The WCC Note

Your Weekly Guide to Harmonizing Clinical Trial Imaging

Volume 4, Number 4 – May 6, 2010 FATTY LIVER: The Epidemic Wolf in Sheep’s Clothing, PART 1 - May 6th, 2010 by worldcare

Nonalcoholic fatty liver disease (NAFLD) has escalated to the number one liver disease in the United States.  No longer just “fatty liver, or fatty liver with focal sparing” noted as almost an afterthought on imaging reports, it has now become an epidemic problem with potential for very real morbidity and mortality.  Afflicting children and adults, its pathogenesis is multifactorial, but its increase prevalence strongly concides with the mounting Western obesity rate.  This issue of  The WCC Note commences a two-part series on hepatic steatosis, beginning with reviews of its prevalence, pathology, and clinical consequences.

How is nonalcoholic fatty liver disease defined?

1.  NAFLD is defined as macrovesicular steatosis in more
than 5% of hepatocytes (1) in the absence of significant
ethol consumption or other specific cause of liver disease.
2.  NAFLD encompasses a spectrum of disease, ranging from:
a.  Simple steatosis
b.  Steatohepatitis (NASH)
c.  Fibrosis and cirrhosis, to
d.  Hepatocellular carcinoma. (2)

How many people have fatty liver?

  1. An estimated 31 million Americans, 31% of men and 16% of women have NAFLD.  It is thought to be the most plausible cause for the elevated serum aminotransferases and/or gamma glutamyl transpeptidase levels recorded in 24% of U.S. adults. (3)
  2. The United States National Institutes of Health estimates that nonalcoholic steatopatitis (NASH) affects 2% to 5% of Americans, with an additional 10% to 20% having fatty liver, i.e. hepatic fat without current inflammation or liver damage. (4)
  3. The true prevalence in children is not known but is reported at 2.5% to 10% and from 8%  to 80% in obese children. (5) NAFLD is reported as a common cause of liver disease in children and adolescents. (1, 6)

Who gets fatty liver?

1.  The most common associations are:
a.  Obesity is the number one cause. Eighty percent of patients with NAFLD are obese, and 80% of  obese
individuals have NAFLD
b.  Type 2 diabetes mellitus
c.  Dyslipidemia (2)
 2.  NAFLD affects children, adolescents, (1,6) and adults.  It affects boys more than girls (1) and men and women
equally. (3)
3.   Insulin resistance is reported as almost universal in adults NAFLD and highly prevalent in afflicted children
and adolescents. (1)
4.   Both genetic and environmental factors are thought to be responsible for the major ethnic variations in
prevalence.  (1) Recently, for example, variants in apolipoprotein C3 gene have shown association with
NAFLD. (7)
5.   The current Western diet, high in saturated fats and fructose, is considered highly responsible. (8)

Why does fatty liver disease occur?  What is the pathogenesis?

1. NAFLD is considered to be the liver’s manifestation of a metobolic syndrome called “syndrome X” or “insulin
resistance syndrome.”  The syndrome links NAFLD with obesity, diabetes mellitus type 2, hypertension, and
hyperlipidemia. (1)
2. Evidence points to a two-hit theory.
a.   The first hit:
i.   The  “first hit” involves accumulation of fat in the liver.
ii.  Free fatty acids (FFA) are elevated in the serum, become oversupplied to the liver, and lead to
steatosis. (2)
b.   The second hit:
i    Steatosis makes the liver vulnerable to additional biochemical insults, the “second hit.”  These include
oxidative stree, mitochondrial dysfunction, pro-inflammatory cytokines, adipocytokine imbalance,
dysregulated apoptosis, and stellate cell activation.  The result can lead to inflammation causing NASH
and fibrosis. (5, 9)

What is the pathology of nonalcoholic fatty liver?

1.  Liver steatosis consist of large and small vesicles of fat, predominantly
triglycerides inside hepatocytes. (3)
2.  The histology may differ between children and adult. (10)

Figure at right: Fatty liver in a 44-year -old man.
Axial contrast-enhanced CT scan shows linear high
attenuation along the hepatic surface (arrow), a finding
that represents pseudoenhancement.   The diaphragm has
attenuation of the fatty liver and thus mimics an enhanced
hepatic capsule. (14)

What is the pathology of nonalcoholic steatohepatitis
(NASH) ?1.     Steatosis, multifocal parenchymal inflammation, Mallory hyaline,
hepatocyte death from ballooning degeneration and also apoptosis, and
sinusoidal fibrosis occur. (3)

What effect does fat have on the liver?1.     NAFLD is suspected to be responsible for up to 70% of chronic hepatitis
cases of “unknown” cause.  Studies suggest that cirrhosis may eventually
develop in up to 10% to 30% of those with NAFLD. (3)
2.     NAFLD may contribute to progression of other liver diseases. (3)

What are some recent nutritionally related studies?

1.  Daily frutose ingestion by patients with NAFLD shows association with increase hepatic fibrosis. (11)
2.  In contradistinction, berry consumption has been shown to enhance liver function. (12)

What other diseases are associated with NAFLD?1.  Chronic kidney disease and retinopathy show higher prevalence in type 1 diabetic patients
who have NAFLD. (13)
2.   Hepatic steatosis is an independent marker for increased cardiovascular risk. (10)

Conclusion:  Nonalcoholic fatty liver disease has become the most common chronic liver disease
in Western children, adolescents, and adults.  It can have association with hepatitis, cirrhosis, and
hepatocellular carcinoma.

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INFILTRATING LOBULAR CARCINOMA, PART 2: MRI Morphology and Kinetics – Vol. 4, Number 3 – March 31, 2010 - March 31st, 2010 by worldcare

A sinister and stealthy marauder, infiltrating lobular carcinoma (ILC) can potentially elude detection due to its pathologic appearance.  As reviewed in the last issue of THE WCC Note, the shape of ILC at pathology varies.  It ranges from tumors with irregular margins; to those displaying diffuse invasion with cells infiltrating single file or loosely associated; to variants with large groups of cells.  The particular pattern influences the MRI appearance of ILC; infiltrating lobular carcinoma may look mass like and possibly explosive, but can look crawling and very subtle.  Understanding this spectrum can help keep ILC from avoiding discovery.

What are the MRI appearances of infiltrating lobular carcinoma?

In our experience, ILC has presented on breast MRI as:

1. An irregular mass or masses with early intense enhancement, often followed by plateau kinetic

2. An irregular mass or masses with lower grade early enhancement followed by progressive/persistent enhancement over time

3. Nonmass type lesion(s) with lower grade early enhancement followed by progressive/persistent enhancement over time

4. Very rarely as an irregular mass with a nearly avascular appearance

The following image sets portray representative examples of ILC, shown with their mammogram and ultrasound, if performed.

Case 1

What MRI enhancement kinetics can occur with infiltrating lobular carcinoma?

To review, in our experience ILC has demonstrated a gamut of kinetics. While the enhancement may appear intense on the early post contrast data sets, some ILC tumors show low grade early enhancement that peaks later and therefore becomes more conspicuous on the later p0st contrast images. The delayed orthogonal plane images may be of particular help in that setting. We have seen the kinetics to be:

1. Early intense, often with plateau over time

2. Early low grade intensity with persistent/progressive increase over time

3. Hypovascular (very rare)

Lopez and Basset summarize the kinetics as tending to show delayed maximal enhancement with washout in only a minority. (1, 2)

What do other authors report as MRI patterns of ILC?

1. Authors report ILC presents on MRI as (1, 2, 3, 4, 5):

a. A solitary irregular or angular mass with spiculated or ill-defined margins, most frequently,

b. A dominant lesion with surrounding multiple enhancing foci,

c. Multiple small enhancing foci with interconnecting enhancing strands or non contiguous clusters,

d. Regional enhancement and architectural distortion,

e. Regional, focal, or multifocal heterogeneous enhancement,

f. Enhancing depta without dominant tumor focus,

g. And with normal findings.

2. Levrini et al from Emilia, Italy (6) reported 21 patients with ILC. They reported the MRI appearances as:

a. Solitary mass with irregular margins (n=8);

b. Mass with smooth margins (n=5);

c. Multiple small enhancing foci with interconnecting enhancing strands (n=4);

d. Dominant lesion surrounded by small foci (n=3)

e. One MR examination was negative.

What are the mammogram appearances of ILC?

1. According to a 2009 review of ILC in Radiographics, Lopez and Bassett report:

a. ILC typically presents as a mass with an opacity that equals or is less than normal fibroglandular tissue. (1)

b. It is commonly not seen on either the craniocaudal view (CC) or mediolateral oblique (MLO), though it is seen more often on the CC than the MLO.

c. The authors summarize the literature regarding the mammographic sensitivity of ILC detection, noting it to be from 57% to 81%, with higher false-negative rates than other invasive cancers due to the difficulty of its mammographic detection.

d. ILC is often a mass with spiculated or ill-defined margines. Rarely, it can present as a round and circumscribed mass.

e. Microcalcifications associated with ILC much less frequently than with invasive ductal carcinoma.

2. A retrospective review of 59 ILC and 59 infiltrating ductal carcinoma (IDC) mammograms in the United Kingdom found:

a. ILC appeared significantly different on the MLO compared to the CC view, while IDC did not.

b. ILC and IDC appeared as spiculated masses more often on the CC than the MLO view.

c. On the MLO view, 41% of ILC appeared as architectural distortions or asymmetric densitites.

d. ILC was often associated with the main glandular density (97%) rather than being isolated (3%)

e. The CC view was optimal for visualizing ILC as a spiculated mass.

f.  Since ILC is often with the main glandular density, optimizing its visualization is critical. (7)

3. A study of 94 ILC lesions on mammography found:

a. 60% masses, of which 71% were irregular and spiculated, 21% were asymmetric densities or calcifications (8)

4. In a 1992 report of 455 pure ILC cases, they showed the following features:

a. Spiculated 28%

b. Architectural distortion 18%

c. Round 1%

d. Microcalcification 24%

e. Skin retraction 25%

f. Nipple retraction 26%

g. Malignancy not diagnosed 57% (9)

What is the sensitivity of imaging to detect ILC?

1. A retrospective study of ILC in 26 women wiht 28 biopsy proven invasive lobular carcinomas yielded the following sensitivities: mammography 79%, sonography 68%, MRI 83%, (12 patients had an MRI exam), and breast-specific gamma imaging (BSGI) 93% (10)

2. The sensitivity of BSGI was 79% for ILC according to the Department of Nuclear Medicine at the Mayo Clinic. (11)

3. MRI was reported as more accurate for ILC tumor size than mammography (12) and can decrease the surgical re-excision rate without increasing the rate of mastectomies, according to authors from The Netherlands. (13)

Conclusion: ILC often appears on MRI as an irregular/spiculated mass or masses, often with plateau kinetic but enhancement can be low grade persistent or, very rarely, negligible. Other patterns include multiple enhancing foci that may have interconnecting strands; nonmass type enhancement; and, reportedly, masses with smoother margins. Careful correlation of the MRI with the mammogram, ultrasound, and any physical exam area of suspicion helps avoid overlooking lesions with subtle to negligible increased vascularity.

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INVASIVE LOBULAR BREAST CARCINOMA: Pathology and genetics reflected by MRI – Vol. 4, Number 2 – March 4, 2010 - March 4th, 2010 by worldcare

Left Mammogram MLO view. Arrow points to palpable area of irregular density and architectural distortion.

Left Mammogram MLO view. Arrow points to palpable area of irregular density and architectural distortion.

Invasive lobular carcinoma (ILC) can elude diagnosis due to its variable appearances.  Knowledge of its pathology explains why this tumor can grow under the radar of mammography and why recognizing the MRI pattern of lobular carcinoma requires special understanding.  This issue of  The WCC Note on invasive lobular carcinoma reviews its gross and microscopic features and summarizes recent literature profiling its genetics, molecular, and biobehavioral footprints.

What is the incidence of invasive lobular carcinoma (ILC)?

  1. ILC represents between 5% and 15% of breast cancer, and often has accompanying in situ lesions.  The histology is diverse, ranging from the classical variety, which has a more favorable outcome, to solid, and to pleomorphic.  The majority are hormone receptor-positive.  HER2 gene overexpression is lower than in infiltrating carcinoma (IDC). (1)
  2. Of the special types of breast cancer, ILC is the most frequent.  Most are histologically low-grade, express hormone receptors, and lack HER2 overexpression.  A variant of ILC is the pleomorphic variety which displays atypical cells with pleomorphic nuclei and is reported to display an aggressive clinical behavior. (2)
  3. ILC was first described by Foot and Stewart in 1941, with subsequent subtypes described in the 1970s and 1980s, including alveolar, solid, pleomorphic, signet ring cell, histiocytoid, and apocrine. (3)
  4. ILC carries distinct prognostic and biological implications compared to IDC. (4)
    a.   A review of 12,206 breast cancer patients from 15 international breast cancer study group trials
    performed  between 1978 and 2002 by the International Breast Cancer Study Group, revealed the following percentages: 70.5% IDC, 6.2% ILC, and 23.2% other.
    b.  The ILC patients were noted to be of an older age and have larger lesions, better differentiation, ER-positive  tumor association, and less vessel invasion.
    c.  The ILC cohort demonstrated a significant early advantage in disease-free survival and overall survival, followed by a significant late advantage for the IDC cohort.
    d.  ILC had association with increased incidence of bone events but decreased regional and lung events. (4)
  5. According to The Centers for Disease Control and Prevention, the ILC incidence decreased 20% between 1999 and 2004.  The CDC Cancer Surveillance Branch reported that the decreased incidence coexisted with reduced use of combined hormone replacement therapy, though they noted that other factors could also be responsible. (5)

What is the gross anatomic appearance of invasive lobular carcinoma?

  1. Roughly one-fourth show diffuse invasion without marked desmoplasia.
  2. Most show irregular margins, appearing firm to hard.
  3. A discrete mass may not be present; instead diffuse thickening may be the hallmark. (6)
  4. Metastases of ILC differ from other breast cancers.  They preferentially involve the peritoneum, retroperitoneum, gastrointestinal tract, ovaries, uterus, and leptomeninges rather than the lungs and pleura. (6)

What is the microscopic appearance of invasive lobular carcinoma?

  1. Single cells infiltrate and can do so in single file or in loose clusters or sheets.
  2. Cells lack cohesion, not forming tubules or papillae.
  3. Tumor cells often align in concentric rings around normal ducts.
  4. Variants include those with large groups of cells and marked pleomorphism. (6)
  5. A report published in Cancer of 530 patients with pure ILC showed:
    a.  57% classic, 19% alveolar, 11% solid, and 13% pleomorphic, signet ring cell, histiocytoid, or apocrine features.
    b.  Significant prognostic factors were noted to be size, nodal involvement, and hormone status, with “classic” type showing lower nodal involvement and lower grade, and “non-classic” types demonstrating an increased number of breast events, decreased disease-free survival, and overall survival. (3)
  6. Nottingham grading of breast carcinoma is a subjective evaluation of three morphologic features: tubule formation, nuclear pleomorphism, and mitosis. (7)

What do we know about the genetics and molecular features of invasive lobular carcinoma?

  1. Most ILCs demonstrate a regional loss on chromosome 16.
    a.  This area involves genes for cell adhesion such as e-cadherin and beta-catenin. (6)
  2. Well-differentiated and moderately differentiated ILC:
    a.  Are usually doploid, have positive hormone receptors, and have associated lobular carcinoma in situ  (LCIS).
    b.  Rarely overexpress HER2/neu. (6)
  3. Poorly-differentiated ILC are:
    a.  Usually aneuploid with negative hormone receptors.
    b.  May overexpress HER2/neu. (6)
  4. The genetics basis of lobular and ductal carcinoma is noted to show a shared genetic abnormality and may share a common precursor lesion. (8)
  5. The molecular framework of classic ILC and pleomorphic ILC were found to be remarkably similar in a study from the Netherlands Cancer Institute published in 2010.  The authors concluded that both pathologies should be considered as a part of a spectrum of lesions.  This Study also compared subtype matched ILC to IDC tumors, finding different expression of genes for cell adhesion, cell-to-cell signaling, and actin cyskeleton signaling. (2)
  6. A common molecular genetic pathway between the pleomorphic and classic variants of ILC had also been reported by researchers from Brisbane, Australia. (9)

What updates have been reported about the biobehavior of ILC?

  1. A 2009 study from Yale University reported their experience with early-stage ILC and IDC.  Patients underwent breast conservation treatment and were followed a median of 6.8 years.  A higher percentage of ILC patients presented at >40 years of age compared to IDC and had more mammographically occult tumors.  ILC patients had higher contralateral breast relapses (26% versus 12%).  At 10 years, no difference was noted in breast relapse nor distant relapse, nor cause-specific survival. (10)
  2. Invasive lobular carcinoma has been reported as almost always ER-positive, and typically lower-grade than IDC.  It has been reported as showing a general decreased response to neoadjuvant chemotherapy compared to IDC but not to a survival disadvantage.  Authors from the Swiss Group of Clinical Cancer Research in Berne, Switzerland note that studies of adjuvant hormonal therapy do not generally distinguish between ILC and IDC. (11)

What do we know about mixed ILC and IDC?

  1. In a study by the University of Nottingham, UK, mixed ductual and lobular breast carcinoma (compared to pure IDC) were reported as showing association with lower grade, ER positivity, and lower frequency of development of distant metastases. (12)
  2. ILC and “mixed” carcinoma tends to be diagnosed in a more advanced stage but displays overall superior survival to IDC, according to authors from Washington University School of Medicine, ILC and mixed carcinoma are more likely to be low-grade, ER- positive, PR-positive but have overall    higher survival than those patients with IDC, despite being diagnosed at a more advanced stage. (13)

Conclusion: Classic invasive lobular carcinoma and its subtypes display a range of gross and microscopic diversity.  Cellular infiltration can be loose or single file and lack desmoplasia, potentially evading detection by mammography and physical exam. and influencing the MRI appearance.

Research and reporting by Margaret D. Phillips, M.D.
Reviewer and publisher:  Stephen J. Pomeranz, M.D.

For full sources and credit, please download the PDF copy of the newsletter here

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2009: Looking Back and Looking Ahead in Imaging – Vol. 3, Number 11 - December 31st, 2009 by worldcare

Last summer while reviewing literature for this newsletter, I spent an afternoon on a porch elevated alongside an Idaho road.  While mountains made a diaphanous blanket of color in the distance, and breezes prickled through tree leaves that flickered and shuffled like molecules in entropy, it occurred to me that our understanding of disease processes, due to our ability to image them, has altered fundamentally since I entered radiology 20 years ago.  Rather like a J.D. Salinger’s Glass family member, I felt a kind of epiphany, as silly as that sounds, sitting in a lawn chair among the plants withering in the mountain heat.  And yet, it is this kind of realization about our profession – that it does not and will not stand still – that makes us so lucky to be a part of it.

As the panorama of molecular, in vivo cellular, and micro environmental imaging spreads before us, along with a continuing stream of new technologies that fire out of laboratories with so many endless possibilities, it is our great fortune to work in a profession that allows us, at its core, to serve as fly wheels of steady utility as diagnosticians and also play a role in medical innovations that are occurring today and that will continue to do so for years to come.

This year’s final issue of The WCC Note veers away from the mainstream of practiced radiology and takes us down less-traveled roads toward some experimental imaging highlights of 2009.  From Dr. Pomeranz and myself, we wish you very happy holidays and a joyous and healthy new year.

- Margaret D. Phillips and Stephen J. Pomeranz

ACCOLADES FOR IMAGING ADVANCES

In 2008, the Nobel Prize in Chemistry Went for the Discovery of Green Fluorescent Protein, Which Revolutionized the Imaging of Small Structures, Allowing In Vivo Cellular Imaging.  What Major Accolades Were Bestowed for Imaging This Year?

  1. Once again, a Nobel Prize went to imaging – this time for techniques that allow digital imaging and electronic communications, such as this newsletter.  These discoveries ultimately revolutionized the practice of radiology.
    a.  In 2009, the Nobel committee awarded the Physics prize for inventing an imaging semiconductor circuit, the charge-coupled device (CCD), and for developments in optical fibers that allowed communications based on transmission of light.
    b.  The prize went to two U.S. researchers, Willard S. Boyle and George E. Smith, from Bell Laboratories in Murray Hill, NJ, as well as Charles K. Kao of the United Kingdom and Hong Kong, China.
    c.  The charge-coupled device came to fruition from a desire to create a memory storage device, and it originated after a 1.5-hour discussion between Drs. Boyle and Smith one afternoon in 1969.  It relied on the photoelectric effect discovered by Einstein, for which Einstein himself won the Nobel Prize in 1921.  Attempting to make advances toward a picture phone, Boyle and Smith imagined arrays of photocells that would emit electrons in proportion to the intensity of incoming light.  The electrons in the photocells would then be read and thereby make an image – changing an optical image to a digital one.
    d.  In an online interview, Drs. Boyle and Smith were asked what set apart Bell Laboratories, which has received seven Nobel Prizes.  Their answers were freedom, intelligent management that allows pursuit of interests, an institution financially well positioned to afford appropriate equipment, and excellent people – allowing fellowship and interchange of ideas.
    e.  Dr. Kao used ultra-pure glass fibers to transmit light in 1966.  Since the frequency of light waves is so much greater than electrical waves, transmission is much faster than with copper cables and radio waves.
  2. The Japan Prize from the Science and Technology Foundation of Japan went to radiologist David Kuhl, M.D. from the University of Michigan.  His work in the 1950s developed radionuclide emission tomography that led to, among other areas, PET scanning.

NEW DIRECTIONS IN IMAGING

What Were Some Experimental or Progressive Techniques Published in 2009 That Reflect New Directions or Hold Promise for the Future?

  1. The in vivo tracking of cells with MRI has undergone clinical study outside the United States using superparamagnetic iron oxide particles.
  2. Imaging atoms within an organic molecule absorbed on a surface was performed with scanning tunneling microscopy.
  3. Breast-specific gamma imaging with a high-resolution gamma camera was reported to show 93 percent sensitivity in 28 biopsy-proved known lobular carcinomas, in a retrospective multicenter study.
  4. Molecular imaging of the breast underwent review with description of, among others, the gene array analysis of tumors, phenotypic imaged tumor differences, MR tumor spectroscopy, and fluorescent probe imaging.
  5. Atherosclerotic plaque was imaged in vivo at the molecular levels by using the MR contrast agent P947 that targets matrix metalloproteinases in plaque.
  6. Using infared imaging guidance, researchers caused subtotal ablation of mice tumors, which resulted in T-cell immune responses and tumor regression.
  7. Minimally invasive autopsy to detect cause of death as an alternative to conventional autopsy was reported to show 93 percent of overall findings and 94 percent of major findings.  The technique used whole-body CT, MR, and ultrasound-guided 12-gauge needle biopsy of the heart, both lungs, liver, both kidneys, and spleen.
  8. Apoptotic (early cell death) processes underwent time-lapse imaging in live cells.  Researchers used a polarity-sensitive biosensor with switchable fluorescence states that allowed only the apoptotic cells to be detected.
  9. Reporter gene imaging of human mesenchymal stem cells implanted in porcine myocardium was performed with PET-CT.
  10. A single atom could be imaged by detecting electrons emerging from its surface using an aberration-corrected electron microscope.

CONCLUSION

The year 2009 saw Nobel Prizes awarded for techniques that ultimately brought about digital imaging and filmless teleradiology, the Japan Prize given for radioisotope tomography leading to PET; and a myriad of experimental imaging science that increasingly refined and exploited visualization of small structures – down to the atomic level.

Research and reporting by Margaret D. Phillips, M.D.
Reviewer and publisher:  Stephen J. Pomeranz, M.D.

For full sources and credit, please download the PDF copy of the newsletter here

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Knee Osteoarthritis: MRI in the Landscape of Current and Potential Treatment – Vol. 3, Number 10 - December 3rd, 2009 by worldcare

Like trying to mend broken glass in the hope that it will shine clearly again, repairing the destruction of knee osteoarthritis (OA) looms as an arduous and complex task – if it can ever be accomplished.

Where is current science, then, on the path to one day preventing, arresting, or reversing this debilitating crippler of joints?  This issue of The WCC Note continues our series on knee OA by examining current literature on treatment and prospective cures, and how MRI is poised to aid monitoring the disease.

As outlined in previous issues of this newsletter, the enormity of knee OA as a population problem – the scope of its occurrence, pathogenesis, and heterogeneity – confounds a simplistic approach to therapy.  Rather than a single disease-modifying drug, surgery, or physical therapy procedure, the idea that multiple influences lead to a common endpoint of joint destruction means that this multi-dimensional disease will, in most cases, always require a multi-faceted treatment approach.

While this can seem like a frustrating and daunting process, it helps to step back and tease apart the fundamental questions at hand, imposing structure on the analysis of this most labyrinthine of common disorders.

TREATMENT

What Treatment Approaches to Knee OA Are Currently Practiced?

  1. At 2008 overview of knee osteoarthritis management in Rheumatic Disease Clinics of North America called for conservative treatment, outlining recommendations from the Task Force of Standing Committee for International Clinical Studies including Therapeutic Trials (ESCISIT).  In summary, the guidelines were:
    a.  Combination nonpharmacologic and phamacologic treatment
    b.  Treatment tailored according to risk factors, such as obesity and activity, age, level of pain, signs of inflammation,and location and extent of structural damage
    c.  Education, exercise, use of appliances, and weight reduction
    d.  Paracetamol (acetaminophen) as the first analgesic used and the preferred long-term choice if efficacy is established
    e.  Topical NSAIDs and capsaicin are efficacious and safe
    f.  NSAIDs can be considered in patients for whom paracetamol is not helpful.  Nonselective NSAIDs or COX-2 inhibitors play a role for a subset of patients
    g.  Opioid analgesics, with or without paracetamol, can be useful in patients for whom NSAIDs are contraindicated or do not work
    h.  Symptomatic, slow-acting drugs such as avocad-soybean unsaponifiables may be of benefit
    i.  Intra-articular injection of long-acting corticosteroids may be useful in settings of pain flare
    j.  Joint replacement becomes a consideration for patients with refractory pain and disability
  2. In the September 2009 Journal of the American Academy of Orthopedic Surgery, authors from The New England Baptist Hospital in Boston reported practice guidelines for knee OA that were developed explicitly aside from knee replacement (arthroplasty).  The authors recommend that patients participate in educational programs regarding self-management, weight loss, exercise, and quadriceps strengthening.  The guidelines recommend taping for short-term pain relief, analgesics, and intra-articular corticosteroids.  The report advises against free-floating interpositional devices and lateral heel wedges for medial compartment knee OA.  The authors note that the group did not come to a recommendation in regards to the use of braces with valgus- or varus-directing forces.

OA & MENISCAL TEARS

Are Meniscal Tears Caused By, or a Result of, OA, And What Does Current Literature Advise About the Role of Surgery for Them?
It is well known that normal menisci are rare in osteoarthritic knees.  While meniscal lesions in healthy knees may result in osteoarthritis due to loss of meniscal function, osteoarthritis may itself lead to mensical tears, which subsequently accelerate the disease.  Proteolytic degradation and shear stress may lead to decreased meniscal tensile strength.  Meniscal tears may then result from teh compromised meniscus being unable to withstand loads and force transmitted during normal joint loading.

Meniscal resection is reported as the procedure most frequently performed by orthopaedic surgeons in the United States.  A recent review called for well-designed, randomized, controlled clinical trials to study the true effects of meniscal resection repair or transplant, or nonsurgical treatments, as compared with placebo or sham treatment.

Noting that a meniscal tear is an almost ubiquitous MRI finding in a person with knee arthritis and is not necessarily responsible for symptoms, Hunter and Low wrote in Rheumatic Disease Clinics of North America that the removal of menisci should not be preformed unless there is clinical locking or extension blockade, since strong evidence supports that even partial meniscectomy increases the risk for worsening osteoarthritis.

Allogenic, xenogenic, or artificial material meniscal replacements have been attempted in younger subjects post-total meniscectomy, but transplant survival is variable and long-term results prove lacking.

Individuals with initial asymptomatic meniscal lesions have a clinical course that shows an increased frequency of symptoms compared to those without meniscal lesions, though the pain and impairment remain of low severity.

MRI T2 measurements of cartilage in patients with osteoarthritis show them to be increased in patients with meniscal tears.  Friedrick, et al., note that this supports the theory of meniscal and hyaline cartilage damage occurring in the setting of osteoarthritis.

SURGERY FOR KNEE OA

What Surgical Approaches Exist, And What Does Recent Literature Report About Them?

  1. Lavage and Debridement: Arthroscopic lavage and debridement are not recommended for routine treatment, as they do not alter disease progression.  In a study involving 92 patients assigned to surgery (and six not undergoing surgery), as well as 86 controlled subjects who received only physical and medical therapy, arthroscopic surgery with surgical lavage and debridement failed to add additional benefit to patients with moderate to severe osteoarthritis over optimized physical and medical therapy.
  2. Microfracture: A technique for therapy of focal chondral defects, the microfracture surgical procedure involves subchondral drilling to crate 4mm-deep pits, into which multipotential stem cells migrate from the subjacent marrow to form fibrocartilaginous tissue repair.
  3. Cell-Based Cartilage Repair:
    a.  Autologous Chondrocyte Implantation (ACI):  In this procedure, chondrocytes are harvested from nonweight-bearing cartilage, cultured in vitro and subsequently reimplanted.  Elegant reviews of the technique geared towards imaging were published in Radiographics in 2007 and 2008.  MRI can depict the state of cartilage healing, as well as the subchondral bone and bone marrow.
    Noting that young individuals with early osteoarthritis who want to remain physically active have limited treatment options, ACI may offer benefit, according to Minas, et al., in a 2009 study.
    ACI can be performed using a polymer-based graft to repair cartilage defects.  While the ACI typically requires a rim of intact cartilage at the periphery of the defect, such a recent report states that a newer technique can allow cartilage repair even when such a rim is not present.  In general, the technique uses chondrocytes harvested from healthy cartilage in nonwweight-bearing regions of the knee and transplants them into areas of defect.  A report from 2009 states that chondrocytes cultivated in a three-dimensional matrix of bioresorbable material avoided the use of covering materials such as periosteum or collagen sheets.  The fibrin polymer matrix provided a scaffold to stabilize the graft.  The authors reported that improvements were still present four years after graft implementation for patients who had undergone the procedure.
    A 2009 study of symptomatic cartilage defects of the knee reported that chondrocyte implantation had better clinical outcomes at 36 months than the microfracture technique.
    b.  Autologous Osteochoncral Autograft Transplantation:  This technique harvests osteochondral plugs from the lateral femoral condyle or trochlear nonweight-bearing areas and transplants them into an area of articular defect.
    c.  Osteochondral Allograft Implantation:  Osteochondral allograft transplantation involves the harvesting of cadaveric bone cartilage.
  4. Osteotomy: Osteotomy can be considered for unicompartmental knee OA, with the intent to shift the weight load away from the damaged compartment.
  5. Arthroplasty (Joint Replacement):
    a.  Joint replacement surgery includes: unicompartmental athroplasty and patellofemoral replacement in selected patients with isolated meial or patellofemoral OA, and total knee arthroplasty for patients with severe OA.

GLUCOSAMINE AND CHONDROITIN

Do Glucosamine and Chondroitin Work?
Glucosamine and chondroitin sulfate, alone or in combination, failed to reduce pain effectively in a study of 1,583 patients with symptomatic knee osteoarthritis.  The analysis suggested that the combination of both medicines may be of benefit to a subgroup of individuals who have moderate to severe knee pain.  Glucosamine, but not ibuprofen, has been shown to alter cartilage turnover in patients with osteoarthritis undergoing physical training.

MRI AS BIOMARKER

How Can MRI Be Used to Grade the Impact of Therapies – Pharmaceutical, Operative, Physical Therapy, and Behavioral Interventions?

  1. MRI can provide semi-quantitative assessment in osteoarthritis because it can detail articular cartilage integrity; subchondral bone-marrow pathology; edema or cysts; subchondral bone attrition; marginally, centrally, and posteriorly positioned osteophytes; meniscal and ligament integrity; synovitis and effusion; and loose bodies.  Three commonly sued whole-joint MRI imaging assessments are:
    a.  Whole-organ MR imaging score (WORMS)
    b.  Knee osteoarthritis scoring system (KOSS)
    c.  Boston leads osteoarthritis knee score (BLOKS)
  2. Cartilage can be reproducibly and accurately measured by MRI.  Cartilage morphology and trabecular bone may be quantitatively measured in the research arena to provide baseline and follow-up monitoring of treatment in OA.  In a clinical trial, cartilage thickness can provide the same level of sensitivity as cartilage volume to estimate cartilage loss.
  3. MRI shows potential value as a biomarker, since studies have indicated that the presence of either bone-marrow lesions or meniscal disease is predictive of those OA patients at greater risk for disease progression.
  4. Very early changes in cartilage biochemistry, prior to joint damage or pain, may be able to be measured by experimental MRI methods of T1-rho and T2.
  5. Specialized research MRI protocols of T2 mapping, T1-rho, sodium MR, and delayed gadolinium-enhanced MRI imaging to assess the macromolecular status of cartilage may be useful in assessing disease-modifying strategies for OA.
  6. Molecular and functional techniques for imaging early osteoarthritis include charged-based methods such as delayed gadolinium-enhanced MRI of cartilage, which is based on teh negatively charged T1-shortening agent gadopentetate dimeglumine.  Hyaline cartilage has negatively charged molecules, similar in charge to gadolinium, and thereby repulses gadolinium when the cartilage is normal and intact.  Conversely, damaged cartilage lacks the negatively charged hydrophilic molecules, allowing the gadolinium into the cartilage proper.
  7. Sodium-23 MR spectroscopy also takes advantage of the negative-fixed charged density (FCD) of cartilage.  In this technique, sodium-23 atoms, which are positively charged, correlate directly with cartilage-fixed charged density.  Sodium-23, therefore, decreases in abnormal cartilage.
  8. In the research arena, cathepsin B-sensitive near-infared fluorescent probes have been used to image osteoarthritic knees in animals.  Since damaged cartilage may release proteases such as cathepsins, this method is used experimentally to image matrix-degrading enzymes.
  9. Since OA is widely thought to result from local mechanical factors in people with systemic susceptibility, the influence of biomechanics in osteoarthritis, and the imaging quantification of them, is both interesting and important.  Joint kinematics assessed with MRI imaging have been preformed with patients supine in the magnet, with some recent work attempted in open-configuration scanners with vertical gaps, which allow standing.

OA PROGRESSION

What Have We Learned About OA Progression from MRI?

  1. Patients with knee OA who display MRI evidence of meniscal damage or extrusion, as assessed by WORMS score, show association with cartilage loss over a 30-month period.
  2. In a 2009 study from the Multicenter Osteoarthritis Study Group (MOST), a longitudinal study of people with, or at high risk for, knee OA, those subjects who had minimal baseline cartilage damage but high body-mass index, meniscal damage, synovitis or effusion, or any baseline severe MRI lesion, had a strongly increased risk of fast cartilage loss.
  3. The finding of MRI-evident bone-marrow lesions (BMLS) shows association with change in knee cartilage over two years in asymptomatic subjects.  As the size of the BMLS increases, there is increased progression of cartilage defects.  The 2008 study included 271 healthy adults with no history of knee injury, knee pain, or clinical knee OA, who underwent knee MRI at baseline and two-year follow-up to study the relationship between presence of BMLS as baseline and cartilage change over two years.
  4. The role of alignment and biomechanics in osteoarthritis underwent review this year in Radiologic Clinics of North America.  Valgus and varus malalignment were reported as increasing risk for OA, with patellar malalignment asociated with patellofemoral OA progression.  MR imaging measurements of kinematics, and measurements of contact area, were both discussed.
  5. The incidence of degenerative cleavage trizonal body tears in patients with moderate to advanced osteoarthritis is over 50 percent in patients over age 50 (personal observation by Dr. Stephen J. Pomeranz).

MRI IN OA CLINICAL TRIALS

What Are Some Examples Where MRI Played a Biomarker Role in OA Clinical Pharmaceutical Trials?

  1. In patients with knee pain on efficacious doses of NSAIDs or acetaminophen, a decrease in effusion volume (quantified by gadolinium-enhanced T1 imaging) was observed and rapidly reversed when treatment was withdrawn.
  2. In a placebo-controlled, double-blind study of 377 knee OA patients, changes in MRI assessment of subchondral bone marrow abnormalities were observed within three months of treatment and were positively correlated with type II collagen degradation (determined by urinary CTX-II).

MRI imaging is a sensitive and early marker of OA that can correlate with drug efficacy. (Contributed by Rick Walovitch, Ph.D., WorldCare Clinical)

CONCLUSION

The complexity of knee osteoarthritis etiologies complicates the search for a single disease modifying therapeutic approach.  Current treatment emphasizes conservative management including mechanical joint preservation measures.  MRI depicts the whole joint nature of the disease and serves as a barometer of its time course.

Research and reporting by Margaret D. Phillips, M.D.
Reviewer and publisher: Stephen J. Pomeranz, M.D.

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