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Issues Concerning Clinical Outcomes in Long-Term Trials of Cellular Therapies for Cartilage Repair. May 15, 2009. Gunnar Knutsen MD, PhD University Hospital North Norway. Universities in Norway. Norwegian RCT ACI versus Microfracture. Northern most University Hospital in the world. Tromsø.

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Issues Concerning Clinical Outcomes in Long-Term Trials of Cellular Therapies for Cartilage Repair.May 15, 2009

Gunnar Knutsen MD, PhD

University Hospital North Norway


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Universities in Cellular Therapies for Cartilage Repair. Norway

Norwegian RCT ACI versus Microfracture

Northern most University Hospital in the world

Tromsø

Trondheim

80 patients

40 patients in each group

Bergen

Oslo

Blinded histological evaluation: SR, Oswestry UK and VI Tromsø Norway


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Tromsø Cellular Therapies for Cartilage Repair.


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JBJS. March 2004 and Oct. 2007 Cellular Therapies for Cartilage Repair.

Level 1 RCT


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RCTs Cellular Therapies for Cartilage Repair.

  • Rare in orthopaedic surgery

  • Low methodological quality

  • What I have learned from our trial…

  • Study design

  • Methods

  • Endpoints: Clinical benefit, Instruments of measurements.

  • Histology, MRI

  • Design a new trial…


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Methods Cellular Therapies for Cartilage Repair.

  • ICRS

  • Lysholm

  • SF-36

  • Tegner

  • Second-look arthroscopy

  • Standing radiographs

  • Histology

  • Failures: Symptomatic non healing of defect and new cartilage operation

  • Statistical M.: SPSS, level of sign. p<0.05


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Macroscopic evaluation ICRS 2 years Cellular Therapies for Cartilage Repair.

ICRS

Normal: 12p

nearly normal: 11-8p

abnormal: 7-4p

severely abnormal: 3-1p

p= 0,170

MACROSCOPIC REPAIR


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LYSHOLM Cellular Therapies for Cartilage Repair.

P=0.227 linear regression

ACI

Micro


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PCS- Physical component SF-36 Cellular Therapies for Cartilage Repair.

ACI

Micro

P= 0.068

Lin.regression


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VAS- Visual Analog pain Score Cellular Therapies for Cartilage Repair.

ACI

P=0.189

Linear regression

Micro


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77.5% Cellular Therapies for Cartilage Repair.


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1. Hyaline predominantly Cellular Therapies for Cartilage Repair.

2. Fibrocartilage- hyaline mixture

3. Fibrocartilage

4. Inadequate biopsies or no repair tissue, predominantly bone

Arrow: may or may not be repair tissue

d: polaraized light


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Histology Cellular Therapies for Cartilage Repair.

1

2

3

4

p = 0.08


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Crosstabulation Histology Cellular Therapies for Cartilage Repair.

P=0.001

P=0.118


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Radiographic results at 5 yrs Cellular Therapies for Cartilage Repair.

  • 25% reduced joint space (<4mm)

  • 33.9% at least Kellgren 2 at five years

  • No significant difference between groups

  • Significant association between OA and pain (Kellgren Lawrence and VAS)


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Age and activity Cellular Therapies for Cartilage Repair.

  • Younger patients (less than 30 yrs. old) in both groups have significant better results.

  • More active patients (Tegner) in both groups have also significantly better clinical scores (Lysholm, VAS and SF 36)


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ACI-M Cellular Therapies for Cartilage Repair.

  • ACI: two-step procedure including arthrotomy

  • Microfracture: Cells have less protection

Cells from the bone-marrow my contribute to both repairs ?


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Conclusion 1 Cellular Therapies for Cartilage Repair.

  • ACI and Microfracture resulted in similar clinical results

  • Nine failures (22.5%) in both groups

  • No significant difference in macroscopic or histological results and no correlation at this point between histology and clinical outcome


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Conclusion 2 Cellular Therapies for Cartilage Repair.

  • Good quality repair-cartilage reduces risk of failure

  • Microfracture: first line treatment for defects located on medial or lateral femoral condyle

  • Younger and more active patients do better

  • Improvements in surgical techniques needed as well as in the field of cellular and molecular biology


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Clinical scores Cellular Therapies for Cartilage Repair.

  • KOOS: Patient –administered:10 minutes

  • Evaluates both short- and long-term consequences of knee injury

  • 42 items in 5 separately scored domains; Pain, other symptoms, ADL, Function in Sport/Rec and knee related QOL

  • Includes WOMAC (24 items) OA Index (pain, function and stiffness)


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KOOS Cellular Therapies for Cartilage Repair.Knee injury and Osteoarthritis Outcome Score

  • Validated in several populations

  • ACL. Knee arthroscopy, Meniscectomy, TKR, ACI

  • Correlation with SF-36. +++

  • KOOS is the recommended self-report measure of pain, function and QOL

  • KOOS responiseveness +++ indicating fewer subjects needed to get significance


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KOOS Cellular Therapies for Cartilage Repair.

  • Generally, the subscale QOL is the most responsive, followed by the subscale Pain and Sport and Recration function.

  • Symptoms and function the last week

  • 5 boxes (score 0-4)

  • 100 (normalized score)


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IKDC Cellular Therapies for Cartilage Repair.

  • Demographic form

  • Current Health Asessment Form

  • Subjective Knee Evaluation Form

  • Knee History Form

  • Surgical Documentation Form

  • Knee Examination Form


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Subjective Knee Evaluation Form - IKDC Cellular Therapies for Cartilage Repair.

  • Symptoms

  • Sport

  • Function

  • 18 items

  • IKDC score max 100


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KOOS versus SF-36 Cellular Therapies for Cartilage Repair.

  • KOOS includes also sport/recreation and knee related quality of life

  • SF-36 well accepted instrument in health research: 8 dimensions; role physical,bodily pain,general health,vitality, social functioning, role emotional and mental health.

  • PCS- Physical Component Summaries

  • PCS the only significant difference at 2 years in our study

  • MCS- Mental Component Summaries


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Outcomes Cellular Therapies for Cartilage Repair.

  • Primary or secondary

  • “Soft”: Clinical outcomes: symptom reduction (incl pain) and function. Placebo, bias.. Patient based: KOOS best instrument in my opinion

  • Functional testing: One leg jumping…e.g.

  • “Hard” –less bias: Failure, TKR (OA)

  • “Surrogate”: Histology, Arthroscopic evaluation/probing, MRI, ultrasound, X-rays,


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Fibrocartilage repair versus hyaline Cellular Therapies for Cartilage Repair.

Bundles of collagen fibers, lying in random irregular manner. Cells more elongated and often more numerous.

Collagen type I

Homogenous matrix. Round or oval shape of the cells often surrounded by lacuna.

Collagen type II

Polarized light


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Kellgren Lawrence 0-4 Cellular Therapies for Cartilage Repair.

Radiological evaluation

Kellgren grade 3


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MRI Cellular Therapies for Cartilage Repair.

  • Quantitative MRI

Non invasive

MRI scoring systems

Use of blinded readers

Techniques improves..

Follow patients and evaluating repair site at different time points

Lozano et al JBJS (Am)2006;88:1349-1352.


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RCT Cellular Therapies for Cartilage Repair.

  • Power calculation

  • Multicenter

  • Randomization- difficult in surgery

  • Standardization of procedure (Surgeons like to do it “my way”)

  • Clear Endpoints- we had too many and they could have been better defined

  • Blinding

  • Rehabilitation

  • Control group: Non operative


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Remember.. Cellular Therapies for Cartilage Repair.

  • Evidence: On top: RCT Level 1

  • On bottom: Experts opinion Level 5

  • However, needing a surgeon- you would like to have an expert

  • Skills- fingertip feeling-intuition are difficult to include in RCTs

  • Surgery is complex

  • Standardization of techniques


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Thank you! Cellular Therapies for Cartilage Repair.