Identification of Macrocyclic Peptide Families from Combinatorial Libraries Containing Noncanonical Amino Acids Using Cheminformatics and Bioinformatics Inspired Clustering.

In the past decade, macrocyclic peptides gained increasing interest as a new therapeutic modality to tackle intracellular and extracellular therapeutic targets that had been previously classified as "undruggable". Several technological advances have made discovering macrocyclic peptides against these targets possible: 1) the inclusion of noncanonical amino acids (NCAAs) into mRNA display, 2) increased availability of next generation sequencing (NGS), and 3) improvements in rapid peptide synthesis platforms. This type of directed-evolution based screening can produce large numbers of potential hit sequences given that DNA sequencing is the functional output of this platform. The current standard for selecting hit peptides from these selections for downstream follow-up relies on the frequency counting and sorting of unique peptide sequences which can result in the generation of false negatives due to technical reasons including low translation efficiency or other experimental factors. To overcome our inability to detect weakly enriched peptide sequences among our large data sets, we wanted to develop a clustering method that would enable the identification of peptide families. Unfortunately, utilizing traditional clustering algorithms, such as ClustalW, is not possible for this technology due to the incorporation of NCAAs in these libraries. Therefore, we developed a new atomistic clustering method with a Pairwise Aligned Peptide (PAP) chemical similarity metric to perform sequence alignments and identify macrocyclic peptide families. With this method, low enriched peptides, including isolated sequences (singletons), can now be clustered into families providing a comprehensive analysis of NGS data resulting from macrocycle discovery selections. Additionally, upon identification of a hit peptide with the desired activity, this clustering algorithm can be used to identify derivatives from the initial data set for structure-activity relationship (SAR) analysis without requiring additional selection experiments.

Autologous microfragmented adipose tissue and leukocyte-poor platelet-rich plasma combined with hyaluronic acid show comparable clinical outcomes for symptomatic early knee osteoarthritis over a two-year follow-up period: a prospective randomized clinical trial.

PURPOSE: The purpose of this prospective randomized clinical trial is to compare the clinical outcomes of three injections of leucocyte-poor platelet-rich plasma (LP-PRP) and hyaluronic acid (HA) to a single dose of autologous microfragmented adipose tissue (AMAT) in patients with mild osteoarthritis at a two-year follow-up. METHODS: Eighty symptomatic knees in fifty patients (mean age: 62.38 ± 11.88 years) with Kellgren-Lawrence grade 0 to 2 osteoarthritis were non blinded, randomly allocated into two equal groups. Group 1 consisted of 40 knees that received autologous LP-PRP + HA; Group 2 consisted of 40 knees treated with a single dose of AMAT injection. The outcomes were measured by Tegner, Marx, Visual Analogue Scale (VAS) for pain, International Knee Documentation Committee, and Knee Injury and Osteoarthritis Outcome Score (KOOS) at 6 (T1), 12 (T2), and 24 (T3) months. Adverse events were recorded at each follow-up timepoint. To assess score differences among subjects of the same gender and age, a subgroup analysis was performed. RESULTS: Both groups had significant clinical and functional improvement at 6, 12, and 24 months (p < 0.05). Comparing the two groups, the AMAT groups showed significantly higher pre-operative Marx score (3.35 ± 4.91 vs. 1.78 ± 3.91) and VAS score (5.03 ± 2.02 vs. 3.85 ± 1.68) (p < 0.05), higher VAS (3.89 ± 2.51 vs. 2.64 ± 2.00) at T2 and KOOS-ADL (79.60 ± 20.20 vs. 65.68 ± 23.62), and lower KOOS-Sports (50.30 ± 30.15 vs. 68.35 ± 30.39) at T3 (p < 0.05). No patient from either group had experienced major adverse effects. In the LP-PRP group 12 (30%) patients presented swelling, redness, and mild pain for one day after injection and two patients had synovitis for two days and required paracetamol and local ice. In AMAT group 5 (12.5%) patients had ecchymosis and bruising at the fat aspiration site for three days. CONCLUSION: AMAT did not show significant superior clinical improvement compared with three LP-PRP combined with HA injections in terms of functional improvement at different follow-up points. Both procedures were safe with no major complications reporting good results at mid-term follow-up, improving knee function, pain, and quality of live regardless of age and gender. LEVEL OF EVIDENCE: Level I-Prospective Randomized Clinical Trial.

Conceptos actuales en el diagnóstico y tratamiento de las lesiones del hueso subcondral / Current concepts in the diagnosis and treatment of subchondral bone injuries

La patología ósea subcondral incluye una amplia gama de patologías, como la artrosis, las fracturas por insuficiencia espontánea, la osteonecrosis y los traumatismos articulares. Todas muestran hallazgos típicos de imágenes de resonancia magnética (RM) denominados lesiones de la médula ósea (LMO). Sin embargo, la etiología y la evolución de las LMO en múltiples afecciones aún no están claras. Además, todavía no existe un protocolo de tratamiento estándar de oro para las LMO, es por esto que se están probando una variedad de modalidades de tratamiento con la esperanza de que puedan reducir el dolor y detener la progresión de la enfermedad. Nuestro propósito es presentar una revisión sobre los conceptos actuales para el diagnóstico y tratamiento de las LMO. Se realizó una revisión de la literatura que incluyó búsquedas en las bases de datos PubMed, Cochrane y Medline utilizando las siguientes palabras clave: lesiones de médula ósea subcondral, hueso subcondral, subcondroplastia, concentrado de médula ósea, plasma rico en plaquetas (PRP) y aumento óseo subcondral. Podemos concluir que el uso de nuevas técnicas biológicas para tratar las LMO, como el PRP y las células de la médula ósea, ha mostrado resultados clínicos prometedores. La investigación futura de las LMO será necesaria para abordar mejor las diferentes patologías y determinar las estrategias terapéuticas adecuadas. Todavía se necesitan estudios randomizados y controlados de alta calidad junto a revisiones sistemáticas para generar guías y recomendaciones para el tratamiento de las LMO.

Subchondral bone pathology includes a wide range of pathologies, such as osteoarthritis, spontaneous insufficiency fractures, osteonecrosis, and trauma. They show typical magnetic resonance imaging (MRI) findings termed bone marrow lesions (BMLs). However, the etiology and evolution of BMLs in multiple conditions remains unclear. There is still no gold standard treatment protocol in treating BML, and a variety of treatment modalities have been tested in the hope that they might reduce pain and stop disease progression.Our purpose was to write a current concepts review about diagnosis and treatment options for BMLs. A literature review was performed that included searches of PubMed, Cochrane, and Medline databases using the following keywords: Bone marrow lesions, subchondral bone, subchondroplasty, bone marrow concentrate, platelet-rich plasma (PRP), subchondral bone augmentation.The use of novel biologic techniques to treat BMLs, such as PRP and Bone Marrow Cells, has yielded promising clinical outcomes. Future research of BMLs will be mandatory to address the different pathologies better and determining appropriate treatment strategies. There is still a need for high-quality RCTs studies and systematic reviews in the future to enhance further treatment strategy in preventing or treating BMLs of the knee.

Short-Term Efficacy of Using a Novel Low-Volume Bone Marrow Aspiration Technique to Treat Knee Osteoarthritis: A Retrospective Cohort Study.

Background: Intra-articular bone marrow concentrate (BMC) and aspirate (BMA) injections have been used with mixed results to treat osteoarthritis (OA). Given the various aspiration and concentration methods available for preparing bone marrow, more data are needed to identify the optimal bone marrow harvesting techniques to treat OA. Methods: This retrospective cohort study examined the effect of using low-volume BMAs harvested using the Marrow Cellution™ (MC) device on 160 patients (262 knees) suffering from pain due to knee OA, KL grades 2-4, that did not respond to conservative treatment. Changes in visual analog scores (VAS) for overall daily activity were examined over a six-month time frame in these patients (63.5 ± 0.97 years of age; 48.1% male). In addition, changes in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Patient Global Impression of Change (PGIC scores) were examined over the same time frame in a smaller subset of patients (95 patients including 172 knees). Results: There was a statistically significant improvement in VAS scores for overall daily activity 6 months postprocedure in the study population, 7.29 ± 0.27 vs. 3.76 ± 0.34 (p < 0.0001), as well as statistically significant improvements in WOMAC scores, 49.3 ± 4.27 vs. 66.3 ± 4.08 (p < 0.0001). On the individual level, 71% of the cases displayed VAS improvements and 61% of the cases displayed WOMAC improvements that exceeded levels previous studies determined to be the minimal clinically important difference (MCID) for knee OA treatments. The improvements in WOMAC scores were also seen in both the WOMAC pain subscore, 52.2 ± 4.39 vs. 72.2 ± 4.36 (p < 0.0001) and the WOMAC function subscore, 51.6 ± 4.67 vs. 69.0 ± 4.36 (p < 0.0001). In addition, the PGIC scores measuring patient satisfaction improved from 4.03 ± 0.26 at 6 weeks postprocedure to 4.65 ± 0.28 at 6 months postprocedure (p < 0.0001). Conclusions: Knee OA patients treated with MC BMA intra-articular injections exhibited significant reductions in VAS pain scores and significant improvements in WOMAC scores that exceeded the minimal clinically important difference thresholds. In addition, reductions in VAS pain scores and improvements in WOMAC scores correlated with higher PGIC scores.

Articular cartilage delamination at eight years following cellular-based repair procedures: a case reports.

This report describes two cases of late cartilage delamination in two young adults after two different autologous cell-based techniques for cartilage restoration: 1. Matrix-assisted autologous chondrocyte implantation (MACI) and 2. Hyaluronic acid-bone marrow aspirate concentrate (HA-BMAC). Both cases demonstrate that even in patients who do not present with any ongoing symptoms after primary surgery, a cellular-based graft's subsequent delamination can occur later. It is possible that regardless of the technique used or the time passed since the surgery, a graft failure may occur at some level, causing delamination of a previously asymptomatic cartilage restoration graft and a traumatic event with long-term follow-up. Surgeons must be alert to this injury and describe histologic findings to determine where failure occurs.

Minimally Invasive Cell-Based Therapy for Symptomatic Bone Marrow Lesions of the Knee: A Prospective Clinical Study at 1 Year.

Bone marrow lesions (BMLs) are typical findings in magnetic resonance imaging present in different pathologies, such as spontaneous insufficiency fractures, osteonecrosis, transient BML syndromes, osteoarthritis, and trauma. The etiology and evolution of BMLs in multiple conditions remain unclear. There is still no gold standard protocol for the treatment of symptomatic BMLs in the knee. The biologic augmentation by Osteo Core Plasty™ is a new treatment modality showing promising results reducing pain with the aim to stop the progression of the disease. The purpose of this prospective study is to report the clinical outcomes and safety of Osteo Core Plasty for the treatment of symptomatic BMLs in the knee. Fifteen patients with symptomatic BMLs of the knee treated with the Osteo Core Plasty technique were included and followed prospectively for a minimum of 12 months. Each patient was evaluated before the surgery and respectively at 6 and 12 months using the Tegner Score, Marx Score, the International Knee Documentation Committee, the Knee Injury and Osteoarthritis Outcome Score divided in pain, activity daily living and quality of life subscale, and the Visual Analog Scale for pain. All clinical scores except Tegner and Marx score showed an overall statistically significant improvement through the entire follow-up (P < 0.05) and a significant improvement (P < 0.05) between each follow-up period (T0 vs. T1; T0 vs. T2; T1 vs. T2). No complications were reported. These preliminary results confirm that biological subchondral bone augmentation by Osteo Core Plasty technique is a safe and effective minimally invasive treatment option for symptomatic BMLs in the knee at 1-year follow-up. There is still a need for high-quality randomized controlled trials studies and systematic reviews in the future to enhance further treatment strategies in preventing or treating BMLs of the knee.

Bone Marrow Aspirate Matrix: A Convenient Ally in Regenerative Medicine.

The rise in musculoskeletal disorders has prompted medical experts to devise novel effective alternatives to treat complicated orthopedic conditions. The ever-expanding field of regenerative medicine has allowed researchers to appreciate the therapeutic value of bone marrow-derived biological products, such as the bone marrow aspirate (BMA) clot, a potent orthobiologic which has often been dismissed and regarded as a technical complication. Numerous in vitro and in vivo studies have contributed to the expansion of medical knowledge, revealing optimistic results concerning the application of autologous bone marrow towards various impactful disorders. The bone marrow accommodates a diverse family of cell populations and a rich secretome; therefore, autologous BMA-derived products such as the "BMA Matrix", may represent a safe and viable approach, able to reduce the costs and some drawbacks linked to the expansion of bone marrow. BMA provides -it eliminates many hurdles associated with its preparation, especially in regards to regulatory compliance. The BMA Matrix represents a suitable alternative, indicated for the enhancement of tissue repair mechanisms by modulating inflammation and acting as a natural biological scaffold as well as a reservoir of cytokines and growth factors that support cell activity. Although promising, more clinical studies are warranted in order to further clarify the efficacy of this strategy.

Two-year clinical outcomes of autologous microfragmented adipose tissue in elderly patients with knee osteoarthritis: a multi-centric, international study.

PURPOSE: The aim of this study is to evaluate the outcomes of autologous microfragmented adipose tissue (MFAT) injection in elderly patients with knee osteoarthritis (OA). We hypothesized that MFAT knee infiltration for the treatment of knee OA would yield good clinical results out to two years follow-up. METHODS: Multi-centric, international, open-label study conducted by orthopedic surgery, and/or regenerative medicine facilities utilizing patient registries. Subjects recruited for eligibility. The primary outcome measure was Knee Injury and Osteoarthritis Outcome Score (KOOS). Outcomes and patient factors were compared to baseline, at six, 12, and 24 months. Statistical models were used to assess KOOS subscores and probability of exceeding the Minimally Clinically Important Difference (MCID) or Patient Acceptable Symptom State (PASS), and to assess the effect of the treatment variables on KOOS - Pain. RESULTS: Seventy-five patients, 120 primary treatments, mean age 69.6 years, (95%CI 68.3-70.9), BMI 28.4 (95%CI 27.3-29.6), with KL grade 2 to 4 knee OA treated with a single MFAT injection. KL grades 2 (15.1%), 3 (56.3%), and 4 (28.6%), with 20.8% of knees having previously undergone surgery. Patients with KL grade 2 disease had the best results in KOOS - Pain (P = 0.001), at six, 12, and 24 months. Including advanced KL grade 3 and 4 osteoarthritis patients, significant functional and quality of life success was seen in 106/120 treatments (88.3%, 66 patients) at all follow-up time points. Fourteen treatments (11.7%, 9 patients) failed prior to the study endpoint. CONCLUSION: This study shows that a single-dose MFAT injection leads to clinical, functional, and quality of life improvement at two years in elderly patients, in KL grades 2 to 4 of knee osteoarthritis. These findings provide evidence that this treatment modality could be a safe and effective option to other commonly available treatments in carefully selected patients.

Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3H)-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor.

Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (7), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule. The resulting improvements in permeability and solubility enabled oral dosing of 7. In vivo evaluation of 7 in combination with the MEK inhibitor cobimetinib demonstrated synergistic pathway inhibition and significant tumor growth inhibition in a KRAS mutant xenograft mouse model.

Clinical Anatomy of the Posterior Meniscofemoral Ligament of Wrisberg: An Original MRI Study, Meta-analysis, and Systematic Review.

BACKGROUND: The posterior meniscofemoral ligament (pMFL) of Wrisberg attaches to the posterior horn of the lateral meniscus and the lateral intercondylar aspect of the medial femoral condyle and passes posteriorly to the posterior cruciate ligament (PCL). The pMFL plays a role in recovery after PCL injuries and offers stability to the lateral meniscus, promoting normal knee function. PURPOSE/HYPOTHESIS: The aim of the magnetic resonance imaging (MRI) arm of this study was to evaluate the prevalence of the pMFL in Polish patients. The purpose of the systematic review and meta-analysis was to evaluate the clinical relevance of the pMFL in knee surgery. It was hypothesized that extensive variability exists in reports on the prevalence, function, and clinical significance of the pMFL. STUDY DESIGN: Cross-sectional study and systematic review; Level of evidence, 3. METHODS: A retrospective MRI investigation was conducted on 100 randomly selected lower limbs of Polish patients (56 male, 44 female) performed in 2019 to determine the prevalence of the pMFL. Additionally, an extensive literature search of major online databases was performed to evaluate all reported data on the pMFL. Assessments of article eligibility and data extraction were completed independently by 2 reviewers, and all disagreements were resolved via a consensus. A quality assessment of the included articles was performed using the Anatomical Quality Assessment tool. RESULTS: In the MRI arm of this study, the pMFL was observed in 73 of the 100 limbs. In the meta-analysis, 47 studies were included, totaling 4940 lower limbs. The pooled prevalence of the pMFL was found to be 70.4% (95% CI, 63.4%-76.9%); the mean length was 27.7 mm (95% CI, 24.8-30.5 mm) and the mean widths were 4.5, 6.1, and 4.1 mm for the meniscal and femoral attachments and midportion, respectively. The mean pMFL thickness was 2.3 mm (95% CI, 1.8-2.7 mm). CONCLUSION: Despite the variability in the literature, the pMFL was found to be a prevalent and large anatomic structure in the knee joint. The shared features of this ligament with the PCL necessitate the consideration of its value in planning and performing arthroscopic procedures of the knee.

"Endourological closure of a malformative vascular source of bleeding using the VortX 0.018" coil®".

AIMS: Renal vascular malformations, congenital or acquired, are sometimes challenging for urologists and interventional radiologists to resolve. Arterovenous fistulas and pseudoaneuryms are usually embolized by interventional radiologists, with a low rate of complications. We propose a new endourological/interventional radiology technique to treat a source of arterovenous bleeding coming from a renal calyx in a minimally invasive way. METHODS: A combined endourological and interventional radiology procedure is described, using a Flexible Fiberoptic Ureteroscopes to undertake a retrograde intrarenal surgery (RIRS) to identify the source of bleeding; subsequently the VortX Coil® is inserted through a microcatheter to stop the bleeding and the correct position of the VortX coil is evaluated. Furthermore, we made a literature research on Pubmed and Medline to look for similar procedures. RESULTS: In case of a renal bleeding that could not be treated by endovascular way, a combined urological and interventional radiology procedure can be undertaken. We did not find similar endourological and interventional radiology procedure on Pubmed and Medline, so this is the first tecnique of endourological closure of a bleeding point using a coil. CONCLUSION: From our experience this could be a mininvasive technique to solve renal bleedings coming from a calyx that are not found by endovascular approach. Indeed, in our knowledge, the technique here described is the first that provides the use of an endovascular coil by endourological way in renal vascular malformations.

The role of bedside assistant during robot assisted radical prostatectomy: Is more experience better? Analysis on perioperative and clinical outcomes.

OBJECTIVES: To analyze the impact of the bedside assistant's experience during RARP. It is believed that the outcome of robotic surgery during Robot Assisted Radical Prostatectomy (RARP) for prostate cancer depends not only on the console surgeon's experience. MATERIALS AND METHODS: All consecutive RARPs from January 2017 to March 2018 were sourced from a prospectively maintained database. All cases were performed by the same surgeon. He was supported by three bedside assistants: one with bedside and console experience, one only with relevant bedside experience, one basically inexperienced. The patient's parameters analyzed: age, Body Mass Index (BMI), previous abdominal surgery, prostate volume (by TRUS), pre-operative PSA, bioptic grading. Surgical outcomes analyzed included skin-to-skin operative time and estimated blood loss; clinical outcomes included length of hospital stay and time to catheter removal; the oncological outcome was represented by positive surgical margin rate. RESULTS: A total of 116 RARPs were identified: 38 RARPs were performed with the console experienced bedside assistant, 38 with the experienced one, 40 with the novice one. The variables were similar between the three groups. As far as outcomes are concerned, there were no statistically significant differences between the three bedside assistants in terms of operative time, estimated blood loss, length of stay, days of catheterization, positive surgical margin rate.

Editorial Commentary: Cartilage Restoration-What Is Currently Available?

In the past 30 years, bone marrow stimulation techniques such as microfracture (MF) have become a popular method to treat symptomatic focal articular cartilage lesions. Nonetheless, recent studies have not shown good long-term clinical outcomes, and MF has produced alterations in the subchondral bone architecture with degenerative changes. Autologous chondrocyte implantation (ACI) has shown good results at 20 years. Second- and third-generation ACI has shown superiority to MF and fewer complications than first-generation ACI. Each treatment option has its advantages and disadvantages. Recent research has shown that better filling of cartilage tissue occurs in patients treated with MF and collagen augmentation than in those treated with MF alone. Research from our clinic has shown that Hyaff scaffold combined with bone marrow aspirate concentrate in a 1-step technique yielded good results in patients with 10 years' follow-up. We believe that high-quality randomized controlled trials are necessary to directly compare all cartilage restoration procedures.

Editorial Commentary: Biological Cartilage Repair Technique-An "Effective, Accessible, and Safe" Surgical Solution for an Old Difficult Biological Problem.

Achieving good long-term outcomes while treating chondral defects has always been a challenge. Several surgical techniques for regeneration of the articular cartilage have been proposed. Among them, osteochondral autograft transplantation and 2-step procedures such as autologous chondrocyte implantation have provided good results, promoting formation of new hyaline-like cartilage tissue, whereas other techniques such as microfracture result in fibrous cartilage and a less durable repair. Single-stage cell-based procedures are an attractive treatment option given the potential for cost savings and avoiding a second-stage procedure. We believe that 1-stage cartilage repair in the knee with a hyaluronic acid-based scaffold embedded with mesenchymal stem cells sourced from bone marrow aspirate concentrate has a prominent role in treating chondral defects because this is a simple technique that could improve the care of patients and be cost-effective in the near future.

Terapias biológicas en artroscopía de rodilla. De las ciencias básicas a la aplicación clínica / Biological therapies in knee arthroscopy. From basic sciences to clinical application

Las estructuras intraarticulares, como el cartílago, el ligamento cruzado anterior (LCA) y los meniscos tienen un potencial de cicatrización limitado una vez que se lesionan. Un mayor conocimiento de las ciencias básicas y el advenimiento de las terapias biológicas han creado un gran interés en la utilización de diferentes estrategias de aumentación, cuyo objetivo es facilitar el proceso de cicatrización de dichas estructuras de la rodilla. Nuestro propósito es presentar una revisión de los conceptos actuales sobre las terapias biológicas en artroscopía de rodilla.Se realizó una revisión de la literatura que incluyó búsquedas en las bases de datos PubMed, Medline, Embase y Cochrane, utilizando las siguientes palabras clave: terapias biológicas, lesión del LCA, lesión meniscal, lesión del cartílago articular, PRP, BMAC, Bio-Ortopedia y Ortobiológicos.Se ha reportado que la utilización de técnicas biológicas de aumentación, incluidas el plasma rico en plaquetas (PRP), la médula ósea concentrada (BMAC) y otras terapias celulares para lesiones del cartílago articular, del LCA y de los meniscos podría facilitar el proceso de cicatrización con resultados clínicos prometedores.Podemos concluir que, efectivamente, existe un creciente interés en la utilización de terapias biológicas en las lesiones de rodilla con resultados clínicos heterogéneos, pero promisorios. Se necesitan estudios adicionales, randomizados, prospectivos, controlados y comparativos para determinar la eficacia real de las diferentes estrategias de aumento biológico en el entorno clínico

Intra-articular structures such as articular cartilage, anterior cruciate ligament (ACL), and menisci have limited healing potential after injury. The greater knowledge of the basic sciences and the advent of biological therapies have created a great interest in the use of different augmentation strategies, whose objective is to facilitate the healing process of these knee structures.To present a current concept review on the use of biological therapies in knee arthroscopy.A literature review was performed that included searches of the PubMed, Medline, Embase and Cochrane databases using the following keywords: Biological therapies, ACL tears, meniscal tears, articular cartilage injury, PRP, BMAC, Bio-Orthopaedics and Orthobiologics.It has been reported that the use of biological augmentation techniques, including Platelet rich plasma (PRP), bone marrow aspirate concentrate (BMAC), and other cellular therapies for injuries to articular cartilage, ACL, and menisci, could facilitate the healing process with promising clinical results.There is a growing interest in the use of biological therapies in knee injuries with heterogeneous but promising clinical results. Additional, randomized, prospective, controlled, and comparative studies are needed to determine the true efficacy of different biological augmentation strategies in the clinical setting

Long-term Clinical Outcomes of One-Stage Cartilage Repair in the Knee With Hyaluronic Acid-Based Scaffold Embedded With Mesenchymal Stem Cells Sourced From Bone Marrow Aspirate Concentrate.

BACKGROUND: Cell-based cartilage repair performed as a single-stage procedure is an important advancement in the treatment of full-thickness cartilage injury and has potential for widespread clinical use. PURPOSE: To investigate the long-term clinical outcomes of cartilage repair in the knee with a hyaluronic acid-based scaffold embedded with bone marrow aspirate concentrate (HA-BMAC) for the treatment of full-thickness cartilage injury. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients underwent treatment of full-thickness chondral injury in the knee with HA-BMAC and were followed prospectively for a minimum of 6 years. Clinical outcomes were examined with patient-reported scoring instruments that consisted of the Tegner Activity Scale, International Knee Documentation Committee (IKDC) subjective score, visual analog scale, and Knee injury and Osteoarthritis Outcome Score (KOOS). Comparative analysis of pre- and postoperative scores was performed, and the effects of patient age, body mass index, lesion size, number of treated lesions, and concurrent treatment with associated procedures were examined. RESULTS: Twenty-three patients (mean age, 48.5 years) were followed prospectively for a mean 8 years (range, 6-10 years). Median cartilage lesion size was 6.5 cm2 (range, 2-27 cm2). At final follow-up, median Tegner, visual analog scale, and IKDC subjective scores were 4, 0.3, and 85, respectively. Final median KOOS subset scores were as follows: Pain, 94; Symptoms, 89; Activities of Daily Living, 99; Sports/Recreation, 85; and Quality of Life, 85. All scores were significantly increased at final follow-up ( P < .001). Comparable median outcome scores were demonstrated after categorization of patients by age, lesion size, treatment of multiple lesions, treatment of multiple knee compartments, and treatment by associated procedures. Rank correlation analysis demonstrated a negative correlation between patient age and final outcome scores of the IKDC, Tegner, and KOOS subsets of Pain, Activities of Daily Living, and Sports/Recreation. No associations were identified between body mass index or lesion size and outcome scores. CONCLUSION: Repair of full-thickness cartilage injury in the knee with a HA-BMAC provides good to excellent clinical outcomes at long-term follow-up in the treatment of small to large lesions. Cartilage repair with HA-BMAC leads to comparatively successful long-term outcomes in the treatment of small or large lesions, single or multiple lesions, and lesions in 1 or 2 compartments, as well as in cases of associated lesion treatment. While good outcomes can be expected among treated patients >45 years of age, outcomes may be comparatively more successful in younger patients.

Testicular metastasis from renal cell carcinoma after nephrectomy and on tyrosine kinase inhibitors therapy: Case report and review.

Renal cell carcinoma has extremely heterogeneous presentation at the diagnosis: it may present as a confined organ disease, locally advanced, metastatic to locoregional lymph nodes or with single or multiple systemic metastases. Since chemotherapy and radiation therapy have not demonstrated efficacy either in primary therapy or in neo-adjuvant or adjuvant therapy for renal clear cell carcinoma, targeted agents like tirosine kinase inhibitors were developed and are largely used in locally advanced and metastatic renal cell carcinoma. Here, we present a rare case of ipsilateral renal cell carcinoma testicle metastasis, after radical nephrectomy and during tyrosine kinase inhibitors therapy. In addition, a retrospective search in PubMed, ScienceDirect, and Web of Science database on testicular metasteses from renal cell carcinoma under tyrosine kinase inhibitors therapy was performed.

Italian consensus statement for the use of allografts in ACL reconstructive surgery.

PURPOSE: Graft choice for primary anterior cruciate ligament reconstruction (ACL-R) is debated, with considerable controversy and variability among surgeons. Autograft tendons are actually the most used grafts for primary surgery; however, allografts have been used in greater frequency for both primary and revision ACL surgery over the past decade. Given the great debate on the use of allografts in ACL-R, the "Allografts for Anterior Cruciate Ligament Reconstruction" consensus statement was developed among orthopedic surgeons and members of SIGASCOT (Società Italiana del Ginocchio, Artroscopia, Sport, Cartilagine, Tecnologie Ortopediche), with extensive experience in ACL-R, to investigate their habits in the use of allograft in different clinical situations. The results of this consensus statement will serve as benchmark information for future research and will help surgeons to facilitate the clinical decision making. METHODS: In March 2017, a formal consensus process was developed using a modified Delphi technique method, involving a steering group (9 participants), a rating group (28 participants) and a peer-review group (31 participants). Nine statements were generated and then debated during a SIGASCOT consensus meeting. A manuscript has been then developed to report methodology and results of the consensus process and finally approved by all steering group members. RESULTS: A different level of consensus has been reached among the topics selected. Strong agreement has been reported in considering harvesting, treatment and conservation methods relevant for clinical results, and in considering biological integration longer in allograft compared to autograft. Relative agreement has been reported in using allograft as the first-line graft for revision ACL-R, in considering biological integration a crucial aspect for rehabilitation protocol set-up, and in recommending a delayed return to sport when using allograft. Relative disagreement has been reported in using allograft as the first-line graft for primary ACL-R in patients over 50, and in not considering clinical results of allograft superior to autograft. Strong disagreement has been reported in using allograft as the first-line graft for primary ACL-R and for skeletally immature patients. CONCLUSIONS: Results of this consensus do not represent a guideline for surgeons, but could be used as starting point for an international discussion on use of allografts in ACL-R. LEVEL OF EVIDENCE: IV, consensus of experts.