web of Knowledge, Cochrane Library, Scopus/EMBASE, and Google Scholar databases according the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines over the years 1966 to 2019. The search term "humeral fracture proximal" was combined with "augmentation"; "polymethylmethacrylate, PMMA"; "cement"; "bone substitutes"; "hydroxyapatite"; "calcium phosphates"; "calcium sulfate"; "cell therapies", and "tissue engineering" to find the literature relevant to the topic under review. RESULTS: A total of 10 clinical studies considered eligible for the review, with a total of 308 patients, were included. Mean age at the time of injury was 68.8 years (range of 58-92). The most commonly described techniques were reinforcing the screw-bone interface with bone PMMA cement (three studies), filling the metaphyseal void with synthetic bone substitutes (five studies), and enhancing structural support with metallic devices (two studies). CONCLUSION: PMMA cementation could improve screw-tip fixation. Calcium phosphate and calcium sulfate injectable composites provided good biocompatibility, osteoconductivity, and lower mechanical failure rate when compared to non-augmented fractures. Mechanical devices currently have a limited role. However, the available evidence is provided mainly by level III to IV studies, and none of the proposed techniques have been sufficiently studied.

The Treatment of Acute Diaphyseal Long-bones Fractures with Orthobiologics and Pharmacological Interventions for Bone Healing Enhancement: A Systematic Review of Clinical Evidence.

BACKGROUND: The healing of long bones diaphyseal fractures can be often impaired and eventually end into delayed union and non-union. A number of therapeutic strategies have been proposed in combination with surgical treatment in order to enhance the healing process, such as scaffolds, growth factors, cell therapies and systemic pharmacological treatments. Our aim was to investigate the current evidence of bone healing enhancement of acute long bone diaphyseal fractures. METHODS: A systematic review was conducted by using Pubmed/MEDLINE; Embase and Ovid databases. The combination of the search terms "long-bones; diaphyseal fracture; bone healing; growth factors; cell therapies; scaffolds; graft; bone substitutes; orthobiologics; teriparatide". RESULTS: The initial search resulted in 4156 articles of which 37 papers fulfilled the inclusion criteria and were the subject of this review. The studies included 1350 patients (837 males and 513 females) with a mean age of 65.3 years old. CONCLUSIONS: General lack of high-quality studies exists on the use of adjuvant strategies for bone healing enhancement in acute shaft fractures. Strong evidence supports the use of bone grafts, while only moderate evidence demineralized bone matrix and synthetic ceramics. Conflicting results partially supported the use of growth factors and cell therapies in acute fractures. Teriparatide showed promising results, particularly for atypical femoral fractures and periprosthetic femoral fractures.

The biology and treatment of acute long-bones diaphyseal fractures: Overview of the current options for bone healing enhancement.

Diaphyseal fractures represent a complex biological entity that could often end into impaired bone-healing, with delayed union and non-union occurring up to 10% of cases. The role of the modern orthopaedic surgeon is to optimize the fracture healing environment, recognize and eliminate possible interfering factors, and choose the best suited surgical fixation technique. The impaired reparative process after surgical intervention can be modulated with different surgical techniques, such as dynamization or exchange nailing after failed intramedullary nailing. Moreover, the mechanical stability of a nail can be improved through augmentation plating, bone grafting or external fixation techniques with satisfactory results. According to the "diamond concept", local therapies, such as osteoconductive scaffolds, bone growth factors, and osteogenic cells can be successfully applied in "polytherapy" for the enhancement of delayed union and non-union of long bones diaphyseal fractures. Moreover, systemic anti-osteoporosis anabolic drugs, such as teriparatide, have been proposed as off-label treatment for bone healing enhancement both in fresh complex shaft fractures and impaired unions, especially for fragility fractures. The article aims to review the biological and mechanical principles of failed reparative osteogenesis of diaphyseal fractures after surgical treatment. Moreover, the evidence about the modern non-surgical and pharmacological options for bone healing enhancement will discussed.

Arthroscopically assisted reduction and internal fixation (ARIF) versus open reduction and internal fixation (ORIF) for lateral tibial plateau fractures: a comparative retrospective study.

BACKGROUND: This study aims to explore if the arthroscopically assisted reduction and internal fixation (ARIF) technique is superior to the traditional open reduction and internal fixation (ORIF) technique in the treatment of tibial lateral plateau fractures. METHODS: Forty patients with tibial plateau fractures (Schatzker type I-III) treated with ARIF or ORIF from 2012 to 2017 were included in this retrospective study. All patients received pre-operative radiographs and CT scans. The patients were divided into two groups (ARIF or ORIF). All patients had a minimum follow-up of 12 months and an average follow-up of 44.4 months. The clinical and radiographic outcomes were evaluated according to the Knee Society Score (KSS) and the modified Rasmussen radiological score. RESULTS: Satisfactory clinical and radiological results were found in 39 out of 40 (97.5%) patients. KSS and modified Rasmussen radiological score were significantly better in ARIF group. The mean KSS was 92.37 (± 6.3) for the ARIF group and 86.29 (± 11.54) for the ORIF group (p < 0.05). The mean modified Rasmussen radiographic score was 8.42 (± 2.24) for the ARIF group and 7.33 (± 1.83) for the ORIF group (p = 0.104). Worst clinical and radiological results were related to concomitant intra-articular lesions (p < 0.05). Meniscal tears were found and treated in 17 out of 40 (42.5%) patients. The overall complication rate was 10%. CONCLUSIONS: Both ARIF and ORIF provided a satisfactory outcome for the treatment of Schatzker I-III tibial plateau fractures. However, ARIF led to better clinical results than ORIF. No statistically significant differences were found in perioperative complications, radiological results, and post-traumatic knee osteoarthritis. LEVEL OF EVIDENCE: Level III.

The impact of magnetic resonance imaging in the diagnostic and classification process of osteoporotic vertebral fractures.

INTRODUCTION: Standard radiographs are still considered as the gold standard for the early assessment of thoraco-lumbar osteoporotic vertebral fractures (OVFs), although several studies demonstrated superior accuracy of magnetic resonance imaging (MRI) in the diagnostic process of OVFs. The aim of this study was to quantify the misdiagnosis rate of OVFs and analyse the impact of MRI on early diagnosis and classification, compared to standard radiographs alone. MATERIALS AND METHODS: A total of 173 patients were enrolled in this study. All participants were 55 years of age or older (60 years for men) and complained acute back pain with suspected thoracolumbar OVFs without history of high-energy trauma. Diagnosis of OVF was initially performed on standard radiographs obtained in the emergency room. Then, all the patients underwent MRI scan with short-tau inversion recovery (STIR) sequencing within 7 days. We compared the level and number of fractures identified on standard radiographs with the MRI scan results. The discordance between radiographic and MRI diagnosis was quantified. Fractures were classified according to AO Spine Classification. RESULTS: Mean age of the study participant was 74.2 years (range 55-92). They were 100 males and 73 females. MRI modified initial diagnosis in 52% (90/173) of our patients: in 43.9% of patients MRI identified one or more new thoracolumbar fracture. In 14 cases (8.1%) MRI disproved the evidence of any thoracolumbar fracture, even those recognized at plain X-rays. Bone bruise was detected by MRI in 19 vertebral bodies in 8 patients (4.6%) at levels that were classified as unremarkable on X-ray alone. In addition, 63 patients (36.4%) presented a total of 93 old fractures. The classification of fracture pattern after MRI changed in 28.90% of the patients (changes mostly involved AO type A1 patterns). CONCLUSIONS: Underdiagnosis of osteoporotic vertebral fractures is a common problem due to a lack of radiographic detection. Our results showed that the extensive use of MRI imaging allows better accuracy in the diagnostic process and in the classification assessment, compared to conventional radiographs. Further investigation should provide additional information about the impact of early MRI on treatment and management of elderly patients with suspected OVFs, including the decision to hospitalize or not, and how it could affect clinical outcome and social costs.

Early Evaluation of Copper Radioisotope Production at ISOLPHARM.

The ISOLPHARM (ISOL technique for radioPHARMaceuticals) project is dedicated to the development of high purity radiopharmaceuticals exploiting the radionuclides producible with the future Selective Production of Exotic Species (SPES) Isotope Separation On-Line (ISOL) facility at the Legnaro National Laboratories of the Italian National Institute for Nuclear Physics (INFN-LNL). At SPES, a proton beam (up to 70 MeV) extracted from a cyclotron will directly impinge a primary target, where the produced isotopes are released thanks to the high working temperatures (2000 °C), ionized, extracted and accelerated, and finally, after mass separation, only the desired nuclei are collected on a secondary target, free from isotopic contaminants that decrease their specific activity. A case study for such project is the evaluation of the feasibility of the ISOL production of 64Cu and 67Cu using a zirconium germanide target, currently under development. The producible activities of 64Cu and 67Cu were calculated by means of the Monte Carlo code FLUKA, whereas dedicated off-line tests with stable beams were performed at LNL to evaluate the capability to ionize and recover isotopically pure copper.