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AHA, ACC Change in Requirement for Surgical Support: Class IIb -> Class III, Level of Evidence A: Supports Nonemergent PCI without Surgical Backup (Change of class IIb, Level of Evidence B).
Larry H Bernstein, MD, FCAP, Author, Curator, Volumes 1,2,3,4,5,6 Co-Editor and Author, Volume Two & Five, Co-Editor and Justin Pearlman, MD, PhD, FACC, Content Consultant to Six-Volume e-SERIES A: Cardiovascular Diseases
Article ID #68: AHA, ACC Change in Requirement for Surgical Support for PCI Performance: Class IIb -> Class III, Level of Evidence A: Support Nonemergent PCI without Surgical Backup (Change of class IIb, Level of evidence B). Published on 7/17/2013
WordCloud Image Produced by Adam Tubman
Voice of content consultant: Justin Pearlman, MD, PhD, FACC
The American Heart Association (AHA) and the American College of Cardiology (ACC) have convened teams of experts to summarize evidence and opinion regarding a wide range of decisions relevant to cardiovascular disease. The system accounts for some of the short comings of “evidence based medicine” by allowing for expert opinion in areas where evidence is not sufficient. The main argument for evidence-based medicine is the existence of surprises, where a plausible decision does not actually appear to work as desired when it is tested. A major problem with adhesion to evidence based medicine is that it can impede adaptation to individual needs (we are all genetically and socially/environmentally unique) and impede innovation. Large studies carry statistical weight but do not necessary consider all relevant factors. Commonly, the AFFIRM trial is interpreted as support that rate control suffices for most atrial fibrillation (AFIB), but half of those randomized to rhythm control were taken off anticoagulation without teaching patients to check their pulse daily for recurrence of AFIB. Thus the endorsed “evidence” may have more to do with the benefits of anticoagulation for both persisting and recurring AFIB and rhythm control may yet prove better than rate control. However, with wide acceptance of a particular conclusion, randomizing to another treatment may be deemed unethical, or may simply not get a large trial due to lack of economic incentive, leaving only the large trial products as the endorsed options. A medication without patent protection, such as bismuth salts for H Pylori infection, lacks financial backing for large trials.
A Scientific Statement From the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology
Reported by Chris Kaiser, Cardiology Editor, MedPage 7/2013
Action Points
Patients with indications for nonemergency PCI who presented at hospitals without on-site cardiac surgery, were randomly assigned to undergo PCI at a hospital without on-site cardiac surgery or at a hospital with on-site cardiac surgery.
The rates of death, myocardial infarction, repeat revascularization, and stroke did not differ significantly between the groups.
Community hospitals without surgical services can safely perform percutaneous coronary intervention (PCI) in low-risk patients — and not refuse higher-risk patients either, the MASS COMM trial found.
Summary
The co-primary endpoint of major adverse cardiac events (MACE) at 30 days occurred at a rate of 9.5% in the 10 hospitals without surgical backup versus 9.4% in the seven hospitals with onsite surgery (P<0.001 for noninferiority), Alice K. Jacobs, MD, of Boston University School of Medicine, and colleagues found.
The other co-primary endpoint of MACE at 12 months was also significant, occurring in 17.3% of patients in hospitals without backup versus 17.8% in centers with surgical services (P<0.001 for non-inferiority), they reported in the study published online by the New England Journal of Medicine. The findings were also reported at the American College of Cardiology meeting.
Study Characteristics and Results
Primary Endpoints
death
myocardial infarction
repeat revascularization
stroke
no significant differences between the two groups at 30 days and at 12 months.
Rate of stent thrombosis at 30 days
similar in both groups (0.6% versus 0.8%) and at 12 months (1.1% versus 2.1%).
Jacobs and colleagues noted that the 2011 PCI guidelines lacked evidence to fully support nonemergent PCI without surgical backup (class IIb, level of evidence B).
CPORT – E trial
Even though those guidelines came out before the results of the CPORT-E trial were published, CPORT-E trial showed similar non-inferiority at 9 months between centers that perform PCI with or without surgical backup in a cohort of nearly 19,000 non-emergent patients. The CPORT-E results were published in the March 2012 issue of the New England Journal of Medicine, and in May three cardiology organizations published an update to cath lab standards allowing for PCI without surgical.
MASS COMM study
To further the evidence, Jacobs and colleagues in 2006 had designed and carried out the Randomized Trial to Compare Percutaneous Coronary Intervention between Massachusetts Hospitals with Cardiac Surgery On-Site and Community Hospitals without Cardiac Surgery On-Site (MASS COMM) in collaboration with the Massachusetts Department of Public Health who collaborated to obtain “evidence on which to base regulatory policy decisions about performing non-emergent PCI in hospitals without on-site cardiac surgery.”
Hospitals without backup surgery were required to perform at least 300 diagnostic catheterizations per year, and operators were mandated to have performed a minimum of 75 PCI procedures per year.
The researchers randomized 3,691 patients to each arm in a 3:1 ratio (without/with backup). The median follow-up was about 1 year.
The median age of patients was 64, one-third were women, and 92% were white. Both groups had similar median ejection fractions at baseline (55%).
The mean number of vessels treated was 1.17 and most patients (84%) had one vessel treated. The mean number of lesions treated was 1.45 and most patients (67%) had one lesion treated.
The indications for PCI were:
1. ST-segment elevated MI (>72 hours before PCI of infarct-related or non–infarct-related artery — 19% and 17%
2. Unstable angina — 45% and 47%
3. Stable angina — 27% and 28%
4. Silent ischemia — 5% and 6%
5. Other — 2.5% and 2.8%
Regarding secondary endpoints, both groups had similar rates of emergency CABG and urgent or emergent PCI at 30 days. Results at 30 days and 12 months were similar for rates of ischemia-driven target-vessel revascularization and target-lesion revascularization. Other endpoints as well were similar at both time points, including
all-cause death
repeat revascularization
stroke
definite or probable stent thrombosis
major vascular complications
Researchers adjusted for a 1.3 greater chance of MACE occurring at a randomly selected hospital compared with another randomly selected hospital and found
the relative risks at 30 days and 12 months “were consistent with those of the primary results” (RR 1.02 and 0.98, respectively).
However, they cautioned that new sites perhaps should be monitored as they gain experience.
A prespecified angiographic review of 376 patients who were in the PCI-without-backup arm and 87 in the other arm showed no differences in
rates of procedural success,
proportion with complete revascularization, or
the proportion of guideline-indicated appropriate lesions for PCI.
Such results show consistent practice patterns between the groups, they noted.
The study had several limitations including the
loss of data for 13% of patients, the
exclusion of some patients for certain clinical and anatomical features, and
not having the power to detect non-inferiority in the separate components of the primary endpoint, researchers wrote.
A simple calculation of patient variables before PCI may help stem the tide of readmission within the first month. Also this week, two blood pressure drugs that benefit diabetics and imaging cardiac sympathetic innervation.
Pre-PCI Factors Predict Return Trip
A new 30-day readmission risk prediction model for patients undergoing percutaneous coronary intervention (PCI) showed it’s possible to predict risk using only variables known before PCI, according to a study published online in Circulation: Cardiovascular Quality and Outcomes.
After multivariable adjustment, the 10 pre-PCI variables that predicted 30-day readmission were older age (mean age 68 in this study), female sex, insurance type (Medicare, state, or unknown), GFR category (less than 30 and 30-60 mL/min per 1.73m2), current or history of heart failure, chronic lung disease, peripheral vascular disease, cardiogenic shock at presentation, admit source (acute and non-acute care facility or emergency department), and previous coronary artery bypass graft surgery.
Additional significant variables post-discharge that predicted 30-day readmission were beta-blocker prescribed at discharge, post-PCI vascular or bleeding complications, discharge location, African American race, diabetes status and modality of treatment, any drug-eluting stent during the index procedure, and extended length of stay.
Author: Larry H Bernstein, MD, FCAP And Curator: Justin D Pearlman, MD, PhD, FACC
Article ID #67: Treatment Options for Left Ventricular Failure – Temporary Circulatory Support: Intra-aortic balloon pump (IABP) – Impella Recover LD/LP 5.0 and 2.5, Pump Catheters (Non-surgical) vs Bridge Therapy: Percutaneous Left Ventricular Assist Devices (pLVADs) and LVADs (Surgical). Published on 7/17/2013
Doctors at the Cleveland Clinic began to suspect in 2012 that something might be wrong with a high-tech implant used to treat patients with advanced heart failure like former Vice President Dick Cheney.
Thoratec Corportation
The HeartMate II is a left ventricular assist device, which contains a pump that continuously pushes blood through the heart.
The number of patients developing potentially fatal blood clots soon after getting the implant seemed to be rising. Then early this year, researchers completed a check of hospital records and their concern turned to alarm.
The data showed that the incidence of blood clots among patients who got the device, called the HeartMate II, after March 2011 was nearly four times that of patients who had gotten the same device in previous years. Patients who developed pump-related clots died or needed emergency steps like heart transplants or device replacements to save them.
“When we got the data, we said, ‘Wow,’ ” said Dr. Randall C. Starling, a cardiologist at Cleveland Clinic.
On Wednesday, The New England Journal of Medicineposted a study on its website detailing the findings from the Cleveland Clinic and two other hospitals about the device. The HeartMate II belongs to a category of products known as a left ventricular assist device and it contains a pump that continuously pushes blood through the heart.
The abrupt increase in pump-related blood clots reported in the study is likely to raise questions about whether its manufacturer, Thoratec Corporation, modified the device, either intentionally or accidentally. By March, the Cleveland Clinic had informed both Thoratec and the Food and Drug Administration about the problems seen there, Dr. Starling said.
Officials at Thoratec declined to be interviewed. But in a statement, the company, which is based in Pleasanton, Calif., said that the HeartMate II had been intensively studied and used in more 16,000 patients worldwide with excellent results. It added that the six-month survival rate of patients who received the device had remained consistently high.
“Individual center experience with thrombosis varies significantly, and Thoratec actively partners with clinicians at all centers to minimize this risk,” the company said in a statement.
Thoratec and other cardiologists also pointed to a federally funded registry that shows a smaller rise in the rate of blood clots, or thrombosis, among patients getting a HeartMate II than the one reported Wednesday by the three hospitals. In the registry, which is known as Intermacs, the rate of pump-related blood clot associated with the HeartMate II rose to about 5 percent in devices implanted after May 2011 compared with about 2 percent in previous years.
The data reported on Wednesday in The New England Journal of Medicine found rates of clot formation two months after a device’s implant had risen to 8.4 percent after March 2011 from 2.2 percent in earlier years. Researchers also suggested in the study that the Intermacs registry might not capture all cases of pump-related blood clots, such as when patients gets emergency heart transplants after a clot forms.
Not only did the rate of blood clots increase, but the clots also occurred much sooner than in the past, according to the study. After March 2011, the median time before a clot was 2.7 months, compared with 18.6 months in previous years. In addition to the Cleveland Clinic, the report on Wednesday included data from Duke University and Washington University in St. Louis.
All mechanical heart implants are prone to producing blood clots that can form on a device’s surface. And experts say that the rate of blood clot formation can be affected by a variety of factors like changes in the use of blood-thinning drugs or the health of a patient.
In a telephone interview, Dr. Starling described the Thoratec officials as cooperative, adding that they have been looking into the problem since March to understand its cause. He said that he could only speculate about the reason for the rapid rise in early blood clots but believed it was probably device-related.
“My belief is that it is something as subtle as a change in software that affects pump flow or heat dissipation near a bearing,” said Dr. Starling, who is a consultant to Thoratec.
Asked about his comments, Thoratec responded that it had yet to determine the reason for even the smaller rise in blood clots seen in the federally funded database. “We have performed extensive analysis on HeartMate II and have not identified any change that would cause the increase observed in the Intermacs registry,” the company said.
In a statement, the F.D.A. said that it was reviewing the findings of the study. “The agency shares the authors concerns about the possibility of increased pump thrombosis,” the F.D.A. said in a statement.
The fortunes of Thoratec, which has been a favorite of Wall Street investors, may depend on its ability to find an answer to the apparent jump in pump-related blood clots. Over the last two years, the company’s stock has climbed from about $30 a share to over $43 a share. In trading Wednesday, Thoratec stock closed at $42.12 a share, up 61 cents. (The New England Journal of Medicine article was released after the stock market closed.)
The HeartMate II has been a lifesaver for many patients like Mr. Cheney in the final stages of heart failure, who got his device in 2010, sustaining them until they get a heart transplant or permanently assisting their heart. Dr. Starling said that he planned to keep using the HeartMate II in appropriate patients at the Cleveland Clinic because those facing death from heart failure had few options.
But the company has also been pushing to expand the device’s use beyond patients who face imminent death from heart failure. For example, the F.D.A. approved a clinical trial for patients with significant, but less severe, heart failure to receive a HeartMate II to compare their outcomes with patients who take drugs for the same condition. Researchers at the University of Michigan Medical Center who are leading the trial said on Wednesday that, based on the lower rates of blood clots seen in the Intermacs registry, they are planning to move forward with the trial.
Dr. Starling and researchers at the Cleveland Clinic tried this spring to get The New England Journal of Medicine to publish a report about the findings at that hospital, but the publication declined, saying the data might simply represent the experience of one facility. As a result, Dr. Starling contacted Duke University and Washington University for their data. When analyzed, it mirrored events at the Cleveland Clinic, he said.
The problems seen with the HeartMate II at the three hospitals were continuing as recently as this summer, when researchers paused the collection of data to prepare Wednesday’s study. The study also noted that a preliminary analysis of data provided by a fourth hospital, the University of Pennsylvania, showed the same pattern of blood clot formation, but that the data had been submitted too late for full analysis.
This account is a vital piece of recognition of very rapid advances in cardiothoracic interventions to support cardiac function mechanically by pump in the situation of loss of contractile function and circulatory output sufficient to sustain life, as can occur with the development of cardiogenic shock. This has been mentioned and its use has been documented in other portions of this series. On the one hand, PCI has a long and steady history in the development of interventional cardiology. This necessitated the availability of thoracic-surgical operative support. The situation is changed, and is more properly, conditional.
I. Impella LD – ABIOMED, Inc.
This micro-axial blood pump can be inserted into the left ventricle via open chest procedures. The Impella LD device has a 9 Fr catheter-based platform and a 21 Fr micro-axial pump and is inserted through the ascending aorta, across the aortic and mitralvalves and into the left ventricle. It requires minimal bedside support and a 9 Fr single-access point requires no priming outside the body.
Impella Recover LD/LP 5.0
The Impella Recover miniaturized impeller pump located within a catheter. The Impella Recover LD/LP 5.0 Support System has been developed to address the need for ventricular support in patients who develop heart failure after heart surgery (called cardiogenic shock) and who have not responded to standard medical therapy. The system is designed to provide immediate support and restore hemodynamic stability for a period of up to 7 days. Used as a bridge to therapy, it allows time for developing a definitive treatment strategy.
The Impella Recover LD 5.0 showing implantation via direct placement into the left ventricle.
Insert B – location in LV
The Impella Recover system is a miniaturized impeller pump located within a catheter. The device can provide support for the left side of the heart using either the
Recover LD 5.0 (implanted via direct placement into the left ventricle) or the
Recover LP 5.0 LV (placed percutaneously through the groin and positioned in the left ventricle).
The microaxial pump of the Recover LP/LD 5.0 can pump up to 4.5 liters per minute at a speed of 33,000 rpm. The pump is located at the distal end of a 9 Fr catheter.
II. IABP VS. Percutaneous LVADS
An intra-aortic balloon pump (IABP) remains the method of choice for mechanical assistance1 in patients experiencing LV failure because of its
proven hemodynamic capabilities,
prompt time to therapy, and
low complication rates.
Percutaneous left ventricular assist devices (pLVADs), such as described above, represent an emerging option for partial or total circulatory support2 and several studies have compared the and efficacy of these devices with intra-aortic balloon pump (IABP) (IABP.)
Despite some randomized controlled trials demonstrating better hemodynamic profiles for pLVADs compared with IABP, there is no difference in 30-day survival or trend toward a reduced 30-day mortality rate associated with pLVADs. Patients treated with pLVADs tended to have a
higher incidence of leg ischemia and
device related bleeding.3
Further, no differences have been detected in the overall use of
positive inotropic drugs or
vasopressors in patients with pLVADs.4,5
However, pLVADs may increase their use for patients not responding to
PCI,
fluids,
inotropes, and
IABP
Therefore, the decision making process on how to treat requires an integrated stepwise approach. A pLVAD might be considered on the basis of
anticipated individual risk,
success rates, and for
postprocedural events.6
Potential Algorithm for Device Selection during High-Risk PCI
Until an alternative modality, characterized by improved efficacy and safety features compared with IABP, is developed, IABP remains the cornerstone of temporary circulatory support.2
Device Comparison for Treatment of Cardiogenic Shock: traditional intra-aortic balloon therapy with Impella 2.5 percutaneous ventricular assist device
1. Percutaneous LVADs in AMI complicated by cardiogenic shock. H Thiele, et al. EHJ 2007;28:2057-2063
2. Cardiogenic shock current concepts and improving outcomes. H R Reynolds et al. Circulation 2008 ;117 :686-697
3. Percutaneous left ventricular assist devices vs. IABP counterpulsation for treatment of cardiogenic shock. J M Cheng, et al. EHJ doi:10.1093/eurheart/ehp292
4. A randomized clinical trial to evaluate the safety and efficacy of a pLVAD vs. IABP for treatment of cardiogenic shock caused by MI. M Seyfarth, et al. JACC 2008;52:1584-8
5. A randomized multicenter clinical study to evaluate the safety and efficacy of the tandem heart pLVAD vs. conventional therapy with IABP for treatment of cardiogenic shock.
6. Percutaneous LVADs in AMI complicated by cardiogenic shock. H Thiele, et al. EHJ 2007;28:2057-2063
The Impella 2.5 is a percutaneously placed partial circulatory assist device that is increasingly being used in high-risk coronary interventional procedures to provide hemodynamic support. The Impella 2.5 is able to unload the left ventricle rapidly and effectively and increase cardiac output more than an intra-aortic balloon catheter can. Potential complications include bleeding, limb ischemia, hemolysis, and infection. One community hospital’s approach to establishing a multidisciplinary program for use of the Impella 2.5 is described.
Patients who undergo high-risk percutaneous coronary intervention (PCI), such as procedures on friable saphenous vein grafts or the left main coronary artery, may have an intra-aortic balloon catheter placed if they require hemodynamic support during the procedure. Currently, the intra-aortic balloon pump (IABP) is the most commonly used device for circulatory support. A newer option that is now available for select patients is the Impella 2.5, a short-term partial circulatory support device or percutaneous ventricular assist device (VAD).
In this article, I discuss the Impella 2.5, review indications and contraindications for its use, delineate potential complications of the Impella 2.5, and discuss implications for nursing care for patients receiving extended support from an Impella 2.5. Additionally, I share our experiences as we developed our Impella program at our community hospital. Routine management of patients after PCI is not addressed.
IABP Therapy: Background
decreases after-load,
decreases myocardial oxygen consumption,
increases coronary artery perfusion, and
modestly enhances cardiac output.1,2
The IABP cannot provide total circulatory support. Patients must have some level of left ventricular function for an IABP to be effective.
Optimal hemodynamic effect from the IABP is dependent on:
the balloon’s position in the aorta,
the blood displacement volume,
the balloon diameter in relation to aortic diameter,
the timing of balloon inflation in diastole and deflation in systole, and
the patient’s own blood pressure and vascular resistance.3,4
Impella 2.5 Catheter – ABIOMED, Inc.
Effect
reduces myocardial oxygen consumption,
improves mean arterial pressure, and
reduces pulmonary capillary wedge pressure.2
The Impella 2.5 has been used for
hemodynamic support during high-risk PCI and for
hemodynamic support of patients with
myocardial infarction complicated by cardiogenic shock or ventricular septal defect,
cardiomyopathy with acute decompensation,
postcardiotomy shock,
off-pump coronary artery bypass grafting surgery, or
heart transplant rejection and
as a bridge to the next decision.9
The Impella provides a greater increase in cardiac output than the other IABP provides. In one trial5 in which an IABP was compared with an Impella in cardiogenic shock patients, after 30 minutes of therapy, the cardiac index (calculated as cardiac output in liters per minute divided by body surface area in square meters) increased by 0.5 in the patients with the Impella compared with 0.1 in the patients with an IABP.
Unlike the IABP, the Impella does not require timing, nor is a trigger from an electrocardiographic rhythm or arterial pressure needed (Table 1). The device received 510(k) clearance from the Food and Drug Administration in June 2008 for providing up to 6 hours of partial circulatory support. In Europe, the Impella 2.5 is approved for use up to 5 days. Reports of longer duration of therapy in both the United States and Europe have been published.8,9
Clinical Research and Registry Findings
Abiomed has sponsored several trials, including PROTECT I, PROTECT II, RECOVER I, RECOVER II, and ISAR-SHOCK.
The PROTECT I study was done to assess the safety and efficacy of device placement in patients undergoing high-risk PCI.10
Twenty patients who had
poor ventricular function (ejection fraction =35%) and had
PCI on an unprotected left main coronary artery or the
last remaining patent coronary artery or graft.
The device was successfully placed in all patients, and the duration of support ranged from 0.4 to 2.5 hours. Following this trial, the Impella 2.5 device received its 510(k) approval from the Food and Drug Administration.
The ISAR-SHOCK trial was done to evaluate the safety and efficacy of the Impella 2.5 versus the IAPB in patients with cardiogenic shock due to acute myocardial infarction.5 Patients were randomized to support from an IABP (n=13) or an Impella (n=12).
The trial’s primary end point of hemodynamic improvement was defined as improved cardiac index at 30 minutes after implantation.
Improvements in cardiac index were greater with the Impella (P=.02).
The diastolic pressure increased more with Impella (P=.002).
There was a nonsignificant difference in the MAP (P=.09), as was the use of inotropic agents and vasopressors similar in both groups of patients.
Device Design: Impella 2.5 Catheter
The Impella 2.5 catheter contains a nonpulsatile microaxial continuous flow blood pump that pulls blood from the left ventricle to the ascending aorta, creating increased forward flow and increased cardiac output. An axial pump is one that is made up of impellar blades, or rotors, that spin around a central shaft; the spinning of these blades is what moves blood through the device.13
The Impella 2.5 catheter has 2 lumens. A tubing system called the Quick Set-Up has been developed for use in the catheterization laboratory. It is a single tubing system that bifurcates and connects to each port of the catheter. This arrangement allows rapid initial setup of the console so that support can be initiated quickly. When the Quick Set-Up is used, the 10% to 20% dextrose solution used to purge the motor is not heparinized. One lumen carries fluid to the impellar blades and continuously purges the motor to prevent the formation of thrombus. The proximal port of this lumen is yellow. The second lumen ends near the motor above the level of the aortic valve and is used to monitor aortic pressure.
The components required to run the device are assembled on a rolling cart and include the power source, the Braun Vista infusion pump, and the Impella console. The Impella console powers the microaxial blood pump and monitors the functioning of the device, including the purge pressure and several other parameters. The console can run on a fully charged battery for up to 1 hour.
Placement of the Device
The Impella 2.5 catheter is placed percutaneously through the common femoral artery and advanced retrograde to the left ventricle over a guidewire. Fluoroscopic guidance in the catheterization laboratory or operating room is required. After the device is properly positioned, it is activated and blood is rapidly withdrawn by the microaxial blood pump from the inlet valve in the left ventricle and moved to the aorta via the outlet area, which sits above the aortic valve in the aorta.
If the patient tolerates the PCI procedure and hemodynamic instability does not develop, the Impella 2.5 may be removed at the end of the case, or it can be withdrawn, leaving the arterial sheath in place, which can be removed when the patient’s activated clotting time or partial thromboplastin time has returned to near normal levels. For patients who become hemodynamically unstable or who have complications during the PCI (eg, no reflow, hypotension, or lethal arrhythmias), the device can remain in place for continued partial circulatory support, and the patient is transported to the critical care setting.
Potential Complications of Impella Therapy
The most commonly reported complications of Impella 2.5 placement and support include
limb ischemia,
vascular injury, and
bleeding requiring blood transfusion.6,9
Hemolysis is an inherent risk of the axial construction, and results in transfusions.5,10
Hemolysis can be mechanically induced when red blood cells are damaged as they pass through the microaxial pump. Other potential complications include
aortic valve damage,
displacement of the distal tip of the device into the aorta,
infection, and
sepsis.
Device failure, although not often reported, can occur.
Patients on Impella 2.5 support who may require
interrogation of a permanent pacemaker or
implantable cardioverter defibrillator
present an interesting situation. In order for the interrogator to connect with the permanent pacemaker or implantable cardioverter defibrillator, the Impella console must be turned off for a few seconds while the signal is established. As soon as the signal has been established, Impella support is immediately restarted.
Impella 2.5 Console Management
The recommended maximum performance level for continuous use is P8. At P8, the flow rate is 1.9 to 2.6 L/min and the motor is turning at 50000 revolutions per minute. When activated, the console is silent. No sound other than alarms is audible during Impella support, unlike the sound heard with an IABP. Ten different performance levels ranging from P0 to P9 are available. As the performance level increases, the flow rate and number of revolutions per minute increase. At maximum performance (P9), the pump rotates at 50000 revolutions per minute and delivers a flow rate of 2.1 to 2.6 L/min. P9 can be activated only for 5-minute intervals when the Impella 2.5 is in use.
IV. PROTECT II Study – Experts Discussion
the use of the Impella support device and the intraortic balloon pump for high-risk percutaneous coronary intervention
DR. SMALLING: Well, the idea about the PROTECT trial is that it would show that using the Impella device to support high-risk angioplasty was not inferior to utilizing the balloon pump for the same patient subset. Ejection fraction’s were in the 30%–35% range. Supposedly last remaining vessel or left main disease or left-main plus three-vessel disease and low EF; so I think that was the screening for entry into the trial.
major adverse cardiac event endpoints
Acute myocardial infarction,
mortality,
bleeding,
mortality was the same. Their endpoints really didn’t show that much difference. In subgroup analysis, they felt that they Impella may have had a little advantage over balloon pump.
DR. KERN: So do you think this study would tip the interventionalist to move in one direction or the other for high-risk angioplasty?
DR. SMALLING: That’s an interesting concept, you know? One has to get to: What is really a high-risk angioplasty. I think you and I are both old enough to remember that back in the mid-’80s, we determined that high-risk angioplasty was a patient with an ejection fraction of 25% or less, with a jeopardy score over 6. The EFs were a little higher. And, I guess, based on our prior experience with other support devices — like, for instance, CPS and then, later on, the Tandem Heart — there really was not an advantage of so-called more vigorous support systems. And so, the balloon pump served as well.
DR. SMALLING:
Those of us that have looked carefully at what it can really do, I think it may get one liter a minute at most, maybe more.1-6 But I think, for all intents and purposes, it doesn’t support at a very vigorous level. So I think personally, if I had someone I was really worried about, I would opt for something more substantial like, for instance, a Tandem Heart device.
DR. KERN: I think this is a really good summary of the study and the. Are there any final thoughts for those of us who want to read the PROTECT II study when it comes out?
DR. SMALLING: We have to consider a $20,000, $25,000 device. Is that really necessary to do something that we could often do without any support at all, or perhaps with a less costly device like a balloon pump.
DR. KERN: We’re going to talk for a few minutes about the PROTECT II study results that were presented here in their form. And Ron, I know you’ve been involved with following the work of the PROTECT II investigators. Were you a trial site for this study?
DR. WAKSMAN: No, actually, we were not, but we have a lot of interest in high-risk PCI and using devices to make this safe — mainly safe — and also effective. We were not investigators, but we did try to look, based on the inclusion/exclusion criteria, on our own accord with the balloon pump. If you recall, this study actually was comparing balloon time to the Impella device for patients who are high-risk PCI.
The composite endpoint was very complicated. They added like probably nine variables there, which is unusual for a study design. … They basically estimated that the event rate on the balloon pump would be higher than what we thought it should be. So we looked at our own data, and we found out that the actual — if you go by the inclusion/exclusion criteria and their endpoints — the overall event rate in the balloon pump would be much lower than they predicted and built in their sample size.
DR. KERN: And, so, the presentation of the PROTECT II trial, was it presented as a positive study or a negative study.
DR. WAKSMAN: Overall the study did not meet the endpoint. So the bottom line, you can call it the neutral study, which is a nice way to say it.
if you go and do all those analyses, you may find some areas that you can tease a P value, but I don’t think that this has any scientific value, and people should be very careful. We’re not playing now with numbers or with statistics, this is about patient care. You’re doing a study — the study, I think, has some flaws in the design to begin with — and we actually pointed that out when we were asked to participate in the study. But if the study did not meet the endpoint, then I think all those subanalyses, subgroups, you extract from here, you add to there, and you get a P value, that means nothing. So we have to be careful when we interpret this, other than as a neutral study that you basically cannot adopt any of the … it did not meet the hypothesis, that’s the bottom line.
A first-in-man study of the Reitan catheter pump for circulatory support in patients undergoing high-risk percutaneous coronary intervention.
Smith EJ, Reitan O, Keeble T, Dixon K, Rothman MT.
Department of Cardiology, London Chest Hospital, United Kingdom.
Catheter Cardiovasc Interv. 2009 Jun 1;73(7):859-65. http://dx.doi.org/10.1002/ccd.21865.
To investigate the safety of a novel percutaneous circulatory support device during high-risk percutaneous coronary intervention (PCI).
BACKGROUND:
The Reitan catheter pump (RCP) consists of a catheter-mounted pump-head with a foldable propeller and surrounding cage. Positioned in the descending aorta the pump creates a pressure gradient, reducing afterload and enhancing organ perfusion.
METHODS:
Ten consecutive patients requiring circulatory support underwent PCI; mean age 71 +/- 9; LVEF 34% +/- 11%; jeopardy score 8 +/- 2.3. The RCP was inserted via the femoral artery. Hemostasis was achieved using Perclose sutures. PCI was performed via the radial artery. Outcomes included in-hospital death, MI, stroke, and vascular injury. Hemoglobin (Hb), free plasma Hb (fHb), platelets, and creatinine (cre) were measured pre PCI and post RCP removal.
RESULTS:
The pump was inserted and operated successfully in 9/10 cases (median 79 min). Propeller rotation at 10,444 +/- 1,424 rpm maintained an aortic gradient of 9.8 +/- 2 mm Hg. Although fHb increased,
there was no significant hemolysis (4.7 +/- 2.4 mg/dl pre vs. 11.9 +/- 10.5 post, P = 0.04, reference 20 mg/dl).
Platelets were unchanged (pre 257 +/- 74 x 10(9) vs. 245 +/- 63, P = NS).
Renal function improved (cre pre 110 +/- 27 micromol/l vs. 99 +/- 28, P = 0.004).
All PCI procedures were successful with no deaths or strokes, one MI, and no vascular complications following pump removal.
CONCLUSIONS:
The RCP can be used safely in high-risk PCI patients.
A coronary angiogram that shows the LMCA, LAD and LCX. (Photo credit: Wikipedia)
English: Simulation of a wave pump human ventricular assist device (Photo credit: Wikipedia)
English: Figure A shows the structure and blood flow in the interior of a normal heart. Figure B shows two common locations for a ventricular septal defect. The defect allows oxygen-rich blood from the left ventricle to mix with oxygen-poor blood in the right ventricle. (Photo credit: Wikipedia)
Metabolic analysis has been widely used in laboratory research applications. One of the main uses in this field was the metabolic phenotyping of mouse models of cardiovascular diseases; this approach was pioneered by the group of Julian Griffin mainly using models of Duchenne muscular distrophy where they were able to show different metabolic profiles associated with the expression of dystrophin and utrophin in heart muscle. In a later work the same group applied the FANCY approach (Functional Analysis by Co-responses in Yeast) to mouse models of cardiac diseases and showed that although the background strain of mice was an important source of metabolic variation, multivariate statistics were able to separate each disease model from the control strain.
Since the beginning of the 21st century the term ‘personalized medicine’ has continuously gained popularity and is now considered an essential trait of present and future medicine. For personalized medicine to be successful, it is necessary to properly identify subjects at increased risk of developing a disease, which patients will respond to a given therapy or how a disease will evolve in each case. In other words it is important to genotype and or phenotype the individual patient so that its individual response to disease and treatment can be predicted.
Sabatine et al. in 2005 showed that it was possible to apply metabolomic analysis in a carefully characterized cohort of patients undergoing exercise stress testing and to differentiate between patients that developed inducible ischemia from the ones that did not. This work was done by analyzing serum samples obtained before, during and after stress testing by high performance liquid chromatography coupled to mass spectroscopy; ischaemic patients had higher circulating levels of metabolites belonging to the citric acid pathway. Ischemic patients had relatively higher lactate levels than non ischemic suggesting an underlying ischemic process although it could not be directly related to myocardial ischemia.
It has been known for a time that patients with heart failure (HF) have an altered heart metabolism and that metabolic modulation (shifting the main substrate from free fatty acids to glucose) improved VO2max, left ventricular ejection fraction, symptoms, resting and peak stress myocardial function, and skeletal muscle energetics. Metabolic modulation as a tool to treat patients with heart failure has attracted interest but the metabolomic analysis has not followed suit until recently when Kang et al. 2011 showed by profiling urine by NMR spectroscopy that it was possible to detect changes between HF patients and controls. It could be interesting to evaluate possible changes in the urine metabolic profile of patients treated with drugs targeting heart metabolism for example, perhexiline or trimetazidine. In conclusion, the future of metabolomics is now. It is clear that metabolomics can be applied to various cardiovascular related diseases, although its clinical value in different settings remains to be determined; this is the next big challenge in the field.
NEW YORK (GenomeWeb News) – The average CEO compensation at publicly traded omics tools and molecular diagnostics firms rose nearly 7 percent year over year in 2012, according to documents filed with the US Securities and Exchange Commission.
Based on proxy statements filed by 28 of the 29 firms in the GenomeWeb Daily NewsIndex, CEO compensation for 2012 averaged more than $4.8 million, up from a little less than $4.5 million in 2011.
One firm, Rosetta Genomics, based in Rehovot, Israel, did not report compensation for its CEO, Kenneth Berlin, either in 2011 or 2012. The firm did not respond to requests for information.
The base salary for CEOs in 2012 averaged $686,017, also up about 7 percent from $644,109 in 2011, according to the proxy statements.
As a total dollar amount, CEO compensation for the 28 companies in the GWDN Index reached about $135.3 million last year, up about 8 percent from $125.7 million, while the base salaries in 2012 totaled $19.2 million, an increase of 6 percent from $18.0 million in 2011.
Executive compensation across all industries has become a lightning rod in recent years with shareholders and the general public seeking greater transparency in how compensation is determined and justification for sometimes extravagant pay perks.
According to Susan Stemper, managing director at executive compensation consulting firm Pearl Meyer & Partners, investors need to scrutinize executive compensation because they provide a window into the strategic direction that a board has set for the business and whether a board’s decisions around CEO pay are competitive and appropriate for the business.
Investors need to focus on how executive compensation levels are designed, said Stemper. “I’d say, ‘Don’t look at the numbers, look at the design,'” she toldGenomeWeb Daily News, adding that, in particular, it is important to focus on achievements made in the past year and how they compare to the company’s goals and objectives.
Setting appropriate compensation levels for executives, which include stock and other option awards, is a tricky art that, in addition to using measurable metrics, often include more difficult to measure factors that are meant to reward executives for their performance during the past year.
Such pay-for-performance components, however, present special challenges to omics tools/MDx firms, Stemper said.
“The challenge is when you’re looking at these sectors where the return from the research and development — if it follows at all — perhaps only follow quarters or years after that initial investment has been made,” she said. “The conundrum that we face is trying to look at this year’s pay and trying to align it with this year’s financial performance of the business.”
In the omics/MDx sector, “you need a lot of shots on goal” before a target is hit, and “you can’t count on all those shots on goal happening in a given year,” Stemper said. “So does it really make sense not to grant the stock, or not award the stock because we didn’t make the shot on goals when we recognize that that is just part of how we do business?”
As a result, companies in the omics tools/MDx space have come to rely on time-vested stock and option grants, which become exercisable after a defined amount of time has elapsed.
“To me, those are the perfect performance-based vehicles, because if the stock price doesn’t perform, the executive is not going to realize the value that you’re reading in the table,” she said. The values for such options that are listed on a company’s proxy statement are based on the value at the time they are issued to the CEO and may go up or down as time passes. “They’ve got 10 years to do it, typically on the term, but the stock price has to exceed, by some measure, what it was at the time of grant,” Stemper added.
Many companies also look at how their competitors compensate their executives as benchmarks for paying their own executives. For example, Illumina’s compensation committee used a peer group of 18 firms to set 2012 compensation levels for their executives, including President and CEO Jay Flatley, whose total compensation for the year dropped 18 percent to $8.2 million.
In its proxy, it said that it “considered a number of factors in defining the peer group, including industry competitors of similar revenue range, net income, growth rates, employee size, and market capitalization range that we believe reflects the market for talent and stockholder investment.”
Illumina said that it targets its direct compensation to its executives at between the 60th percentile and 75th percentile of compensation that executives in its peer group receive. The largest component of the total direct compensation is delivered through equity-based awards in order to retain its executives, while aligning their interests with those of its shareholders, it said in its proxy, although it may “deviate from these general target levels to reflect the executive’s experience, the executive’s sustained performance level, and market factors as deemed appropriate by the compensation committee.”
Such a peer group approach, though, also provides challenges, because in such a niche market, the pool of such firms is shallow, Stemper said, and different firms may be at different stages of the business cycle. They may not have similar experiences in terms of success and regulatory approvals, either, or may have dissimilar financial dynamics.
Because of this, firms often include in their benchmark peer groups companies that may be analogous to where they are in terms of their business but which have only the vaguest connection, if any, to what they do. Affymetrix, for instance, included in its peer group for 2012 Nordion, a health science firm that provides targeted therapies, sterilization technologies, and medical isotopes. Genomic Health, meanwhile, looked at, among others, ultrasound shop FujiFilm Sonosite to determine its compensation levels, and Thermo Fisher Scientific had diversified manufacturing and technology company Emerson Electric in its peer group.
In niche markets, such as the omics tools/MDx space, “it will be difficult to simply say ‘I want to look at the median'” compensation offered by competitors, Stemper said. “It’s more likely going to be ‘I want to look at the universe at a dataset level and understand where we believe our CEO fits in best.'”
2012 Winners
Among the firms in the GWDN Index, the CEO with the highest year-over-year compensation increase in 2012 was Thermo Fisher’s Marc Casper, whose total compensation climbed 146 percent to almost $13.6 million from $5.5 million in 2011. The uptick was largely driven by a stock award of $10.4 million granted in 2012, compared to none in 2011.
Two other CEOs whose compensation doubled year over year in 2012 were Bruker’s Frank Laukien, who took in $1.9 million last year, compared to $892,100 in 2011, and Exact Sciences’ Kevin Conroy, whose compensation reached $2.7 million from $1.3 million in 2011.
Frank Witney of Affymetrix had the biggest year-over-year drop, 76 percent, as his 2012 compensation of $657,291 was down from $2.7 million in 2011. The drop-off is largely attributable to a decrease in stock awards in 2012 to $115,750, compared to $1.4 million the year before. Witney became president and CEO of Affy on July 1, 2011.
Another whose compensation narrowed significantly was Waters’ Douglas Berthiaume, who made $1.1 million in 2012, down 60 percent from $2.6 million the year before. Also, William Moffitt, the former CEO of Nanosphere, who was succeeded this past February by Michael McGarrity, saw his compensation fall 48 percent to $457,885 in 2012 from $885,946 in 2011.
And GenMark Diagnostics’ Hany Massarany’s 2012 compensation was down 33 percent at $1.3 million last year from $2.0 million in 2011.
Among the CEOs of firms in the GWDN Index, Danaher’s Lawrence Culpraked in the most in compensation last year, making $21.9 million in total compensation, up from $21.7 million in 2011. Four others made more than $10 million in 2012: Thermo Fisher’s Casper; William Sullivan of Agilent with $10.1 million; Life Technologies’ Greg Lucier with $10.3 million; and PerkinElmer’s Robert Friel with $10.8 million.
* These authors contributed equally; # Corresponding author (rnir@sbhsciences.com).
I. Introduction
Glioblastoma multiform is a fast-growing, invasive central nervous system tumor that forms from glial (supportive) tissue of the brain and spinal cord. Glioblastoma multiform also called glioblastoma or glioma along with grade III/IV astrocytoma and abbreviated herein and elsewhere as GBM. It usually occurs in adults and affects the brain more often than the spinal cord. Brain tumor patients with GBM have a severely major unmet medical need. Current treatment for stage IV glioblastoma provides only 16-month median survival from time of diagnosis.
There has been and continues to be a tremendous amount of research with the goal of finding a cure for brain tumors, yet there are only 3 FDA approved drugs for this indication, BCNU in the form of Gliadel® wafers, temozolomide (Temodar®), since 2005 and most recently, 2009 bevacizumab (Avastin®; 10 mg/Kg intra venous) for recurrent GBM. Patients with grade IV glioma undergoing surgical resection of the tumor combined with radiation therapy (RT) to prevent any remaining cancer cells from regrowing have shown historical median survival of 11.5 to 12 months. The first FDA approved glioma treatment was the Gliadel wafer that is placed in the brain tumor bed after surgery, where it degrades, releasing the drug carmustine. This treatment that included surgery and radiation has been shown to extend the median survival of these patients to about 14 months approximately 2 months longer than the group that received placebo wafers (Westphal M, 2003, 2006), (Attenello FJ, 2008). However, the rate of complications, including an increase in cerebrospinal fluid leaks and intracranial hypertension, has limited their use (Nagpal S., 2012). The current ‘gold standard’ treatment to which all new experimental treatments are compared is temozolomide. Patients with high grade glioma receiving surgery, temozolomide and radiation therapy have a mean survival of 14.5 to 16 months (Stupp R, 2005), (Grossman SA, 2010). Avastin (bevacizumab), is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A) administered by intravenous infusion and has been approved for treating the recurrence of glioma only after the cancer has become refractory to temozolomide (Cohen MH, 2009), (Chamberlain MC, 2010). Still, GBM remains one of the two worst-case scenarios in the spectrum of cancer, sharing with pancreatic cancer a less than 5% five-year survival rate.
Due to the current success of polyunsaturated fatty acid (PUFA) based therapeutics including Lovasa (GlaxoSmithKline/ Reliant Pharmaceuticals) and Vascepa (Amarin) for high triglycerides with mixed dyslipidemia, there seems to be a renewed interest in PUFA’s therapeutic effects in different disease indications, especially cancer.
The scientific literature reports various results for the many different PUFA forms and their affects in a wide variety of cancer cell line tests. The use of PUFA in the clinical setting has shown a slight enhancement of tamoxifen treatment in breast cancer patients when taken as an oral supplement (Kenny FS, 2000). But the lack of clear clinical improvement predominates in most trials such as those for bladder cancer (Harris NM, 2002) and pancreatic cancer (Johnson CD, 2001). Intravenous infusion of the polyunsaturated fatty acid gamma linolenic acid (GLA) for pancreatic cancer patients had met with little success in extending these patients’ lives (Johnson CD, 2001).
We hypothesize that the systemic administration of PUFAs has had limited success in cancer treatment mainly due to their being highly protein bound in the blood upon infusion and the need for an apparently high local concentration in the vicinity of the cancer tissue. In the face of the confounding data for the utility of PUFAs in cancer treatment, our hypothesis has been supported by the promising results found in a small, but uncontrolled pilot clinical trial using a protocol entailing local application of GLA directly into the resected tumor bed of High Grade GBM patients (Das UN, 1995).
II. Polyunsaturated fatty acids in Glioblastoma
Fatty acids are key nutrients that affect early growth and development, as well as chronic and other diseases. A fatty acid containing more than one carbon double bond is termed polyunsaturated fatty acid (PUFA). PUFA affect the prevalence and severity of cardiovascular disease, diabetes, inflammation, cancer, and age-related functional decline. PUFA are components of the structural phospholipids in cell membranes; they modulate cellular signaling, cellular interaction, and membrane fluidity. The two most important groups of PUFA are the Omega 3 and Omega 6 fatty acids. Alpha-linolenic acid (ALA or 18 : 3n-3) is the parent of Omega 3 fatty acids, and linoleic acid (LA or 18 : 2n-6), the parent of the n-6 PUFA family. The human body is unable to readily synthesize ALA, and LA, classifying them both as essential fatty acids that one must ingest in the diet. LA and ALA are converted to their respective n-6 and n-3 PUFA families by a series of independent reactions of which both pathways require the same enzymes, Δ6 Desaturase and Δ5 Desaturase, for desaturation and elongation (Sprecher H, 2002).
Common polyunsaturated fatty acid forms tested for their anti-tumor effect include gamma linolenic acid (GLA), arachidonic acid (AA) from the n-6 series and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from the n-3 series. One of the most promising PUFA in the development of cancer therapeutics is the GLA. GLA is a carboxylic acid with an 18-carbon chain and three cis double bonds. Although the cytotoxicity of GLA, AA, EA and DHA is very high in cancer cell-lines, GLA shows the greatest specificity of destroying only cancerous cells and leaving non-cancerous cells intact (Bégin ME, 1986) (Das UN, 1991). For this reason we will narrow the focus of this review to GLA.
In-Vitro analysis of GLA on various cancer cell lines
GLA has shown cytotoxicity to a number of cancer cell lines including breast (ZR-75-11), lung (A-549), prostate (PC-3) (Begin ME, 1986), pancreas (Ravichandran D, 2000), liver (Itoh S, 2010). GLA was the most effective in selectively killing the tumor cells. In a co-culture experiment wherein normal human skin fibroblasts (CCD-41-SK) and human breast cancer cells (ZR-75-1) were grown together in a Petri dish and supplemented with GLA, only human breast cancer cells were eliminated without any effect on normal skin fibroblasts (Bégin ME, 1986).
The studies outlined below focus on GBM:
Bell et al, (1999) examined the invasion and growth of cell spheroids of human GBM cell lines U87, U373 and MOG-G-CCM. The spheroids were grown on collagen with up to 1 mM GLA for 5 days. Measurements showed that low concentrations of GLA (< 100uM) increased both apoptosis and proliferation while higher concentrations (>250 uM) significantly impaired spheroid growth. All spheroid preparations showed 100% growth inhibition after 5 days of culture with 500–1000 uM GLA. Similar experiments by Leaver HA et al, [2002a] found that the Lithium (Li+) salt of GLA was more potent than GLA, most likely due to its increased solubility. Li+GLA showed statistically significant pro-apoptotic and anti-proliferative effects in C6 rat glioma cell line culture at 40 uM PUFA as observed using the MTT assay compared to nontreated controls. Meglumine gammalinolenate (MeGLA) was also developed for enhancing the water solubility of the PUFA and it showed greater activity than Li+GLA (Ilc K, 1999). Work reported by Scheim (Scheim DE, 2009) on human cell cultures derived from human GBM biopsy treated with 500 uM GLA showed complete cytotoxicity to the cancerous cells, while maintaining complete viability in noncancerous cell organ cultures from human biopsy.
III.Mechanism of Action for GLA against cancer cells
The mechanisms by which PUFA act on normal and cancerous cells are complex and not well understood. In tumor cells, addition of PUFAs results in the generation of free radicals, enhancement of lipid peroxidation and the suppression of cell rescue proteins and pathways thereby leading to cell apoptosis. However, in normal cells, supplementation of PUFAs produce adequate amounts of lipoxins, resolvins and protectins that protect the cells from free radicals and reactive oxygen species, suppress inflammation and prevent actions of mutagens and carcinogens (Das UN and Madhavi N, 2011).
A. Free radical generation:
In vitro experiments testing the cytotoxic effects of PUFA has shown that GLA application induced lipid peroxidation products may have a high affinity to Bcl-2, an integral membrane oncoprotein that is unique in its ability to suppress apoptosis. This interaction prevents Bcl-2 from suppressing apoptosis even in cancer cells. Haldar et al (1995) concluded that Bcl-2 is deactivated upon phosphorylation and Bodur et al (2012), have shown that the exposure to 4-hydroxynonenal (HNE) the main aldehydic product of plasma LDL peroxidation induces Bcl-2 phosphorylation (Haldar S, 1995), (Bodur C, 2012).
To decipher the mechanism of the cytotoxic action of GLA and other fatty acids, cyclo-oxygenase, lipoxygenase inhibitors, and anti-oxidants and free radical quenchers have been added to cancer cell line cultures. The GLA may induce different cell death pathways in different cell lines. In HeLa cells, indomethacin, a cyclo-oxygenase and inhibitor, and NDGA, a lipoxygenase inhibitor, that were added to cell cultures were ineffective in blocking the cytotoxic action of GLA and DHA (Das UN and Madhavi N, 2011). However, SOD and Vitamin E, both free radical scavengers blocked the tumoricidal action of GLA on human cervical carcinoma, (HeLa) cells, human leukemia, HL-60 cells, breast cancer, ZR-75-1, cells (Das UN, 1991, 2007), (Sagar PS, 1995). The increased production of free radicals by GLA treated cancer cells may be one of the reasons for enhanced cytotoxicity of glioma tumors seen in the pilot human clinical trials.
B. GLA influence on Angiogenesis:
Inclusion of GLA in a 3D matrix culture system of the rat aortic ring assay, significantly inhibited angiogenesis in a concentration-dependent manner and a significant reduction of vascular endothelial cell motility was observed (Cai J, 1999). Localized administration of GLA to orthotopically implanted C6 glioma cell line in the rat brain decreased the tumor cell’s protein expression of the pro-angiogenic factor vascular endothelial growth factor (VEGF) by 71% (± 16%) and the VEGF receptor Flt1 by 57% (± 5.8%) (Miyake JA, 2009). The GLA treatment reduced the micro vessel density of the tumors by 41% compared to control tumors. In addition, the GLA treatment caused a significant decrease in ERK1 and ERK2 protein expression of (27 ± 7.7%) and (31±8.7%), respectively. More recently, Miyake et al report that neoangiogenesis is regulated through the ERK1/2 pathway (Miyake M, 2013).
C. GLA influence on cancer related genes:
Miyake et al, [2009] examined the changes in cancer related gene expression in C6 glioma cells growing in rat brains when treated with local GLA brain infusion as compared to vehicle controls. The GLA treatment shows evidence for the upregulation of proteins that would inhibit cell cycle growth and division and induce apoptosis. The expression of p53 was increased (44 ±16%) by GLA as compared to control.
The tumor suppressor protein p53 has many mechanisms of anticancer function, playing a role in apoptosis, genomic stability, and inhibition of angiogenesis. The mechanisms by which p53 works include: activating DNA repair proteins when DNA has sustained damage; arresting growth by holding the cell cycle at the G1/S regulation point if DNA damage is recognized allowing for repair or it can initiate apoptosis, or it can initiate programmed cell death, if DNA damage proves to be irreparable (Liang Y, 2013). Similarly, the expression of p27 (another tumor suppressor protein) was also increased (27 ± 7.3%) in GLA treated animals (Miyake JA, 2009).
D. Caspase:
Apoptosis is induced by caspase signaling pathways in many cells (Kim R, 2002) (Philchenkov A, 2004). One of the mechanisms of apoptosis involves a mitochondrial signaling pathway, which entails the efflux of cytochrome c from mitochondria to the cytosol (Ge H, 2009). Cytosolic cytochrome c together with Apaf-1 activates caspase-9, which then activates caspase-3 (Cain K, 2002), (Wang X, 2001). Caspase-3 play an important role in apoptosis and degrades proteins such as PARP, which is a nuclear enzyme implicated in many cellular process including apoptosis and DNA repair. Studies by Ge et al, (2009) suggest that GLA treatment induces a dose-dependent increase in cytochrome c and activation of caspase-3 that correlates with the apoptosis of human chronic myelogenous leukemia K562 cells (Kong X, 2006). Further, the apoptosis could be inhibited by a pan-caspase inhibitor (z-VAD-fmk) (Ge H, 2009).
E. Ku Proteins:
The heterodimeric Ku70/Ku80 protein complex is important for DNA repair and plays an important role in double strand breaks especially in gamma irradiation resistant tumor cells where high levels of these proteins are related to hyper proliferation and carcinogenesis (Gullo, 2006). Ku proteins have shown that loss or reduction in their expression causes increased DNA damage and micronucleus formation in the presence of radiation (Yang QS, 2008). GLA treatment of C6 rat glioma cells was accompanied by a 71% reduction in Ku80 protein expression and a 39% increase in the number of micronuclei detected by Hoechst fluorescence, as well as a 49% reduction of cells in S-phase even at concentrations that do not produce significant increases in apoptosis when measured within only a 24 hour exposure (Benadiba M, 2009).
IV. In Vivo effect of GLA
As previously discussed, GLA has been reported to have effects in many cancers in vivo with treatments ranging from direct anti-tumor activity in clinical studies with injected GLA to dietary supplementation as an adjuvant to more traditional chemotherapy (Fetrow CW, 1999) (Kleijnen J, 1994). There are a number of anecdotal reports of increased response and duration, but none of these studies have shown convincing evidence to support the continued use of GLA against any specific cancer subtype. In one small clinical pancreatic cancer study using an injectable form of GLA there was some apparent benefit (Fearon KC, 1996), which failed to be reproduced in a larger study (Johnson CD, 2001). Other tumor types for which there have been reports regarding use of GLA in cancer include breast cancer (Kenny FS, 2000, 2001), (Menendez JA, 2004, 2005) bladder cancer (Harris NM, 2002) and even leukemia (Kong X, 2009). In even earlier studies, PUFAs including GLA were shown to have some efficacy against both chemically induced skin carcinogenesis in mice (Ramesh G, 1998) and hepatocarcinoma models in rats (Ramesh G, 1995) although again, these studies were not definitive. A recurring theme seems to be that for utility, the GLA needs to be present at reasonably high doses in the vicinity of the tumor, indicating the some form of local delivery must be considered, or perhaps some kind of targeted therapy.
A. GLA tumorcidal effect on rat glioma:
The Leaver group (Leaver HA, 2002 b) continued their work examining the effects of GLA treatment. Rats with orthotopically placed C6 glioma tumor in their brains were locally infused with PBS vehicle or GLA solution from 200 uM to 2 mM. The most active was 2 mM, infused at 1 ul/hr over 7 days. In contrast 1mM total dose had no significant difference from the controls. In the positive response group, tumor regression, increased apoptosis and decreased proliferation were observed. Minimal effects on normal neuronal tissue was detected, with the caveat that their methods were not comprehensive (see discussion on safety, section IV.B. and Conclusion discussion, section VI). Tumor volume was less than 50% of controls in the 2 mM infused rats. However, histology and TUNEL reactivity of the remaining tumor indicated that this may be an under-estimate of residual viable tumor as substantial areas of treated tumors showed characteristics of necrotic tissue and apoptotic cell death. Supporting this hypothesis, tumor tissue sections evaluated by IHC with the proliferative marker Ki67 in the 2mM GLA treated animals showed < 20% of PBS control expression. Note: in these experiments there was no initial debulking surgery of the tumor mass.
Further studies by Miyake JA et al, (2009) showed that increasing the concentration of GLA delivered to the implanted C6 cell glioma in rat brains by treating them with 5 mM GLA/d in cerebrospinal fluid (CSF) caused an even greater decrease in C6 tumor growth in vivo. The average tumor area was reduced by 75 ± 8.8% in comparison with CSF alone. VEGF protein expression was reduced 77 ± 16%. GLA had an inhibitory effect on vessel number causing a 44 ± 5.4% reduction in tumor micro vessel density.
While the in vivo data have a mixed response when looking at different tumor types and delivery methods, it appears that there may be some utility in GBM, particularly when the drug is delivered locally. Further exploration of delivery methods for GBM and other tumor types need to be explored including the use of more targeted therapies such as targeted nano-particle delivery and even antibody-drug conjugates (ADC). The research models also need to reinforce and support if possible the clinical observation of efficacy seen with direct intratumoral (or resected cavity) delivery noted in previous studies carried out in India.
B. Safety Studies in the Canine Model:
A safety study in 3 healthy dogs showed that daily injection of 0.25 mg in 1ml of saline for six days into the brain parenchyma under aseptic conditions was found to be safe (Das U N, 1995). CT scan and gross examination of the meninges and subarachnoid space as well as histopathological exams showed no abnormality and no difference between injected side and non-injected side. None of the animals developed any side effects or complications due to the procedure or GLA injection. Note that humans were given 1 mg GLA per day (see next section). These are at best preliminary findings and further evaluation of safety in normal brain tissues and CSF need to be considered.
V. Clinical application of GLA for Glioma Patients
The most compelling argument for the usefulness of GLA in the treatment of glioblastoma comes from a series of open label, non-randomized trials that were run in India by Drs. Das and Reddy nearly 2 decades ago. In these studies, summarized below, they found that direct administration of the GLA to the tumor site via infusion over several days provided no observable toxicities or side effects although there were not complete cognitive or behavioral studies done on the patients. It remains to be shown that there are no significant liabilities to the administration of GLA to brain cancer patients to provide both an extension of life (overall survival benefit) as well as not impinging on the quality of life for the patient.
A. Recurrent glioma patients:
The initial study treating patients with local administration of GLA was performed on patients with recurrent GBM. GLA was injected directly into the tumor and/or an Ommaya reservoir was used to deliver the GLA to the tumor bed after surgical tumor resection followed by standard RT (see Naidu MR , 1992). This procedure not only showed substantial efficacy but also there were no drug related side effects. Although only a small group of 6 patients, 3 of the 6 were alive at their last follow-up check-in 2 yrs 4 months to 2 yrs 8 months. These patients with recurrent glioma when administered the GLA therapy were in critical condition with life expectancy of 9 months or less. A 50 % survival at ~ 2.5 yrs is much better than historic average of 27% survival at 2 years in primary glioma patients with what is now the “gold standard” treatment of radiation and temozolomide and thus warranted further study.
B. GLA treatment of primary tumor patients:
The next study performed was on patients with grade III Astrocytoma and Grade IV glioblastoma receiving their first intervention. Patients underwent neurosurgery to remove as much of tumor as possible. Before closure of the dura, 1 mg GLA was instilled into the tumor bed and cerebral catheter and reservoir were positioned for subsequent injections. On day 7 post operation, a baseline CT brain scan was taken. One mg daily of GLA in 2-3 ml of sterile saline was instilled for 10 days before a repeat CT scan was taken for comparison This procedure not only showed substantial efficacy but also there were no drug related side effects. Surgery plus RT supplemented with GLA treatment extended patient survival for 80% of treated patients (12/15) to 34 months with very limited drug-related side effects (Das U N, 1995).
VI. Conclusion
As some of the patients (Trial B, above) were alive and apparently well more than 2 years after receiving treatment, it is rather incredible that this treatment has not been more widely tested in the west in the last 18 years. It is likely due to the fact that no robust and reproducible preclinical studies have come forward and that more standard GLP toxicology studies were not done. Safety needs to be the first concern and whether in rats, dogs or monkeys, if direct delivery of GLA to the brain cavity is the best treatment, then it is imperative to have these studies carried out with a full analysis of both histopathological findings as well as the more indirect cognitive and behavioral studies that will be very important in human therapy. As direct delivery to the brain is not a typical therapeutic approach, it remains to be seen what the regulatory agencies will demand for this kind of novel treatment. The most pressing need is to have a thorough assessment of normal brain tissue exposure at the doses that are likely to be administered to a human and to include some surgical intervention (slicing through the brain) to mimic the surgical resection of the glioma. Thus just delivering to the cerebrospinal fluid, while an intermediate assessment tool, may not have full predictive value for the adjuvant application of GLA in the treatment of glioblastoma. For true safety studies, multiples of the minimum efficacious dose would ideally be done to ensure that there is a safety margin for dose administration errors. These studies are enabled by Alzet mini-pump technologies as well as direct cannulation and a sterile port for the daily administration of drugs to the test subject.
As systemic exposures will be minimized from direct brain delivery of small amounts such as the 1-2 mg per day in the referenced trials, there would be almost no way to evaluate for typical toxicology organ effects, coupled with the fact that GLA is an endogenous component of fatty acid metabolism. With drugs such as Gliadel® having been used, with its poor safety profile (Based on Pharmacy Codes: The oral LD50 in rat and mouse are 20 mg/kg and 45 mg/kg, respectively. Side effects include leukopenia, thrombocytopenia, and nausea.) Toxic effects include pulmonary fibrosis and bone marrow toxicity). Moreover, recent studies showing combining carmustine with temozolomide reduces survival time compared to temozolomide alone (Prados MD, 2004). The safety hurdle is fairly low for this devastating and fast growing tumor, however, that is not an excuse to forgo the safety studies that apparently were casually done previously and have kept this potential therapy out of the mainstream medicine for the past 18 years.
Taken together, these reports from the intriguing conundrum provided by the various outcomes of the animal efficacy studies to the patient feeding studies and the various delivery routes tested suggest that there is some rationale for utility of GLA in the treatment of cancer. Disciplined and well-controlled studies need to be undertaken with GLA / GLA salt or derivative forms of GLA that may have better pharmaceutical properties coupled with optimal delivery of the agent to the tumor with or without another therapy (chemotherapy or electrical field therapy ).
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Leaver HA, Bell HS, Rizzo MT, Ironside JW, Gregor A,Wharton SB, Whittle IRl. “Antitumour and pro-apoptotic actions of highly unsaturated fatty acids in glioma.” Prostaglandins, Leukotr. Ess. Fatty Acids 66.1 (2002): 19-29.
Leaver HA, Wharton SB, Bell HS, Leaver-Yap IM, Whittie IR. “Highly unsaturated fatty acid induced tumour regression in glioma pharmacodynamics and bio-availability of gamma linolenic acid in an implantation glioma model: effects on tumour biomass, apoptosis and neuronal tissue histology.” Prostaglandins Leukot Ess. Fatty Acids 67.5 (2002 b): 283-92.
Liang Y, Liu J, Feng Z. “The regulation of cellular metabolism by tumor suppressor p53.” Cell Biosci. 3.1 (2013): 9.
Menendez JA, Ropero S, Lupo R, Colmer R. “Omega-6 polyunsaturated fatty acid gamma-linolenic acid (18:3n-6) enhances docetaxel (Taxotere) cytotoxicity in human breast carcinoma cells: Relationship to lipid peroxidation and HER-2/neu expression.” Oncology Reports. 2004;11:1241-1252., 11.6 (2004): 1241-52.
Menendez JA, Vellon L, Colomer R, Lupu R. “Effect of gamma-linolenic acid on the transcriptional activity of the Her-2/neu (erbB-2) oncogene.” J Natl Cancer Inst. (2005): 1611-15.
Miyake JA, Benadiba M, Colquhoun A. “Gamma-linolenic acid inhibits both tumour cell cycle progression and angiogenesis in the orthotopic C6 glioma model through changes in VEGF, Flt1, ERK1/2, MMP2, cyclin D1, pRb, p53 and p27 protein expression.” Lipids Health Dis. 8 (2009): 8.
Miyake M, Goodison S, Urquidi V, Gomes Giacoia E, Rosser CJ. “Expression of CXCL1 in human endothelial cells induces angiogenesis through the CXCR2 receptor and the ERK1/2 and EGF pathways.” Lab Invest. 93.7 (2013): 768-78.
Nagpal S. “The role of BCNU polymer wafers (Gliadel) in the treatment of malignant glioma.” Neurosurg Clin N Am 23.2 (2012): 289-95.
Naidu MR, Das UN, Kishan A. Intratumoral gamma-linolenic acid therapy of human gliomas.
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Prados MD, Yung WK, Fine HA, Greenberg HS, Junck L, Chang SM, Nicholas MK, Robins HI, Mehta MP, Fink KL, Jaeckle KA, Kuhn J, Hess KR, Schold SC Jr; study, North American Brain Tumor Consortium. “Phase 2 study of BCNU and temozolomide for recurrent glioblastoma multiforme: North American Brain Tumor Consortium study.” Neuro Oncol. 6.1 (2004):33-7.
Ramesh G, Das UN. “Effect of dietary fat on diethylnitrosamine induced hepatocarcinogenesis in Wistar rats.” Cancer Lett. 95.1-2 (1995): 237-45.
Ramesh G, Das UN. “Effect of evening primrose and fish oils on two-stage skin carcinogenesis in mice.” Prostaglandins Leukot Essent Fatty Acids. 59.3 (1998): 155-61.
Ravichandran D, Cooper A, Johnson CD. “Effect of lithium gamma-linolenate on the growth of experimental human pancreatic carcinoma.” Eur J Cancer. 36.3 (2000): 423-7.
Scheim DE. “Cytotoxicity of unsaturated fatty acids in fresh human tumor explants: concentration thresholds and implications for clinical efficacy.” Lipids in Health and Disease 8:54 (2009).
Sagar PS, Das UN. “Cytotoxic action of cis-unsaturated fatty acids on human cervical carcinoma (HeLa) cells in vitro.” Prostaglandins Leukot Ess. Fatty Acids 53.4 (1995): 287-99
Sprecher H. “The roles of anabolic and catabolic reactions in the synthesis and recycling of polyunsaturated fatty acids.” Prostaglandins Leukot Essent Fatty Acids 67.2-3 (2002): 79-83.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO and European Organisation for Re for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups and the National Cancer Institute of Canada Clinical Trials Group. “Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma.” N Engl J Med 352.10 (2005): 987-96.
Wang, X. “The expanding role of mitochondria in apoptosis.” Genes Dev 15.22 (2001): 2922-33.
Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jääskeläinen J, Ram Z. “A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma.” Neuro Oncol. 5.2 (2003): 79-88.
Westphal M, Ram Z, Riddle V, Hilt D, Bortey E and Executive Committee of the Gliadel Study Group. “Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial.” Acta Neurochir (Wien). 48.3 (2006): 269-75.
Yang QS, Gu JL, Du LQ, Jia LL, Qin LL, Wang Y, Fan FY. “ShRNA-mediated Ku80 gene silencing inhibits cell proliferation and sensitizes to gamma-radiation and mitomycin C induced apoptosis in esophageal squamous cell carcinoma lines.” J Radiat Res. 49.4 (2008): 399-407.
BACE1 Inhibition role played in the underlying Pathology of Alzheimer’s Disease
Merck Presents Findings from Phase 1b Study of Investigational BACE Inhibitor, MK-8931, in Patients with Alzheimer’s Disease
Sunday, July 14, 2013 8:30 am EDT
“Further evaluation of MK-8931 continues in our EPOCH study, a Phase II/III trial in patients with mild to moderate Alzheimer’s.”
Merck, known as MSD outside the United States and Canada, today announced the presentation of results from a Phase Ib study showing a dose-dependent decrease in β amyloid levels in cerebral spinal fluid (CSF) following administration of MK-8931, Merck’s investigational oral β-site amyloid precursor protein cleaving enzyme (BACE1 or β secretase) inhibitor, in patients with mild to moderate Alzheimer’s disease (AD). In the study, β amyloid levels were analyzed as a measure of BACE activity. The data were presented during an oral session at the Alzheimer’s Association International Conference (AAIC) in Boston, July 13-18 (Abstract O1-06-05).
“The amyloid β reduction observed with MK-8931 may offer an opportunity to further understand the role BACE1 inhibition plays in the underlying pathology of Alzheimer’s disease,” said Darryle Schoepp, Ph.D., vice president of Neuroscience Early Development and Discovery Sciences, Merck. “Further evaluation of MK-8931 continues in our EPOCH study, a Phase II/III trial in patients with mild to moderate Alzheimer’s.”
Results of MK-8931 Phase Ib Study
The randomized, double-blind, placebo-controlled multiple dose study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamic profile of MK-8931 in patients with mild to moderate AD (n=32). Patients were randomized to receive one of three doses (12 mg, 40 mg and 60 mg) orally of MK-8931 or placebo once-daily for seven days. Samples of CSF were collected via a lumbar catheter and analyzed for levels of amyloid β 40 (Aβ40), amyloid β 42 (Ab42) and soluble amyloid precursor protein β (sAPPb) as biomarkers of BACE1 activity.
In this study, administration of MK-8931 at doses of 12, 40 and 60 mg resulted in a dose-dependent and sustained reduction in the levels of Ab40, a measure of BACE1 activity, in CSF from baseline of 57, 79 and 84 percent, respectively. The mean percentage of baseline in biomarkers Aβ40, Aβ42 and sAPPβ for each dose of MK-8931 as measured following a seven day dosing period is shown in the table.
Dose MK-8931
*Ab40
[TWA 0-24hrs (90% CI)]
*Ab42
[TWA 0-24hrs (90% CI)]
*sAPPb
[TWA 0-24hrs (90% CI)]
12 mg
(n=8)
43%
(37-49%)
47%
(39-54%)
37%
(32-41%)
40 mg
(n=8)
21%
(15-27%)
29%
(21-36%)
17%
(13-22%)
60 mg
(n=8)
16%
(10-22%)
19%
(11-26%)
12%
(7-17%)
*Percentage concentration relative to baseline averaged over 24 hours following administration of MK-8931 for 7 days (time weighted average from 0-24 hours post dose, (TWA 0-24hrs).
CI=confidence interval
No serious adverse events or study discontinuations due to adverse events were recorded. Analysis of vital signs and laboratory assessments, including liver function tests, showed no statistically significant changes related to the administration of MK-8931. Adverse events reported in two or more subjects in at least one dose group included: headache, dizziness, nausea, vomiting, insomnia and back pain. All adverse events were generally mild to moderate in intensity and transient in duration. No dose-dependent increase in the incidence of adverse events was observed.
Previously, Merck researchers presented findings of a single dose Phase I study at the 2012 American Academy of Neurology (AAN) Annual Meeting, which demonstrated that administration of MK-8931 to healthy volunteers resulted in a reduction of Ab40 CSF levels of greater than 90 percent from baseline.
Other MK-8931 Presentations at AAIC 2013
Consistency of BACE1-mediated Brain Amyloid Production Inhibition by MK-8931 in Alzheimer’s Patients and Healthy Young Adults (Oral Session; July 17, 2013; 2:15 PM; Presentation #O4-05-05)
About the EPOCH Study
EPOCH (NCT01739348) is a 78-week, randomized, placebo-controlled, parallel-group, double-blind Phase II/III clinical trial to evaluate the efficacy and safety of three oral doses of MK-8931 (12, 40 or 60 mg) administered daily versus placebo in patients with mild to moderate AD. The study is currently enrolling the 200 patient Phase II portion of the study and is anticipated to enroll up to 1,700 patients in the main Phase III cohort. The primary efficacy outcomes of the study are the change from baseline in Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) score and the change from baseline in the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) score.
About BACE Inhibition and MK-8931
The amyloid hypothesis asserts that the formation of amyloid peptides that lead to amyloid plaque deposits in the brain is a primary contributor to the underlying cause of Alzheimer’s disease. BACE is believed to be a key enzyme in the production of amyloid β peptide. Evidence suggests that inhibiting BACE decreases the production of amyloid β peptide and may therefore reduce amyloid plaque formation and modify disease progression.
Merck is advancing several innovative mechanisms in Alzheimer’s disease, including candidates designed to modify disease progression and improve symptom control. Merck’s major effort in disease modification is our lead BACE inhibitor, MK-8931, and Merck is continuing to develop other BACE inhibitor candidates.
About Merck
Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter,Facebook and YouTube.
Merck Forward-Looking Statement
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.
Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.
Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2012 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).
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Vascular Surgery: International, Multispecialty Position Statement on Carotid Stenting, 2013 and Contributions of a Vascular Surgeon at Peak Career – Richard Paul Cambria, MD
Author and Curator: Aviva Lev-Ari, PhD, RN
Article ID #66: Vascular Surgery: International, Multispecialty Position Statement on Carotid Stenting, 2013 and Contributions of a Vascular Surgeon at Peak Career – Richard Paul Cambria, MD. Published on 7/14/2013
WordCloud Image Produced by Adam Tubman
Part One:
Vascular Surgery International, Multispecialty Position Statement on Carotid Stenting, 2013
Part Two:
Contributions of a Vascular Surgeon at Peak Career – Richard Paul Cambria, MD, Chief, Division of Vascular and Endovascular Surgery Co-Director, Thoracic Aortic Center @ MGH
I. Recollection of a visit at Dr. Cambria’s Office, 2004
II. Shadowing Dr. Cambria in OR @MGH
III. Dr. Cambria: Selection of Contributions to Scientific Research on Vascular Surgery
IV. Cardiovascular Clinical Observational Experience – Aviva Lev-Ari, PhD, RN
V. Cases with Complications: CEA and CAS
Part Three:
On 8/1/2013, Cleveland Clinic Reports Equivalence between carotid endarterectomy (CEA) and open-heart surgery (OHS) and carotid artery stenting (CAS) followed by coronary artery bypass graft (CABG) surgery or non-CABG cardiac surgery
Part One:
Vascular Surgery International, Multispecialty Position Statement on Carotid Stenting, 2013 Part
No other invasive intervention procedure in the history of Vascular Surgery has stormed the profession more than the two treatment options for carotid artery partial to complete blockage than Carotid endarterectomy (CEA) and Carotid angioplasty and stenting (CAS).
The debate required evidence based resolution for the two treatment options in terms of patient outcomes and adverse events. As the title of the Position statement explained below, the verdict is non equivocal: Routine Carotid Stenting is inferior to Carotid endarterectomy (CEA) from a patient safety and outcomes.
In conclusion, current global evidence shows that, even in the best academic centers, CAS is less effective (causing more strokes) and more expensive than CEA. It is premature that some guidelines have recently added support for routine practice CAS as an alternative to CEA for
asymptomatic43,44 and
low/ average surgical risk symptomatic patients43–45
because CAS may easily be misinterpreted by readers as being equivalent for
stroke prevention46 and
historical procedural standards were cited.
CAS, for these patients, should still only be performed and paid for within well‐designed, adequately powered trials. The US Center for Medicare and Medicaid Services is doing its job and setting an excellent global example. It is protecting Medicare beneficiaries from routine practice procedures, which are currently more likely to harm them and waste finite resources47 that could be used for their advantage. Meanwhile, we need to reassess the current routine practice role of CEA and deliver optimal current medical treatment to all who need it.
Clinical Trials Results
To avoid misguidance from calls for more routine practice (nontrial) carotid angioplasty/stenting (CAS), we need to distinguish relevant facts and patients’ best interests from all else (distractions). A recent editorial by White and Jaff1 is one publication which illustrates this need particularly well. First, these authors are correct in reminding us that the responsibility of physicians is to provide best patient care, putting aside personal interest. This is inherent in any profession.2 However, misconception, bias, and conflict of interest exist. Therefore, healthcare payment organizations, such as the US Center for Medicare and Medicaid Services are important gatekeepers to facilitate patient access to interventions that are likely to help them, as opposed to all others.
It is also true that CAS and carotid endarterectomy (CEA) result in better outcomes when patients are carefully selected and skilled operators perform the procedures in experienced centers.1 We would add that key indicators (such as 30‐day periprocedural stroke/death rates) must be accurately measured in routine (real‐world) practice, particularly as stroke and death rates here may be unacceptably higher than in trials. 3–5 Therefore, it is most appropriate, as suggested by White and Jaff,1 that coverage for carotid procedures be dependent on facility accreditation and audited measurement of key standards indicators in all practices performing these procedures.
This is a priority issue. White and Jaff1 also correctly state “a major change in evidence based stroke prevention strategies will require clinical trial data.,7,8 meta‐analyses, and routine practice.9–14 Most of these data relate to low/average risk symptomatic patients and demonstrate that, for these patients, even in the best academic centers, CAS is consistently associated with significantly higher rates of stroke or death (during or after the periprocedural period) compared with CEA.
It is incorrect that CREST “failed to show a difference in overall stroke rate between CAS and CEA” as stated by White and Jaff.1 In CREST, for average surgical risk symptomatic patients, the periprocedural stroke and death rates were 6.0% for CAS versus 3.2% for CEA (hazard ratio, 1.89; 95% confidence interval, 1.11–3.21; P=0.02).8
The higher periprocedural risk of stroke or death with CAS is particularly evident in the most senior patients (>68–70 years),13,15,16 those undergoing the procedure <7 days of incident cerebral or retinal ischemic symptoms17 (when CEA has the highest stroke prevention potential),18 those undergoing CAS outside clinical trials,19 and those with certain anatomic features.20 No study has shown that CAS is more effective than CEA in preventing stroke. Further, most analyses show that CAS costs considerably more,21–24 despite calculations derived from CREST results.25 No randomized trial has been adequately powered to compare the procedural and longer term risk of CAS on stroke or death in low/average risk asymptomatic patients. However, in CREST, the direction of effect was toward nearly twice the risk (periprocedural stroke/death rate was 2.5% for CAS versus 1.4% for CEA; hazard ratio, 1.88; 95% confidence interval, 0.79–4.42; P=0.15).8 This was consistent with the significantly higher periprocedural stroke rates seen in CREST CAS‐treated symptomatic patients8 and nontrial CAS‐treated asymptomatic patients.9,26
Meanwhile, medical treatment for asymptomatic carotid disease has improved significantly since past randomized trials of medical treatment alone versus additional CEA.27–32 Medical treatment consists of identification of risk factors for heart and vascular disease and risk reduction using healthy lifestyles and appropriate drugs. Improvement in medical treatment is clear from robust analyses of all published comparable, quality stroke rate calculations (including from, and within, randomized surgical trials) of patients with 50% to 99% asymptomatic carotid stenosis. This knowledge is not, as claimed by White and Jaff,1 derived from short‐cut extrapolation from coronary artery trials. Using the same standardized rate calculations, we are now seeing an average annual rate of ipsilateral stroke of ≈0.5% with medical treatment alone.30,33,34 This is about 3X— lower than that of asymptomatic CREST CAS‐treated patients and about half the rate of asymptomatic CREST CEA‐treated patients.7,9 This low rate with medical treatment is likely to fall further with improvements in efficacy, definition, and implementation.
However, recently published rate calculations indicate that, at most, only ≈2.5% of low/average CEA risk patients with 50% to 99% asymptomatic carotid stenosis will receive a stroke prevention benefit from CEA or CAS during their remaining average 10‐year lifetime if they receive good, current medical treatment (assuming the procedural risk of stroke/death is always zero).35 This indicates that a one‐size‐fits‐all procedural approach for these asymptomatic patients is now unlikely to be beneficial overall. We need to be much more selective. Research is required to determine which asymptomatic subgroups now benefit from carotid procedures in addition to current optimal medical treatment.
We have found no direct information about the influence of current medical treatment in patients with low/average CEA risk symptomatic carotid stenosis. However, improving results for medically treated asymptomatic patients27–32 and procedural trial asymptomatic and symptomatic patients8 indicate that a 6% periprocedural risk of
stroke or
death (the current standard) is now too high.
New randomized and risk stratification studies are required using current optimal medical treatment and procedural methods.36 For example,
improved plaque37 and
thrombus identification38 or
embolic signal detection39 above and below the stenosis
may help better identify carotid plaques responsible for carotid territory ischemic symptoms. Further, the best approach for patients with high surgical risk carotid stenosis remains uncertain because risk of stroke or death has not been measured with any standard of medical treatment or adequate procedural trials. However, some registries show significantly higher risks of stroke/death with CAS compared with CEA in asymptomatic and symptomatic high surgical risk patients.40
Incidence of MI
Calls from other authors for more routine CAS on the grounds of lower periprocedural myocardial infarction (MI) rates compared with CEA are distracting.41 MI is not a measure of stroke prevention efficacy, even though it is an important procedural complication. The inclusion of periprocedural MI with stroke and death in the primary outcome measure in CREST resulted in primary outcome equivalence between CAS and CEA. However, it did not result in efficacy equivalence. In CREST, 1.1% (14/1262) of CAS patients had periprocedural clinical MI (biomarkers plus chest pain/ECG evidence) compared with 2.3% (28/1240) of CEA patients7 (P=0.03). However, periprocedural stroke was nearly twice as common (81/2502; 3.2%)7 as periprocedural clinical MI (42/2502; 1.7%) and, as mentioned above, CAS caused almost twice as many of these strokes as CEA.Further, in CREST, the mortality rate up to 4 years was equally poor for CREST patients with periprocedural stroke (20%),42 periprocedural clinical MI (19%),41 or periprocedural biomarker‐positive only MI (25%).41 Finally, nonfatal stroke was associated with a poorer quality of life at 1 year than nonfatal MI.7 Therefore, MI is a measure of carotid procedural risk (not benefit) and must be considered separately from stroke risk. Moreover, in CREST, CAS‐associated stroke was more troublesome for patients than CEA‐associated MI.
Conclusion
Calls for More Routine Carotid Stenting Are Currently Inappropriate, 3/2013
Carotid artery disease, also called carotid artery stenosis, occurs when the carotid arteries, the main blood vessels that carry oxygenated blood to the brain, become narrowed. The narrowing of the carotid arteries is most commonly related to atherosclerosis (a buildup of plaque, which is a deposit of fatty substances, cholesterol, cellular waste products, calcium, and fibrin in the inner lining of an artery). Atherosclerosis, or “hardening of the arteries,” is a vascular disease (disease of the arteries and veins). Carotid artery disease is similar to coronary artery disease, in which blockages occur in the arteries of the heart, and may cause a heart attack.
Click Image to Enlarge
To better understand how carotid artery disease affects the brain, a basic review of the anatomy of the circulation system of the brain follows.
What are the carotid arteries?
The main supply of blood to the brain is carried by the carotid arteries. The carotid arteries branch off from the aorta (the largest artery in the body) a short distance from the heart, and extend upward through the neck carrying oxygen-rich blood to the brain.
There are four carotid arteries: the right and left internal carotid arteries and the right and left external carotid arteries. One pair (external and internal) is located on each side of the neck. Just as a pulse can be felt in the wrists, a pulse can also be felt on either side of the neck over the carotid arteries.
Click to Enlarge
Why are the carotid arteries important?
Because the carotid arteries deliver blood to the brain, carotid artery disease can have serious implications by reducing the flow of oxygen to the brain. The brain needs a constant supply of oxygen in order to function. Even a brief interruption in blood supply can cause problems. Brain cells begin to die after just a few minutes without blood or oxygen. If the narrowing of the carotid arteries becomes severe enough to block blood flow, or a piece of atherosclerotic plaque breaks off and obstructs blood flow to the brain, a stroke may occur.
What causes carotid artery disease?
Atherosclerosis is the most common cause of carotid artery disease. It is unknown exactly how atherosclerosis begins or what causes it. Atherosclerosis is a slow, progressive, vascular disease that starts as early as childhood. However, the disease has the potential to progress rapidly. It is generally characterized by the accumulation of fatty deposits along the innermost layer of the arteries. If the disease process progresses, plaque formation may take place. Plaque is made up of deposits of smooth muscle cells, fatty substances, cholesterol, calcium, and cellular waste products. This thickening narrows the arteries and can decrease blood flow or completely block the flow of blood to the brain.
Risk factors associated with atherosclerosis include:
Older age
Male
Family history
Race or ethnicity
Genetic factors
Hyperlipidemia (elevated fats in the blood)
Hypertension (high blood pressure)
Smoking
Diabetes
Obesity
Diet high in saturated fat
Lack of exercise
A risk factor is anything that may directly increase or be associated with a person’s chance of developing a disease. It may be an activity, such as smoking, diet, family history, or many other things. Different diseases have different risk factors.
Although these risk factors increase a person’s risk, they do not necessarily cause the disease. Some people with one or more risk factors never develop the disease, while others develop disease and have no known risk factors. Knowing your risk factors to any disease can help to guide you into the appropriate actions, including changing behaviors and being clinically monitored for the disease.
What are the symptoms of carotid artery disease?
Carotid artery disease may be asymptomatic (without symptoms) or symptomatic (with symptoms). Asymptomatic carotid disease is the presence of a significant amount of atherosclerotic buildup without obstructing enough blood flow to cause symptoms. However, a sufficiently tight stenosis will not always cause symptoms. Symptomatic carotid artery disease may result in either a transient ischemic attack (TIA) and/or a stroke (brain attack).
A transient ischemic attack (TIA) is a sudden or temporary loss of blood flow to an area of the brain, usually lasting a few minutes to one hour. Symptoms go away entirely within 24 hours, with complete recovery. Symptoms of a TIA may include, but are not limited to, the following:
Sudden weakness or clumsiness of an arm and/or leg on one side of the body
Sudden paralysis (inability to move) of an arm and/or leg on one side of the body
Loss of coordination or movement
Confusion, decreased ability to concentrate, dizziness, fainting, and/or headache
Numbness or loss of sensation (feeling) in the face
Numbness or loss of sensation in an arm and/or leg
Temporary loss of vision or blurred vision
Inability to speak clearly or slurred speech
TIA may be related to severe narrowing or blockage or from small pieces of an atherosclerotic plaque breaking off, traveling through the bloodstream, and lodging in small blood vessels in the brain. With TIA, there is rarely permanent brain damage.
Call for medical help immediately if you suspect a person is having a TIA, as it may be a warning sign that a stroke is about to occur. Not all strokes, however, are preceded by TIAs.
Stroke is another indicator of carotid artery disease. The symptoms of a stroke are the same as for a TIA. A stroke is loss of blood flow (ischemia) to the brain that continues long enough to cause permanent brain damage. Brain cells begin to die after just a few minutes without oxygen. The area of dead cells in tissues is called an infarct.
The area of the brain that suffered the loss of blood flow will determine what the physical or mental disability may be. This may include impaired ability with movement, speech, thinking and memory, bowel and bladder function, eating, emotional control, and other vital body functions. Recovery from the specific ability affected depends on the size and location of the stroke. A stroke may result in problems, such as weakness in an arm or leg or may cause paralysis, loss of speech, or even death.
The symptoms of carotid artery disease may resemble other medical conditions or problems. Always consult your doctor for a diagnosis.
How is carotid artery disease diagnosed?
In addition to a complete medical history and physical examination, diagnostic procedures for carotid artery disease may include any, or a combination, of the following:
Auscultation (listening to) of carotid arteries. Placement of a stethoscope over the carotid artery to listen for a particular sound called a bruit (pronounced brew-ee). A bruit is an abnormal sound that is produced by blood passing through a narrowed artery. A bruit is generally considered a sign of an atherosclerotic artery; however, an artery may be diseased without producing this sound.
Carotid artery duplex scan. A type of vascular ultrasound study performed to assess the blood flow of the carotid arteries. A carotid artery duplex scan is a noninvasive (the skin is not pierced) procedure. A probe called a transducer sends out ultrasonic sound waves at a frequency too high to be heard. When the transducer (like a microphone) is placed on the carotid arteries at certain locations and angles, the ultrasonic sound waves move through the skin and other body tissues to the blood vessels, where the waves echo off of the blood cells. The transducer picks up the reflected waves and sends them to an amplifier, which makes the ultrasonic sound waves audible. Absence or faintness of these sounds may indicate an obstruction to the blood flow.
Magnetic resonance imaging (MRI). A diagnostic procedure that uses a combination of large magnets, radiofrequencies, and a computer to produce detailed images of organs and structures within the body. To have this test done, you lie inside a big tube while magnets pass around your body. It is very loud. Sometimes it is done with IV contrast injected into your veins and sometimes not.
Magnetic resonance angiography (MRA). A noninvasive diagnostic procedure that uses a combination of magnetic resonance technology (MRI) and intravenous (IV) contrast dye to visualize blood vessels. Contrast dye causes blood vessels to appear opaque on the MRI image, allowing the doctor to visualize the blood vessels being evaluated.
Computed tomography scan (also called a CT or CAT scan). A diagnostic imaging procedure that uses a combination of X-rays and computer technology to produce horizontal, or axial, images (often called slices) of the body. A CT scan shows detailed images of any part of the body, including the bones, muscles, fat, and organs. CT scans are more detailed than general X-rays. Like an MRI, it is sometimes done with IV contrast injected into your veins and sometimes not.
Angiography. An invasive procedure used to assess the degree of blockage or narrowing of the carotid arteries by taking X-ray images while a contrast dye in injected. The contrast dye helps to visualize the shape and flow of blood through the arteries as X-ray images are made.
Treatment for carotid artery disease
Specific treatment for carotid artery disease will be determined by your doctor based on:
Your age, overall health, and medical history
Extent of the disease
Your signs and symptoms
Your tolerance of specific medications, procedures, or therapies
Expectations for the course of the disease
Your opinion or preference
Carotid artery disease (asymptomatic or symptomatic) in which the narrowing of the carotid artery is less than 50 percent is most often treated medically. Asymptomatic disease with less than 70 percent narrowing may also be treated medically, depending on the individual situation.
Medical treatment for carotid artery disease may include:
Modification of risk factors. Risk factors that may be modified include smoking, elevated cholesterol levels, elevated blood glucose levels, lack of exercise, poor dietary habits, and elevated blood pressure.
Medications. Medications that may be used to treat carotid artery disease include:
Antiplatelet medications. Medications used to decrease the ability of platelets in the blood to stick together and cause clots. Aspirin, clopidogrel, and dipyridamole are examples of antiplatelet medications.
Antihyperlipidemics. Medications used to lower lipids (fats) in the blood, particularly cholesterol. Statins are a group of antihyperlipidemic medications, and include simvastatin, atorvastatin, and pravastatin, among others. Studies have shown that certain statins can decrease the thickness of the carotid artery wall and increase the size of the lumen (opening) of the artery.
Antihypertensives. Medications used to lower blood pressure. There are several different groups of medications which act in different ways to lower blood pressure.
In people with narrowing of the carotid artery greater than 50 to 69 percent, a more aggressive treatment may be recommended, particularly in people with symptoms. Surgical treatment decreases the risk for stroke after symptoms such as TIA or minor stroke, especially in people with an occlusion (blockage) of more than 70 percent who are good candidates for surgery.
Surgical treatment of carotid artery disease includes:
Carotid endarterectomy (CEA). Carotid endarterectomy is a procedure used to remove plaque and clots from the carotid arteries, located in the neck. Endarterectomy may help prevent a stroke from occurring in people with symptoms with a carotid artery narrowing of 70 percent of more.
Illustration of Carotid Endarterectomy (Click to Enlarge)
Carotid artery angioplasty with stenting (CAS). Carotid angioplasty with stenting is an option for patients who are high risk for carotid endarterectomy. This is a minimally invasive procedure in which a very small hollow tube, or catheter, is advanced from a blood vessel in the groin to the carotid arteries. Once the catheter is in place, a balloon may be inflated to open the artery and a stent is placed. A stent is a cylinder-like tube made of thin metal-mesh framework used to hold the artery open. Because there is a risk of stroke from bits of plaque breaking off during the procedure, an apparatus, called an embolic protection device, may be used. An embolic protection device is a filter (like a small basket) that is attached on a guidewire to catch any debris that may break off during the procedure.
Carotid Artery Angioplasty with Stenting (CAS) Click to Enlarge
Carotid Artery Disease and Stroke: Prevention and Treatment – John Hopkins
VIEW VIDEO –
Carotid Endarterectomy with Temporary Bypass – A Fifty year old procedure
Docteur Jean VALLA
Chirurgien Cardiovasculaire et Thoracique
AIHR/ACCA – Ancien Chirurgien des Hôpitaux Universitaires.
Membre de la Société de Chirurgie Thoracique et Cardiovasculaire de Langue Française Conventionné
Carotid artery stenosis is the narrowing of the carotid arteries. These are the main arteries in the neck that supply blood to the brain. Carotid artery stenosis, also called carotid artery disease, is a major risk factor for ischemic stroke.The narrowing is usually caused by plaque in a blood vessel. Plaque forms when cholesterol, fat and other substances build up in the inner lining of an artery.Depending on the degree of stenosis and the patient’s overall condition, carotid artery stenosis can usually be treated with surgery. The procedure is called carotid endarterectomy. It removes the plaque that caused the carotid artery to narrow. Carotid endarterectomy has proven to benefit patients with arteries stenosed (narrowed) by 70 percent or more. For people with arteries narrowed less than 50 percent, anti-clotting medicine is usually prescribed to reduce the risk of ischemic stroke.
VIEW VIDEO –
Carotid angioplasty and stenting (CAS) – Mayo Clinic
In carotid angioplasty and stenting, a long hollow tube called a catheter is inserted in the femoral artery in the groin area. The catheter is then maneuvered through the arteries until it reaches the narrowing in the carotid artery in the neck. An umbrella-shaped filter is inserted beyond the narrowing to catch any plaque or debris that may break off during the procedure. Then, a tiny balloon at the end of the catheter is inflated to push the plaque to the side and widen the vessel. A small metal coil called a stent is inserted into the vessel. The stent serves as a scaffold to help prevent the artery from narrowing again.
Contributions of a Vascular Surgeon at Peak Career – Richard Paul Cambria, MD, Chief, Division of Vascular and Endovascular Surgery Co-Director, Thoracic Aortic Center @ MGH
I. Recollection of a visit at Dr. Cambria’s Office @MGH, 2004
The author arrived for a 4PM appointment @ MGH with a referral from NWH for a Carotid artery duplex scan that in 2004 was not performed at NWH. The consultation appointment with Dr. Kwolek CJ, a vascular surgeon trained under Dr. RP Cambria, took place in Dr. Cambria’s Office. Few minutes into the patient Medical History interview, Dr. Kwolek was called for an emergency in the OR and asked me to wait for him till he comes back. I looked around and found myself in a 14’x22′ Room, the Office of Dr. Richard Cambria @ MGH, Chief Vascular Surgery and among the Top ten in the World. Except for the glass entrance door and the wide window to the right of the entrance – 3 1/2 walls from the ceiling to one yard above the floor where completely covered with framed Awards, licenses, renewed licenses, Pictures with graduating Medical Students, Pictures with Faculty, with Patients and in the OR. I waited for Dr. Kwolek’s return for the completion of my Medical History Interview about 30 minutes. I used that time to walk along the walls in Dr. Cambria’s Office and read the framed Exhibits. It was clear to me that this Office will need, one day, in the future, to become a Museum @MGH, for most significant milestones in Vascular Surgery, a branch of Cardiothoracic Surgery. Dr. Kwolek returned and completed the interview, scheduled my Lab appointment and the next appointment to discuss the duplex scan results.
II. Shadowing Dr. Cambria in OR @MGH
Per section IV, below which described the author’s Cardiovascular Clinical Observational Experience, I recorded my Shadowing experience at the OR @MGH, including Dr. Cambria performing a CEA on a 84 year old women under going aorta valve replacement (performed by Dr. Walker) priot to a CEA performed by Dr. Cambria. It was all captivating to watch his double gloved hands performing sutures on a >95% blocked carotid artery prior to incision.
The dexterity and the speed of Dr. Cambria’s fingers’ movement, could only have reminded me of World #1 Harp Player: Nicanor Zabaleta, which I met in person, in the presence of my prominent Harp teacher, on his US Tour in 11/1989. He was awarded the Premio Nacional de Música of Spain in 1982 and six years later, in 1988, he was elected to the Real Academia de Bellas Artes de San Fernando. Dr. Cambria’s and Mr. Zabaleta’s fingers dexterity and eye hand coordination, both are of the rarest endowments in fine motor precision and perfection with Worldly finest outcomes in art, Surgery is Art, the mastering of the Harp is Art, too.
The Author in the OR — Mass General Hospital, Boston
Cardiac Surgery – Operating Room
Supervisor: Dr. J. Walker, Cardiac Surgeon
Experience: Shadowing Open Heart Surgery at MGH
1/24/2005: Carotid Artery endarterectomy operation by Dr. Richard Cambria
1/24/2005: Mitral Valve Replacement by Dr. Jennifer Walker
1/26/2005: Aorta Valve Replacement and Coronary Artery Bypass Grafting by Dr. Jennifer Walker
[Saphenous vein harvested from the leg and Radial vein harvested from the right arm]
III. Dr. Cambria: Selection of Contributions to Scientific Research on Vascular Surgery
The Author covered In Part One, Dr. Cambria’s participation in and contribution to the International, Multispecialty Position Statement on Carotid Stenting, 2013.
In Part Two Section II, I share with the e-Reader watching Dr. Cambria in the Surgical Theater performing CEA
In Part Two Section III, I am carrying with me the heavy weight of my Recollections from a Visit to his Office in 2004, my experience shadowing Dr. Cambria in the OR @MGH on 1/24/2005. Now I am giving back.
I became aware that both events have impacted favorably my 7/2013, Editorial decision, for a forthcoming book on Cardiovascular Disease in 2013. The Editorial decision is two fold:
the selection and representation of a prominent Vascular Surgery Center in the US, @MGH, and
my personal decision to select a Vascular Surgeon at Peak Career – Richard Paul Cambria, MD @MGH.
The decision to focus on Peripheral Vascular Surgery @MGH as described in Dr. Richard P Cambria’s research had yielded one Sub-Chapter (5.5) in Chapter 5
Chapter 5
Invasive Procedures by Surgery versus Catheterization
in Volume Three in a forthcoming three volume Series of e-Books on Cardiovascular Diseases
This very Sub-Chapter, 5.5, represents milestones in Dr. Cambria as a Vascular Surgeon. His eminent profile as a Vascular Surgery Researcher, is now in:
IV. Cardiovascular Clinical Observational Experience – Aviva Lev-Ari, PhD, RN
Brigham and Women’s Hospital, Boston. MA
Cardiac ICU, Coronary Care Unit, Medical Rounds [100 hours] June 2006-November 2006
Brigham and Women’s Hospital, Boston. MA
CDIC – Cardiovascular Diagnostic and Interventional Center
Angiography & Interventional Radiology [100 hours] March 2006-August 2006
Experience shadowing the daily activities of three Physician Assistants
1. attended consultation appointments with patient candidate for procedures: fibroid embolization
2. patient candidate for intra-vertebral cement injection in fractured vertebrae in spinal column, L-9 – Kyphoplasty vertebral augmentation
3. drainage of bile leakage – biliary duct obstruction
4. attended invasive procedures in the Angiography Lab
5. attended 7:30AM department meeting on all cases scheduled for procedures in the Lab for the day
6. discussed procedure outcomes and patient follow ups with PAs
7. Shadowing PAs and Interventional Radiologists performing angiography.
– VENOUS ACCESS PROCEDURES – TUNNELED CATHETER AND PORT PLACEMENT
– DIALYSIS ACCESS MANAGEMENT – ARTERIOVENOUS FISTULA/GRAFT.
ANGIOGRAMS/ANGIOPLASTIES
Mass General Hospital, Boston
Cardiac Catheterization Lab
Supervisor: Dr. Igor Palacios, Director, Cath Lab
Experience Shadowing in the Cath Lab at MGH
1/19/2005: stenting – MI case, mitral valve opening with balloon
The cerebral hyperperfusion syndrome is a very rare complication after revascularization of the carotid artery and accompanied by postoperative or postinterventional hypertension in almost all patients. We report a case of a 77-year-old man who developed a complete aphasia and increased right-sided weakness following endovascular treatment of severe occlusive disease of the left internal carotid artery. We discuss the risk and management of cerebral hyperperfusion syndrome after carotid artery stenting.
Introduction
Neurological complications following carotid artery stenting (CAS) are usually ischemic in nature, due to embolization or occlusion of the carotid artery. However, in a small subset of patients, cerebral hyperperfusion causes postinterventional neurological dysfunction, characterized by ipsilateral headache, focal seizure activity, focal neurological deficit, and ipsilateral intracerebral edema or hemorrhage. A high clinical suspicion and early diagnosis will allow early initiation of therapy and preventing fatal brain swelling or bleeding in patients with peri- and postinterventional cerebral hyperperfusion syndrome (CHS).
Discussion
In 1981, Sundt et al. [1] described a triad of complications that included atypical migrainous phenomena, transient focal seizure activity, and intracerebral hemorrhage after CEA and used the term cerebral hyperperfusion syndrome (CHS). The first report on CHS after CAS was published by Schoser et al. [2]. They described a 59-year-old woman with ipsilateral putaminal hemorrhage that was diagnosed on the 3rd day after CAS of a high-grade stenosis of the left ICA. Outcome in this case was not fatal. The patient recovered with a mild upper limb paresis. McCabe et al. [3] were the first to report the occurrence of fatal ICH soon after CAS. Only a few hours after the procedure, neurological symptoms occurred without any prodromata (severe headache, nausea, and seizures) postulated by Sundt et al. [1] to be an obligate component of CHS. CT of the brain revealed extensive ICH and the patient died 18 days later. Abou-Chebl et al. [4] reported a retrospective single-center study on 450 patients who had been treated with CAS. Three patients (0.67%) developed ICH after the intervention. Further reports on results and complications after CAS have been published [5]. Nearly all reports on CHS after carotid revascularizations in general and CAS in particular have in common patients who had high-grade stenoses in the treated vessel.
CHS following surgical or endovascular treatment of severe carotid occlusive disease is thought to be the result of impaired cerebral autoregulation, hypertension, ischemia-reperfusion injury, oxygen-derived free radicals, baroreceptor-dysfunction, and intraprocedural ischemia [6]. Chronic cerebral hypoperfusion due to critical stenosis leads to production of vasodilatory substances. Autoregulatory failure results in the cerebral arterioles being maximally dilated over a long period of time, with subsequent loss of their ability to constrict when normal perfusion pressure is restored. The degree of microvascular dysautoregulation is proportional to the duration and severity of ischemia determined by the severity of ipsilateral stenosis and poor collateral flow.
Hypertension plays an important role in the development of CHS. In the absence of cerebral autoregulation, cerebral blood flow is directly dependent on the systemic blood pressure. The restoration of normal blood flow to chronically underperfused brain can result in edema, capillary breakthrough, and perivascular and macroscopic hemorrhages aggravated by peri- and postinterventional hypertension [6, 7]. The risk factors for CHS after CAS are summarized in Table 1.
The classic clinical presentation includes ipsilateral headache, seizures or focal neurological deficit, and ipsilateral intracerebral edema or hemorrhage. The diagnosis can be made readily with color Doppler ultrasound of the carotid artery and especially with transcranial Doppler (TCD) of the middle cerebral artery [9]. An increase in peak blood flow velocity of >100% is predictive of postinterventional hyperperfusion. Diffusion weighted MRI or single photon emission computed tomography (SPECT) could also be performed for diagnosis [10]. Angiography normally shows normal findings.
The prognosis of CHS depends on timely recognition of hyperperfusion and adequate treatment of hypertension before cerebral edema or hemorrhage develops. The prognosis following intracerebral bleeding is very poor, with mortality over 50% and significant morbidity of 80% in the survivors [4, 6]. The prognosis of CHS in patients without cerebral edema or hemorrhage is clearly better especially when they are identified and treated early. The most important aspects in preventing and treating this syndrome are early identification, careful monitoring, and control of blood pressure ideally in a high-dependency unit setting. In our special case, early diagnosis of CHS and immediate intensive medical treatment of blood pressure could prevent devastating cerebral edema or hemorrhage following CAS.
Conclusion
CHS, which is characterized by ipsilateral headache, hypertension, seizures, and focal neurological deficits, is a rare but devastating complication following carotid artery stenting. Hypertension is the most important risk factor. The diagnosis can be confirmed quickly by TCD, DWI, or SPECT. Especially peri- or postinterventional TCD monitoring should be available to identify patients with hyperperfusion who may benefit from intensive blood pressure management ideally in a specialized intensive care unit.
Abbreviations
CAS:
Carotid artery stenting
CCA:
Common carotid artery
CEA:
Carotid endarterectomy
CHS:
Cerebral hyperperfusion syndrome
CT:
Computed tomography
CVR:
Cerebrovascular reactivity
DWI:
Diffusion-weighted imaging
ICA:
Internal carotid artery
ICH:
Intracerebral haemorrhage
MRI:
Magnetic resonance imaging
SPECT:
Single photon emission computed tomography
TCD:
Transcranial Doppler.
REFERENCES
T. M. Sundt Jr., F. W. Sharbrough, and D. G. Piepgras, “Correlation of cerebral blood flow and electroencephalographic changes during carotid endarterectomy. With results of surgery and hemodynamics of cerebral ischemia,” Mayo Clinic Proceedings, vol. 56, no. 9, pp. 533–543, 1981.View at Scopus
B. G. H. Schoser, C. Heesen, B. Eckert, and A. Thie, “Cerebral hyperperfusion injury after percutaneous transluminal angioplasty of extracranial arteries,” Journal of Neurology, vol. 244, no. 2, pp. 101–104, 1997. View at Publisher · View at Google Scholar · View at Scopus
D. J. H. McCabe, M. M. Brown, and A. Clifton, “Fatal cerebral reperfusion hemorrhage after carotid stenting,” Stroke, vol. 30, no. 11, pp. 2483–2486, 1999. View at Scopus
A. Abou-Chebl, J. S. Yadav, J. P. Reginelli, C. Bajzer, D. Bhatt, and D. W. Krieger, “Intracranial hemorrhage and hyperperfusion syndrome following carotid artery stenting: risk factors, prevention, and treatment,” Journal of the American College of Cardiology, vol. 43, no. 9, pp. 1596–1601, 2004. View at Publisher · View at Google Scholar · View at Scopus
J.-H. Buhk, L. Cepek, and M. Knauth, “Hyperacute intracerebral hemorrhage complicating carotid stenting should be distinguished from hyperperfusion syndrome,” American Journal of Neuroradiology, vol. 27, no. 7, pp. 1508–1513, 2006. View at Scopus
W. F. Morrish, S. Grahovac, A. Douen et al., “Intracranial hemorrhage after stenting and angioplasty of extracranial carotid stenosis,” American Journal of Neuroradiology, vol. 21, no. 10, pp. 1911–1916, 2000. View at Scopus
R. Gupta, A. Abou-Chebl, C. T. Bajzer, H. C. Schumacher, and J. S. Yadav, “Rate, predictors, and consequences of hemodynamic depression after carotid artery stenting,” Journal of the American College of Cardiology, vol. 47, no. 8, pp. 1538–1543, 2006. View at Publisher · View at Google Scholar · View at Scopus
M. B. Sánchez-Arjona, G. Sanz-Fernández, E. Franco-Macias, and A. Gil-Peralta, “Cerebral hemodynamic changes after carotid angioplasty and stenting,” American Journal of Neuroradiology, vol. 28, pp. 640–644, 2007.
Y. Kaku, S. I. Yoshimura, and J. Kokuzawa, “Factors predictive of cerebral hyperperfusion after carotid angioplasty and stent placement,” American Journal of Neuroradiology, vol. 25, pp. 1403–1408, 2004.
Patient came to her appointment as part of a standard pre-operative evaluation for removal of a uterine myoma. She had a history of stroke with residual slurred speech, making it difficult to understand her. Accordingly, I assumed I would see some carotid stenosis, but her ultrasound showed a stunning 70-99% stenosis in her right internal carotid artery and full occlusion of her left internal carotid artery.
Flow in the common carotid arteries looked fine. The plaque itself in the internal carotid arteries was relatively hypoechoic and not easily visualized in brightness mode, so bidirectional color flow at the proximal internal carotid arteries was surprising. Adding power Doppler allowed me to conclude that there was presence of flow on the right, though minimal, and absolutely no flow in the left internal carotid artery.
Upon completion of the exam, I called the ER and spoke with the doctor, who asked me to bring Rose to the ER. Unfortunately, due to the location of the right internal carotid artery stenosis in the bony canal and total occlusion of the left internal carotid artery, surgery was not an option for clearing out the carotid plaque, but doctors believed she could continue functioning well with collateral vasculature carrying blood to her brain.
Thankfully, the patient passed her other pre-operative tests, consented to her surgery, and underwent general anesthesia with no complications. An 8-cm malignant mass was removed from her uterus and her prognosis is good.
opinion/26redberg.html. Last accessed Jan 8, 2013.
Part Three:
Cleveland Clinic Reports Equivalence between carotid endarterectomy (CEA) and open-heart surgery (OHS) and carotid artery stenting (CAS) followed by coronary artery bypass graft (CABG) surgery or non-CABG cardiac surgery
Stent first, then heart surgery, for patients with severe carotid/coronary disease
Cleveland, OH – With the absence of randomized, controlled clinical trials to address the optimal management of patients with severe carotid and coronary artery disease, a new retrospective study suggests the best tactic is a staged approach that sees the patient undergo carotid artery stenting (CAS) followed by coronary artery bypass graft (CABG) surgery or non-CABG cardiac surgery [1].
Investigators report that a combined approach that includes carotid endarterectomy (CEA) and open-heart surgery (OHS) is equivalent in terms of short-term outcomes with the staged CAS-OHS procedure. Beyond one year, however, the staged CAS-OHS approach resulted in the lowest risk of all-cause mortality, stroke, and MI when compared with a combined CEA-OHS procedure and staged CEA-OHS.
“The surgeons get very worried about doing operations on these patients because they don’t want to do a beautiful job on the bypass only to have the patient have a stroke,” lead investigator Dr Mehdi Shishehbor(Cleveland Clinic, OH) told heartwire.
Shishehbor said that when patients are undergoing open-heart surgery, whether it’s CABG or valve surgery, they are screened for carotid artery disease, given the heightened risk of stroke when undergoing heart surgery. As a result, various teams from neurology, vascular surgery, and interventional cardiology are called to address the safety of the surgery in the setting of severe carotid disease, said Shishehbor.
“These patients are the sickest of the sick in the sense that they have two conditions that are occurring concomitantly,” he said. “These are not patients who just have carotid disease. There are many patients who have moderate or mild carotid disease who undergo open-heart surgery with no problem. These are people with severe disease, those with more than 80% stenosis in one of their carotid arteries or maybe both. They also have severe coronary artery disease. These are people with left-main or three-vessel disease who are destined to undergo bypass.”
The whole point is to prevent stroke
In the study, published this week in the Journal of the American College Cardiology, the investigators reported data on 350 patients who underwent carotid revascularization and cardiac surgery. These included 45 patients who were treated with a staged CEA-OHS approach (OHS performed a median of 14 days after CEA), 110 who were treated with a staged CAS-OHS procedure (OHS performed a median of 47 days after CEA), and 195 patients treated with a combined CEA-OHS procedure. OHS is defined as CABG, CABG plus other cardiac procedures, or non-CABG cardiac surgery (isolated valve or aortic-repair surgery). In total, just 8% of procedures were non-CABG surgeries.
In a propensity-adjusted analysis analyzed by intention-to-treat, the 30-day risk of death, stroke, and MI was similar between the staged CAS-OHS and combined CEA-OHS procedures. The highest risk of the composite end point was observed in patients who underwent staged CEA-OHS.
At one year and beyond (median follow-up was 3.7 years), the staged CAS-OHS patients had the lowest risk of death, stroke, and MI. Compared with staged CEA-OHS, those treated with CAS-OHS had a 67% lower risk of death, stroke, and MI and a 65% lower risk compared with combined CEA-OHS.
Unadjusted comparison of primary/secondary end points
Event
Staged CEA-OHS,n=45 (%)
Combined CEA-OHS,n=195 (%)
Staged CAS-OHS,n=110 (%)
p
Overall 30-d risk post-OHS
31
10
10
0.003
Death
7
5
6
0.75
Stroke
2
7
2
0.11
MI
24
0.5
3
<0.001
Overall composite risk 1 y and beyond
27
39
12
<0.001
Death
38
39
11
<0.001
Stroke
2.2
1.5
0
0.37
MI
0
3.1
2.7
0.5
“In the long term, stenting [followed by OHS] definitely did better than the combined approach,” said Shishehbor. “What’s also important is that with the combined approach, the reason they didn’t do very well is because they had a higher rate of stroke in the perioperative period. . . . Remember the whole point of doing this is to prevent stroke. This is why we feel the combined approach is a little bit inferior to the staged CAS/open-heart-surgery approach. If you have a 7% risk of stroke in the 30-day perioperative period, that doesn’t appear to be the best option for the majority of patients.”
To heartwire, Shishehbor said that while the patients were well matched, the patients undergoing stenting tended to be sicker. For example, they were more likely to have symptomatic carotid stenosis and were more likely to have undergone a previous carotid revascularization. Shishehbor also said that clinical events occurring between the initial carotid artery revascularization procedure and OHS were included in the analysis. These deaths, strokes, and MIs were identified and accounted for in the data.
In an editorial accompanying the study [2], Drs Ehtisham Mahmud and Ryan Reeves (University of California, San Diego) say the work by the Cleveland Clinic group is strengthened by the propensity-adjusted analysis and long follow-up beyond the perioperative period. Most important, they say the study provides clarity for the management of patients with carotid and coronary disease.
“For patients presenting with an acute coronary syndrome requiring urgent coronary revascularization in whom waiting three to four weeks is not safe, combined CEA-OHS is the optimum revascularization strategy, though associated with higher neurological ischemic events,” write Mahmud and Reeves.
“However, for patients with a stable or an accelerating anginal syndrome who can wait three to four weeks to complete dual antiplatelet therapy [DAPT] after carotid stenting, staged CAS followed by OHS leads to superior early and long-term outcomes.”
Since completing the analysis, Shishehbor said there have been discussions with colleagues in vascular surgery, vascular medicine, cardiac surgery, and cardiology to establish the optimum way to treat patients with severe carotid and coronary disease. “The bottom line is that there will never be a randomized, clinical trial in this setting,” he told heartwire. “I hope there would be, but I doubt it. So I think papers like this are critical because we’re doing these procedures to prevent stroke. It’s important that we pick the right procedure for the right patient.”
Confounded by registry requirements
Shishehbor is also concerned about the scrutiny carotid stenting is under from the Centers for Medicare&Medicaid Services(CMS). Currently, the CMS reimburses procedures for asymptomatic patients only if they are included in one of the industry-funded and -maintained registries. He believes the scrutiny has led to a dwindling number of clinicians with the expertise capable of doing the procedure, and this is concerning, since the present analysis shows there are cohorts of asymptomatic patients who would benefit from the treatment.In addition, to be included in a registry, an asymptomatic patient must receive DAPT with aspirin andclopidogrel for four weeks. If the patient does not meet the DAPT requirements, they can’t be included in the registry. However, Shishehbor said, many of these patients have significant coronary disease and can’t wait four weeks. As a result, they are treated with a combined CEA-OHS approach, an approach that is associated with a higher risk of stroke.
Shishehbor reports serving as a speaker and consultant for Abbot Vascular, Medtronic, and Gore but waives all compensation for his work. Mahmud reports trial support from Boston Scientific and Abbott Vascular. In addition,he consults for Cordis andthe Medicines Companyand serves on the speaker‘s bureau for Medtronic. Disclosures for the coauthors are listed in the paper.
Sources
Shishehbor MH, Venkatachalam S, Sun Z, et al. A direct comparison of early and late outcomes with three approaches to carotid revascularization and open heart surgery. J Am Coll Cardiol 2013; available at: http://content.onlinejacc.org.
Mahmud E, Reeves R. Carotid revascularization prior to open heart surgery: The data driven treatment strategy. J Am Coll Cardiol 2013; available at: http://content.onlinejacc.org.
Annual treatment costs for musculoskeletal diseases in the US are roughly 7.7% (~ $849 billion) of total gross domestic product. Such disorders are the main cause of physical disability in US (I). The challenges of drug delivery for bone regeneration and reconstruction has been previously reported here by Dr. Aviral Vatsa (I-IV), herein, we will discussed the different needs for bone regeneration and the potential use if nanotechnology.
Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. However, there are complex clinical conditions in which bone regeneration is required in large quantity, such as for skeletal reconstruction of large bone defects created by trauma, infection, tumour resection and skeletal abnormalities, or cases in which the regenerative process is compromised, including avascular necrosis, atrophic non-unions and osteoporosis (1,2).
Regenerative medicine offers a way to improve ‘local’ strategies in terms of tissue engineering and gene therapy, or even ‘systemic’ enhancement of bone repair. To make regenerative medicine successful, three elements are required: stem cells, scaffolds, and growth factors (3).
Bones
Bone is a tough supporting tissue and functions in both movement and the maintenance of postural stability by working cooperatively with muscles as well as play a role in calcium metabolism. Despite its hard structure it exist in a dynamic turnover known as bone remodeling. There are two types of bone structures that naturally remodel during the a year:
cortical bone (~3%/year)
cancellous bone (~30%/year)
Jimi J et al. The schematic outlines of the bone remodeling cycle and the balance of bone resorption and bone formation
At the remodeling sites, osteoblasts produce new bone, while osteoclasts resorb existing bone. Each cell type seems to be regulated by a variety of hormones and by local factors. If the balance between bone formation and resorption is lost by uncontrolled production of these regulators, the bone structure will be damaged, and the subject would be susceptible to osteoporosis and osteopetrosis (2).
Current Clinical approaches:
Standard approaches widely used in clinical practice to stimulate or augment bone regeneration include distraction osteogenesis and bone transport.
As well as the use of a number of different bone-grafting methods, such as (1):
Autologous bone grafts – considered as the ‘gold standard‘ bone-grafting material, as it combines all properties required in a bone-graft material: osteoinduction (bone morphogenetic proteins (BMPs) and other growth factors), osteogenesis (osteoprogenitor cells) and osteoconduction (scaffold)
Allografts – obtained from human cadavers or living donors, which bypasses the problems associated with harvesting and quantity of graft material. Allogeneic bone is available in many preparations, including demineralised bone matrix (DBM), morcellised and cancellous chips, corticocancellous and cortical grafts, and osteochondral and whole-bone segments, depending on the recipient site requirements.
Bone-graftsubstitutes or growth factors – developed as alternatives to autologous or allogeneic bone grafts. They consist of scaffolds made of synthetic or natural biomaterials that promote the migration, proliferation and differentiation of bone cells for bone regeneration. Commonly performed surgical procedure to augment bone regeneration in a variety of orthopaedic and maxillofacial procedures.
The Masquelet technique is a two-step procedure for bone regeneration and reconstruction of long-bone defects. It is based on the concept of a “biological” membrane, which is induced after application of a cement spacer at the first stage and acts as a ‘chamber’ for the insertion of non-vascularised autograft at the second stage (2, 4).
There are non-invasive methods of biophysical stimulation, such as low-intensity pulsed ultrasound (LIPUS) and pulsed electromagnetic fields (PEMF) (1).
Limitations of Current approaches: Most of the current strategies for bone regeneration exhibit relatively satisfactory results. However, there are associated drawbacks and limitations to their use and availability, and even controversial reports about their efficacy and cost-effectiveness.
New Approaches:
New methods for studying this process, such as quantitative three-dimensional microcomputed tomography analyses, finite element modelling, and nanotechnology have been developed to further evaluate the mechanical properties of bone regenerate at the microscopic level. Here are some examples of the latest developments as reviewed by Dimitriou R at el (1).
BMPs and growth factors – They induce the mitogenesis of mesenchymal stem cells (MSCs) and other osteoprogenitors, and their differentiation towards osteoblasts. BMP-2 and BMP-7 have been licensed for clinical use since 2002 and 2001 respectively (5). These two molecules have been used in a variety of clinical conditions including non-union, open fractures, joint fusions, aseptic bone necrosis and critical bone defects. Platelet-derived growth factor (PDFG), transforming growth factor-β (TGF-b), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) have been also implicated in bone regeneration, with different functions in terms of cell proliferation, chemotaxis and angiogenesis. One current approach to enhance bone regeneration and soft-tissue healing by is local application of growth factors is the use of platelet-rich plasma alongside the autograph. BMPs are also being used in bone-tissue engineering.
MSCs – The current approach of delivering osteogenic cells directly to the regeneration site includes use of bone-marrow aspirate from the iliac crest, which also contains growth factors. It is a minimally invasive procedure to enhance bone repair, and produces satisfactory results (1). Overall, however, there are significant ongoing issues with quality control with respect to delivering the requisite number of MSCs/osteoprogenitors to effect adequate repair responses. Issues of quantity and alternative sources of MSCs are being extensively investigated. Novel approaches in terms of cell harvesting, in vitro expansion and subsequent implantation are promising.
Scaffolds and Bone substitutes – synthetic bone substitutes and biomaterials are already widely used in clinical practice for osteoconduction. DBM (Demineralized bone matrix) and collagen are biomaterials, used mainly as bone-graft extenders, as they provide minimal structural support. A large number of synthetic bone substitutes are currently available, such as HA, β-TCP and calcium-phosphate cements, and glass ceramics. These are being used as adjuncts or alternatives to autologous bone grafts. Especially for regeneration of large bone defects, where the requirements for grafting material are substantial, these synthetics can be used in combination with autologous bone graft, growth factors or cells (6). Improved biodegradable and bioactive three-dimensional porous scaffolds are being investigated, as well as novel approaches using nanotechnology, such as magnetic biohybrid porous scaffolds acting as a crosslinking agent for collagen for bone regeneration guided by an external magnetic field or injectable scaffolds for easier application.
Tissue Engineering – The tissue-engineering approach is a promising strategy added in the field of bone regenerative medicine, which aims to generate new, cell-driven, functional tissues, rather than just to implant non-living scaffolds. In essence, bone-tissue engineering combines progenitor cells, such as MSCs (native or expanded) or mature cells (for osteogenesis) seeded in biocompatible scaffolds and ideally in three-dimensional tissue-like structures (for osteoconduction and vascular ingrowth), with appropriate growth factors (for osteoinduction), in order to generate and maintain bone (7). Bone-tissue engineering is in its early stages, and there are many issues of efficacy, safety and cost to be addressed before general clinical application can be achieved.
Gene Therapy – This involves the transfer of genetic material into the genome of the target cell, allowing expression of bioactive factors from the cells themselves for a prolonged time. Gene transfer can be performed using a viral (transfection) or a non-viral (transduction) vector, and by either an in vivo or ex vivo gene-transfer strategy. There are issues of cost, efficacy and biological safety that need to be answered.
Nanotechnology and Bone Regeneration
Nanotechnology has been greatly utilized for bone tissue engineering strategies. It has been employed to overcome some of the current limitations associated with bone regeneration methods including insufficient mechanical strength of scaffold materials, ineffective cell growth and osteogenic differentiation at the defect site, as well as unstable and insufficient production of growth factors to stimulate bone cell growth (8,9).
To mimic the natural bone nanocomposite architecture, novel biomaterials and nanofabrication techniques are currently being employed and many different nanostructures have already been designed and tested. Electrospinning has been extensively applied to create bone nanofiber scaffolds and biomaterials typically used for this purpose, including synthetic organic polymers such as PCL, PLGA, PLLA, Chitosan, and silk fibroin.
Among the materials used for bone-reconstruction, PLLA is a biocompatible polymer with the advantage of being highly. biodegradable. For this reason, PLLA have received the approval of the Food and Drug Administration (FDA) to be use in bone reconstructive surgery (10).
PLLA nanofibers are often functionalized to improve their biological performance with peptides such as RGD (Arg-Gly-Asp); with osteogenic molecules such as hydroxyapatite; or with proteins such as collagen and the growth factor bone morphogenic protein 2 (BMP-2). It was found that direct incorporation of BMP-2 into PLLA nanofibers enhances the osteoinductivity of the scaffolds.
Current orthopedic implants fail in an appropriate osteo-integration limiting implant lifespan. Titanium, as a biocompatible material, has been used to enhance implant incorporation in bone for dental, craniofacial, and orthopedic applications. Studies have demonstrated that nanoporous titanium dioxide (TiO2) surface modification alters nanoscale topography improving soft tissue attachment on titanium implants surface (11). For example, the uses of nanoporous TiO2 surface-modified implants, in a human dental clinical study, showed that TiO2 thin film increased adherence in early healing of the human oral mucosa and reduced marginal bone resorption (11).
Another example are rosette nanotubes. Bioactive helical rosette nanotubes are self-assembled nanomaterials, formed in water from synthetic DNA base analogs that mimic the helical nanostructure of collagen in bone. This technology has been used to create a biomimetic nanocomposite combined with nanocrystalline hydroxyapatite, and biocompatible hydrogels which increased osteoblast adhesion.
Carbon nanotubes (CNTs) are other suitable scaffold materials that have proved to support osteoblast proliferation. CNTs possess exceptional mechanical, thermal, and electrical properties, facilitating their use as reinforcements or, in combination with other biomaterials, to improve and to support bone growth.
Nanotechnology and clinical trials
Clinical therapies implying the use of nanotechnology in bone regeneration are still in the beginning stages.
BDSint – Recently, the bone healing ability of a nanocomposite (DBSint®), approved for clinical use, constituted by biomimetic nanostructured Mg-hydroxyapatite and human demineralized bone matrix has been investigated. The clinical-radiographic and histomorphometry study in subjects undergoing high tibial osteotomy, demonstrated that these nanocomposites are safe and effective. Yet the long term outcome is still to be defined (8, 12).
BioOsss and BioGides – Schwarz et al. undertook a four-year study of patients treated of moderate intrabony peri-implantitis defects using either a nanocrystalline hydroxyapatite or a natural bone mineral (BioOsss spongiosa granules) in combination with a collagen membrane (BioGides) and found bone reconstruction (8, 13).
Here are some of the ongoing clinical trials for use of nanotechnology in bone regeneration (Perán M et al (8)):
NCT00729716 – Comparison of BioCart™II With Microfracture for Treatment of Cartilage Defects of the Femoral Condyle BioCart™II scaffold Cartilage ————Phase 2.
NCT01183637 – Evaluation of “Kensey Nash Corp” an Acellular Osteochondral Graft for Cartilage Lesions Pilot Trial (EAGLE Pilot) bioresorbable scaffold Bone/ Cartilage————-Phase 2
NCT01218945 – Development of Bone Grafts Using Adipose-Derived Stem Cells and Different Scaffolds Bone scaffold Bone——– recruiting participants
NCT01435434 – Mononucleotide Autologous Stem Cells and Demineralized Bone Matrix in the Treatment of Non-Union/Delayed Fractures Ignite®ICS injectable scaffold Bone——————Not yet recruiting
Summary:
The advantages of nanomaterials as therapeutic and diagnostic tools are vast, due to design flexibility, small sizes, large surface-to-volume ratio, and ease of surface modification. The potential of these bio-devices has shown promising results in vitro, and some of them have also been successfully tested in vivo with animal models. Nevertheless, the gap between laboratory and medical application of these nanotechnological advances is still wide (8).
Although some successful devises have already being tested in clinical trials and the data produced by these studies is highly encouraging, the safety of nanomedicine is not yet fully defined and more clinical studies still need to be conducted to translate nanotechnological devices to the clinic.
Reference:
1. Dimitriou R, Jones E, McGonagle D and Giannoudis P.V. Bone regeneration: current concepts and future directions. BMC Medicine 2011, 9:66. http://www.biomedcentral.com/1741-7015/9/66
2. Jimi E., Hirata S., Osawa K., Terashita M., Kitamura C., and Fukushima H. The Current and Future Therapies of Bone Regeneration to Repair Bone Defects. International Journal of Dentistry Volume 2012 (2012), Article ID 148261. doi:10.1155/2012/148261. http://www.hindawi.com/journals/ijd/2012/148261/
3. G. C. Gurtner, M. J. Callaghan, and M. T. Longaker, “Progress and potential for regenerative medicine,” Annual Review of Medicine, vol. 58, pp. 299–312, 2007. http://www.ncbi.nlm.nih.gov/pubmed/17076602
4. Masquelet AC, Begue T: The concept of induced membrane for reconstruction of long bone defects.Orthop Clin North Am 2010, 41(1):27-37. http://www.ncbi.nlm.nih.gov/pubmed/19931050
7. Jones E, English A, Churchman SM, Kouroupis D, Boxall SA, Kinsey S, Giannoudis PG, Emery P, McGonagle D: Large-scale extraction and characterization of CD271+ multipotential stromal cells from trabecular bone in health and osteoarthritis: implications for bone regeneration strategies based on uncultured or minimally cultured multipotential stromal cells. Arthritis Rheum 2010, 62(7):1944-1954. http://onlinelibrary.wiley.com/doi/10.1002/art.27451/abstract;jsessionid=4573A69E4561194C83A97EC302CD20CB.d04t02
8. Perán M., García MA., Lopez-Ruiz E., Jiménez G and Marchal JA. How Can Nanotechnology Help to Repair the Body?Advances in Cardiac, Skin, Bone, Cartilage and Nerve Tissue Regeneration. Materials 2013, 6, 1333-1359; doi:10.3390/ma6041333 http://www.mdpi.com/1996-1944/6/4/1333
10. Schofer, M.D.; Roessler, P.P.; Schaefer, J.; Theisen, C.; Schlimme, S.; Heverhagen, J.T.; Voelker, M.; Dersch, R.; Agarwal, S.; Fuchs-Winkelmann, S.; Paletta, J.R. Electrospun PLLA nanofiber scaffolds and their use in combination with BMP-2 for reconstruction of bone defects. PLoS One 2011, 6, e25462. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182232/
11. Wennerberg, A.; Frojd, V.; Olsson, M.; Nannmark, U.; Emanuelsson, L.; Johansson, P.; Josefsson, Y.; Kangasniemi, I.; Peltola, T.; Tirri, T.; et al. Nanoporous TiO(2) thin film on titanium oral implants for enhanced human soft tissue adhesion: a light and electron microscopy study. Clin. Implant. Dent. Relat. Res. 2011, 13, 184–196. http://www.ncbi.nlm.nih.gov/pubmed/19681943
12. Dallari, D.; Savarino, L.; Albisinni, U.; Fornasari, P.; Ferruzzi, A.; Baldini, N.; Giannini, S. A prospective, randomised, controlled trial using a Mg-hydroxyapatite-demineralized bone matrix nanocomposite in tibial osteotomy. Biomaterials 2012, 33, 72–79. http://www.ncbi.nlm.nih.gov/pubmed/21955688
13. Schwarz, F.; Sahm, N.; Bieling, K.; Becker, J. Surgical regenerative treatment of peri-implantitis lesions using a nanocrystalline hydroxyapatite or a natural bone mineral in combination with a collagen membrane: a four-year clinical follow-up report. J. Clin. Periodontol. 2009, 36, 807–814. http://www.ncbi.nlm.nih.gov/pubmed/19637997
Many radiologists expects that Tomosynthesis will eventually replace conventional mammography due to the fact that it increases the sensitivity of breast cancer detection. This claim is supported by new peer-reviewed publications. In addition, the patient’s experience during Tomosynthesis is less painful due to a lesser pressure that is applied to the breast and while presented with higher in-plane resolution and less imaging artifacts the mean glandular dose of digital breast Tomosynthesis is comparable to that of full field digital mammography. Because it is relatively new, Tomosynthesis is not available at every hospital. As well, the procedure is recognized for reimbursement by public-health schemes.
A good summary of radiologist opinion on Tomosynthesis can be found in the following video:
Recent studies’ results with digital Tomosynthesis are promising. In addition to increase in sensitivity for detection of small cancer lesions researchers claim that this new breast imaging technique will make breast cancers easier to see in dense breast tissue. Here is a paper published on-line by the Lancet just a couple of months ago:
Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study
Background Digital breast tomosynthesis with 3D images might overcome some of the limitations of conventional 2D mammography for detection of breast cancer. We investigated the effect of integrated 2D and 3D mammography in population breast-cancer screening.
Methods Screening with Tomosynthesis OR standard Mammography (STORM) was a prospective comparative study. We recruited asymptomatic women aged 48 years or older who attended population-based breast-cancer screening through the Trento and Verona screening services (Italy) from August, 2011, to June, 2012. We did screen-reading in two sequential phases—2D only and integrated 2D and 3D mammography—yielding paired data for each screen. Standard double-reading by breast radiologists determined whether to recall the participant based on positive mammography at either screen read. Outcomes were measured from final assessment or excision histology. Primary outcome measures were the number of detected cancers, the number of detected cancers per 1000 screens, the number and proportion of false positive recalls, and incremental cancer detection attributable to integrated 2D and 3D mammography. We compared paired binary data with McNemar’s test.
Findings 7292 women were screened (median age 58 years [IQR 54–63]). We detected 59 breast cancers (including 52 invasive cancers) in 57 women. Both 2D and integrated 2D and 3D screening detected 39 cancers. We detected 20 cancers with integrated 2D and 3D only versus none with 2D screening only (p<0.0001). Cancer detection rates were 5·3 cancers per 1000 screens (95% CI 3.8–7.3) for 2D only, and 8.1 cancers per 1000 screens (6.2–10.4) for integrated 2D and 3D screening. The incremental cancer detection rate attributable to integrated 2D and 3D mammography was 2.7 cancers per 1000 screens (1.7–4.2). 395 screens (5.5%; 95% CI 5.0–6.0) resulted in false positive recalls: 181 at both screen reads, and 141 with 2D only versus 73 with integrated 2D and 3D screening (p<0·0001). We estimated that conditional recall (positive integrated 2D and 3D mammography as a condition to recall) could have reduced false positive recalls by 17.2% (95% CI 13.6–21.3) without missing any of the cancers detected in the study population.
Interpretation Integrated 2D and 3D mammography improves breast-cancer detection and has the potential to reduce false positive recalls. Randomised controlled trials are needed to compare integrated 2D and 3D mammography with 2D mammography for breast cancer screening.
Funding National Breast Cancer Foundation, Australia; National Health and Medical Research Council, Australia; Hologic, USA; Technologic, Italy.
Introduction
Although controversial, mammography screening is the only population-level early detection strategy that has been shown to reduce breast-cancer mortality in randomised trials.1,2 Irrespective of which side of the mammography screening debate one supports,1–3 efforts should be made to investigate methods that enhance the quality of (and hence potential benefit from) mammography screening. A limitation of standard 2D mammography is the superimposition of breast tissue or parenchymal density, which can obscure cancers or make normal structures appear suspicious. This short coming reduces the sensitivity of mammography and increases false-positive screening. Digital breast tomosynthesis with 3D images might help to overcome these limitations. Several reviews4,5 have described the development of breast tomosynthesis technology, in which several low-dose radiographs are used to reconstruct a pseudo-3D image of the breast.4–6
Initial clinical studies of 3D mammography, 6–10 though based on small or selected series, suggest that addition of 3D to 2D mammography could improve cancer detection and reduce the number of false positives. However, previous assessments of breast tomosynthesis might have been constrained by selection biases that distorted the potential effect of 3D mammography; thus, screening trials of integrated 2D and 3D mammography are needed.6
We report the results of a large prospective study (Screening with Tomosynthesis OR standard Mammography [STORM]) of 3D digital mammography. We investigated the effect of screen-reading using both standard 2D and 3D imaging with tomosynthesis compared with screening with standard 2D digital mammography only for population breast-cancer screening.
Methods
Study design and participants
STORM is a prospective population-screening study that compares mammography screen-reading in two sequential phases (figure)—2D only versus integrated 2D and 3D mammography with tomosynthesis—yielding paired results for each screening examination. Women aged 48 years or older who attended population-based screening through the Trento and Verona screening services, Italy, from August, 2011, to June, 2012, were invited to be screened with integrated 2D and 3D mammography. Participants in routine screening mammography (once every 2 years) were asymptomatic women at standard (population) risk for breast cancer. The study was granted institutional ethics approval at each centre, and participants gave written informed consent. Women who opted not to participate in the study received standard 2D mammography. Digital mammography has been used in the Trento breast-screening programme since 2005, and in the Verona programme since 2007; each service monitors outcomes and quality indicators as dictated by European standards, and both have published data for screening performance.11,12
Procedures
All participants had digital mammography using a Selenia Dimensions Unit with integrated 2D and 3D mammography done in the COMBO mode (Hologic, Bedford, MA, USA): this setting takes 2D and 3D images at the same screening examination with a single breast position and compression. Each 2D and 3D image consisted of a bilateral two-view (mediolateral oblique and craniocaudal) mammogram. Screening mammograms were interpreted sequentially by radiologists, first on the basis of standard 2D mammography alone, and then by the same radiologist (on the same day) on the basis of integrated 2D and 3D mammography (figure). Thus, integrated 2D and 3D mammography screening refers to non-independent screen reading based on joint interpretation of 2D and 3D images, and does not refer to analytical combinations. Radiologists had to record whether or not to recall the participant at each screen-reading phase before progressing to the next phase of the sequence. For each screen, data were also collected for breast density (at the 2D screen-read), and the side and quadrant for any recalled abnormality (at each screen-read). All eight radiologists were breast radiologists with a mean of 8 years (range 3–13 years) experience in mammography screening, and had received basic training in integrated 2D and 3D mammography. Several of the radiologists had also used 2D and 3D mammography for patients recalled after positive conventional mammography screening as part of previous studies of tomosynthesis.8,13
Mammograms were interpreted in two independent screen-reads done in parallel, as practiced in most population breast-screening programs in Europe. A screen was considered positive and the woman recalled for further investigations if either screen-reader recorded a positive result at either 2D or integrated 2D and 3D screening (figure). When previous screening mammograms were available, these were shown to the radiologist at the time of screen-reading, as is standard practice. For assessment of breast density, we used Breast Imaging Reporting and Data System (BI-RADS)14 classification, with participants allocated to one of two groups (1–2 [low density] or 3–4 [high density]). Disagreement between readers about breast density was resolved by assessment by a third reader.
Our primary outcomes were the number of cancers detected, the number of cancers detected per 1000 screens, the number and percentage of false positive recalls, and the incremental cancer detection rate attributable to integrated 2D and 3D mammography screening. We compared the number of cancers that were detected only at 2D mammography screen-reading and those that were detected only at 2D and 3D mammography screen-reading; we also did this analysis for false positive recalls. To explore the potential effect of integrated 2D and 3D screening on false-positive recalls, we also estimated how many false-positive recalls would have resulted from using a hypothetical conditional false-positive recall approach; – i.e. positive integrated 2D and 3D mammography as a condition of recall (screening recalled at 2D mammography only would not be recalled). Pre-planned secondary analyses were comparison of outcome measures by age group and breast density.
Outcomes were assessed by excision histology for participants who had surgery, or the complete assessment outcome (including investigative imaging with or without histology from core needle biopsy) for all recalled participants. Because our study focuses on the difference in detection by the two screening methods, some cancers might have been missed by both 2D and integrated 2D and 3D mammography; this possibility could be assessed at future follow-up to identify interval cancers. However, this outcome is not assessed in the present study and does not affect estimates of our primary outcomes – i.e. comparative true or false positive detection for 2D-only versus integrated 2D and 3D mammography.
Statistical analysis
The sample size was chosen to provide 80% power to detect a difference of 20% in cancer detection, assuming a detection probability of 80% for integrated 2D and 3D screening mammography and 60% for 2D only screening, with a two-sided significance threshold of 5%. Based on the method of Lachenbruch15 for estimating sample size for studies that use McNemar’s test for paired binary data, a minimum of 40 cancers were needed. Because most screens in the participating centres were incident (repeat) screening (75%–80%), we used an underlying breast-cancer prevalence of 0·5% to estimate that roughly 7500–8000 screens would be needed to identify 40 cancers in the study population.
We calculated the Wilson CI for the false-positive recall ratio for integrated 2D and 3D screening with conditional recall compared with 2D only screening.16 All of the other analyses were done with SAS/STAT (version 9.2), using exact methods to compute 95 CIs and p-values.
Role of the funding source
The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author (NH) had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results
7292 participants with a median age of 58 years (IQR 54–63, range 48–71) were screened between Aug 12, 2011, and June 29, 2012. Roughly 5% of invited women declined integrated 2D and 3D screening and received standard 2D mammography. We present data for 7294 screens because two participants had bilateral cancer (detected with different screen-reading techniques for one participant). We detected 59 breast cancers in 57 participants (52 invasive cancers and seven ductal carcinoma in-situ). Of the invasive cancers, most were invasive ductal (n=37); others were invasive special types (n=7), invasive lobular (n=4), and mixed invasive types (n=4).
Table 1 shows the characteristics of the cancers. Mean tumour size (for the invasive cancers with known exact size) was 13.7 mm (SD 5.8) for cancers detected with both 2D alone and integrated 2D and 3D screening (n=29), and 13.5 mm (SD 6.7) for cancers detected only with integrated 2D and 3D screening (n=13).
Of the 59 cancers, 39 were detected at both 2D and integrated 2D and 3D screening (table 2). 20 cancers were detected with only integrated 2D and 3D screening compared with none detected with only 2D screening (p<0.0001; table 2). 395 screens were false positive (5.5%, 95% CI 5.0–6.0); 181 occurred at both screen-readings, and 141 occurred at 2D screening only compared with 73 at integrated 2D and 3D screening (p<0.0001; table 2). These differences were still significant in sensitivity analyses that excluded the two participants with bilateral cancer (data not shown).
5.3 cancers per 1000 screens (95% CI 3.8–7.3; table 3) were detected with 2D mammography only versus 8.1 cancers per 1000 screens (95% CI 6.2–10.4) with integrated 2D and 3D mammography (p<0.0001). The incremental cancer detection rate attributable to integrated 2D and 3D screening was 2.7 cancers per 1000 screens (95% CI 1.7–4.2), which is 33.9% (95% CI 22.1–47.4) of the cancers detected in the study population. In a sensitivity analysis that excluded the two participants with bilateral cancer the estimated incremental cancer detection rate attributable to integrated 2D and 3D screening was 2.6 cancers per 1000 screens (95% CI 1.4–3.8). The stratified results show that integrated 2D and 3D mammography was associated with an incrementally increased cancer detection rate in both age-groups and density categories (tables 3–5). A minority (16.7%) of breasts were of high density (category 3–4) reducing the power of statistical comparisons in this subgroup (table 5). The incremental cancer detection rate was much the same in low density versus high density groups (2.8 per 1000 vs 2.5 per 1000; p=0.84; table 3).
Overall recall—any recall resulting in true or false positive screens—was 6.2% (95% CI 5.7–6.8), and the false-positive rate for the 7235 screens of participants who did not have breast cancer was 5.5% (5.0–6.0). Table 6 shows the contribution to false-positive recalls from 2D mammography only, integrated 2D and 3D mammography only, and both, and the estimated number of false positives if positive integrated 2D and 3D mammography was a condition for recall (positive 2D only not recalled). Overall, more of the false-positive rate was driven by 2D mammography only than by integrated 2D and 3D, although almost half of the false-positive rate was a result of false positives recalled at both screen-reading phases (table 6). The findings were much the same when stratified by age and breast density (table 6). Had a conditional recall rule been applied, we estimate that the false-positive rate would have been 3.5% (95% CI 3.1–4.0%; table 6) and could have potentially prevented 68 of the 395 false positives (a reduction of 17.2%; 95% CI 13.6–21.3). The ratio between the number of false positives with integrated 2D and 3D screening with conditional recall (n=254) versus 2D only screening (n=322) was 0.79 (95% CI 0.71–0.87).
Discussion
Our study showed that integrated 2D and 3D mammography screening significantly increases detection of breast cancer compared with conventional mammography screening. There was consistent evidence of an incremental improvement in detection from integrated 2D and 3D mammography across age-group and breast density strata, although the analysis by breast density was limited by low number of women with breasts of high density.
One should note that we investigated comparative cancer detection, and not absolute screening sensitivity. By integrating 2D and 3D mammography using the study screen-reading protocol, 1% of false-positive recalls resulted from 2D and 3D screen-reading only (table 6). However, significantly more false positives resulted from 2D only mammography compared with integrated 2D and 3D mammography, both overall and in the stratified analyses. Application of a conditional recall rule would have resulted in a false-positive rate of 3.5% instead of the actual false-positive rate of 5.5%. The estimated false positive recall ratio of 0.79 for integrated 2D and 3D screening with conditional recall compared with 2D only screening suggests that integrated 2D and 3D screening could reduce false recalls by roughly a fifth. Had such a condition been adopted, none of the cancers detected in the study would have been missed because no cancers were detected by 2D mammography only, although this result might be because our design allowed an independent read for 2D only mammography whereas the integrated 2D and 3D read was an interpretation of a combination of 2D and 3D imaging. We do not recommend that such a conditional recall rule be used in breast-cancer screening until our findings are replicated in other mammography screening studies—STORM involved double-reading by experienced breast radiologists, and our results might not apply to other screening settings. Using a test set of 130 mammograms, Wallis and colleagues7 report that adding tomosynthesis to 2D mammography increased the accuracy of inexperienced readers (but not of experienced readers), therefore having experienced radiologists in STORM could have underestimated the effect of integrated 2D and 3D screen-reading.
No other population screening trials of integrated 2D and 3D mammography have reported final results (panel); however, an interim analysis of the Oslo trial17 a large population screening study has shown that integrated 2D and 3D mammography substantially increases detection of breast cancer. The Oslo study investigators screened women with both 2D and 3D mammography, but randomised reading strategies (with vs without 3D mammograms) and adjusted for the different screen-readers,17whereas we used sequential screen-reading to keep the same reader for each examination. Our estimates for comparative cancer detection and for cancer detection rates are consistent with those of the interim analysis of the Oslo study.17 The applied recall methods differed between the Oslo study (which used an arbitration meeting to decide recall) and the STORM study (we recalled based on a decision by either screen-reader), yet both studies show that 3D mammography reduces false-positive recalls when added to standard mammography.
An editorial in The Lancet18 might indeed signal the closing of a chapter of debate about the benefits and harms of screening. We hope that our work might be the beginning of a new chapter for mammography screening: our findings should encourage new assessments of screening using 2D and 3D mammography and should factor several issues related to our study. First, we compared standard 2D mammography with integrated 2D and 3D mammography the 3D mammograms were not interpreted independently of the 2D mammograms therefore 3D mammography only (without the 2D images) might not provide the same results. Our experience with breast tomosynthesis and a review6 of 3D mammography underscore the importance of 2D images in integrated 2D and 3D screen-reading. The 2D images form the basis of the radiologist’s ability to integrate the information from 3D images with that from 2D images. Second, although most screening in STORM was incident screening, the substantial increase in cancer detection rate with integrated 2D and 3D mammography results from the enhanced sensitivity of integrated 2D and 3D screening and is probably also a result of a prevalence effect (ie, the effect of a first screening round with integrated 2D and 3D mammography). We did not assess the effect of repeat (incident) screening with integrated 2D and 3D mammography on cancer detection it might provide a smaller effect on cancer detection rates than what we report. Third, STORM was not designed to measure biological differences between the cancers detected at integrated 2D and 3D screening compared with those detected at both screen-reading phases. Descriptive analyses suggest that, generally, breast cancers detected only at integrated 2D and 3D screening had similar features (eg, histology, pathological tumour size, node status) as those detected at both screen-reading phases. Thus, some of the cancers detected only at 2D and 3D screening might represent early detection (and would be expected to receive screening benefit) whereas some might represent over-detection and a harm from screening, as for conventional screening mam mography.1,19 The absence of consensus about over-diagnosis in breast-cancer screening should not detract from the importance of our study findings to applied screening research and to screening practice; however, our trial was not done to assess the extent to which integrated 2D and 3D mammography might contribute to over-diagnosis.
The average dose of glandular radiation from the many low-dose projections taken during a single acquisition of 3D mammography is roughly the same as that from 2D mammography.6,20–22 Using integrated 2D and 3D entails both a 2D and 3D acquisition in one breast compression, which roughly doubles the radiation dose to the breast. Therefore, integrated 2D and 3D mammography for population screening might only be justifiable if improved outcomes were not defined solely in terms of improved detection. For example, it would be valuable to show that the increased detection with integrated 2D and 3D screening leads to reduced interval cancer rates at follow-up. A limitation of our study might be that data for interval cancers were not available; however, because of the paired design we used, future evaluation of interval cancer rates from our study will only apply to breast cancers that were not identified using 2D only or integrated 2D and 3D screening. We know of two patients from our study who have developed interval cancers (follow-up range 8–16 months). We did not get this information from cancer registries and follow-up was very short, so these data should be interpreted very cautiously, especially because interval cancers would be expected to occur in the second year of the standard 2 year interval between screening rounds. Studies of interval cancer rates after integrated 2D and 3D mammography would need to be randomised controlled trials and have a very large sample size. Additionally, the development of reconstructed 2D images from a 3D mammogram23 provides a timely solution to concerns about radiation by providing both the 2D and 3D images from tomosynthesis, eliminating the need for two acquisitions.
We have shown that integrated 2D and 3D mammography in population breast-cancer screening increases detection of breast cancer and can reduce false-positive recalls depending on the recall strategy. Our results do not warrant an immediate change to breast-screening practice, instead, they show the urgent need for randomised controlled trials of integrated 2D and 3D versus 2D mammography, and for further translational research in breast tomosynthesis. We envisage that future screening trials investigating this issue will include measures of breast cancer detection, and will be designed to assess interval cancer rates as a surrogate endpoint for screening efficacy.
Contributors
SC had the idea for and designed the study, and collected and interpreted data. NH advised on study concepts and methods, analysed and interpreted data, searched the published work, and wrote and revised the report. DB and FC were lead radiologists, recruited participants, collected data, and commented on the draft report. MP, SB, PT, PB, PT, CF, and MV did the screen-reading, collected data, and reviewed the draft report. SM collected data and reviewed the draft report. PM planned the statistical analysis, analysed and interpreted data, and wrote and revised the report.
Conflicts of interest
SC, DB, FC, MP, SB, PT, PB, CF, MV, and SM received assistance from Hologic (Hologic USA; Technologic Italy) in the form of tomosynthesis technology and technical support for the duration of the study, and travel support to attend collaborators’ meetings. NH receives research support from a National Breast Cancer Foundation (NBCF Australia) Practitioner Fellowship, and has received travel support from Hologic to attend a collaborators’ meeting. PM receives research support through Australia’s National Health and Medical Research Council programme grant 633003 to the Screening & Test Evaluation Program.
References
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2 Glasziou P, Houssami N. The evidence base for breast cancer screening. Prev Med 2011; 53: 100–102.
3 Autier P, Esserman LJ, Flowers CI, Houssami N. Breast cancer screening: the questions answered. Nat Rev Clin Oncol 2012; 9: 599–605.
4 Baker JA, Lo JY. Breast tomosynthesis: state-of-the-art and review of the literature. Acad Radiol 2011; 18: 1298–310.
5 Helvie MA. Digital mammography imaging: breast tomosynthesis and advanced applications. Radiol Clin North Am 2010; 48: 917–29.
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8 Bernardi D, Ciatto S, Pellegrini M, et al. Prospective study of breast tomosynthesis as a triage to assessment in screening. Breast Cancer Res Treat 2012; 133: 267–71.
9 Michell MJ, Iqbal A, Wasan RK, et al. A comparison of the accuracy of film-screen mammography, full-field digital mammography, and digital breast tomosynthesis. Clin Radiol 2012; 67: 976–81.
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13 Bernardi D, Ciatto S, Pellegrini M, et al. Application of breast tomosynthesis in screening: incremental effect on mammography acquisition and reading time. Br J Radiol 2012; 85: e1174–78.
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A very good and down-to-earth comment on this article was made by Jules H Sumkin who disclosed that he is an unpaid member of SAB Hologic Inc and have a PI research agreement between University of Pittsburgh and Hologic Inc.
“ The results of the study by Stefano Ciatto and colleagues1 are consistent with recently published prospective,2,3 retrospective,4 and observational5 reports on the same topic. The study1 had limitations, including the fact that the same radiologist interpreted screens sequentially the same day without cross-balancing which examination was read first. Also, the false-negative findings for integrated 2D and 3D mammography, and therefore absolute benefit from the procedure, could not be adequately assessed because cases recalled by 2D mammography alone (141 cases) did not result in a single detection of an additional cancer while the recalls from the integrated 2D and 3D mammography alone (73 cases) resulted in the detection of 20 additional cancers. Nevertheless, the results are in strong agreement with other studies reporting of substantial performance improvements when the screening is done with integrated 2D and 3D mammography.
I disagree with the conclusion of the study with regards to the urgent need for randomised clinical trials of integrated 2D and 3D versus 2D mammography. First, to assess differences in mortality as a result of an imaging-based diagnostic method, a randomised trial will require several repeated screens by the same method in each study group, and the strong results from all studies to date will probably result in substantial crossover and self-selection biases over time. Second, because of the high survival rate (or low mortality rate) of breast cancer, the study will require long follow-up times of at least 10 years. In a rapidly changing environment in terms of improvements in screening technologies and therapeutic interventions, the avoidance of biases is likely to be very difficult, if not impossible. The use of the number of interval cancers and possible shifts in stage at detection, while appropriately accounting for confounders, would be almost as daunting a task. Third, the imaging detection of cancer is only the first step in many management decisions and interventions that can affect outcome. The appropriate control of biases related to patient management is highly unlikely. The arguments above, in addition to the existing reports to date that show substantial improvements in cancer detection, particularly with the detection of invasive cancers, with a simultaneous reduction in recall rates, support the argument that a randomised trial is neither necessary nor warranted. The current technology might be obsolete by the time results of an appropriately done and analysed randomised trial is made public.”
In order to better link the information given by “scientific” papers to the context of daily patients’ reality I suggest to spend some time reviewing few of the videos in the below links:
The following group of videos is featured on a website by Siemens. Nevertheless, the presenting radiologists are leading practitioners who affects thousands of lives every year – What the experts say about tomosynthesis. – click on ECR 2013
Breast Tomosynthesis in Practice – part of a commercial ad of the Washington Radiology Associates featured on the website of Diagnostic Imaging. As well, affects thousands of lives in the Washington area every year.
The pivotal questions yet to be answered are:
What should be done in order to translate increase in sensitivity and early detection into decrease in mortality?
What is the price of such increase in sensitivity in terms of quality of life and health-care costs and is it worth-while to pay?
An article that summarises positively the experience of introducing Tomosynthesis into routine screening practice was recently published on AJR:
Stephen L. Rose1, Andra L. Tidwell1, Louis J. Bujnoch1, Anne C. Kushwaha1, Amy S. Nordmann1 and Russell Sexton, Jr.1
Affiliation: 1 All authors: TOPS Comprehensive Breast Center, 17030 Red Oak Dr, Houston, TX 77090.
Citation: American Journal of Roentgenology. 2013;200:1401-1408
ABSTRACT :
OBJECTIVE. Digital mammography combined with tomosynthesis is gaining clinical acceptance, but data are limited that show its impact in the clinical environment. We assessed the changes in performance measures, if any, after the introduction of tomosynthesis systems into our clinical practice.
MATERIALS AND METHODS. In this observational study, we used verified practice- and outcome-related databases to compute and compare recall rates, biopsy rates, cancer detection rates, and positive predictive values for six radiologists who interpreted screening mammography studies without (n = 13,856) and with (n = 9499) the use of tomosynthesis. Two-sided analyses (significance declared at p < 0.05) accounting for reader variability, age of participants, and whether the examination in question was a baseline were performed.
RESULTS. For the group as a whole, the introduction and routine use of tomosynthesis resulted in significant observed changes in recall rates from 8.7% to 5.5% (p < 0.001), nonsignificant changes in biopsy rates from 15.2 to 13.5 per 1000 screenings (p = 0.59), and cancer detection rates from 4.0 to 5.4 per 1000 screenings (p = 0.18). The invasive cancer detection rate increased from 2.8 to 4.3 per 1000 screening examinations (p = 0.07). The positive predictive value for recalls increased from 4.7% to 10.1% (p < 0.001).
CONCLUSION. The introduction of breast tomosynthesis into our practice was associated with a significant reduction in recall rates and a simultaneous increase in breast cancer detection rates.
Here are the facts in tables and pictures from this article
Other articles related to the management of breast cancer were published on this Open Access Online Scientific Journal:
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