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The Bone & Joint Journal
Vol. 101-B, Issue 1_Supple_A | Pages 46 - 52
1 Jan 2019
León SA Mei XY Safir OA Gross AE Kuzyk PR

Aims

The aim of this study was to report the outcome of femoral condylar fresh osteochondral allografts (FOCA) with concomitant realignment osteotomy with a focus on graft survivorship, complications, reoperation, and function.

Patients and Methods

We identified 60 patients (16 women, 44 men) who underwent unipolar femoral condylar FOCA with concomitant realignment between 1972 and 2012. The mean age of the patients was 28.9 years (10 to 62) and the mean follow-up was 11.4 years (2 to 35). Failure was defined as conversion to total knee arthroplasty, revision allograft, or graft removal. Clinical outcome was evaluated using the modified Hospital for Special Surgery (mHSS) score.


The Bone & Joint Journal
Vol. 105-B, Issue 8 | Pages 880 - 887
1 Aug 2023
Onodera T Momma D Matsuoka M Kondo E Suzuki K Inoue M Higano M Iwasaki N

Aims. Implantation of ultra-purified alginate (UPAL) gel is safe and effective in animal osteochondral defect models. This study aimed to examine the applicability of UPAL gel implantation to acellular therapy in humans with cartilage injury. Methods. A total of 12 patients (12 knees) with symptomatic, post-traumatic, full-thickness cartilage lesions (1.0 to 4.0 cm. 2. ) were included in this study. UPAL gel was implanted into chondral defects after performing bone marrow stimulation technique, and assessed for up to three years postoperatively. The primary outcomes were the feasibility and safety of the procedure. The secondary outcomes were self-assessed clinical scores, arthroscopic scores, tissue biopsies, and MRI-based estimations. Results. No obvious adverse events related to UPAL gel implantation were observed. Self-assessed clinical scores, including pain, symptoms, activities of daily living, sports activity, and quality of life, were improved significantly at three years after surgery. Defect filling was confirmed using second-look arthroscopy at 72 weeks. Significantly improved MRI scores were observed from 12 to 144 weeks postoperatively. Histological examination of biopsy specimens obtained at 72 weeks after implantation revealed an extracellular matrix rich in glycosaminoglycan and type II collagen in the reparative tissue. Histological assessment yielded a mean overall International Cartilage Regeneration & Joint Preservation Society II score of 69.1 points (SD 10.4; 50 to 80). Conclusion. This study provides evidence supporting the safety of acellular UPAL gel implantation in facilitating cartilage repair. Despite being a single-arm study, it demonstrated the efficacy of UPAL gel implantation, suggesting it is an easy-to-use, one-step method of cartilage tissue repair circumventing the need to harvest donor cells. Cite this article: Bone Joint J 2023;105-B(8):880–887


The Bone & Joint Journal
Vol. 99-B, Issue 1 | Pages 51 - 58
1 Jan 2017
van der Woude JAD Wiegant K van Heerwaarden RJ Spruijt S Emans PJ Mastbergen SC Lafeber FPJG

Aims

Knee joint distraction (KJD) is a relatively new, knee-joint preserving procedure with the goal of delaying total knee arthroplasty (TKA) in young and middle-aged patients. We present a randomised controlled trial comparing the two.

Patients and Methods

The 60 patients ≤ 65 years with end-stage knee osteoarthritis were randomised to either KJD (n = 20) or TKA (n = 40). Outcomes were assessed at baseline, three, six, nine, and 12 months. In the KJD group, the joint space width (JSW) was radiologically assessed, representing a surrogate marker of cartilage thickness.


The Journal of Bone & Joint Surgery British Volume
Vol. 94-B, Issue 4 | Pages 504 - 509
1 Apr 2012
Bentley G Biant LC Vijayan S Macmull S Skinner JA Carrington RWJ

Autologous chondrocyte implantation (ACI) and mosaicplasty are methods of treating symptomatic articular cartilage defects in the knee. This study represents the first long-term randomised comparison of the two techniques in 100 patients at a minimum follow-up of ten years. The mean age of the patients at the time of surgery was 31.3 years (16 to 49); the mean duration of symptoms pre-operatively was 7.2 years (9 months to 20 years). The lesions were large with the mean size for the ACI group being 440.9 mm2 (100 to 1050) and the mosaicplasty group being 399.6 mm2 (100 to 2000). Patients had a mean of 1.5 previous operations (0 to 4) to the articular cartilage defect. Patients were assessed using the modified Cincinnati knee score and the Stanmore-Bentley Functional Rating system. The number of patients whose repair had failed at ten years was ten of 58 (17%) in the ACI group and 23 of 42 (55%) in the mosaicplasty group (p < 0.001).

The functional outcome of those patients with a surviving graft was significantly better in patients who underwent ACI compared with mosaicplasty (p = 0.02).


The Journal of Bone & Joint Surgery British Volume
Vol. 94-B, Issue 4 | Pages 488 - 492
1 Apr 2012
Vijayan S Bartlett W Bentley G Carrington RWJ Skinner JA Pollock RC Alorjani M Briggs TWR

Matrix-induced autologous chondrocyte implantation (MACI) is an established technique used to treat osteochondral lesions in the knee. For larger osteochondral lesions (> 5 cm2) deeper than approximately 8 mm we have combined the use of two MACI membranes with impaction grafting of the subchondral bone. We report our results of 14 patients who underwent the ‘bilayer collagen membrane’ technique (BCMT) with a mean follow-up of 5.2 years (2 to 8). There were 12 men and two women with a mean age of 23.6 years (16 to 40). The mean size of the defect was 7.2 cm2 (5.2 to 12 cm2) and were located on the medial (ten) or lateral (four) femoral condyles. The mean modified Cincinnati knee score improved from 45.1 (22 to 70) pre-operatively to 82.8 (34 to 98) at the most recent review (p < 0.05). The visual analogue pain score improved from 7.3 (4 to 10) to 1.7 (0 to 6) (p < 0.05). Twelve patients were considered to have a good or excellent clinical outcome. One graft failed at six years.

The BCMT resulted in excellent functional results and durable repair of large and deep osteochondral lesions without a high incidence of graft-related complications.


The Bone & Joint Journal
Vol. 103-B, Issue 11 | Pages 1686 - 1694
1 Nov 2021
Yang H Kwak W Kang SJ Song E Seon J

Aims. To determine the relationship between articular cartilage status and clinical outcomes after medial opening-wedge high tibial osteotomy (MOHTO) for medial compartmental knee osteoarthritis at intermediate follow-up. Methods. We reviewed 155 patients (155 knees) who underwent MOHTO from January 2008 to December 2016 followed by second-look arthroscopy with a mean 5.3-year follow-up (2.0 to 11.7). Arthroscopic findings were assessed according to the International Cartilage Repair Society (ICRS) Cartilage Repair Assessment (CRA) grading system. Patients were divided into two groups based on the presence of normal or nearly normal quality cartilage in the medial femoral condyle: good (second-look arthroscopic) status (ICRS grade I or II; n = 70), and poor (second-look arthroscopic) status (ICRS grade III or IV; n = 85) groups at the time of second-look arthroscopy. Clinical outcomes were assessed using the International Knee Documentation Committee (IKDC) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and 36-Item Short Form survey. Results. Significant improvements in all clinical outcome categories were found between the preoperative and second-look arthroscopic assessments in both groups (p < 0.001). At the latest follow-up, the mean IKDC and WOMAC scores in the good status group further improved compared with those at the time of second-look arthroscopic surgery (p < 0.001), which was not shown in the poor status group. The mean IKDC (good status, 72.8 (SD 12.5); poor status, 64.7 (SD 12.1); p = 0.002) and mean WOMAC scores (good status, 15.7 (SD 10.8); poor status, 21.8 (SD 13.6); p = 0.004) significantly differed between both groups at the latest follow-up. Moreover, significant correlations were observed between ICRS CRA grades and IKDC scores (negative correlation; p < 0.001) and WOMAC scores (positive correlation; p < 0.001) at the latest follow-up. Good cartilage status was found more frequently in knees with the desired range of 2° to 6° valgus correction than in those with corrections outside this range (p = 0.019). Conclusion. Second-look arthroscopic cartilage status correlated with clinical outcomes after MOHTO at intermediate-term follow-up, despite the relatively small clinical differences between groups. Cite this article: Bone Joint J 2021;103-B(11):1686–1694


The Bone & Joint Journal
Vol. 97-B, Issue 3 | Pages 318 - 323
1 Mar 2015
Verdonk P Dhollander A Almqvist KF Verdonk R Victor J

The treatment of osteochondral lesions is of great interest to orthopaedic surgeons because most lesions do not heal spontaneously. We present the short-term clinical outcome and MRI findings of a cell-free scaffold used for the treatment of these lesions in the knee. A total of 38 patients were prospectively evaluated clinically for two years following treatment with an osteochondral nanostructured biomimetic scaffold. There were 23 men and 15 women; the mean age of the patients was 30.5 years (15 to 64). Clinical outcome was assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Tegner activity scale and a Visual Analgue scale for pain. MRI data were analysed based on the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system at three, 12 and 24 months post-operatively. There was a continuous significant clinical improvement after surgery. In two patients, the scaffold treatment failed (5.3%) There was a statistically significant improvement in the MOCART precentage scores. The repair tissue filled most of the defect sufficiently. We found subchondral laminar changes in all patients. Intralesional osteophytes were found in two patients (5.3%). We conclude that this one-step scaffold-based technique can be used for osteochondral repair. The surgical technique is straightforward, and the clinical results are promising. The MRI aspects of the repair tissue continue to evolve during the first two years after surgery. However, the subchondral laminar and bone changes are a concern. Cite this article: Bone Joint J 2015; 97-B:318–23


The Journal of Bone & Joint Surgery British Volume
Vol. 90-B, Issue 5 | Pages 597 - 604
1 May 2008
Selmi TAS Verdonk P Chambat P Dubrana F Potel J Barnouin L Neyret P

Autologous chondrocyte implantation is an established method of treatment for symptomatic articular defects of cartilage. CARTIPATCH is a monolayer-expanded cartilage cell product which is combined with a novel hydrogel to improve cell phenotypic stability and ease of surgical handling. Our aim in this prospective, multicentre study on 17 patients was to investigate the clinical, radiological, arthroscopic and histological outcome at a minimum follow-up of two years after the implantation of autologous chondrocytes embedded in a three-dimensional alginate-agarose hydrogel for the treatment of chondral and osteochondral defects. Clinically, all the patients improved significantly. Patients with lesions larger than 3 cm. 2. improved significantly more than those with smaller lesions. There was no correlation between the clinical outcome and the body mass index, age, duration of symptoms and location of the defects. The mean arthroscopic International Cartilage Repair Society score was 10 (5 to 12) of a maximum of 12. Predominantly hyaline cartilage was seen in eight of the 13 patients (62%) who had follow-up biopsies. Our findings suggest that autologous chondrocyte implantation in combination with a novel hydrogel results in a significant clinical improvement at follow-up at two years, more so for larger and deeper lesions. The surgical procedure is uncomplicated, and predominantly hyaline cartilage-like repair tissue was observed in eight patients


The Journal of Bone & Joint Surgery British Volume
Vol. 88-B, Issue 2 | Pages 203 - 205
1 Feb 2006
Krishnan SP Skinner JA Carrington RWJ Flanagan AM Briggs TWR Bentley G

We prospectively studied the clinical, arthroscopic and histological results of collagen-covered autologous chondrocyte implantation (ACI-C) in patients with symptomatic osteochondritis dissecans of the knee. The study included 37 patients who were evaluated at a mean follow-up of 4.08 years. Clinical results showed a mean improvement in the modified Cincinnati score from 46.1 to 68.4. Excellent and good clinical results were seen in 82.1% of those with juvenile-onset osteochondritis dissecans but in only 44.4% of those with adult-onset disease. Arthroscopy at one year revealed International Cartilage Repair Society grades of 1 or 2 in 21 of 24 patients (87.5%). Of 23 biopsies, 11 (47.8%) showed either a hyaline-like or a mixture of hyaline-like and fibrocartilage, 12 (52.2%) showed fibrocartilage. The age at the time of ACI-C determined the clinical outcome for juvenile-onset disease (p = 0.05), whereas the size of the defect was the major determinant of outcome in adult-onset disease (p = 0.01)


The Journal of Bone & Joint Surgery British Volume
Vol. 87-B, Issue 5 | Pages 640 - 645
1 May 2005
Bartlett W Skinner JA Gooding CR Carrington RWJ Flanagan AM Briggs TWR Bentley G

Autologous chondrocyte implantation (ACI) is used widely as a treatment for symptomatic chondral and osteochondral defects of the knee. Variations of the original periosteum-cover technique include the use of porcine-derived type I/type III collagen as a cover (ACI-C) and matrix-induced autologous chondrocyte implantation (MACI) using a collagen bilayer seeded with chondrocytes. We have performed a prospective, randomised comparison of ACI-C and MACI for the treatment of symptomatic chondral defects of the knee in 91 patients, of whom 44 received ACI-C and 47 MACI grafts. Both treatments resulted in improvement of the clinical score after one year. The mean modified Cincinnati knee score increased by 17.6 in the ACI-C group and 19.6 in the MACI group (p = 0.32). Arthroscopic assessments performed after one year showed a good to excellent International Cartilage Repair Society score in 79.2% of ACI-C and 66.6% of MACI grafts. Hyaline-like cartilage or hyaline-like cartilage with fibrocartilage was found in the biopsies of 43.9% of the ACI-C and 36.4% of the MACI grafts after one year. The rate of hypertrophy of the graft was 9% (4 of 44) in the ACI-C group and 6% (3 of 47) in the MACI group. The frequency of re-operation was 9% in each group. We conclude that the clinical, arthroscopic and histological outcomes are comparable for both ACI-C and MACI. While MACI is technically attractive, further long-term studies are required before the technique is widely adopted


The Bone & Joint Journal
Vol. 105-B, Issue 9 | Pages 953 - 960
1 Sep 2023
Cance N Erard J Shatrov J Fournier G Gunst S Martin GL Lustig S Servien E

Aims

The aim of this study was to evaluate the association between chondral injury and interval from anterior cruciate ligament (ACL) tear to surgical reconstruction (ACLr).

Methods

Between January 2012 and January 2022, 1,840 consecutive ACLrs were performed and included in a single-centre retrospective cohort. Exclusion criteria were partial tears, multiligament knee injuries, prior ipsilateral knee surgery, concomitant unicompartmental knee arthroplasty or high tibial osteotomy, ACL agenesis, and unknown date of tear. A total of 1,317 patients were included in the final analysis, with a median age of 29 years (interquartile range (IQR) 23 to 38). The median preoperative Tegner Activity Score (TAS) was 6 (IQR 6 to 7). Patients were categorized into four groups according to the delay to ACLr: < three months (427; 32%), three to six months (388; 29%), > six to 12 months (248; 19%), and > 12 months (254; 19%). Chondral injury was assessed during arthroscopy using the International Cartilage Regeneration and Joint Preservation Society classification, and its association with delay to ACLr was analyzed using multivariable analysis.


The Bone & Joint Journal
Vol. 104-B, Issue 6 | Pages 657 - 662
1 Jun 2022
Barlow T Coco V Shivji F Grassi A Asplin L Thompson P Metcalfe A Zaffagnini S Spalding T

Aims

Meniscal allograft transplantation (MAT) for patients with symptomatic meniscal loss has demonstrated good clinical results and survivorship. Factors that affect both functional outcome and survivorship have been reported in the literature. These are typically single-centre case series with relatively small numbers and conflicting results. Our aim was to describe an international, two-centre case series, and identify factors that affect both functional outcome and survival.

Methods

We report factors that affect outcome on 526 patients undergoing MAT across two sites (one in the UK and one in Italy). Outcomes of interest were the Knee injury and Osteoarthritis Outcome Score four (KOOS4) at two years and failure rates. We performed multiple regression analysis to examine for factors affecting KOOS, and Cox proportional hazards models for survivorship.


The Bone & Joint Journal
Vol. 106-B, Issue 7 | Pages 662 - 668
1 Jul 2024
Ahmed I Metcalfe A

Aims

This study aims to identify the top unanswered research priorities in the field of knee surgery using consensus-based methodology.

Methods

Initial research questions were generated using an online survey sent to all 680 members of the British Association for Surgery of the Knee (BASK). Duplicates were removed and a longlist was generated from this scoping exercise by a panel of 13 experts from across the UK who provided oversight of the process. A modified Delphi process was used to refine the questions and determine a final list. To rank the final list of questions, each question was scored between one (low importance) and ten (high importance) in order to produce the final list.


The Bone & Joint Journal
Vol. 103-B, Issue 8 | Pages 1367 - 1372
1 Aug 2021
Plancher KD Brite JE Briggs KK Petterson SC

Aims

The patient-acceptable symptom state (PASS) is a level of wellbeing, which is measured by the patient. The aim of this study was to determine if the proportion of patients who achieved an acceptable level of function (PASS) after medial unicompartmental knee arthroplasty (UKA) was different based on the status of the anterior cruciate ligament (ACL) at the time of surgery.

Methods

A total of 114 patients who underwent UKA for isolated medial osteoarthritis (OA) of the knee were included in the study. Their mean age was 65 years (SD 10). No patient underwent a bilateral procedure. Those who had undergone ACL reconstruction during the previous five years were excluded. The Knee injury Osteoarthritis Outcome Score Activities of Daily Living (KOOS ADL) function score was used as the primary outcome measure with a PASS of 87.5, as described for total knee arthroplasty (TKA). Patients completed all other KOOS subscales, Lysholm score, the Western Ontario and McMaster Universities Osteoarthritis Index, and the Veterans Rand 12-item health survey score. Failure was defined as conversion to TKA.


The Journal of Bone & Joint Surgery British Volume
Vol. 85-B, Issue 2 | Pages 223 - 230
1 Mar 2003
Bentley G Biant LC Carrington RWJ Akmal M Goldberg A Williams AM Skinner JA Pringle J

Autologous chondrocyte implantation (ACI) and mosaicplasty are both claimed to be successful for the repair of defects of the articular cartilage of the knee but there has been no comparative study of the two methods. A total of 100 patients with a mean age of 31.3 years (16 to 49) and with a symptomatic lesion of the articular cartilage in the knee which was suitable for cartilage repair was randomised to undergo either ACI or mosaicplasty; 58 patients had ACI and 42 mosaicplasty. Most lesions were post-traumatic and the mean size of the defect was 4.66 cm. 2. The mean duration of symptoms was 7.2 years and the mean number of previous operations, excluding arthroscopy, was 1.5. The mean follow-up was 19 months (12 to 26). Functional assessment using the modified Cincinatti and Stanmore scores and objective clinical assessment showed that 88% had excellent or good results after ACI compared with 69% after mosaicplasty. Arthroscopy at one year demonstrated excellent or good repairs in 82% after ACI and in 34% after mosaicplasty. All five patellar mosaicplasties failed. Our prospective, randomised, clinical trial has shown significant superiority of ACI over mosaicplasty for the repair of articular defects in the knee. The results for ACI are comparable with those in other studies, but those for mosaicplasty suggest that its continued use is of dubious value


The Bone & Joint Journal
Vol. 101-B, Issue 7 | Pages 824 - 831
1 Jul 2019
Mahmoud EE Adachi N Mawas AS Deie M Ochi M

Aim

Mesenchymal stem cells (MSCs) have several properties that may support their use as an early treatment option for osteoarthritis (OA). This study investigated the role of multiple injections of allogeneic bone marrow-derived stem cells (BMSCs) to alleviate the progression of osteoarthritic changes in the various structures of the mature rabbit knee in an anterior cruciate ligament (ACL)-deficient OA model.

Materials and Methods

Two months after bilateral section of the ACL of Japanese white rabbits aged nine months or more, either phosphate buffered saline (PBS) or 1 x 106 MSCs were injected into the knee joint in single or three consecutive doses. After two months, the articular cartilage and meniscus were assessed macroscopically, histologically, and immunohistochemically using collagen I and II.


The Bone & Joint Journal
Vol. 100-B, Issue 3 | Pages 285 - 293
1 Mar 2018
Nakamae A Adachi N Deie M Ishikawa M Nakasa T Ikuta Y Ochi M

Aims

To investigate the risk factors for progression of articular cartilage damage after anatomical anterior cruciate ligament (ACL) reconstruction.

Patients and Methods

A total of 174 patients who underwent second-look arthroscopic evaluation after anatomical ACL reconstruction were enrolled in this study. The graded condition of the articular cartilage at the time of ACL reconstruction was compared with that at second-look arthroscopy. Age, gender, body mass index (BMI), ACL reconstruction technique, meniscal conditions, and other variables were assessed by regression analysis as risk factors for progression of damage to the articular cartilage.


The Bone & Joint Journal
Vol. 99-B, Issue 3 | Pages 337 - 343
1 Mar 2017
Ahmed I Salmon L Roe J Pinczewski L

Aims

The aim of this study was to investigate the long-term clinical and radiological outcome of patients who suffer recurrent injuries to the anterior cruciate ligament (ACL) after reconstruction and require revision surgery.

Patients and Methods

From a consecutive series of 200 patients who underwent primary reconstruction following rupture of the ACL, we identified 36 who sustained a further rupture, 29 of whom underwent revision surgery. Patients were reviewed prospectively at one, two, seven, 15 and about 20 years after their original surgery. Primary outcome measures were the number of further ruptures, the posterior tibial slope (PTS), and functional and radiological outcomes. These were compared with a gender and age matched cohort of patients who underwent primary ACL reconstruction only.


The Bone & Joint Journal
Vol. 97-B, Issue 7 | Pages 924 - 932
1 Jul 2015
Lee MC Ha C Elmallah RK Cherian JJ Cho JJ Kim TW Bin S Mont MA

The aim of this study was to assess the effect of injecting genetically engineered chondrocytes expressing transforming growth factor beta 1 (TGF-β1) into the knees of patients with osteoarthritis. We assessed the resultant function, pain and quality of life.

A total of 54 patients (20 men, 34 women) who had a mean age of 58 years (50 to 66) were blinded and randomised (1:1) to receive a single injection of the active treatment or a placebo. We assessed post-treatment function, pain severity, physical function, quality of life and the incidence of treatment-associated adverse events. Patients were followed at four, 12 and 24 weeks after injection.

At final follow-up the treatment group had a significantly greater improvement in the mean International Knee Documentation Committee score than the placebo group (16 points; -18 to 49, vs 8 points; -4 to 37, respectively; p = 0.03). The treatment group also had a significantly improved mean visual analogue score at final follow-up (-25; -85 to 34, vs -11 points; -51 to 25, respectively; p = 0.032). Both cohorts showed an improvement in Western Ontario and McMaster Osteoarthritis Index and Knee Injury and Osteoarthritis Outcome Scores, but these differences were not statistically significant. One patient had an anaphylactic reaction to the preservation medium, but recovered within 24 hours. All other adverse events were localised and resolved without further action.

This technique may result in improved clinical outcomes, with the aim of slowing the degenerative process, leading to improvements in pain and function. However, imaging and direct observational studies are needed to verify cartilage regeneration. Nevertheless, this study provided a sufficient basis to proceed to further clinical testing.

Cite this article: Bone Joint J 2015;97-B:924–32.


The Journal of Bone & Joint Surgery British Volume
Vol. 94-B, Issue 10 | Pages 1377 - 1381
1 Oct 2012
Jaiswal PK Bentley G Carrington RWJ Skinner JA Briggs TWR

We analysed whether a high body mass index (BMI) had a deleterious effect on outcome following autologous chondrocyte implantation (ACI) or matrix-carried autologous chondrocyte implantation (MACI) for the treatment of full-thickness chondral defects of the knee from a subset of patients enrolled in the ACI vs MACI trial at The Royal National Orthopaedic Hospital.

The mean Modified Cincinnati scores (MCS) were significantly higher (p < 0.001) post-operatively in patients who had an ideal body weight (n = 53; 20 to 24.9 kg/m2) than in overweight (n = 63; 25 to 30 kg/m2) and obese patients (n = 22; > 30 kg/m2). At a follow-up of two years, obese patients demonstrated no sustained improvement in the MCS. Patients with an ideal weight experienced significant improvements as early as six months after surgery (p = 0.007). In total, 82% of patients (31 of 38) in the ideal group had a good or excellent result, compared with 49% (22 of 45) of the overweight and 5.5% (one of 18) in the obese group (p < 0.001). There was a significant negative relationship between BMI and the MCS 24 months after surgery (r = -0.4, p = 0.001).

This study demonstrates that obese patients have worse knee function before surgery and experience no sustained benefit from ACI or MACI at two years after surgery. There was a correlation between increasing BMI and a lower MCS according to a linear regression analysis. On the basis of our findings patient selection can be more appropriately targeted.