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.

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.

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

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

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.

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

The silent disposition of amyloid occurs the same way, insidiously laying down and killing brain cells without heralding its presence.  How, then, do we know Alzheimer’s disease is taking hold in a life?  This entry of The WCC Note examines recent literature on the diagnosis and biomarkers of Alzheimer’s disease.

DIAGNOSIS

How is Alzheimer’s Disease Diagnosed?
Currently, no single definitive test marks the disease.  A combination of mental status exams, blood markers, cerebral spinal fluid (CSF) markers, and brain imaging studies helps to secure the diagnosis.

IMAGING’S ROLE

How Does Imaging Play a Role at the Gross Anatomic Level?
What Is the Alzheimer’s Disease Neuroimaging Initiative (ADNI)?

• In April 2009, results from the ADNI, published in Radiology, reported that semi-automated quantitative MRI can identify a brain atrophy pattern predictive of clinical mental decline.  The study examined 84 people with mild Alzheimer’s disease (AD), 175 with mild cognitive impairment (MCI), and 139 healthy controls.
• Results showed that atrophy in the mesial and lateral temporal, isthmus cingulate, and orbitofrontal areas helps to distinguish control subjects from AD subjects, with 83% sensitivity and 93% specificity.  People with MCI whose MRIs showed the AD atrophy pattern displayed significantly greater one-year clinical decline, brain loss, and progression to probable AD than those whoe MRIs did not (29% of those with MCI and AD atrophy, compared to 8% with MCI without AD atrophy).
• The superior temporal gyrus showed significant atrophy in a subgroup of MCI subjects with AD atrophy.  The authors hypothesize that this portends a greater risk of mental decline.
• Brain MRIs showed differential rates of temporoparietal region atrophy in prodromal AD, according to a 2008 report in Neurology.  People who developed AD during the study showed greater atrophy in the hippocampus, entorhinal cortex, temporal pole, middle temporal gyrus, and inferior temporal gyrus compared to individuals with stable MCI.
• Subjects with MCI underwent fractional anisotropy, apparent diffusion coefficient, and cortical thickness measurements, which were then compared to those of the controls.  Results revealed decreased fractional anisotropy and increased apparent diffusion coefficient in white matter of the frontal, temporal, and parietal lobes in people with MCI, according to data in the American Journal of Neuroradiology.
• Hippocampal atrophy rates add value over whole-brain volume measurements is distinguishing AD, MCI, and controls, according to a study from the Netherlands.  The hippocampal atrophy rate proved especially valuable in discriminating MCI from controls.
• In a study of the Mayo Clinic, gray-matter atrophy patterns correlated with neurofibrillary tangles at autopsy pathology.  The authors note that this validates MRI three-dimensional atrophy patterns as surrogate indicators of AD pathology.
• The Alzheimer’s Disease Neuroimaging Initiative (ADNI) began in October 2004 as a five-year collaboration effort between the National Institute on Aging, the National Institute of Bioimaging and Bioengineering, private pharmaceutical companies, the U.S. Food and Drug Administration, and several nonprofit foundations.  With a $60 million budget, ADNI seeks to examine the mental status, brain structure, and brain function of 200 people with AD, 400 people with mild cognitive impairment, and 200 elderly controls.  Subject recruitment involves more than 50 sites in the United States and Canada.

IMAGING AND BIOMARKERS

Why Are Imaging and Biomarkers Important in AD?
Developing sensitive and specific tools to diagnose and quantify AD prior to memory loss is critical to disease prevention and monitoring therapy.  Evaluating interventions need to be done in people who have not yet sustained irreparable brain cell loss.  Recent disappointing outcomes in vaccine trials, for example, underscore the need for such subjects.

As noted in a recent editorial, markers will identify AD pathology in normal elders or those with mild symptoms; help predict future mental decline; mark progression; and stratify subjects into groups.

Large-scale, international, controlled multicenter trials performing Phase III development of imaging and CSF biomarkers include the U.S., European, Australian, and Japanese Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the German Dementia Network.

BLOOD-BASED MARKERS

Are There Any Blood-Based Alzheimer’s Disease Markers?
No currently accepted biomarkers of sporadic AD exist.  Since AD can alter peripheral tissue, examination for blood constituent footprints of the disease has involved the following:

• Peripheral blood mononuclear cells are being studied for their molecular signatures of DNA, RNA, and protein.
• While plasma studies of A are reported as inconsistent, decreased plasma A 42 relative to A 40 may increase AD risk.
• Short-wavelength near-infared spectrophotometry of blood plasma differentiated AD from normal elderly controls with 80% sensitivity and 77% specificity.
• A 42 was shown to be elevated in plasma of familial AD mutation carriers, and data suggest the levels may decrease with disease progression before overt AD occurs.

CSF MARKERS

What Are the CSF Biomarkers for Alzheimer’s Disease?

• As reported recently in Nature, “concentrations of amyloid peptides, particularly one called amyloid-61-42, are low in the cerebrospinal fluid of patients with Alzheimer’s disease compared to healthy controls because the plaques are thought to suck them out of circulation, and concentrations of tau protein and phosphorylated tau are high.
• CSF A 42, tau, and hyperphosphorylated tau protein (p-tau) can differentiate people with mild cognitive impairment (MCI) from those with AD.  They may show changes that predict future AD in currently asymptomatic people.
• In the setting of very mild AD, lower CSF A 42, high tau or p-tau181, or high tau/A 42 ratios predict a more rapid onset of dementia.
• A recent CSF study from the Netherlands included 177 patients with AD, examining CSF amyloid 1-42, tau and tau phosphorylated at threonine 181 (p-tau).  The authors reported different clusters of CSF biomarker levels and found them to correlate with cognition.  Patients with very high CSF tau and p-tau displayed worse memory, mental speed, and executive function.
• In subjects who are familial AD mutation carriers, the ratio of A 43 to A 60 was reduced in the CSF of nondemented subjects.  Elevated t-tau and p-tau181 proved to be sensitive presymptomatic disease indicators.
• CSF marker variability, however, proved high between and also within centers, according to a recent report.

CONCLUSION

While no single finding affords the diagnosis of Alzheimer’s disease, the brain MRI pattern of atrophy in the mesial and lateral temporal, isthmus cingulate, and the orbitofrontal areas provides 83% sensitivity and 93% specificity.  In Alzheimer’s CSF amyloid is decreased, while tau is increased.  Pursuit of suitable blood markers continues.

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

APPEARANCE & SYMPTOMS

What is the MRI appearance of rheumatoid arthritis?

1. Early RA often first affects the wrist, MCP, and MTP joints.  Abnormalities include:
   a.  Synovitis.  Thickening of the synovial membrane, appearing as quick enhancement after gadolinium on T1-weighted, fat-suppressed images.
   b.  Tenosynovitis.  Any tendon may be involved, but flexor digitorum, extensor digitorum, and extensor carpi ulnaris are frequent.
   c.  Bone erosions.  Sharply marginated trabecular bone loss with cortical defects and often with snynovitis.  More frequently in the capitate, triquetrum, lunate, raial aspect of the second and third MCPs, and lateral fifth metatarsal.
   d.  Bone-marrow edema, usually at the synovial membrane insertion where a small gap between it and the cartilage leaves a “bare area.”
   e.  Bursitis.  Between or beneath metatarsal heads.
2. Additional joints of involvement may include these:
   a.  Knees:  Synovitis, effusion, subsequent erosions.
   b.  Shoulders:  RA incidence and prevalence increase to about age 85.  RA onset in the elderly has been described as having striking large-joint involvement, particularly of the shoulders, hips, and wrists (with sparing of the hands mimicking polymyalgia rheumatica).
   c.  Hips:  When RA is advanced, it may result in acetabular protusion from axial migration.
   d.  Elbows:
   1.  More than half of RA patients
   2.  RA is the most common rheumatological cause of elbow instability
   3.  Isolated elbow involvement is present in only 5% of cases
   4.  Synovitis, joint capsule distention causes patients to hold the elbow flexed, leading to risk of flexion deformity
   5.  Laxity of annular ligament with radial head instability
   6.  Laxity of anterior medial ligament, leading to valgus instability
   7.  Trochlear erosion can lead to proximal ulnar subluxation
   e.  Hand:  Radial and ulnar aspects of the bases of the hand, proximal phalanxes, and PIP joints, typically sparing the DIPs.
   f.  Additional wrist:  Marginal erosion of the styloid tip.
   g.  Cervical spine:
   1.  Laxity of transverse ligament with subluxation of atlantoaxial joint, most commonly anterior type
   2.  Vertical subluxation with odontoid superiorly migrating
   3.  Erosions of odontoid process and apophyseal joints
   4.  Subluxation of lower cervical spine, most commonly at C3-4
   5.  Thoracic and lumbar involvement proves rare
   h.  Clavicle:  Distal clavicular, pencil-like erosions.
3. Technique:  Yao, et al., report contrast-enhanced, T1-weighted images depict more periarticular bone findings in RA than fat-suppressed, T2-weighted images.

ASYMPTOMATIC CHANGES

Do the MRI or immunologic changes of RA occur before a patient has symptoms?
Yes.  RA immunological changes with anti-CRP and RF occur years before clinically apparent disease, which may then be triggered by the proper genetic milieu in combination with environmental factors – such as heavy smoking.  Ultrasound and MRI may show synovitis when the clinical findings are still nonexistent.

POSITIVE MRI FINDINGS

What do positive RA MRI findings mean, even when a person has no symptoms?

1. A direct relationship exists between subclinical synovitis in asymptomatic patients and joint structural damage, with MRI and ultrasound imaging evidence predicting subsequent progression in such patients.  As written in a 2009 article in Nature Clinical Practice Rheumatology, studies have shown synovial inflammation can persist even in clinical remission.  The report profiled a recent study of 102 patients with RA who were receiving DMARDs and were thought to be in remission clinically, but 19% of whom demonstrated significant radiologic disease progression at one year.  Imaging-detected baseline synovitis presaged the likelihood of progression.  The authors state that conventional criteria for remission prove insensitive to low-level disease; therefore, the assessment should be made by imaging.
2. MRI findings prove common in early RA, and bone-marrow edema independently predicts radiographic damage.

INTERVENTION

What is the optimal time to intervene in RA?
Noting that bone damage occurs early, the argument for early disease-modifying agent (DMA) therapy has received attention.

Conclusion:  Immunological features occur in rheumatoid arthritis years before clinically apparent disease.  MRI may afford early RA diagnosis even when serology proves negative, which is important because early disease-modification therapy better protects long-term joint function.  MRI can document active RA disease and continued joint destruction – even in asymptomatic patients thought to be in clinical remission.

As researchers mine innovative science to understand and optimally combat rheumatoid arthritis (RA), perhaps the best way to view the cornerstone role MRI plays in its diagnosis and management is to first step back and see how it fits into the larger foundation of disease knowledge.

In recent years, molecular, microenvironmental, genetic, and epigenetic research on RA joined growing immunological advances to further elucidate the origin and inflammatory erosive events accompanying the disease.  These investigations provided new tools in teh form of biological agents (disease-modifying antirheumatic drugs, or DMARDs) to halt RA progression.

The following questions and answers outline larger scientific inquiries to RA and summarize some of the recent reports regarding MRI’s relationship to them.

DIAGNOSIS WITHOUT MRI

How is rheumatoid arthritis diagnosed without benefit of MRI?
Historically, a combination of factors coalesced to identify a patient’s arthritis as rheumatoid.  Twenty-two years ago, in 1987, these included a set of revised criteria from the American Rheumatism Association.  At that time, a diagnosis warranted consideration if four criteria were met, or the first three were present for at least six weeks’ duration:

1. Morning stiffness lasting at least one hour
2. Soft-tissue swelling or fluid in at least three simultaneous joint areas, at least one in a wrist, MCP, or PIP joint
3. Symmetric arthritis
4. Rheumatoid nodules
5. Abnormal serum rheumatoid factor (RF)
6. Erosions or bone decalcification on hand/wrist radiographs

Rheumatoid factor is an antibody directed against IgG and may or may not be present in rheumatoid arthritis patients.  It is not specific, and may also be found in healthy elderly individuals, as well as in people with other autoimmune and infectious diseases.

A more recently discovered autoantibody called cyclic citrullinated peptide antibody (anti-CCP) has been reported as more specific than RF for diagnosing RA and predicting erosive disease.  Combined RF and anti-CCP may be better than either alone for diagnosing very early RA.

DIAGNOSIS WITH MRI

How does MRI help in RA diagnosis, especially early on in the disease?

1. Currently, MRI factors into the diagnosis because it can help establish an RA diagnosis in people with negative anti-CCP and normal radiographs, according to research at Lille University Hospital in Lille, France.  The authors followed 30 outpatients for one year and found MRI of the hands (T1 fat saturation with contrast) to show MCP erosions in RA patients with 70% specificity, 64% sensitivity.
2. In individuals in whom RA was clinically suspected but who lacked RF and radiographic erosions, a comparison of contrast-enhanced MRI of the hand versus anti-CCP revealed assessment of imaging synovitis with bone erosions or bone marrow edema provided a sensitivity of 100% for RA with one false positive (psoriatic arthritis), and a 78% specificity.  This compared to an anti-CCP sensitivity of 23%, specificity of 100%.  The 2008 study of 40 patients was performed by authors from the Department of Rheumatology in Barcelona, Spain.
3. Unclassified arthritis (despite biochemical and radiograph testing) can be classified as RA with the help of contrast-enhanced MRI of the wrist and MCP joints of the symptomatic hand and whole-body bone scan, according to Department of Rheumatology at Copenhagen University Hospital at Hvidovre (Denmark).  Danish researchers examined patients with unclassified arthritis and, at two-year follow-up, noted a correct classification as RA or non-RA in 39 of the 41 subjects using such imaging.
4. Noting that the 1987 American College of Rheumatology criteria have limited utility in clinical practice due particularly to early diagnostic insensitivity, coupled with the need to institute prompt therapy to prevent detrimental outcome, Keen, et al. reviwed the literature supporting the ability of MRI to detect:
   a.  Bone erosions many months prior to plain films;
   b.  More erosions than radiography;
   c.  Bone edema as a forerunner to erosion development;
   d.  Synovitis and tenosynovitis.

Conclusion:  MRI may afford early rheumatoid arthritis diagnosis, even when serology proves negative, which is important because early disease modification therapy better protects long-term joint function.

Rheumatoid Arthritis: How MRI Changes Our Understanding
Rheumatoid arthritis (RA) afflicts 1.3 million Americans.  A systemic disease, it affects the joints, skin, blood vessels, heart, lungs, and muscles.  While most prevalent between ages 40 to 70, it occurs at all ages, afflicting women two to three times more than men.  The ability of MRI to depict soft tissue and bone marrow has widened our perception of the disease and made MRI a modality of choice for RA diagnosis, assessment, and subsequently, clinical trial evauation.

The joint pathology occurs in stages:

1. Synovium swells and becomes hyperplastic.
2. Inflammatory cells infiltrate synovium.
3. Vascularity increases from vasodilatation and angiogenesis.
4. Organized fibrin covers some synovium and releases into the joint as rice bodies.
5. Osteoclastic activity occurs in subjacent bone, with erosions, cysts, and osteoporosis developing.
6. Masses of synovium, inflammatory cells, granulation, and fibroblasts, called pannus, occur.
7. Inflamed cells release enzymes that destroy cartilage and bone.

This issue of The WCC Note continues our series outlining some of the recent literature on RA.  This week’s articles address searches to elucidate the etiology of rheumatoid arthritis, since understanding its pathogenesis is requisite to optimally preventing or arresting joint destruction.

PATHOGENESIS FACTORS

The Components of Pathogenesis
General theory holds RA to be an autoimmune disease incited by an arthritogenic antigen in a genetically susceptible person.  Each of these factors – genetic susceptibility, antigen, and autoimmune reaction – plays a role.

1. Genetic susceptibility
   a.  Genetic factors predispose to RA, though their overall contribution is estimated at 50 percent or less.  Other nongenetic but gene-regulating factors may influence a person’s susceptibility to RA and disease severity.  Called epigenetic factors, these are heritable alterations in gene expression without changes in nucleotide sequences – in other words, changes not encoded directly by DNA sequence of the specific gene, but instead such entities as DNA methylation or noncoding RNAs.  Strieholt, et al., reviewed such epigenetic processes in RA.  The authors note that epigenetic modifications, while not fixed in DNA code, can be stable during a person’s life or can be altered by individual lifestyle differences.  Environmental triggers are hypothesized to participate in the RA by causing epigenetic modifications, which are thought to play a major role in RA’s development.
2. Autoimmune reaction
   a.  Reviewing what MRI has told us about the pathogenesis of RA, McGonagle and Tan report that MRI-demonstrated synovitis shows high correlation to histological grades of synovitis and tissue vascularity, and appears to confirm RA as primarily a disease of synovium.  They state their studies show erosions occur secondarily due to synovitis, with sites of joint compression possibly more prone to erosion, and that effective treatment of synovitis is crucial to successful therapy.
   b.  To determine the cellular components of MRI bone edema in RA, Dalbeth, et al., examine 11 patients with RA who were undergoing orthopedic surgery.  They found an increased number of osteoclasts, RANKL (Receptor Activator for Nuclear factor KappaB Ligand), macrophages, and plasma cells in samples with MRI bone edema, concluding that RA bone erosions result from activitation of local bone resorption of subchondral bone as well as synovial invasion.
   c.  Histopathological studies depict lymphocytes and osteoclasts in subchondral bone that could mediate erosions from the marrow toward the joint, according to a report from the Department of Molecular Medicine and Pathology at the University of Auckland, New Zealand.  The authors state that animal models show evidence that this cellular infiltrate corresponds to MRI bone edema, supporting the notion that bone-marrow pathology helps drive joint damage.
   d.  Macrophages of RA patients possess signaling pathways that drive continued production of pro-inflammatory mediators in effected joints.  Noting that current pharmaceuticals are biological agents blocking a cytokine (tumor necrosis factor) produced predominantly from macrophages, authors from Imperial College of Science, Technology and Medicine in London, U.K., discuss the various signaling mechanisms in innate immune cells.

Conclusion:  Several recent studies advance our understanding of the origin of rheumatoid arthritis, theorized to be an autoimmune disease triggered in a genetically susceptible person by an inciting antigen.  Areas under continued scrutiny include patient epigenetic factors, the dominant role of synovitis, and evolving evidence that bone-marrow pathology participates in joint damage.  Research documents the cornerstone role magnetic resonance imaging has played in furthering out knowledge about the disease.

Achieving not only symptomatic but pathologic remission proves critical to long-term joint function because – once the ravages of arthritis result in cartilage, bone, ligament, or tendon destruction – the ability to restore full structural and functional native joint integrity is forever lost.

In an issue of The WCC Note later this year, we will venture into the realm of the experimental, taking a foray into the laboratory bendh work being done to attempt to achieve cellular reprogramming and exogenous cartilage creation – work being furthered by medical imaging.  Current emphasis, however, rests with early disease discovery and tailored treatment, attempting to mitigate the dire consequences of unchecked pathologic joint processes.

This week’s issue begins a series that will summarize some of the arthritis-related literature published over the past year, citing several recent studies that advance our understanding of the origins of arthritis and the cornerstone role magnetic resonance imaging plays in its diagnosis and monitoring.

We will begin our next entry with a review of rheumatoid arthritis literature, where MRI has played a role in challenging previously held notions of pathogenesis and has become a predictor of erosion and disease progression.

MRI Helps Translate Thought Into Sound for Man with “Locked-In Syndrome”
When Jean-Dominique Bauby wrote his stunning and transcendent memoir, The Diving Bell and the Butterfly, he communicated it letter by letter by blinking his left eye.  Bauby suffered from “locked-in syndrome,” a rare neurological disorder that paralyzes all voluntary muscles except those controlling eye movements.

For such patients, no means of communication exist except nonvocal ones.  However, a recent article describes an advance which could someday allow these individuals to communicate through sound instead of gestures.  Naturenews reports a study that used an implanted brain electrode to permit a man with locked-in syndrome to create vowel sounds, after using functional brain MRI to assess his speech.

Scientists from Boston University placed the electrode in the speech area of the man’s brain and a computer decoded the brain signals.  The electrode activated a speech synthesizer that accurately replicated three vowel sounds.  As reported at the Society for Neuroscience’s annual meeting in November 2008, the team will subsequently work on computer decoding of consonants to allow the creation of complete words.  Naturenews notes that functional MRI or electrodes placed on the skull could also be used to decode brain speech.

Conclusion:  A man with locked-in syndrome was able to create audible vowel sounds using an implanted brain electrode and speech synthesizer, after having his thoughts analyzed by functional MRI.

IMAGING ANGIOGENESIS

Exploiting Novel Molecules That Create and Comprise Cancer Vessels
The new blood vessels that grow and sustain cancer originate when stimulated to occur by molecules released from cancer cells.  These molecular activators of angiogenesis include a host of proteins and small molecules.  The study of these factors may bring to fruition new and robust imaging for tumor detection and surveillance, as well as innovative therapeutic modalities for tumor cure.  The two molecules thought to be the most important sustainers of tumor growth are vascular endothelial factor (VEGF) and basic fibroblast growth factor (bFGF).  Other activators of angiogenesis include prostaglandins E1 and E2, nicotinamide, and interleukin 8, among others.  The resultant new tumor vessels display their own molecules, providing more investigative avenues to target.  The following article highlights one recent attempt to exploit these molecular features of cancer.

NANO-PARTICLES/CANCER

Imaged Nanoparticles Target Cancer Vessels and Decrease Tumor Size
Integrin ανβ3 comprises one factor found on some tumor vascularity.  Researchers at University of California, San Diego created a nanoparticle targeted at integrin that was linked with the chemotherapeutic agent doxorubicin.  The authors made it fluorescent and injected it into a live mouse pancreatic cancer model.  As reported in Proceedings of the National Academy of Science, the authors noted modest decreased primary tumor growth, but significant reduction in the draining lymph-node metastases.  Featured in Naturenews, the study also reported that the treatment reduced metastases in a mouse kidney cancer model.

Conclusion:  Fluorescent nanoparticles, linked with a chemotherapeutic agent, that were targeted at molecules found exclusively on new vessels have been reported to decrease metastases in mice pancreatic and kidney cancers.

Speech Content and Speaker Identification Reflected in Functional Brain MR Images
Attempts to create machines capabile of recognizing human speech commenced in the 1950s, yet the human brain’s ability to understand speech and identify its speaker has proved a profoundly complex and nuanced higher-order function, difficult to mechanically replicate.  Untangling the threads of this intricate process has progressed recently, as researchers examined listeners’ brain auditory cortexes and used neural “fingerprints” to decipher what, and to whom, the subjects were listening.  Researchers from the University of Maastricht, Netherlands, used imaging combined with multivariate statistical pattern recognition of speech sounds to examine the brains’ receptive speech pathways.  Initially, seven participants listened to the speech sounds of three Dutch vowels from three Dutch speakers.  The distinct brain activation patterns underwent scrutiny with high-resolution functional MR imaging (fMRI), the sounds evoking responses in the superior temporal cortexes of the subjects.  As reported in Science, the researchers subsequently expanded on their work by using functional MRI brain images and their response patterns to decode sounds and their speakers.

Conclusion:  Early work by Dutch researchers has deciphered speech content and speaker identification using functional MRI imaging.

IMAGING ANGIOGENESIS

Imaging the Many Faces of Tumor Angiogenesis
The National Cancer Institute describes tumor angiogenesis as a proliferating blood vessel network that penetrates malignant tumors to provide oxygen and nutrients and remove wastes.  Creation of this neovascularity requires molecules released from the tumor cells, and without these molecular signals and their resultant new vessel formation, the cancers cannot progress.

These molecular investigators cause a cascade of events, initially activating host tissue genes that subsequently incite proteins to be produced, which then initiate the new vessels to grow.  The presence of this increased blood flow produces a local environmental change that can be perceived by dynamic contrast-enhanced imaging.

Conclusion:  In this and upcoming issues of The WCC Note, studies will be profiled to illustrate examples in which current and developing imaging techniques capture and exploit angiogenesis, a fundamental biological feature of cancer.

MRI: LEUKEMIA

MRI of Angiogenesis in Leukemia Portends Decreased Chemotherapy Response
A cancer of the blood cells, leukemia strikes blood-forming tissue such as bone marrow, sending an abnormal number of cells into the blood stream.  In the United States, an estimated 44,270 new cases will be diagnosed in 2008.

A recent study in the journal Blood examined dynamic contrast MRI in patients with acute myeloid leukemia (AML) and correlated it with their outcomes.  The authors, from National Taiwan University Hospital in Taipei, prospectively imaged 78 patients with AML at diagnosis and after induction chemotherapy.  Bone-marrow angiogenesis assessment consisted of three factors: peak enhancement ratio (reflecting tissue perfusion), amplitude (denoting vascularity), and volume transfer constant (indicative of vascular permeability).

The results showed peak and amplitude findings decreased significantly with remission.  Those individuals presenting with higher peak or amplitude values exhibited shorter disease-free and overall survival.  Along with old age and unfavorable karyotype, higher peak value at diagnosis independently predicted overall survival.

Conclusion:  Authors reporting a study in Blood showed that heightened bone-marrow angiogenesis on MRI in leukemia patients predicted adverse outcomes.  They suggest the information may help profile which individuals could benefit from anti-angiogenic therapy.