2-Substituted 1,5-benzothiazepine-based HDAC inhibitors exert anticancer activities on human solid and acute myeloid leukemia cell lines.

Herein, we report the development of a new series of histone deacetylase inhibitors (HDACi) containing a 2-substituted 1,5-benzothiazepine scaffold. First, a virtual combinatorial library (∼1.6 × 103 items) was built according to a convenient synthetic route, and then it was submitted to molecular docking experiments on seven HDACs isoforms belonging to classes I and II. Integrated computational filters were used to select the most promising ones that were synthesized through an optimized approach, also amenable to generating both racemic and enantioenriched benzothiazepine-based derivatives. The obtained compounds showed potent HDAC inhibitory activity, especially those containing the sulphone moiety, endowed with IC50 in the nanomolar range. In addition, in vitro outcomes of our synthesized compounds demonstrated a cytotoxic effect on U937 and HCT116 cell lines and an arrest in the G2/M phase (13 ≤ IC50 ≤ 18 µM). Finally, Western blot analyses outlined the modulation of the histone acetyl markers such as H3K9/14, acetyl-tubulin, and the apoptotic indicator p21 in both cancer cell lines, disclosing a good HDAC inhibitor activity exerted by the designed items. Given the key role of HDACs in many cellular pathways, which makes these enzymes appealing and "hot" drug targets, our findings highlighted the importance of these 2-substituted 1,5-benzothiazepine-based compounds (both in the reduced and oxidized version) for the development of novel epidrugs.

SuperPath approach is a recommendable option in frail patients with femoral neck fractures: a case-control study.

INTRODUCTION: The treatment of intracapsular femoral neck fractures (FNFs) in the elderly is usually based on hip replacement, both total hip arthroplasty (THA) and hemiarthroplasty (HA). Recently, several tissue-sparing approaches for hip arthroplasty had been described with promising results in terms of hospitalization length, blood loss and dislocation rate. The aim of the present study was to compare the blood loss and the transfusion rate in a cohort of patients with FNF treated using an HA through both the SuperPath (SP) and the traditional posterolateral (PL) approaches. MATERIALS AND METHODS: We retrospectively collected data from patients affected by FNFs between January 2018 and February 2020. All patients with intracapsular FNF treated with a single HA implant (Profemur L, MicroPort Orthopedics Inc., USA) via PL or SP approaches were included. Exclusion criteria were pathological fractures, polytrauma and preoperatively transfused patients. RESULTS: Thirty-five patients were included and analysed in the present study. 17 patients were classified in the SP group, and 18 in the PL one. The rate of antithrombotic therapy was higher in the SP group compared with the PL group [10 (58, 82%) vs 4 (22, 2%)]. While the two groups did not differ in terms of preoperative haemoglobin (Hb), 48 h postoperative Hb and Hb reduction, a significative difference was observed in terms of blood transfusion rate (1 SP vs 9 PL, p = 0.0072). CONCLUSIONS: The SuperPath approach in patients with FNF under antithrombotic therapy assures lower transfusion rate, potentially reducing complication rates and improving patients' outcomes.

Preliminary results of autologous adipose-derived stem cells in early knee osteoarthritis: identification of a subpopulation with greater response.

PURPOSE: The purpose of this study was to report the clinical and functional results of a series of patients with early knee osteoarthritis (KOA) treated with the intra-articular injection of autologous adipose-derived stem cells (aASCs) plus arthroscopic debridement. The hypothesis was that protocol would significantly improve the clinical and functional outcomes in patients with early KOA. METHODS: Fifty-two patients with early KOA, who received arthroscopic debridement followed by percutaneous injection of aASCs, were enrolled into the study and retrospectively analyzed with an average follow-up of 15.3 (range, 6 to 24) months. Patients were assessed through the IKS knee and function scores and VAS pain scale. RESULTS: The mean IKS knee score improved from 37.4 (range, 14 to 79) points pre-operatively to 62.6 (range, 27 to 95) points at the latest follow-up (p < < 0.01). The mean IKS function score improved from 57.2 (range, 25 to 100) points pre-operatively to 83.0 (range, 35 to 100) points at the latest follow-up (p < < 0.01). The mean VAS score decreased from 8.5 (range, 3 to 10) pre-operatively to 5.1 (range, 0 to 8) at the latest follow-up (p < < 0.01). Additionally, patients with a pre-operative VAS score greater than 8 were found to show greater clinical and functional benefits compared with patients with VAS score lower than 8. CONCLUSIONS: The knee injection of aASCs associated to arthroscopic debridement increased significantly the clinical and functional scores in patients with early KOA at a mid-term follow-up, especially those with higher pre-operative VAS scores.

Unicompartimental knee arthroplasty metallosis treated with uni-on-uni revision: A case report.

BACKGROUND: Metallosis is the result of metallic wear debris in the soft tissues and is associated to both local and systemic inflammatory response. Metallosis has been reported after total hip and total knee arthroplasty (TKA), but rarely after a unicompartimental knee arthroplasty (UKA). In the context of UKA metallosis, surgeons often opt for revision using a TKA. However, in this paper, the authors successfully treated UKA revising the metal back only. CASE SUMMARY: Prior to treat our patient we conducted a literature research through which we identified eleven cases of metallosis after UKA, ten (90.9%) were treated revising using though a TKA. Only one case was managed through a uni-on-uni revision, reporting high knee function. Our patient complained worsening pain and function after a snap occurred at 16 mo after UKA implantation. At 18 mo following surgical debridment and uni-on-uni revision surgery, our patient exhibited a relevant improvement in Oxford Knee Score and a reduction of metal ion levels in the blood. CONCLUSION: Our study highlights that in case of metallosis after UKA, the treatment may be based on surgical debridement and just revising the mobilized components.

The role of the fracture liaison service in the prevention of atypical femoral fractures.

Osteoporosis and fragility fractures (FFs) are considered critical health problems by the World Health Organization (WHO) because of high morbidity, mortality, and healthcare costs. The occurrence of a FF raises the risk of a subsequent fracture (refracture). The hip is the most common site of fragility refracture, and its onset is associated with a further increase in patient's morbidity, mortality, and socioeconomic burden. Therefore, the prevention of refracture is essential. In this context, fracture liaison service (FLS) demonstrated to be able to reduce FF risk and also improve patients' adherence to anti-osteoporotic treatments, particularly for bisphosphonates (BPs). However, long-term and high adherence to BPs may lead to atypical femoral fractures (AFFs). These latter are tensile side stress fractures of the femur, with high rates of complications, including delayed and non-healing. An effective FLS should be able to prevent both FF and AFF. A comprehensive and interdisciplinary approach, through the involvement and education of a dedicated team of healthcare professionals (i.e. orthopedic, geriatrician, primary care physician, rehabilitation team, and bone nurse) for evaluating both FF and AFF risks might be useful to improve the standard of care.

Fragility Fractures of the Acetabulum: Current Concepts for Improving Patients' Outcomes.

The incidence of fragility fractures of the acetabulum (FFA) is constantly increasing. Generally, these fractures are related to a fall on the greater trochanter involving the anterior column. The management of FFA is extremely difficult considering both patients' comorbidities and poor bone quality. Both non-operative and several operative treatment protocols are available, and the choice among them is still ambiguous. The proposed surgical techniques for FFA [namely open reduction and internal fixation (ORIF), percutaneous fixation and total hip arthroplasty (THA)] are associated with a high complication rate. The treatment with the higher early mortality is the ORIF + THA, while the one with the lowest is the non-operative. However, at longer follow-up, this difference dreadfully change is becoming the opposite. Frequently ORIF, percutaneous fixation, and non-operative treatment need a subsequent re-operation through a THA. This latter could be extremely difficult, because of poor bone quality, acetabular mal union/non-union, bone gaps and hardware retention. However, the outcomes of each of the proposed treatment are mostly poor and controverted; therefore, a comprehensive patient evaluation and an accurate fracture description are required to appropriately manage acetabular fracture in the elderly.

Extracapsular femoral neck fractures treated with total hip arthroplasty: identification of a population with better outcomes.

Background: Femoral neck fractures (FNF) are associated to patient's disability, reduced quality of life and mortality. None of the fixation devices commonly used for extracapsular (EC) FNF (i.e., dynamic hip screws (DHS) and intramedullary nails (IN)) is clearly superior to the other, especially in case of unstable fractures (31.A2 and 31.A3 according to AO/OTA classification). The aim of our study was to identify a sub-population of patients with EC fractures in which better outcomes could be obtainable using total hip arthroplasty (THA). Methods: All patients with EC unstable fractures treated with THA were included in the present study. Demographic data, American Society of Anesthesiologists (ASA) score, hospitalization length, transfusion rate, implant-related complications and mortality rate were collected. Clinical outcomes were evaluated using the Oxford Hip Score (OHS), while patients' general health status through the 12 Item Short Form questionnaires (SF-12). Results: 30 patients (7 male; 23 female) with a mean age of 78.8 years were included. The 1-year mortality rate was 13.3%. The mean OHS was 27.5, while the mean SF-12 were 45.84 for the mental item and 41.6 for the physical one. Age was the only factor associated with the OHS and patients older than 75 years presented a 12- fold higher risk of developing bad outcomes. Conclusions: THA seems to be a viable option for unstable EC fractures, with good clinical outcomes, especially in patients younger than 75 years of age. The mortality rate associated with THA in EC fractures is low and anyway comparable with IN.

Why Use Adipose-Derived Mesenchymal Stem Cells in Tendinopathic Patients: A Systematic Review.

The aim of the present systematic review was to provide a clear overview of the clinical current research progress in the use of adipose-derived mesenchymal stem cells (ASCs) as an effective therapeutic option for the management of tendinopathies, pathologies clinically characterized by persistent mechanical pain and structural alteration of the tendons. The review was carried out using three databases (Scopus, ISI Web of Science and PubMed) and analyzed records from 2013 to 2021. Only English-language papers describing the isolation and manipulation of adipose tissue as source of ASCs and presenting ASCs as treatment for clinical tendinopathies were included. Overall, seven clinical studies met the inclusion criteria and met the minimum quality inclusion threshold. Data extraction and quality assessment were performed by groups of three reviewers. The available evidence showed the efficacy and safety of ASCs treatment for tendinopathies, although it lacked a clear description of the biomolecular mechanisms underlying the beneficial properties of ASCs.

Atypical periprosthetic femoral fractures of the hip: A PRISMA compliant systematic review.

INTRODUCTION: Long-term use of bisphosphonates (BPs) is associated with Atypical Femoral Fracture (AFF). Theoretically, periprosthetic femoral fractures (PFF) should be excluded from the diagnosis of AFF. However, recently several studies reported the occurrence of PPFs around a hip arthroplasty presenting features of an AFF. The present study describes the characteristics of Atypical Periprosthetic Femoral Fracture (APFF) and evaluates the effectiveness of their management through a PRISMA compliant systematic review of the published case reports and series. MATERIALS AND METHODS: A literature search was performed using "periprosthetic fracture" and "atypical femoral fracture" as keywords. Patients demographics, drug use, clinical and imaging characteristics, stem fixation and classification, management strategies for APFF and patients' outcomes, were also collected. RESULTS: The present review included and analysed 17 patients from 12 studies. All APFFs occurred in females with a mean age of 75.9 years of age (range 43-87). In 11 patients, APFFs occurred around an uncemented stem, and in 6 around a cemented stem. Ten fractures were incomplete, and 7 complete. Conservative management was effective in 4 of 10 patients with incomplete fracture, while all patients with complete fractures underwent open reduction and internal fixation. A fracture non-union was observed in 5 patients and further surgery was required. DISCUSSIONS: APFFs share several clinical and imaging characteristics with AFF. An appropriate and early diagnosis may allow to improve the outcome of these fractures, the management of which should be based on the same principles of that of AFFs. CONCLUSIONS: Considering the low quality of published articles and the heterogeneity of the treatment used, a clear recommendation of the most appropriate treatment cannot be formulated.

Hallux rigidus treated with adipose-derived mesenchymal stem cells: A case report.

BACKGROUND: First metatarsophalangeal joint arthritis (FMTPA), also known as hallux rigidus, is the most frequent degenerative disease of the foot. Diagnosis is made through both clinical and radiological evaluation. Regenerative medicine showed promising results in the treatment of early osteoarthritis. The aim of the present study was to report the results of a case of FMTPA treated with the injection of autologous adipose-derived mesenchymal stem cells. CASE SUMMARY: A gentleman of 50 years of age presented with a painful hallux rigidus grade 2 resistant to any previous conservative treatment (including nonsteroidal anti-inflammatory drugs and hyaluronic acid injections). An injection of autologous adipose-derived mesenchymal stem cells into the first metatarsophalangeal joint was performed. No adverse events were reported, and both function and pain scales improved after 9 mo of follow-up. CONCLUSION: The FMTP joint injection of mesenchymal stem cells improved symptoms and function in our patient with FMTPA at 9 mo of follow-up.

Fractures around Trochanteric Nails: The "Vergilius Classification System".

INTRODUCTION: The fractures that occurred around trochanteric nails (perinail fractures, PNFs) are becoming a huge challenge for the orthopaedic surgeon. Although presenting some specific critical issues (i.e., patients' outcomes and treatment strategies), these fractures are commonly described within peri-implant ones and their treatment was based on periprosthetic fracture recommendations. The knowledge gap about PNFs leads us to convene a research group with the aim to propose a specific classification system to guide the orthopaedic surgeon in the management of these fractures. MATERIALS AND METHODS: A steering committee, identified by two Italian associations of orthopaedic surgeons, conducted a comprehensive literature review on PNFs to identify the unmet needs about this topic. Subsequently, a panel of experts was involved in a consensus meeting proposing a specific classification system and formulated treatment statements for PNFs. Results and Discussion. The research group considered four PNF main characteristics for the classification proposal: (1) fracture localization, (2) fracture morphology, (3) fracture fragmentation, and (3) healing status of the previous fracture. An alphanumeric code was included to identify each characteristic, allowing to describe up to 54 categories of PNFs, using a 3- to 4-digit code. The proposal of the consensus-based classification reporting the most relevant aspects for PNF treatment might be a useful tool to guide the orthopaedic surgeon in the appropriate management of these fractures.

Neglected femoral neck fractures in cerebral palsy: a narrative review.

Hip fractures are severe conditions with a high morbidity and mortality, especially when the diagnosis is delayed, and if formulated over 30 days after the injury, is termed a 'neglected femoral neck fracture' (NFNF).Cerebral palsy (CP) is probably one of the major risk factors for NFNF in Western countries, mainly because of both cognitive and motor impairments. However, considering the high prevalence of fractures in these patients, the incidence of NFNF in this population is probably underestimated, and this condition might result in persistent hip or abdominal pain.Several techniques are available for the treatment of NFNF (i.e. muscle pedicle bone graft, fixation with fibular graft, valgisation osteotomy), but most of them could affect motor function.Motor function must be preserved for as long as possible, in order to enhance the quality of life of CP patients.After discussing published NFNF cases in CP patients and available treatment options, a practical approach is proposed to facilitate the orthopaedic surgeon to both early identify and appropriately manage these challenging fractures. Cite this article: EFORT Open Rev 2020;5:58-64. DOI: 10.1302/2058-5241.5.190019.

How to improve the outcomes of surgically treated proximal humeral osteoporotic fractures? A narrative review.

Proximal humeral fractures (PHF) are the third most common non-vertebral fragility fractures after hip and distal radius. It still controversial which treatment might be more appropriate, and surgically treated outcomes depends also on an appropriate technique. In order to clarify surgical indications, tips and pitfall a narrative review was conducted. Pinning, external fixation, plating and internal fixators has each one its advantages and disadvantages. During the procedure an appropriate use of the fixation device and handling of the soft tissue might be associated with better outcomes. Calcar comminution, varus angulation, medial dislocation of the shaft, fracture-dislocation are factors that could lead to choose a replacement. Hemiarthroplasty and reverse total shoulder arthroplasty are the most common prosthesis used in PHF. The restoration of humeral length and tuberosities might lead to an improvement in clinical outcomes and prosthesis survivorship.

Atypical periprosthetic femoral fractures of the hip: characterisation of three cases.

INTRODUCTION: Long-term use of bisphosphonates (BPs) has been associated with a specific type of tensile side femoral stress fracture known as Atypical Femoral Fracture (AFF). Theoretically periprosthetic femoral fractures (PFF) should be excluded from the diagnosis of AFF. However, emerging evidence correlates prolonged BPs use with the occurrence of a type of PFF with an atypical pattern (atypical PFF, APFF). The aim of the present study is to report 3 cases of APFF treated at a single centre. METHODS: Clinical and radiographic records of PFF that occurred between January 2016 and August 2018 were retrospectively reviewed. All patients meeting the American Society for Bone and Mineral Research (ASBMR) criteria for definition of PFF were included. Management strategies for APFF and patient outcomes, including fracture healing and hip function (assessed by the Oxford Hip Score [OHS]) were collected. RESULTS: 3 patients in the study period were identified as APFF (1 incomplete, 2 complete). All patients were females with a mean age of 83.3 years. All patients were treated with lateral plating. The application of a contralateral strut allograft resulted in fracture healing in cases of complete fractures. Mean OHS at final follow-up was 34.3. CONCLUSIONS: Despite occurring around a hip stem like PFF, APFF had peculiar clinical and radiographic features, making them more similar to AFF. Therefore, the orthopaedic surgeon should also consider the natural history and healing problems associated with AFF prior in order to choose the most appropriate management for APFF.