Cartilage repair using mesenchymal stem cell (MSC) sheet and MSCs-loaded bilayer PLGA scaffold in a rabbit model

Purpose

The integration of regenerated cartilage with surrounding native cartilage is a major challenge for the success of cartilage tissue-engineering strategies. The purpose of this study is to investigate whether incorporation of the power of mesenchymal stem cell (MSC) sheet to MSCs-loaded bilayer poly-(lactic-co-glycolic acid) (PLGA) scaffolds can improve the integration and repair of cartilage defects in a rabbit model.

Methods

Rabbit bone marrow-derived MSCs were cultured and formed cell sheet. Full-thickness cylindrical osteochondral defects (4 mm in diameter, 3 mm in depth) were created in the patellar groove of 18 New Zealand white rabbits and the osteochondral defects were treated with PLGA scaffold (n = 6), PLGA/MSCs (n = 6) or MSC sheet-encapsulated PLGA/MSCs (n = 6). After 6 and 12 weeks, the integration and tissue response were evaluated histologically.

Results

The MSC sheet-encapsulated PLGA/MCSs group showed significantly more amounts of hyaline cartilage and higher histological scores than PLGA/MSCs group and PLGA group (P < 0.05). In addition, the MSC sheet-encapsulated PLGA/MCSs group showed the best integration between the repaired cartilage and surrounding normal cartilage and subchondral bone compared to other two groups.

Conclusions

The novel method of incorporation of MSC sheet to PLGA/MCSs could enhance the ability of cartilage regeneration and integration between repair cartilage and the surrounding cartilage. Transplantation of autologous MSC sheet combined with traditional strategies or cartilage debris might provide therapeutic opportunities for improving cartilage regeneration and integration in humans.     

A novel nano-structured porous polycaprolactone scaffold improves hyaline cartilage repair in a rabbit model compared to a collagen type I/III scaffold: in vitro and in vivo studies

Purpose

To develop a nano-structured porous polycaprolactone (NSP-PCL) scaffold and compare the articular cartilage repair potential with that of a commercially available collagen type I/III (Chondro-Gide^®) scaffold.

Methods

By combining rapid prototyping and thermally induced phase separation, the NSP-PCL scaffold was produced for matrix-assisted autologous chondrocyte implantation. Lyophilizing a water–dioxane–PCL solution created micro and nano-pores. In vitro: The scaffolds were seeded with rabbit chondrocytes and cultured in hypoxia for 6 days. qRT–PCR was performed using primers for sox9, aggrecan, collagen type 1 and 2. In vivo: 15 New Zealand White Rabbits received bilateral osteochondral defects in the femoral intercondylar grooves. Autologous chondrocytes were harvested 4 weeks prior to surgery. There were 3 treatment groups: (1) NSP-PCL scaffold without cells. (2) The Chondro-Gide^® scaffold with autologous chondrocytes and (3) NSP-PCL scaffold with autologous chondrocytes. Observation period was 13 weeks. Histological evaluation was made using the O’Driscoll score.

Results

In vitro: The expressions of sox9 and aggrecan were higher in the NSP-PCL scaffold, while expression of collagen 1 was lower compared to the Chondro-Gide^® scaffold. In vivo: Both NSP-PCL scaffolds with and without cells scored significantly higher than the Chondro-Gide^® scaffold when looking at the structural integrity and the surface regularity of the repair tissue. No differences were found between the NSP-PCL scaffold with and without cells.

Conclusion

The NSP-PCL scaffold demonstrated higher in vitro expression of chondrogenic markers and had higher in vivo histological scores compared to the Chondro-Gide^® scaffold. The improved chondrocytic differentiation can potentially produce more hyaline cartilage during clinical cartilage repair. It appears to be a suitable cell-free implant for hyaline cartilage repair and could provide a less costly and more effective treatment option than the Chondro-Gide^® scaffold with cells.     

One-step osteochondral repair with cartilage fragments in a composite scaffold

Purpose

This study proposes a single-step therapeutic approach for osteochondral defects using autologous cartilage fragments loaded onto a scaffold composed of a hyaluronic acid (HA) derivative, human fibrin glue (FG) and autologous platelet-rich-plasma (PRP), in a rabbit model. The aim is to demonstrate the in vitro outgrowth of chondrocytes from cartilage fragments and the in vivo formation of a functional repair tissue.

Methods

In vitro: minced articular cartilage was loaded onto two different types of scaffold (paste or membrane) according to two different HA preparations (injectable HA-derivative or HA-derivative felt). In vivo: trochlear osteochondral defects were created in 50 adult rabbits, which were then assigned to 5 different treatment groups: cartilage fragments loaded onto membrane scaffolds with FG (Group 1) or without FG (Group 2); membrane scaffolds alone with FG (Group 3) or without FG (Group 4); empty defects (Group 5). Membrane scaffolds were used “in vivo” for simpler preparation and better adhesive properties. Repair processes were evaluated histologically and by immunohistochemistry at 1, 3, and 6 months.

Results

An in vitro time-dependent cell outgrowth from cartilage fragments was observed with both types of scaffolds. At 6 months, in vivo, cartilage fragment-loaded scaffolds induced significantly better repair tissue than the scaffold alone using histological scoring. Repair in Group 2 was superior to that in any of the control groups (p < 0.05).

Conclusion

Autologous cartilage fragments loaded onto an HA felt/FG/PRP-scaffold provided an efficient cell source, and allowed for an improvement of the repair process of ostechondral defects in a rabbit model. Human FG, however, hampered the rabbit healing process. These results may have clinical relevance as they show the potential of a novel one-stage repair technique for osteochondral defects.     

Culture of human bone marrow-derived mesenchymal stem cells on of poly(l-lactic acid) scaffolds: potential application for the tissue engineering of cartilage

Purpose

Due to the attractive properties of poly(l-lactic acid) (PLLA) for tissue engineering, the aim was to determine the growth and differentiation capacity of mesenchymal stromal cells (MSCs) in PLLA scaffolds and their potential use in the treatment of cartilage diseases.

Methods

MSCs were cultured in PLLA films and thin porous membranes to study adherence and proliferation. Permeability and porosity were determined for the different scaffolds employed. The optimal conditions for cell seeding were first determined, as well as cell density and distribution inside the PLLA. Scaffolds were then maintained in expansion or chondrogenic differentiation media for 21 days. Apoptosis, proliferation and chondrogenic differentiation was assessed after 21 days in culture by immunohistochemistry. Mechanical characteristics of scaffolds were determined before and after cell seeding.

Results

MSCs uniformly adhered to PLLA films as well as to porous membranes. Proliferation was detected only in monolayers of pure PLLA, but was no longer detected after 10 days. Mechanical characterization of PLLA scaffolds showed differences in the apparent compression elastic modulus for the two sizes used. After determining high efficiencies of seeding, the production of extracellular matrix (ECM) was determined and contained aggrecan and collagens type I and X. ECM produced by the cells induced a twofold increase in the apparent elastic modulus of the composite.

Conclusions

Biocompatible PLLA scaffolds have been developed that can be efficiently loaded with MSCs. The scaffold supports chondrogenic differentiation and ECM deposition that improves the mechanics of the scaffold. Although this improvement does not met the expectations of a hyaline-like cartilage ECM, in part due to the lack of a mechanical stimulation, their potential use in the treatment of cartilage pathologies encourages to improve the mechanical component.     

Osteochondral regeneration using a novel aragonite-hyaluronate bi-phasic scaffold in a goat model

Purpose

The objective of this study was to examine whether different mechanical modifications and/or impregnation of hyaluronic acid (HA) might enhance aragonite-based scaffold properties for the regeneration of cartilage and bone in an animal model.

Methods

Bi-phasic osteochondral scaffolds were prepared using coralline aragonite with different modifications, including 1- to 2-mm-deep drilled channels in the cartilage phase (Group 1, n = 7) or in the bone phase (Group 2, n = 8), and compared with unmodified coral cylinders (Group 3, n = 8) as well as empty control defects (Group 4, n = 4). In each group, four of the implants were impregnated with HA to the cartilage phase. Osteochondral defects (6 mm diameter, 8 mm depth) were made in medial and lateral femoral condyles of 14 goats, and the scaffolds were implanted according to a randomization chart. After 6 months, cartilage and bone regeneration were evaluated macroscopically and histologically by an external laboratory.

Results

Group 1 implants were replaced by newly formed hyaline cartilage and subchondral bone (combined histological evaluation according to the ICRS II-2010 and O’Driscoll et al. 34 ± 4 n = 7). In this group, the cartilaginous repair tissue showed a smooth contour and was well integrated into the adjacent native cartilage, with morphological evidence of hyaline cartilage as confirmed by the marked presence of proteoglycans, a marked grade of collagen type II and the absence of collagen type I. The average scores in other groups were significantly lower (Group 2 (n = 8) 28.8 ± 11, Group 3 (n = 8) 23 ± 9 and Group 4 (empty control, n = 4) 19.7 ± 15).

Conclusions

The implants with the mechanical modification and HA impregnation in the cartilage phase outperformed all other types of implant. Although native coral is an excellent material for bone repair, as a stand-alone material implant, it does not regenerate hyaline cartilage. Mechanical modification with drilled channels and impregnation of HA within the coral pores enhanced the scaffold’s cartilage regenerative potential. The modified implant shows young hyaline cartilage regeneration. This implant might be useful for the treatment of both chondral and osteochondral defects in humans.     

Human cartilage fragments in a composite scaffold for single-stage cartilage repair: an in vitro study of the chondrocyte migration and the influence of TGF-β1 and G-CSF

Purpose

Minced chondral fragments are becoming popular as a source of cells for cartilage repair, as a growing interest is developing towards one-stage procedures to treat cartilage lesions. The purpose of this study is to (A) compare cell outgrowth from cartilage fragments of adult and young donors using two different types of scaffolds and (B) evaluate the influence of transforming-growth-factor-β1 (TGF-β1) and granulocyte colony-stimulating factor (G-CSF) on chondrocyte behaviour.

Methods

In part (A) cartilage fragments from adult and young donors were either loaded onto an HA-derivative injectable paste scaffold or onto an HA-derivative membrane scaffold. Construct sections were then examined for cell counting after 1, 2 and 3 months. In part (B) only membrane scaffolds were prepared using cartilage fragments from young donors. Constructs were cultured either in standard growth medium or in the presence of specific growth factors, such as TGF-β1 or G-CSF or TGF-β1 + G-CSF. After 1 month, construct sections were examined for cell counting. Expression of chondrocyte markers (SOX9, CD151, CD49c) and proliferative markers (β-catenin, PCNA) was assessed using immunofluorescence techniques, both in unstimulated construct sections and in cells from unstimulated and stimulated construct cultures.

Results

Part (A): histological analysis showed age-dependent and time-dependent chondrocyte migration. A significant difference (p < 0.05) was observed between young and older donors at the same time point. No difference was detected between the two types of scaffolds within the same group at the same time point. Part (B): after 1 month, the number of migrating cells/area significantly increased due to exposure to TGF-β1 and/or G-CSF (p < 0.05). Immunofluorescence revealed that outgrowing cells from unstimulated scaffold sections were positive for SOX9, CD151, CD49c and G-CSF receptor. Immunofluorescence of cells from construct cultures showed an increase in β-catenin in all stimulated groups and an increased PCNA expression in G-CSF-exposed cultures (p < 0.05).

Conclusion

Outgrowing cells may represent a subset of chondrocytes undergoing a phenotypic shift towards a proliferative state. TGF-β1, and to a greater extent G-CSF, may accelerate this outgrowth. The clinical relevance of this study may involve a potential future clinical application of scaffolds preloaded with growth factors as an additional coating for chondral fragments. Indeed, a controlled delivery of G-CSF, widely employed in various clinical settings, might improve the repair process driven by minced human cartilage fragments during one-stage cartilage repair.     

Use of innovative biomimetic scaffold in the treatment for large osteochondral lesions of the knee

Purpose

Large osteochondral defects involve two different tissues characterized by different intrinsic healing capacity. Different techniques have been proposed to treat these lesions with results still under discussion. The aim of the study is to evaluate the clinical outcome of 19 patients treated with a type I collagen–hydroxyapatite nanostructural biomimetic osteochondral scaffold at minimum follow-up of 2 years.

Methods

Twenty lesions, 19 patients were treated with this scaffold implantation. The lesions size went from 4 to 8 cm² (mean size 5.2 ± 1.6 cm²). All patients were clinically evaluated using the International Repair Cartilage Society score, the Tegner Score and EQ-VAS. MRI was performed at 12 and 24 months after surgery and then every 12 months and evaluated with magnetic resonance observation of cartilage repair tissue scoring scale.

Results

The IKDC subjective score improved from a mean score of 35.7 ± 6.3 at the baseline evaluation to 67.7 ± 13.4 at 12-month follow-up (p < 0.0005). A further improvement was documented from 12 to 24 months (mean score of 72.9 ± 12.4 at 24 months) (p < 0.0005). The IKDC objective score confirmed the results. The Tegner activity score improvement was statistically significant (p < 0.0005). The EQ-VAS showed a significant improvement from 3.15 ± 1.09 to 7.35 ± 1.14 (p < 0.0005) at 2-year follow-up. The lesion’ site seems to influence the results showing a better outcome in the patients affected in the medial femoral condyle.

Conclusions

The use of the MaioRegen scaffold is a good procedure for the treatment for large osteochondral defects where other classic techniques are difficult to apply. It is an open one-step surgery with promising stable results at medium follow-up.

Level of evidence

IV.     

Failed cartilage repair for early osteoarthritis defects: a biochemical, histological and immunohistochemical analysis of the repair tissue after treatment with marrow-stimulation techniques

Purpose

To examine the entire repair tissue resulting from marrow-stimulation techniques in patients with early osteoarthritis.

Methods

The repair tissue and adjacent articular cartilage after failed marrow-stimulation techniques (microfracture and Pridie drilling) of 5 patients (47–65 years old) with cartilage defects and radiographic early osteoarthritis (Kellgren–Lawrence grading 1 and 2) was removed during total joint arthroplasty (mean time until analysis: 8.8 months), analysed by histology, polarized light microscopy, immunohistochemistry, biochemistry and by histological score systems.

Results

Macroscopic cartilage repair assessment revealed ICRS grades of II (nearly normal) and III (abnormal). Cartilage defects were mostly completely filled with a fibrocartilaginous tissue that had small and large fissures. Cartilage-specific stains of the repair tissue were more intense than the surrounding native cartilage but reduced compared with normal articular cartilage. The subchondral bone was incompletely restored. A new tidemark was absent. The repair tissue always showed positive immunoreactivity for types II and X collagen, and was sometimes positive for type I collagen. Proteoglycan contents of the repair tissue were generally higher than of the surrounding cartilage. The repair tissue was always more cellular than the adjacent articular cartilage. Histological scoring of the repair tissue revealed a mean Sellers score of 17.6 ± 3.0 and an ICRS grading of 7–9.

Conclusion

Failed marrow stimulation of articular cartilage defects in patients with early osteoarthritis is characterized by fibrocartilaginous repair. The balance of cell number to extracellular matrix is shifted towards an increased cell number in this tissue. Articular cartilage repair did not reach the quality of normal hyaline articular cartilage.

Level of evidence

IV.     

18F-FDG PET/CT is a valuable tool for relapsing polychondritis diagnose and therapeutic response monitoring

Objectives

To retrospectively investigate the role of ¹⁸ F–fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) for the diagnosis and therapeutic response in relapsing polychondritis (RP) patients.

Methods

¹⁸F-FDG PET/CT findings were reviewed in six RP patients. The initial scans were performed for all patients, follow-up scans were performed during steroid therapy for five patients. Changes in the abnormal lesions and the maximal standard uptake value (SUV_max) were analyzed.

Results

The initial PET/CT scans revealed intense FDG uptake in the cartilages for all six patients. The lesions of abnormal FDG uptake were tracheal/bronchial cartilage (n = 4), costicartilage (n = 4), nasal cartilage (n = 3), cricoid cartilage (n = 3), auricular cartilage (n = 3), arytenoid cartilage (n = 3), thyroid cartilage (n = 2), hyoid cartilage (n = 1) and mediastinum lymph node (n = 1). The mean visual score and the mean SUV_max were 2.96 ± 0.20 and 4.10 ± 0.6. The intense uptake reduced or disappeared during steroid therapy for five patients, the mean visual score and the mean SUV_max were 1.58 ± 1.4 and 1.51 ± 1.4.

Conclusions

¹⁸F-FDG PET/CT enables the acquisition of both morphologic and glucose metabolic of the related cartilage structures. It plays a valuable role in assessing almost all cartilage and detecting RP, which is a better selection of a biopsy site as well as therapeutic response monitoring.     

Autologous collagen-induced chondrogenesis technique (ACIC) for the treatment of chondral lesions of the talus

Purpose

Autologous collagen-induced chondrogenesis technique (ACIC) combines microfractures with the use of an injectable atelocollagen matrix that allows performing the whole cartilage repair treatment arthroscopically. The aim of this study was to evaluate the in vitro cytocompatibility of this biomaterial using human bone marrow mesenchymal stem cells and human chondrocytes. Moreover, the preliminary data of five patients affected by chondral lesion of the talus treated with the ACIC technique are shown.

Methods

Human bone marrow mesenchymal stem cells and human chondrocytes were seeded on solid and pre-solid atelocollagen scaffolds. Cell–scaffold constructs were cultured for 7 days and then prepared for histological analyses. Arthroscopic ACIC was performed in five patients affected by chondral lesions of the talus; they were clinically evaluated with AOFAS, VAS and Tegner score before and then after 6 months from surgery.

Results

In vitro results showed that both bone marrow mesenchymal stem cells and chondrocytes were able to efficiently colonize the whole construct, from the surface to the core, only when seeded on the pre-solid atelocollagen scaffold, but not on its solid form. No adverse events were observed in the patients treated with the ACIC technique; a significant improvement in VAS pain scale and in AOFAS score was found at 6 months follow up.

Conclusion

Injectable atelocollagen can be considered a feasible scaffold for cartilage repair treatment, in particular if used in its pre-solid form. ACIC leads to good clinical results in the treatment for chondral lesions of the talus even if longer follow-up and a higher number of patients are necessary to confirm these data.

Level of evidence

IV.     

Nicotine-induced chondrogenic differentiation of human bone marrow stromal cells in vitro

Purpose

Nicotine has been reported that it has a dose-dependent effect on matrix mineralization by human bone marrow cells. However, there is no relevant research concerning on chondrogenic differentiation potential of bone marrow stromal stem cells (BMSCs) treated with nicotine in vitro. The aims of the study were to examine the effects of nicotine (0, 10^?7, 10^?6 and 10^?5 M) on the proliferation and chondrogenic differentiation of BMSCs from three healthy donors in vitro.

Methods

BMSCs proliferation was analyzed by CCK8 assay and real-time polymerase chain reaction was used to assay the expression of type II collagen, aggrecan, type I collagen and type X collagen. The proteoglycan content was stained by Alcian blue, and the sulfated glycosaminoglycan (sGAG) content of BMSCs was quantified spectrofluorometrically using dimethylmethylene blue.

Results

The cell viability was not significantly impaired until up to a concentration of 10^?5 M nicotine. Nicotine promoted the proliferation and enhanced the expression of type II collagen at the level up to 10^?6 M (P < 0.05). The expression of aggrecan was reduced at the concentration of 10^?5 M nicotine at day 14 (P < 0.05), and there was no significant difference in aggrecan gene expression at 10^?7 and 10^?6 M nicotine levels compared to control group (n.s.). Also the fibroblastic and hypertrophic gene expressions were down-regulated in the chondrogenic medium with 10^?7–10^?5 M nicotine (P < 0.05).

Conclusion

It was implied that local application of nicotine at an appropriate concentration may be a promising approach for enhancing chondrogenic differentiation capacity of BMSCs in cell-based cartilage tissue engineering. Also these results indicate that nicotine maybe a potentially useful drug for the treatment of Osteoarthritis.     

Cartilage extra-cellular matrix biomembrane for the enhancement of microfractured defects

Purpose

The purpose of the study was to evaluate whether the biomembrane made of cartilage extracellular matrix, designed to provide cartilage-like favourable environments as well as to prevent against washout of blood clot after microfracture, would enhance cartilage repair compared with the conventional microfracture technique.

Methods

A prospective trial was designed to compare the biomembrane cover after microfracture with conventional microfracture among patients with grade III–IV symptomatic cartilage defect in the knee joint. Patients aged 18–60 years were assigned to either the microfracture/biomembrane (n = 45) or microfracture groups (n = 19). Among them, 24 knees in the microfracture/biomembrane and 12 knees in the microfracture were followed up for 2 years. Cartilage repair was assessed with magnetic resonance imagings taken 6 months, 1 year, and 2 years postoperatively, and the clinical outcomes were also recorded.

Results

Compared with conventional microfracture, microfracture/biomembrane resulted in greater degree of cartilage repair (p = 0.043). In the intra-group analysis, while microfracture showed moderate to good degree of cartilage repair in nearly 50 % of the patients (47 % at 6 months to 50 % at 2 years; n.s.), microfracture/biomembrane maintained an equivalent degree of repair up to 2 years (88 % at 6 months to 75 % at 2 years; n.s.). The clinical outcome at 2 years also showed improved knee score and satisfaction and decreased pain in each group, but the difference between the two groups was not statistically significant.

Conclusions

Compared with conventional microfracture, biomembrane cover after microfracture yielded superior outcome in terms of the degree of cartilage repair during 2 years of follow-up. This implies that initial protection of blood clot and immature repair tissue at the microfractured defect is important for the promotion of enhanced cartilage repair, which may be obtained by the application of a biomembrane.

Level of evidence

Prospective comparative study, Level II.     

Diffusion-weighted imaging of focal renal lesions: a meta-analysis

Objectives

Contrast-enhanced MRI can only distinguish to a limited extent between malignant and benign focal renal lesions. The aim of this meta-analysis is to review renal diffusion-weighted imaging (DWI) to compare apparent diffusion coefficient (ADC) values for different renal lesions that can be applied in clinical practice.

Methods

A PubMed search was performed to identify relevant articles published 2004–2011 on renal DWI of focal renal lesions. ADC values were extracted by lesion type to determine whether benign or malignant. The data table was finalised in a consensus read. ADC values were evaluated statistically using meta-regression based on a linear mixed model. Two-sided P value <5 % indicated statistical significance.

Results

The meta-analysis is based on 17 studies with 764 patients. Renal cell carcinomas have significant lower ADC values than benign tissue (1.61?±?0.08?×?10^-3 mm²/s vs 2.10?±?0.09?×?10^-3 mm²/s; P?<?0.0001). Uroepithelial malignancies can be differentiated by lowest ADC values (1.30?±?0.11?×?10^-3 mm²/s). There is a significant difference between ADC values of renal cell carcinomas and oncocytomas (1.61?±?0.08?×?10^-3 mm²/s vs 2.00?±?0.08?×?10^-3 mm²/s; P?<?0.0001).

Conclusions

Evaluation of ADC values can help to determine between benign and malignant lesions in general but also seems able to differentiate oncocytomas from malignant tumours, hence potentially reducing the number of unnecessarily performed nephrectomies.

Key Points

? This meta-analysis assesses the role of diffusion-weighted MRI in renal lesions. ? ADC values obtained by DW MRI have been compared for different renal lesions. ? ADC values can help distinguish between benign and malignant tumours. ? Differentiating oncocytomas from malignant tumours can potentially reduce inappropriate nephrectomies.     

Diffusion-weighted MR imaging for differentiating borderline from malignant epithelial tumours of the ovary: pathological correlation

Objectives

To investigate diffusion-weighted (DW) magnetic resonance (MR) imaging for differentiating borderline from malignant epithelial tumours of the ovary.

Methods

This retrospective study included 60 borderline epithelial ovarian tumours (BEOTs) in 48 patients and 65 malignant epithelial ovarian tumours (MEOTs) in 54 patients. DW imaging as well as conventional MR imaging was performed. Signal intensity on DW imaging was assessed and apparent diffusion coefficient (ADC) value was measured. The results were correlated with histopathology and cell density.

Results

The majority of MEOTs showed high signal intensity on DW imaging, whereas most BEOTs showed low or moderate signal intensity (P?=?0.000). The mean ADC value of the solid components in BEOTs (1.562?±?0.346?×?10^?3 mm²/s) was significantly higher than in MEOTs (0.841?±?0.209?×?10^?3 mm²/s). A threshold value of 1.039?×?10^?3 mm²/s permitted the distinction with a sensitivity of 97.0 %, a specificity of 92.2 % and an accuracy of 96.4 %. There was an inverse correlation between ADC value and cell density (r?=??0.609; P?=?0.0000) which was significantly lower in BEOTs than in MEOTs.

Conclusions

DW imaging is useful for differentiating borderline from malignant epithelial tumours of the ovary.

Key Points

? DW MR imaging is useful for differentiating BEOTs from MEOTs. ? Patients with BEOTs are treated differently from patients with MEOTs. ? Conservative fertility-sparing laparoscopic surgery can be performed in patients with BEOTs. ? BEOTs often affect young women of childbearing age.     

Dynamic contrast-enhanced and ultra-high-resolution breast MRI at 7.0 Tesla

Objective

To assess the feasibility of 7-T contrast-enhanced breast MRI in patients with suspicious masses.

Methods

Twenty patients with 23 suspicious breast masses on conventional imaging (mean size 13 mm, range 5–27 mm) were examined at 7 T. The MRI protocol included a dynamic series with injection of 0.1 mmol/kg gadobutrol (seven consecutive 3D T1-weighted gradient echo sequences, resolution 1?×?1?×?2 mm³, temporal resolution 63 s) and ultra-high-resolution imaging (T1-weighted 3D gradient echo sequence, resolution 0.45?×?0.57?×?0.45 mm³). Two observers (R1 and R2) independently judged the examinations on image quality and classified lesions according to BI-RADS. The added value of ultra-high-resolution imaging was assessed.

Results

The image quality was deemed excellent in 1 and 0, good in 10 and 12, sufficient in 8 and 8, and insufficient in 1 and 0 for R1 and R2 respectively. Twenty of the 23 lesions were identified at 7-T MRI by both observers. All histopathologically proven malignant lesions (n?=?19) were identified and classified as BI-RADS-MRI 4 or 5. Ultra-high-resolution imaging increased reader confidence in 88 % (R1) and 59 % (R2) of acquisitions.

Conclusion

The study shows the feasibility of dynamic contrast-enhanced 7-T breast MRI, where all malignant mass lesions were identified by two observers.

Key Points

? Magnetic resonance imaging is important in the evaluation of breast cancer. ? Recently, 7-T MRI has become available. ? The 7-T dynamic contrast-enhanced breast MRI is feasible in patients. ? The 7-T breast examinations are amenable to evaluation according to BI-RADS.     

Peripherally inserted central catheter placement in cancer patients with profound thrombocytopaenia: a prospective analysis

Objective

No studies have specifically evaluated the safety of peripherally inserted central catheter (PICC) placement in patients with profound thrombocytopaenia. We prospectively determined the frequency of haemorrhagic complications of PICC placement in cancer patients with uncorrected profound thrombocytopaenia.

Methods

Profound thrombocytopaenia was defined as a platelet count <50?×?10⁹/l. No patients received transfusions before or after the procedure. Three types of adverse effects were analysed: minor oozing, mild haematoma and major haemorrhage.

Results

One hundred and forty-three PICC implantations in 101 cancer patients were prospectively included in the study: seven patients (7 %) had a solid tumour and 94 (93 %) a haematological malignancy. Among these 143 procedures in thrombocytopaenic patients, 93 (65 %) were performed with a platelet count 20–50?×?10⁹/l and 50 (35 %) had lower than 20?×?10⁹/l. No major haemorrhage was observed. Minor oozing was observed in six implantations (4 %) and mild haematoma in two (1.5 %), for a total of eight minor haemorrhagic adverse events (5.5 %). In patients with a platelet count <20?×?10⁹/l, 1/50 (2 %) had minor oozing and none had minor haematoma.

Conclusions

In cancer patients with uncorrected profound thrombocytopaenia, the incidence of adverse events after PICC implantation was low, and was limited to minor haemorrhagic adverse events.

Key Points

? PICC placement has high technical success in profound thrombocytopaenic cancer patients. ? Few adverse events are encountered after PICC placement, limited to minor haemorrhage. ? PICC placement does not routinely require platelet transfusion in patients with thrombocytopaenia. ? Such PICC placement still seems safe when the platelet count is <20?×?10 ⁹ /l.     

Effects of bone marrow or mesenchymal stem cell transplantation on oral mucositis (mouse) induced by fractionated irradiation

Background and purpose

Oral mucositis is a severe and dose limiting early side effect of radiotherapy for head-and-neck tumors. This study was initiated to determine the effect of bone marrow- and mesenchymal stem cell transplantation on oral mucositis (mouse tongue model) induced by fractionated irradiation.

Material and methods

Daily fractionated irradiation (5?×?3 Gy/week) was given over 1 (days 0–4) or 3 weeks (days 0–4, 7–11, 14–18). Each protocol was terminated (day 7 or 21) by graded test doses (5 dose groups, 10 animals each) in order to generate complete dose–effect curves. The incidence of mucosal ulceration, corresponding to confluent mucositis grade 3 (RTOG/EORTC), was analyzed as the primary, clinically relevant endpoint. Bone marrow or mesenchymal stem cells were transplanted intravenously at various time points within these fractionation protocols.

Results

Transplantation of 6?×?10⁶, but not of 3?×?10⁶ bone marrow stem cells on day ??1, +?4, +?8, +?11 or +?15 significantly increased the ED₅₀ values (dose, at which an ulcer is expected in 50?% of the mice); transplantation on day +?2, in contrast, was ineffective. Mesenchymal stem cell transplantation on day ??1, 2 or +?8 significantly, and on day +?4 marginally increased the ED₅₀ values.

Conclusion

Transplantation of bone marrow or mesenchymal stem cells has the potential to modulate radiation-induced oral mucositis during fractionated radiotherapy. The effect is dependent on the timing of the transplantation. The mechanisms require further investigation.     

The effect of a six-month training program followed by a marathon run on knee joint cartilage volume and thickness in marathon beginners

Purpose

The purpose of this study was to investigate the effect of a 6-month period of intensive running followed by the participation at a marathon run on cartilage volume and thickness in knees of marathon beginners.

Methods

Ten asymptomatic marathon beginners underwent a supervised 6-month training program, which was finalized by the participation at a marathon run. Three-dimensional quantitative magnetic resonance imaging was performed before the training program (baseline measurements) and 1 day after the marathon (follow-up measurements). Cartilage volume and thickness of the medial and lateral femur, medial and lateral tibia, and patella were measured using semiautomated cartilage segmentation and three dimensional data postprocessing.

Results

Significant differences between baseline and follow-up measurements were observed at the lateral femur, where cartilage volume and thickness decreased by a mean of 3.2 ± 3.0 % (p = 0.012) and 1.7 ± 1.6 % (p = 0.010), respectively. No significant changes in cartilage volume and thickness were observed at the medial and lateral tibia, the medial femur, and the patella.

Conclusion

Significant cartilage loss was observed at the lateral femur; however, the measured values are comparable to previously reported precision errors for quantitative cartilage measurement and thus most likely not of clinical relevance. High-impact forces during long-distance running are well tolerated even in marathon beginners and do not lead to clinical relevant cartilage loss.

Level of evidence

IV.     

Feasibility of in vivo diffusion tensor imaging of articular cartilage with coverage of all cartilage regions

Objectives

To investigate the value of diffusion tensor imaging (DTI) of articular cartilage to differentiate healthy from osteoarthritis (OA) subjects in all cartilage regions.

Methods

DTI was acquired sagittally at 7 T in ten healthy and five OA (Kellgren-Lawrence grade 2) subjects with a line scan diffusion tensor sequence (LSDTI). Three healthy volunteers and two OA subjects were examined twice to assess the test-retest reproducibility. Averaged mean diffusivity (MD) and fractional anisotropy (FA) were calculated in each cartilage region (femoral trochlea, lateral and medial femoral condyles, patella, and lateral and medial tibia).

Results

The test-retest reproducibility was 2.9 % for MD and 5.6 % for FA. Averaged MD was significantly increased (+20 %, p?<?0.05) in the OA subjects in the lateral femoral condyle, lateral tibia and the femoral trochlea compartments. Averaged FA presented a trend of lower values in the OA subjects (-12 %), which was only significant for the lateral tibia.

Conclusions

In vivo DTI of articular cartilage with coverage of all cartilage regions using an LSDTI sequence is feasible, shows excellent reproducibility for MD and FA, and holds potential for the diagnosis of OA.

Key points

? DTI of articular cartilage is feasible at 7 T in all cartilage regions ? DTI of articular cartilage can potentially differentiate healthy and OA subjects     

The safety and efficacy of magnetic targeting using autologous mesenchymal stem cells for cartilage repair

Purpose

A new cell delivery system using magnetic force, termed magnetic targeting, was developed for the accumulation of locally injected cells in a lesion. The aim of this study was to assess the safety and efficacy of mesenchymal stem cell (MSC) magnetic targeting in patients with a focal articular cartilage defect in the knee.

Methods

MSC magnetic targeting for five patients was approved by the Ministry of Health Labour and Welfare of Japan. Autologous bone marrow MSCs were cultured and subsequently magnetized with ferucarbotran. The 1.0-T compact magnet was attached to a suitable position around the knee joint to allow the magnetic force to be as perpendicular to the surface of the lesion as possible. Then 1?×?10⁷ MSCs were injected into the knee joint. The magnet was maintained in the same position for 10 min after the MSC injection. The primary endpoint was the occurrence of any adverse events. The secondary endpoints were efficacy assessed by magnetic resonance imaging (MRI) T2 mapping and clinical outcomes using the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation and the Knee Injury and Osteoarthritis Outcome Score (KOOS).

Results

No serious adverse events were observed during the treatment or in the follow-up period. Swelling of the treated knee joint was observed from the day after surgery in three of the five patients. The swelling resolved within 2 weeks in two patients. MRI showed that the cartilage defect areas were almost completely filled with cartilage-like tissue. MOCART scores were significantly higher 48 weeks postoperatively than preoperatively (74.8?±?10.8 vs 27.0?±?16.8, p?=?0.042). Arthroscopy in three patients showed complete coverage of their cartilage defects. Clinical outcome scores were significantly better 48 weeks postoperatively than preoperatively for the IKDC Subjective Knee Evaluation (74.8?±?17.7 vs 46.9?±?17.7, p?=?0.014) and knee-related quality-of-life (QOL) in the KOOS (53.8?±?26.4 vs 22.5?±?30.8, p?=?0.012).

Conclusion

Magnetic targeting of MSCs was safely performed and showed complete coverage of the defects with cartilage-like tissues and significant improvement in clinical outcomes 48 weeks after treatment. The magnetic targeting of MSCs is useful as a minimally invasive treatment for cartilage repair.

Level of evidence

IV.