Friday, June 29, 2012

FDA Panel Discussing Safety of Metal-On-Metal Hip Implants

By Jennifer Corbett Dooren

Wall Street Journal
 
WASHINGTON--The Food and Drug Administration on Wednesday convened a two-day advisory panel meeting to discuss the safety of metal hip implants, amid concerns there are more side effects than with implants made out of such materials as ceramic or plastic.

The advisory panel is being asked to make recommendations whether additional warnings and other information is needed for metal hip systems, and to make recommendations about which types of patients would benefit the most from metal implants as well those who shouldn't get them. The panel is not being asked to discuss regulatory changes like requiring the devices to go through more stringent clinical testing.

In 2010, Johnson & Johnson's (JNJ) DePuy Orthopaedics Inc. recalled 93,000 of its ASR total hip implants after they were linked to higher failure rates than other implants. The ASR device is no longer sold but is still implanted in many patients, and the company faces about 6,000 lawsuits.

One of the safety concerns involves the wear on the implants and its breaking down of the metal, which in some patients causes joint and muscle destruction and other health problems.

Elizabeth Frank, an FDA medical reviewer, said Tuesday that patients vary in their reactions to metal particulate, with some having a severe inflammatory response to having no reaction.

Because hip implants were on the market before FDA started regulating medical devices in 1976, such companies as DePuy and Wright Medical Group Inc. (WMGI) only need to show a hip implant is similar to a device already on the market and don't need to conduct clinical studies showing safety and effectiveness, a process that has been criticized by some policy makers and many patients.

Major changes to devices, however, do require additional testing, and hip resurfacing systems, including ones made by Smith & Nephew PLC (SNN), are required to go through FDA's premarket approval process, which requires companies to conduct clinical studies in humans looking at the devices' performance. The FDA said other companies with metal hip implants on the market include Biomet Inc., Zimmer Holdings Inc. (ZMH) and Encore Medical L.P.

There are about 400,000 hip implant surgeries in the U.S. each year. About 25% of surgeries involve metal-on-metal implants, according to recent U.S. government data.

Information from patient registries outside of the U.S. suggest more patients need to have the metal implants fixed than other types of implants. The U.S. doesn't have a national registry and studies looking at implant failure rates in the U.S. have been mixed. Some data suggest women have higher failure, or revision rates, compared to men while other data suggests there might be more problems with implants that have a larger component, called the femoral head, than smaller components.

"Could it be the size of the head when we are attributing all the problems to metal?" said Raj Rao, a panel member from the orthopaedic surgery department of the Medical College of Wisconsin.

Although the panel had not formally started addressing FDA's questions Wednesday, preliminary discussion suggests the panel may struggle to adopt clear recommendations given the number of products and conflicting data.

"I don't believe the failure mechanism of these devices is the same," said Edward Cheng, a panelist from the University of Minnesota Medical School and Cancer Center.

Information prepared for the meeting by the FDA showed there's been almost 17,000 adverse-event reports submitted to FDA involving the metal-on-metal implants from 1992 through 2011. There were 22,000 for nonmetal hip implants. Of the metal-on-metal reports, about 12,000 were submitted in 2011 with 9,000 attributed to the DePuy ASR. The reports cited problems including the need for revision--or additional surgery to fix or replace the implant--pain, dislocation and bone infections.

In a presentation to the panel, Paul Voorhorst, the director for biostatistics and data management for DePuy Orthopaedics, said not all "metal-on-metal implants are the same and each should be evaluated on its own merits." Mr. Voorhorst didn't specifically mention the recalled ASR product and instead focused on another product. However, he said the company believes all patients with joint replacements need to be monitored

FDA panel sees little use for metal-on-metal hips

By Matthew Perrone on June 28, 2012

Business Week

WASHINGTON (AP) — Government health experts said Thursday there are few reasons to continue using metal-on-metal hip implants, amid growing evidence that the devices can break down early and expose patients to dangerous metallic particles.

The Food and Drug Administration asked its 18-member panel to recommend guidelines for monitoring more than a half-million U.S. patients with metal hip replacements. The devices were originally marketed as a longer-lasting alternative to older ceramic and plastic models. But recent data from the U.K. and other foreign countries suggests they are more likely to deteriorate, exposing patients to higher levels of cobalt, chromium and other metals.

While the FDA has not raised the possibility of removing the devices from the market, most panelists said there were few, if any, cases where they would recommend implanting the devices.
"I do not use metal-on-metal hips, and I can see no reason to do so," said Dr. William Rohr of Mendocino Coast District Hospital, who chaired the meeting.

For decades nearly all orthopedic implants were coated with plastic or ceramic. But in the last 10 years some surgeons began to favor all-metal implants, after laboratory tests suggested the devices would be more resistant to wear and reduce the chances of dislocation.

But recent data gathered from foreign registries shows the devices fail at a higher rate than older implants. That information comes on top of nearly 17,000 reports to the FDA of problems with the implants, which sometimes require invasive surgery to replace them.

The pain and inflammation reported by patients is usually caused by tiny metal particles that seep into the joint, damaging the surrounding tissue and bone. The long-term effects of elevated metal levels in the bloodstream are not clear, though some studies have suggested links to neurological and heart problems.

About 400,000 Americans get a hip replacement each year to relieve pain and restore motion affected by arthritis or injury. Metal hips accounted for about 27 percent of all hip implants in 2010, down from nearly 40 percent in 2008. Doctors have begun turning away from the implants amid several high-profile recalls, including J&J's recall of 93,000 metal hips in 2010.

FDA's experts said Thursday that patients complaining of pain and other symptoms should get regular X-rays and blood testing for metal levels. However, panelists pointed out the problems with the accuracy of blood tests and the difficulties of interpreting the results. There are no standard diagnostic kits for sale that test for chromium and other metals

For patients who are not experiencing pain, panelists said annual X-rays would be sufficient to monitor their implants.

If the FDA ultimately follows the group's advice, U.S. recommendations would be less involved than those already in place overseas.

Earlier this year U.K. regulators recommend that all people who have the implants get yearly blood tests to make sure no dangerous metals are seeping into their bodies.

FDA regulators have suggested they want to take more time to sort out the differences between various implants and patient groups before making recommendations.
"The truth is there are different types of hips and different types of patients," said Dr. William Maisel, FDA's chief scientist for devices, in an interview last week. "Understanding the characteristics of patients who experience adverse events is very important."

Women and overweight people are among the groups that are more likely to have an implant failure.
With little definitive data on U.S. hip implants, the agency has asked manufacturers like Johnson & Johnson, Zimmer Holdings Inc. and Biomet Inc. to conduct long-term, follow-up studies of more than 100 metal-on-metal hips on the U.S. market.

FDA scientists say the studies will help "fill in the blanks" on a number of scientific questions, including the long-term effects of metal particles.

But public health advocates say it could take a decade before that information is available.
"Keeping these metal-on-metal hips on the market for the next five to 10 years while research is conducted is not ethical," said Diana Zuckerman, president of the National Research Center for Women & Families, during a public comment session at the meeting. "If the companies want to sell metal-on-metal hips, they should be required to prove their safety first."

 

Thursday, June 28, 2012

F.D.A. Hearing to Focus on Replacement Hips


The Food and Drug Administration will start a two-day hearing on Wednesday meant to help doctors find ways to better monitor the risks posed by all-metal replacement hips.
C.J. Gunther for The New York Times
The ball section of an artificial hip removed during surgery at Massachusetts General Hospital.


                          
Once promoted by industry and doctors as an innovative orthopedic breakthrough, the devices have failed prematurely in thousands of cases, causing many patients to undergo repeat surgeries and producing crippling injuries in some of them. As they wear, the devices shed tiny particles of metallic debris that can damage a patient’s muscle and tissue.
      
Experts caution that definitive answers are not likely to emerge from the hearing. And they add that neither government, industry nor the medical profession appear eager to address the fundamental issue raised by the episode: Why were these devices implanted in 500,000 people without adequate testing?
      
“There was not enough data to support” their widespread use, said Dr. Henrik Malchau, an orthopedic surgeon at Massachusetts General Hospital in Boston.
      
Under F.D.A. rules, orthopedic implant makers did not have to run clinical trials of the hips before marketing them, nor were they required to follow patients afterward to see how they fared. Doctors embraced the implants without evidence they were better or more durable than existing ones.
Many doctors say they adopted the devices believing they would help reduce a complication of hip replacement — the possibility of implant dislocation.
      
The use of all-metal hips has fallen sharply in recent years. Still, the failure to put safeguards in place before their sale has also complicated efforts to assess dangers, said Dr. Malchau and other experts.
For example, while the F.D.A. took the unusual step in May 2011 of ordering five producers of all-metal hips to undertake studies to examine how patients were faring, the agency has so far approved the study plan of only one manufacturer, Biomet.
      
The agency rejected initial proposals from four other companies, including the two industry leaders, the DePuy division of Johnson & Johnson and Zimmer. Representatives of those companies and others said they were working with the F.D.A. to resolve its concerns.
      
However, the simple fact that the agency is now debating study designs with device manufacturers nearly a decade after these products were first sold is deeply troubling, said one expert, Dr. Art Sedrakyan of Cornell-Weill Medical Center in New York.
      
Also, as it turns out, at least one major manufacturer, DePuy, has clinical data in hand about two all-metal implants that it has yet to release.
       
In an interview, Dr. Ivan M. Tomek of Dartmouth-Hitchcock Medical Center in Lebanon, N.H., said he was an investigator on a study started in 2006 in which patients received one of two metal hip models made by DePuy — either a model known as the ASR or a model known as the Pinnacle.
Dr. Tomek said the study enrolled about 250 patients nationwide and that patients were followed for about two years. He added, however, that DePuy had never publicly released the study’s data.
      
DePuy recalled the ASR in 2010 but continues to maintain that the all-metal Pinnacle is safe. The company faces hundreds of patient lawsuits involving both products.
      
Asked about the trial, a DePuy spokeswoman, Mindy Tinsley, said the company was still analyzing follow-up data from patients enrolled in 2009, the study’s last year.
      
Generally speaking, nearly all models of all-metal hips have higher failure rates than traditional implants made from a combination of materials like metal and plastic. The rates of early failure vary between different models, with the highest failure rate associated with the DePuy ASR.
       
Getting a fix on specific failure rates is difficult because this country, unlike Britain and Australia, for example, does not have an orthopedic registry that follows patient outcomes.
      
For doctors and patients, one of the biggest problems with metal hips is detecting whether the metallic debris generated by an implant is damaging a patient’s tissue or muscle or how to best monitor for such problems. In recent months, device producers have not been providing new information, Dr. Tomek said. “There has not been much coming from the implant companies,” he said.
      
Also, regulators in Britain have taken a more aggressive approach than their counterparts in the United States in setting guidelines about how the devices should be monitored. F.D.A. officials said that they had questions about the validity of the tests used to make such recommendations.
      
For example, agency officials said that they had concerns about the accuracy of blood tests to measure the level of metallic ions in a patient’s blood as well as about the reliability of magnetic resonance imaging scans used to detect tissue damage. At the F.D.A. meeting, experts will be asked to make recommendations about the use of such tests.
      
There seems to be little current appetite, said experts like Dr. Malchau of Massachusetts General to address the bigger issues of whether such implants should be required to undergo clinical testing before being sold or only be used initially in small groups of closely monitored patients.
      
In addition, he and other experts wonder whether most orthopedic surgeons have embraced the lesson of the all-metal fiasco or whether they will simply jump at the next “innovation” offered by industry.
In either case, he said, future patients need to better protect themselves by demanding that their surgeon provide data showing that the implant they are recommending has a long, proven track record.
       
“If you are buying a new refrigerator or appliance, you go to Consumer Report,” he said. “The data is out there.”

Smith and Nephew hip implant recalled worldwide

 



Medsafe statement, 8 June 2012
Smith and Nephew hip implant recalled worldwide
A hip implant with a metal liner is being recalled in New Zealand and worldwide by its overseas manufacturer.

Smith and Nephew, a UK company, says its R3 hip implant metal liner is not performing as well as desired.

139 of the implants have been supplied to New Zealand.
70,889 hip implants have been carried out in New Zealand in the past 11 years - of those 6,225 have been metal-on-metal implants.

In New Zealand, the number of metal-on-metal implant devices recalled has been 525 for the ASR, 41 for the Mitch implant, and 139 for the Smith and Nephew.

Medsafe, New Zealand medicines and medical device regulator, says Smith and Nephew are contacting surgeons to alert them of the recall, ask them to contact affected patients, and advise them of the need for greater monitoring of their patients.

Derek Fitzgerald, Medsafe Head of Compliance Management, says many patients with these implants and other metal-on-metal implants will not be affected by this problem.
“The recall does not mean patients with the implant will necessarily require revision surgery however as a precaution patients with this implant will be followed up more frequently by their doctor.
“If patients experience any discomfort or pain they should see their GP or surgeon as they normally would following any surgery on a joint.

This recall is the third worldwide of a metal-on-metal implant, with the De Puy ASR recall in 2010, and the Mitch TR implant earlier this year.
 
The three recalls of metal-on-metal hip implants represent less than 1 per cent of the hip replacements done in this country in the past 11 years.

Medsafe will follow-up with the manufacturers to ensure specialists have been contacted and patients notified.

For further information, contact senior communications advisor Kevin McCarthy, 021 832 459.
Background

The Smith and Nephew R3 metal liners were first used in Europe and Australia in 2007, NZ in 2008 and globally from 2009.
 
A liner is the bearing surface, or cup, that the head of an artificial hip rotates in. The surfaces can be constructed of metal, ceramics and plastics.

Smith and Nephew have recalled the product as the United Kingdom and Australian joint registries are both reporting the metal liners are having higher revision rates than for R3 implants that use other liners.

There is a heightened awareness worldwide of possible higher revision rates in such devices. The risk to patients is from localised tissue damage.
Information about joint implants and revisions is collected by a register run by the New Zealand Orthopaedic Association.

Information for consumers about metal-on-metal implants has been published on the Medsafe website, and made available to surgeons here:
http://www.medsafe.govt.nz/hot/RecallActionNoticesNew/MetalOnMetalHipImplants/MetalonMetalHipImplantsFAQ.asp


Wednesday, June 27, 2012

Metal-on-metal hip implants need more consistent testing to help lower high failure rates that lead to risky replacement surgeries, a report by regulators said.

Bloomberg News

Regulators Ask for Help to Better Monitor Metal Hip Implants
By Anna Edney on June 25, 2012

Metal-on-metal hip implants made byJohnson & Johnson (JNJ) (JNJ) and Zimmer Holding Inc. (ZMH) (ZMH) need more consistent testing to help lower high failure rates that lead to risky replacement surgeries, a report by regulators said.

The Food and Drug Administration staff said agency advisers meeting on the devices this week should consider when and how patients should undergo imaging and ion testing to measure the metal’s effect on surrounding tissue, according to documents posted on the agency’s website today.
The Food and Drug Administration will convene an advisory panel meeting June 27 and 28 to discuss the implants, which have been the subject of thousands of patient lawsuits. The metal devices have been linked to almost 16,800 adverse events in the U.S. from 2000-2011, regulators said in a report last week.

In general, the overall use of metal-on-metal has diminished quite a bit,” Matthew Taylor, an analyst with Barclays Capital Inc., said by telephone. “Physicians are cautious about using these.”
The DePuy unit of New Brunswick, New Jersey-based J&J began recalling hip devices in 2010, after more than 12 percent failed within five years. About 74 percent of 12,137 incident reports to the FDA in 2011 involved that device, the agency reported.

J&J faces more than 6,000 lawsuits related to the metal-on-metal hips in federal and state courts. In May 2011, the FDA asked hip implant makers to conduct post-market studies.

While the majority of patients with the implants do well, surgeons need to know what to do if they exhibit high levels of metal in their blood, said Joshua Jacobs, a surgeon and vice president of the American Academy of Orthopaedic Surgeons, in a telephone interview. Metal ions can damage tissue and require revision surgery to replace the old device.

Imaging Role

The FDA’s advisers have been asked to consider the role of imaging in patients who exhibit signs of problems and those that don’t. They will also weigh who should be tested for metal ion levels, and how the result would be used by the physician.

“Soft tissue imaging of the hip may be the most effective means to identify a soft tissue reaction in a patient,” FDA staff said in the document.

Metal-on-metal hip implant use peaked in 2006 and 2007 at an estimated 30 percent of the market and is now about 10 percent, Barclay’s Taylor said. Other implants include those made of ceramic and polyethylene. The ball and socket are each made of metal on the implants in question.

Adverse Events

Adverse event reports in 2011 totaled 12,137 for the metal-on-metal devices, compared with 6,332 associated with other types of hip implants, according to an FDA document. The most-reported side effect was revision, meaning surgery to remove or replace the implant. Revisions totaled 14,131 in metal-on-metal hip implants followed by 8,704 reports of pain.

FDA staff assessed all available literature to attempt to compare metal implants to the other versions and determined the rate of replacement surgery for metal implants “is likely not lower” than the rate associated with other implants, according to the documents posted today.

A review of international and U.S. registries also found higher rates of revisions for metal implants. The national registry in England and Wales found the rate of replacement surgeries after five years for metal-on-metal implants was 6.2 percent, almost three times as high as other versions. A registry of implant procedures in Minneapolis and St. Paul, Minnesota, established by provider HealthEast Care System found metal-on-metal systems were associated with a four times higher occurrence of revision surgeries than metal and polyethylene.

If the FDA restricts metal-on-metal implants, companies such as Biomet Inc., based in Warsaw, Indiana, won’t be significantly affected, Taylor said.

“Most of the companies have a full line of hip products they can sell so they’d just be swapping it out with the other hip products,” he said.

[connie:  Sure the revision rates are higher in countries where they are monitoring everything including the largest population; asymptomatic patients who have MoM hips.  The current policy from the FDA, ulike agiencies in other countires, is that we have a completely hands off approach to the preponderance of MOM patients and that is:  if the patient is not complaining, lets let sleeping dogs lie. I sure hope someone at this meeting today does something to ensure that every single last patient who has a hip implant is provided with two tests:
  •  MRI  specifiying the use of the Mavrick protocal and
  • chromium and cobalt blood tests.]

Tuesday, June 26, 2012

My surgeon says 18 months to heal from revision

I had another 3 month revision follow up from my surgery in November of last year.  Had 4 agenda items:

(1) Why am I not healing as expected?
  • I am still limping when I get up from a chair. Why?  In my last visit, he told me it would take a good year to heal from a revision surgery.  This time he said it would 18 months.  I am skeptical about recovering from this.
 (2)  Should I have another MRI to see if there is fluid accumulating on my hip joint which is causing this problem or additional tissue damage perhaps?

  • He has not been able to get the MRIs working to the extent that HSS (hospital in NYC that is an orthopeidic speciality hospital.)  He said he was skeptical about using the protocals available locally since the resolution of the MRIs were not great.  He suggested that we wait for another 3 months and then go to NYC to get the MAVRIC protocal.

 (3) Communicate the oxidative stress observation that may have linked the renal cancer reoccurance following a 5 year "cured" diagnosis with the hip revsion. 
  • No comment.  He listened but made not one comment.  I showed him the diagram that I have published in previous posts.  He said he would put it with my other documents.
(4) When will my Cr and Co levels go back to normal?
  • In his experience, most patients do go back to normal but it takes time.  I am almost normal in the Cr levels but not the Co levels.

He asked that I come back in 3 months.  I did tell him that my orthopedic consult did run some tests on whether I am allergic to these products.

Sunday, June 24, 2012

June 27-28, 2012: Orthopaedic and Rehabilitation Devices Panel of the Medical Devices Advisory Committee Meeting Announcement

Center Date Time Location
CDRH June 27-28, 2012 7:30 a.m. - 7:00 p.m. Hilton Washington DC North/Gaithersburg
Salons A, B, C, and D
620 Perry Pkwy.
Gaithersburg, MD 20877
301–977–8900

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

The meeting will be webcast live and free of charge on both days and can be accessed at the following Web address:

On June 27, Day 1 http://fda.yorkcast.com/webcast/Viewer/?peid=12f84ea095b445d78e9b115f495392731d2 disclaimer icon 3


Should the FDA adopt the British regulations for patient monitoring of the MoM hips

I had addressed the "yes" side of this question in a post recently:  http://www.mydepuyhiprecall.com/2012/06/study-shows-metal-on-metal-hip-patients.html

In that document, I had argued that the British standard for monitoring asymptomatic patients was appropriate which included the need to monitor these patients for the life of the implant with both blood tests and MRIs.

The "no" side of the argument:  the British regulations were put in place without testing what they should or should not recommend.

Recently I had a chance to speak to someone who is involved in these discussions.  His point was:  I don't know what the correct monitoring procedure is for asymptomatic patients.  Why?

 Instituting mandatory testing for patients may result in the over testing you see with breast exams for example which now typically are annually.  There have been a lot of studies recently in that area recommending against doing annual breast exams due to the potential patient risk.  Consistent exposure to the radiation is problematic over time.  They now say if you continue to expose a  woman annually to radiation risk with mammograms, if she started out at 40 with no cancer, at age 50, she would have increased her chances for cancer by  continued radiation  exposure by 30%. (Some say 1% per year and some say up to 3% per year.)

My responce to that would be the hip exams should be done with MRIs not x rays.  MRIs don't have radiation exposure.  Blood tests are benign.

The other think he mentioned was that doctors not the FDA treat patients.  Well that is true however, many orthopedic surgeons DO NOT have the knowledge to deal with these issues and in my opinion require some guidance as to what they should and should not be doing with patients.  I would not go to a great surgeon and seek advise on the implications of research questions.  Surgeons are not researchers!  You wouldn't  seek a surgical opinion from a researcher would you?

FDA Hip Implant Approach Called Flawed

 

 
 
Post-marketing studies of metal-on-metal hip implants, ordered last year by the FDA, will be much less useful than they could be unless the agency changes its approach, doctors charged.

The required studies have been slow to get under way, and "methodologic issues will limit the usefulness of the information that emerges from these studies," wrote Joshua Rising, MD, MPH, of the Pew Charitable Trusts in Washington, D.C., and two colleagues in an online New England Journal of Medicine Perspective article.

Unexpectedly high rates of device failure and local and systemic inflammatory reactions associated with metal-on-metal hip replacements have prompted regulators in the U.S. and Europe to take a closer look at these products.

In May 2011, the FDA ordered manufacturers of metal-on-metal devices to conduct surveillance studies on patients who had received their products, requiring them to submit protocols for the agency's approval.

But as of Monday, Rising and colleagues wrote, protocols for fewer than one-quarter of the 104 devices covered by the FDA order had been approved. For 80 of the products, the FDA listed the study plans as "pending" or "overdue."

Even for those that had been approved, Rising and colleagues indicated, "it was unclear whether any studies had begun."

More seriously, the group argued, the FDA's requirements for the studies were excessively loose.

"One significant shortcoming is that each manufacturer is permitted to conduct its own independent study on its product or products. The resulting lack of harmonization among studies will lead to challenges in pooling the data and making cross-product comparisons," Rising and colleagues wrote.

They pointed out, for example, that the FDA did not specify how the companies should measure chromium and cobalt ions in blood -- a key marker of metal-on-metal implant dysfunction. The resulting variability will "introduce uncertainty into attempts to pool results," the group contended.

Rising and colleagues also worried that the FDA does not have authority to require post-marketing studies to extend more than 3 years, which may be inadequate to judge the performance of devices that are supposed to last 15 years, as is the case with metal-on-metal hip implants. Even the worst-performing of such implants have shown 5-year failure rates of less than 5%.

One advantage to the slow start for most of the studies is that it is not too late for the FDA to require more harmonization of protocols, Rising and colleagues suggested.

They also called for the U.S. to establish comprehensive device registries -- not limited to metal-on-hip implants -- like those in other countries. They noted that the first warning signals about metal-on-metal devices emerged from an Australian registry.

Such registries could benefit device manufacturers, Rising and colleagues contended, by reducing their costs for post-marketing surveillance and by providing better clinical feedback that, in turn, helps them develop safer and more effective products.

Next week, the FDA will hold an advisory committee meeting about metal-on-metal implants to review the existing data and future research needs.

This meeting "would be an opportune time for the FDA to address the slow start to these studies -- and to signal that substantial penalties may be assessed against any manufacturer that is responsible for delays in finalizing protocols," Rising and colleagues wrote.

Friday, June 22, 2012

Systemic Coblat ion effects following MoM hip replacement

2010 Dec;81(6):756-64.

Cobalt ions induce chemokine secretion in a variety of systemic cell lines.

Source

UCD Clinical Research Centre, UCD School of Medicine and Medical Sciences, Mater Misericordiae University Hospital, Ireland. bdevitt@hotmail.com

Abstract

BACKGROUND AND PURPOSE:

Metal ion toxicity both locally and systemically following MoM hip replacements remains a concern. Cobalt ions have been shown to induce secretion of proinflammatory chemokines locally; however, little is known about their effect systemically. We investigated the in vitro effect of cobalt ions on a variety of cell lines by measuring production of the proinflammatory chemokines IL-8 and MCP-1.

METHOD:

Renal, gastrointestinal, and respiratory epithelium and also neutrophils and monocytes were exposed to cobalt ions at 4, 12, 24, and 48 hours.

RESULTS:

We found that cobalt ions enhanced the secretion of IL-8 and MCP-1 in renal epithelial cells, gastric and colon epithelium, monocytes and neutrophils, and small airway epithelial cells but not in alveolar cells. Secretion of IL-8 and MCP-1 was markedly elevated in renal epithelium, where a 16-fold and 7-fold increase occurred compared to controls. There was a 6-fold and 4-fold increase in IL-8 and MCP-1 secretion in colon epithelium and a 4-fold and 3-fold increase in gastric epithelium. Small airway epithelial cells showed a maximum increase in secretion of 8-fold (IL-8) and of 4-fold (MCP-1). The increase in chemokine secretion observed in alveolar cells was moderate and did not reach statistical significance. Monocytes and neutrophils showed a 2.5-fold and 2-fold increase in IL-8 secretion and a 6-fold and 4-fold increase in MCP-1 secretion at 48 and 24 hours, respectively.

INTERPRETATION:

These data demonstrate the potent bioactivity of cobalt ions in a variety of cell types and the potential to induce a proinflammatory response.


xxx

Chemokines (Greek -kinos, movement) are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells.  Some chemokines are considered pro-inflammatory and can be induced during an immune response to recruit cells of the immune system to a site of infection, while others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development





Wednesday, June 20, 2012

Progress with 2nd opinions on hip revision and cancer recurrence

I have finished with my consults for the renal cell carcinoma diagnosis and have discussed the connection between the renal cell carcenoma and the hip revision extensively with leading experts in thier respective fields.  I have seen 4 physicians about this link between the hip and the recurrence of cancer:
  • 1 had no idea
  • 1 said the argument could be made between the oxidative stress associated with the hip revision and the recurrence of my renal cell.
  • 1 said yes, there  certainly could be this connection
  • 1 said, very plausible but we can't prove it (not that I was trying to prove it.)  My goal in this exercise was to choose the appropriate treatment for the renal cell after understanding how this recuured when I was released as "cured" from  the initial renal cell nephrectomy 5 years ago.
Given that the oxidative stress issue is an immune/molecular approach to cancer, I will be choosing a treatment for my renal cell that is immune based rather than using the standard of care (angiogenics.)

It was interesting that I found 66 articles in Pub med connecting oxidative stress to renal cell  and it seems to be well accepted that hip surgeries (especially revisions) are associated with creating oxidative stress.  There has been however one study published in the last year questioning whether there is oxidative stress with hip revisions which was conducted  by McGill University researchers.

I have to take a shot and my one shot is going to be with immune therapy based on what I have learned.  I believe there is a very very strong possibility that the revision caused the cancer to recur earlier than it would have otherwise.  Likely, it may have surfaced at some point but we don;t know.

I have written on this topic quite a bit and if you want to look up oxidative stress in the blog  search bar, you will find all of those posts. 

Had I known then what I know now, I might have reconsidered this revision and then suffered the consequence of the high metal levels and the osteolysis.  I often wonder whether both approaches would likely result in cancer.....either the cancer  recurring from the original kidney or having a new one form from the high metal levels over the long run?

Interesting questions.

Tuesday, June 19, 2012

High incidence of pseudotumour formation after large-diameter metal-on-metal total hip replacement: A prospective cohort study.

See 1 article found by title matching your search:

2012 Jun;94(6):755-61.

Bosker BH, Ettema HB, Boomsma MF, Kollen BJ, Maas M, Verheyen CC.

Source

Isala Klinieken, Department of Orthopaedic Surgery and Traumatology, Groot Wezenland 20, 8011 JW Zwolle, The Netherlands.

Abstract

Peri-articular soft-tissue masses or 'pseudotumours' can occur after large-diameter metal-on-metal (MoM) resurfacing of the hip and conventional total hip replacement (THR). Our aim was to assess the incidence of pseudotumour formation and to identify risk factors for their formation in a prospective cohort study. A total of 119 patients who underwent 120 MoM THRs with large-diameter femoral heads between January 2005 and November 2007 were included in the study. Outcome scores, serum metal ion levels, radiographs and CT scans were obtained. Patients with symptoms or an identified pseudotumour were offered MRI and an ultrasound-guided biopsy. There were 108 patients (109 hips) eligible for evaluation by CT scan at a mean follow-up of 3.6 years (2.5 to 4.5); 42 patients (39%) were diagnosed with a pseudotumour. The hips of 13 patients (12%) were revised to a polyethylene acetabular component with small-diameter metal head. Patients with elevated serum metal ion levels had a four times increased risk of developing a pseudotumour. This study shows a substantially higher incidence of pseudotumour formation and subsequent revisions in patients with MoM THRs than previously reported. Because most revision cases were identified only after an intensive screening protocol, we recommend close monitoring of patients with MoM THR.

The Financial Impact of Joint Registries in Identifying Poorly Performing Implants


J Arthroplasty. 2012 Jun 6. [Epub ahead of print]


Source


Baylor College of Medicine, One Baylor Plaza, Houston, Texas.

Abstract


We analyzed the effect of the Australian National Joint Registry on the cost of joint arthroplasty through identification of implants with higher than expected failure rates. From 2003 to 2007, 242 454 primary joint arthroplasties were performed in Australia at a total cost of $4.1 billion. Of these cases, 19 224 were performed using components identified by the Registry as poorly performing. If all of these cases were performed using average-performing designs, the number of revisions would have dropped by 28.6%. We also predicted that over a 5-year period after Registry identification, 32 807 primary procedures would be performed using poorly performing implants. If implants of average longevity were selected instead, we predict that 25.8% fewer revision procedures would be needed, ranging from 7% in unicompartmental knee replacement to 47% in total hip arthroplasty. This change in practice is expected to save 10.2% of direct costs, corresponding to $14 million over a 5-year period.

Sunday, June 17, 2012

Smith & Nephew pulls metal-on-metal hip component


LONDON | Fri Jun 1, 2012 12:31pm EDT

LONDON (Reuters) - Smith & Nephew is withdrawing a component of one of its all-metal artificial hip systems, following a higher than normal level of patient problems with the device.

The voluntary recall will add to concerns about the safety of metal-on-metal hips, although the British company said on Friday the issues with its system were different to those seen with some other all-metal implants.

A small number of patients experienced problems including infections, fractures and dislocations - but there was no evidence of "metallosis", or the build-up of metallic debris in the body, a spokesman said.

Smith & Nephew is withdrawing the optional metal liner, or cup, component of its R3 Acetabular System. Surgeons, however, will still be able to use the system using alternative non-metal liners and the company said it did not anticipate any delays to surgery.

The decision follows an analysis of clinical results showing that 1.6 percent of patients with the system needed revision surgery each year, which is above the 1 percent guideline set by Britain's National Institute for Health and Clinical Excellence.

"We regularly review the effectiveness of our products and are not satisfied with the clinical results of this component," said Andy Weymann, Smith & Nephew's chief medical officer.

Approximately 7,700 of the metal liners have been implanted since the component was introduced in 2007. Procedures using the component accounted for less than 1 percent of Smith & Nephew's global hip implant revenue last year.

Metal-on-metal hips were developed to be more durable than traditional implants, which combine a ceramic or metal ball with a plastic socket.

But recent experience suggests they may actually do worse, prompting the high-profile recall of one device made by Johnson & Johnson.

(Reporting by Ben Hirschler. Editing by Jane Merriman)

Saturday, June 16, 2012

Study shows metal on metal hip patients not getting blood tests!


Data emerging from Dr. Tom Joyce's  patient survey shows that some UK patients are having trouble getting blood tests done. As part of its medical device alert issued in February 2012, the MHRA  (agency in England that is equivalent to the FDA in the US) included an appendix on management recommendations for patients with metal-on-metal hip replacement implants. They give advice on the frequency of blood tests for different classes of metal-on-metal hips and patients may find this useful when talking to their doctor.

While this information is for England, Scotland and Wales, I thought the format was really easy to follow in terms of the directives and not too much different than the US guidelines.  [I gotta tell you, this is quite a bit more reasonable than the US guidelines.  NOTE:  FOR ASYMPTOMATIC PATIENTS WITH THE DEPUY HIP, THEY RECOMMEND BLOOD TESTS ANNUALLY FOR THE LIFE OF THE IMPLANT.  NOTE ALSO, THEY RECOMMEND AN MRI IN ALL CASES where a Depuy MoM hip has been implanted.  These recommendations are far more reasonable than those sanctioned by the FDA.  These directivies should immediately be adopted by the FDA.  Show your Surgeon this chart if they are giving you a problem with giving you a blood test when you are asymptompatic with a MOM Depuy hip.  England has much more experience with this hip and in fact they were the first to raise the issue surrounding the MoM hip.]




The questionnaire about people's experiences with metal-on-metal hip implants is now available. If you have such an implant, please consider completing it here.

I wrote about this questionnaire in a prior blog:  Survey Participation requested by Dr. Tom Joyce's group at New Castle University in England: Patient experiences with the Depuy Hip and others.....

Thursday, June 14, 2012

3rd Oncology consult relating to the link between the reoccurance of the cancer, the hip revision and treatment options

I saw my last Oncologist from a top treatment facility. As those who read this blog know, I have developed a recurrence of renal cell carcinoma shortly following my hip revision and I wanted to understand whether there was a connection between the recurrence of the cancer and the revision surgery and then determine whether this event this will or will not influence the treatment I select.

Out of the three oncologists I saw, I first one didn't know. The second one didn't know but thought the explanation I provided of oxidative stress was plausible. the third one thought the hip revision could very well have caused the cancer to reoccur earlier than perhaps it may have shown up on its own.

Given these responses, my thought is I am going to seek out treatment from a metabolic and immune based treatment rather than looking at angiogenesis which works to shrink the vesicles enabling the tumor to survive.

I still have my orthopedic consult remaining to discuss this feedback with. In that meeting, I would like to be very sure that I understand the relationship between the oxidative stress that is formed when the Cr6 is oxidized to Cr 3 in the diagram that I have published on several occasions. that process can be found here:
http://www.mydepuyhiprecall.com/2012/05/great-pictorial-to-illustrate-metal-on.html
I would also like to clarify wheather that process is persistently exposed to oxidative stress (on going.) If it turns out to be persistent, I will focus on a potential metabolic approach for treatment. My reason for doing so is that I need to treat the whole picture not merely the symptom (tumor itself.) Given this treatment is not a "standard of care", I will have to pursue clinical trials.


Some additional random points:


(1) Inflammation is a big area of study in medical research because it plays a key role in cancer.

(2) Inflammation is the seen to be virtually the same in different disorders.

(3) By studying inflammation, a better understanding may result in treating things like cancer.

(4) Inflammation is the activation of the immune system in response to infection, irritation, or other things.

(5) Although the pathophysiology is not quite understood reactive oxygen species (ROS) is has often been associated with many conditions such as cancer.

(6) ROS has also been associated with the oxidation of the metals (Cr 6 to Cr 3.)

(7) In fact, in inflammatory diseases the antioxidant defense systemis compromised, as evidenced by increased markers of oxidative stress, and decreased levels of protective antioxidant enzymes.

(8) Oxidative stressplays an important role in carcinogenesis because of induction of DNA damage and its effects on intracellular signal transduction pathways

(9) Oxidative stress plays an important role in the growth and progression of renal cell carcenoma.

Wednesday, June 13, 2012

Is it Chromium or Cobalt that is the biggest culpret in metalosis?

Acta Biomater. 2012 Jun 8. [Epub ahead of print]

Cobalt from metal-on-metal hip replacements maybe the clinically relevant active agent responsible for periprosthetic tissue reactions.

Source

Department of Orthopaedic Surgery, Imperial College and Imperial College Healthcare NHS Trust, Charing Cross Hospital Campus, Fulham Palace Rd, London W6 8RF, UK.

Abstract

Some types of metal-on-metal (MOM) hip replacements have unacceptably high rates of failure, such as the Ultima TPS MOM hip with 13.8% failure at 5 years. This has been attributed to an inflammatory reaction following the release of cobalt (Co) and chromium (Cr) from the bearing surfaces and modular junctions. There is in vitro evidence that Co is more important than Cr in the inflammatory process, but there are no reported human tissue studies of the analysis of the implant-derived metal. To better understand the mechanism of failure of the "Ultima TPS" hip implant, we studied the distribution, relative amounts and chemical form of cobalt (Co) and chromium (Cr) in periprosthetic tissue taken at revision surgery from 6 patients. We made a comparison with tissue from 6 patients with current generation, large diameter MOM hips (the Non-Ultima group). Both types of implants had Co-Cr bearing surfaces but the Ultima type had a titanium (Ti) acetabular cup and a cemented CoCr stem that had macroscopic corrosion of the femoral stem at revision surgery. Both types of hip can cause an adverse tissue response but its severity is likely to be affected by the amount and type of implant-derived metal released from the hip. All patients were revised due to severe pain in the absence of infection. Synchrotron X-ray spectroscopy was used to map the tissue samples for Co and Cr. 63,173 tissue areas (4 x 4 microns) were analysed for their relative amounts of Co and Cr and some of these underwent detailed analysis to determine the oxidation state of the Co (4 patients) and Cr (6 patients). The findings differed according to the hip type: Co was much more abundant in the Ultima hips and had a ratio of Co to Cr that was ten times greater than the Non-Ultima hips (p=0.011). This was independent of the concentration of the metals at those locations. Interestingly, the oxidation states of the most abundant chemical forms of Co and Cr were similar for both hip types: Co was a mixture of metallic (zero oxidation state) and a Co(II) species; Cr was Cr(III) in both types of hips. We attribute the greater amount of Co in the periprosthetic tissues of the Ultima TPS to the accelerated corrosion of the femoral stem, which occurs when used together with a MOM bearing. Interestingly, the oxidation state of the Co in the tissues did not differ between the groups so that the dose rather than type of Co appears to be the biologically relevant issue. This may be generalizable to other MOM hip designs that use a cemented CoCr femoral stem and titanium acetabular component and implant designs that can minimise the Co release may have increased longevity. Furthermore, biocompatibility tests that rely on Co induced readouts maybe the most realistic.

Tuesday, June 12, 2012

Johnson & Johnson – A Tall Order Even for Don Draper

June 11, 2012 from the pop tort.com

Sunday, June 10, 2012

The cobalt ladder

I repeatedly get questions on what levels of  Cobalt are toxic.  I have never seen the word toxic used by anyone.

Here is the Cobalt ladder:


1ppb
physiologic

2ppb
upper normal limit for patients with hip resurfacing

5ppb
abnormal ware

10 ppb
60% show ARMD (adverse reaction to metal debris) within 3 years

20ppb
metalosis

(remember ppb and micrograms per liter are the same.)

Here is another post you might look at:

http://www.mydepuyhiprecall.com/2011/06/is-there-accepted-cut-off-level-for.html

The identification of high serum levels of metal ions is an indication that the hip is functioning poorly.

2. There is no accepted cut off level [of what is bad or really poor.]

3. There is an overall consensus that the blood cobalt or chromium level of a well functioning hip is is approx 2 ug/l (which is the equivalent to 2 parts per billion.)

4. There is a correlation between the metal ion concentrations of serum and component wear.

5. Serum chromium ion levels of greater than 17 parts per billion and serum cobalt ion levels of greater than 19 parts per billion are likely to be associated with metalosis.

6. Elevated metal ion levels have been used to identify patients with metalosis, pseudo tumors and the like.

7. Blood levels are doubled in in painful hips compared with well-functioning hips.

8. Other studies have found that by using a cut off of 4 parts per billion, the cases of problem issues rose from 75% to 90%.

Thursday, June 7, 2012

Yet another similarity between A new model of Carcinogenesis and the processes used to describe metal induced interacelluar effects

Food for thought:

Excertps from Metal on metal hip resurfacing arthroplasty; Oxford University; Acta Orthopaedica 2008.

Reactions with metal ions can lead to generation of free radicals:  reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can in turn cause cellular dysfunctions.  Inside the cells, Cr6 is oxidized to cr3 in a series of steps to generate free radicals......Free radicals catalyze the oxidation of protein and phospholipids (a process known as lipid peroxidation.)...Permanent modification of genetic material resulting from this "oxidative damage" represents the first step in mutagensis, carcinogensis and ageing.  Although no evidence has been found for direct binding of Co to DNA, direct binding of Cr3 to DNA is well documented (Wolf et al. 1989).  In cells, 2 main processes exist to correct DNA aberrations to restore the integrity of the genome:  BER and NER.  Under stimulation by Co2 and Cr6, both of these repair mechanisms are inhibited. [added by Connie/when you have revision surgery, these processes come into play.]

Now lets look at The view of a new model of Carcinogenesis

excerpts from  Molecular Medicine  2012 Mar-Apr;16(3-4); 144-153

....According to this new model, the development of any cancer requires that the future tumor cell both acquires a complex set of DNA alterations and develops an alteration in the metabolism of O2.  It is widely acknowledged that the altered genome of tumor cells plays a key role in carcinogenesis.  Evidence suggest that an alteration in the metabolism of O2 from the pathway generates energy to the pathway that produces ROS (reactive oxygen species) may also play an important role in the development of cancer......Most carcinogenic agents have been shown to induce DNA alterations.  Most carcinogenic agents also induce oxidative stress....Most chemical carcinogens need to be enzymatically activated to become genotoxic......

Targeting the Altered Oxygen metabolism of tumor cells for the treatment of cancer

Cancer cells have an alteration in the metabolism of O2 which results in increased glycolytic activity.  the high glycolytic  activity of cancer cells is essential yo their survival. The O2 metabolism of cancer cells can be exploited to kill cancer less selectively by increasing the cellular levels of H2O2and or by attenuating glucolysis.  These effects could be achieved by the use of peroxidant agents and glycolysis inhibitors, alone or in combination.

The role of ROS in the activity of may anticancer agents is increasingly  being acknowledged and induction of oxidative stress by peroxidant agents is emerging as an attractive anticancer strategy.

All just completely fascinating isn't it?  all of this stuff is connected.  I wish I would have taken some molecular biology,  immunology and biochemistry courses in lieu of piano lessons!

One more item:

The role of oxidative stress in carcinogenesis.

Source

Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. jklauni@iupui.edu

Abstract

Chemical carcinogenesis follows a multistep process involving both mutation and increased cell proliferation. Oxidative stress can occur through overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Important to carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation (induced by oxidant-induced DNA damage), as well as modification of gene expression. In particular, signal transduction pathways, including AP-1 and NFkappaB, are known to be activated by reactive oxygen species, and they lead to the transcription of genes involved in cell growth regulatory pathways. This review examines the evidence of cellular oxidants' involvement in the carcinogenesis process, and focuses on the mechanisms for production, cellular damage produced, and the role of signaling cascades by reactive oxygen species

Wednesday, June 6, 2012

A bit more information about how I am selecting my cancer therapy to consider the hip issues

Hi guys!

I have been through 2 of the 3 top notch cancer teams in the country for consults on my particular cancer.  As you know, I have grave concerns about two things:
(1) how did this cancer reoccur so quickly after my hip revision? Is there a relationship?
(2) What is going to happen when I dump the "chemicals" in my system to deal with the cancer on top of the metals. I use the word chemicals broadly here because "Chemo" as it is defined, does not work on renal cell carcinoma.    Renal cell carcinoma and melanoma are the two types of cancers that coincidentally respond well with Immune based therapy.

Here is the key concept I have learned:
  • "Cancer may develop when the immune system breaks down or does not function properly". By develop, it is possible that it can start  as a new cancer or it can re-appear after you are in remission or "cured" as was the case in my situation.  There is around a 2% chance, that once you have had a nephrectomy with a localised cancer in situ and a tumor around 2 Cm in size, of a recurrence which is why they call the nephrectomy (removal of the affected kidney) curative.
In my case, the carcinoma was not initially caused by the hip.  I know that to be the case.  I am not however satisfied at all that there is no relationship between the recurrence of the cancer and the hip.  I believe at this point, there is a relationship between the two. ( If my final consults disagree, I will share that with you.)

In fact, I am so convinced that there is a link that I will likely not opt for the standard of care for this cancer (Sutent for renal cell which is an anti angiogenic approach to the kidney tumor therapy.)  Currently, I am looking at all of the immune based therapies, most of which are in clinical trials.

I fell so confident that it was likely the immune reaction to the hip surgery that prompted this recurrence, that I will choose an immune therapy to deal with it.  I have a few other experts to discuss this with before I make my final decision and will try to share what I have learned.

This is not the same as saying the metals in the hip caused the cancer. I think based on what I have read, there is a good chance that the metals in the hip may over time but the long term studies have not been undertaken.  I do think at this point that my recurrence did have a lot to do with my hip revision.  If that is so, my tumor growths should respond really well to this therapy....I hope.

(1) We know the physiologic process that occurs when the metals are put into the system  (see below.)
(2) We know that revision surgery causes a surge in these metals to be dumped into the system because the surgeon is removing something that is very well entrenched in your body.  Revision surgery is not fun.  It entails a very traumatic cleaning (debriding) of the whole area and then removing the bad hip and replacing it with a new one.  Ouch! If any of you have partners who build things around the house, their workshop is what a surgical table looks like for a revision!
(3)  We know it is the immune system that comes into play when these metals are disbursed.  The body performs a number of  functions to rid itself of this metal debris.  (see below.)
(4) We know if the immune system is weakened significantly, cancer might appear at some point, but we don't seem to have a handle on the ability of  these metals to prompt a cancer patient who was "cured" or in remission, to  have the cancer re-occur.

These issues are being explored.  If my team and I  conclude that we are going to forgo the standard of care for immune based therapy, the  process undertaken by the hip to rid the system of these metals  will have been a major consideration in doing so.  like I said, I have two more consults to see.  Not everyone will agree but hopefully, I can get some level of consensus in the group on the choice of therapy.

If you want to see how the immune system works with the hip, you can look at these posts:


A great pictorial to illustrate the metal on metal oxidation process (5 of 5 in a series)

A separate series that is well written and very easy to understand.

Review of the Cell biology surrounding metal on metal hips (1 of x in a series)

Review of the Cell biology surrounding metal on metal hips (2 of x in a series)

Review of the Cell biology surrounding metal on metal hips (3 of x in a series)

Review of the Cell biology surrounding metal on metal hips (4 of x in a series)

Review of the Cell biology surrounding metal on metal hips (5 of x in a series)

Review of the Cell biology surrounding metal on metal hips (6 of x in a series)

Review of the Cell biology surrounding metal on metal hips (7 of x in a series)

Review of the Cell biology surrounding metal on metal hips (8 of x in a series)

Review of the Cell biology surrounding metal on metal hips (9 of x in a series)


While I know that the use of the metal on metal hips has dropped considerably, were I a patient who had cancer, especially renal or melanoma, personally, I would stay away from metal on metal.  I would opt for other materials. I don't believe the risk is worth it.  Maybe in 10 years, someone will perform a study.  Too late.

If I make very strong statements like this, I want to remind the readers of the following:
  • I am not a doctor
  • I am not a trained medical professional
  • I am not a medical professional in any way
  • I am well read in this topic
It really helps me to write these posts so that I have a good logic based questions  for my meetings with the consults.  I can surely tell you that these cancer guys (oncologists) are not trained in hips.  If you have concerns, it is your job as the patient to make the physician aware of your medical background or potential complications.  While the top consults do review all records prior to your arriving at  the consult, they are likely to gloss over things that they may not see connections to immediately.  You are your always your best advocate.