Tuesday, July 10, 2007

Is fat grafting a Lumpectomy defect in the future for breast reconstruction?


Fat grafting the breast is a controversial topic. A biotech firm claims to have come up with a feasible model for immediate reconstruction of lumpectomy defects involving injecting stem cells from fatty liposuction aspirate of a patient's abdomen. The process from Cytori Therapeutics is called Celution™ . The San Diego Times-Union featured this a few months ago here.



From Forbes Magazine:






In the technique, adipose (fat) tissue is taken from the patient, using a minor liposuction-like procedure. The tissue is then placed into the Celution system, and processing begins. An hour or so later, a dose of regenerative cells is delivered back to the patient, injected in the breast. Fat tissue contains many types of cells, (Thomas) Baker said, but the stem cells and regenerative cells are the "stars" that make the reconstruction possible










Now it's unwise to blow off the wisdom of a guy like Dr. Tom Baker, the Miami plastic surgeon of historic contributions to our field (particularly in face-lift surgery & by virtue of him literally inventing the first effective chemical peel in the late 1950's), but I have some doubts about this. It's going to take at least 10-15 years of incredibly close follow-up to make any kind of conclusion about the effect of stem cell fat-grafting a breast with cancer. The premise of injecting pleuripotent (cells which can "turn" into other cells in layman's terms) stem cells into an organ that's cancer-prone sets off lots of alarm bells. Like "regular" fat grafts, you presumably are going to create mammogram artifacts, which is something you have to approach carefully in someone with a personal history of breast cancer. The American Society of Plastic Surgeons has come out on the record in 2006 against fat grafting of the breast for just such concerns.

Also, on a more practical level, who is going to pay for this?

Most lumpectomy sites don't require any treatment for starters. As I understand this kind of stem-cell "transplant", it takes several hours to harvest and prepare the cells which is expensive time in an O.R. In an era where reimbursement for surgeons performing breast cancer reconstruction has fallen nearly 75-80% since 1990, I cannot imagine this being adopted by Medicare or other 3rd party insurance payers and if they do it will not be economically feasible to perform it. This is what happened to surgery using your own tissues (ie. TRAM flaps), the congress mandated coverage for breast cancer reconstruction in legislation, but Medicare and insurers subsequently made it difficult to earn a living doing it, particularly in the case of muscle flaps or microsurgical reconstructions.


The stem-cell potential of this kind of technology seems to have much more practical potential in areas like ischemic heart disease and neurodegenerative processes IMO then reconstructive Plastic Surgery. If the price comes down, use for cosmetic injections in the face might also be an interesting indication.


7 comments:

rlbates said...

I agree. It will be interesting to see how this plays out.

Anonymous said...

i know cytoritx from a personal level, and over the past two years have let go of many engineering/legal/admin staff to cut costs... they are far to early on in the game to have a real "solution" and there are many other companies out there making the same "cell washing machines" (layman terms) some even further along. i personally believe that cytoritx is making waves in hopes of boosting their stocks which until recently wernt worth much. but at the same time making desperate people think there is a "safe" solution close at hand, and thats just sad and dangerous...

Dr. Rob Oliver said...

I can't comment on the corporate or financial aspects of the company as I have no idea of their status. From a practical standpoint I have a hard time imagining the "killer app" yet for this particular technology which would make investors rich from what I know.

We're at such a primative stage with stem-cell research that it's hard to sort hype from hope (and vice versa).

From a Plastic Surgery POV it just sounds like an overly expensive way to harvest fat grafts that's going to collide with the realities of socialized medicine budgets for any reconstructive surgery indication.

Anonymous said...

I am a regular reader of this blog and know Cytori from a personal level also because being an investor in the company for some years now. There are some wrong statements made from poster number 2 which I intend to correct.

you stated: "over the past two years have let go of many engineering/legal/admin staff to cut costs"

That is only partly right: numbers of employees remained almost constant during the last two years. Cytori currently even employs roughly 40 employees more than at the end of 2005. But they more and more shifted their business focus to the Stem Cell segment in the latest years - adding researchers and egineers there while laying off people from the bioresorbable business unit which they even sold recently.

You also stated: "...they are far to early on in the game to have a real "solution" and there are many other companies out there making the same "cell washing machines" (layman terms) some even further along"

It is up to the medical authorities to decide wether the therapy is safe and effective or "way to early". The Eurepean Medical Authorities granted approval for the device and the therapy after Cytori submited data from their safety trial in Japan. A second, larger efficiency trial to seek reimbursement in Europe will start later in the year.

Marc Hedrick, the President of Cytori, is a former professor of UCLA university where he and his scientific team in 1999/2000 exclusively discovered that stem cells reside in adipose tissue and subsequently decided to set up a start up which developed the Celution device.

This developement did cost 7 years and cost them almost 100 million $ so far. Cytori besides a spin off from UPIT University has the world wide exclusive licence to extract stem cells from adipose tissue so while there might be other "cell extracting and washing machines" none of these is either able or allowed to extract stem cells from adipose tissue as the process is patented!

Medical Equipment manufacturer Olympus Corporation from Japan did conduct due diligence for almost 12 months (looking into the research papers and patents) before entering a collaboration with Cytori (45 million $ invesment by them so far) which further validates the technology.

Olympus is busy for 20 months now to set up a new factory in Nagano, Japan where the third generation of Celution will be manufactured beginning in 2009. Olympus currently employs more than 100 people for developing the next generation of the device and the manufacturing setup.

To separate stem cells from adipose tissue the Celution device follows a 3 step process:

1) Digesting the adipose tissue with the Celase-Agent in the Celution device, to liquify and destroy cross linking between the cell mass

2) Centrifuging to absorb red blood vessel and other stuff your don´t need for treatment

3) Separating and concentrating a defined cell mixture via patented enzymatic disposables. This cell fraction contains the pure stem cells + progenitor cells of different cell types.

The enzymatic disposables have to be plugged into the device and can be used for one time only.

The cell separation process alone just takes one hour. Plus anesthesia plus liposuction plus mixture of stem cells and fat graft + plus injection process - all in all takes several hours.

The cost for a reconstruction or augmentation procedure will be 2.000 to 3.000 $ (per cardrigde/disposable) which is almost the same as you have to pay for implants from Mentor or Allergan. The device itself will cost somewhere between 10.000-30.00 $.

Besides the disposable you have to add the costs of a standardized breast augmentation procedure (doctor, nurse, equiptment, anesthesia, regeneration care...) - as you have when you use implants.

Augmentation is limited to 150 ml per breast (two cup sizes).

Taking cells from the patients own adipose tissue and separating them with the Celution device provides the following advantages in comparison to bone marrow or other adult cell sources and donors:

Cytori takes the patients own cells - so called autologous cells vs. allogeneic. Means no immune reaction, no disease transmission.

Adipose tissue contains a 50 to 100 fold higher number of stem and regenerative cells per cc than bone marrow. Adipose tissue itself can be harvested in much larger quantities than bone marrow which additionally enhances the number of potentially harvestable stem cells.

This signficant higher starting number offers a "clinically sufficient dose" to effectively regenerative damaged tissue. No minipulation (=cultivation) of the cells needed.

Bone marrow offers significant lesser amount of cells so that you have to culture them in the laboratory on a seeder for several days or weeks to get a sufficient number of cells.

This cell culturing might cause malignancy of cells - i.e. tumors, costs a lot of money under GMP rules to controll the quality and much time to send them to the lab, grow and send back to the hospital. Additionally during cultivation the cells loose much of it´s potency!

Celution is a one stop shop: The cells never leave the operating device before giving back to the patient. The one time usable disposables and cartridges secure a sufficient level of sterility and a standardized quality in cell separation.

Newsweek just published a more in depth article that corrected some of the misinformation from SCI magazine:
http://www.msnbc.msn.com/id/19813730/site/newsweek/

Further information here:
http://www.timesonline.co.uk/tol/news/uk/health/article1364726.ece

By the way just have a look at their advisory board for the heart therapies. This is the absolute top-notch gang of all cardiologists world wide. Just check their Bio´s Some much about scientific reputation of Cytori´s work.

Best
Fabian

Dr. Rob Oliver said...

Again, I'll leave any speculation on the finances of this company to others.

I'll reiterate that the economic model and rationale of this for breast reconstruction does not work, and the pending "socialization" of US healthcare makes it even less likely to be adopted IMO.

I think there's absolutely tremendous potential for this in Plastic surgery, but it's going to be for cosmetic indications and financed by patients. I do not think injecting this into breast tissue for augmentation is going to be either widely adopted or endorsed as it will raise costs tremendously, take longer to perform, and give less reliable volumes of material then implants.

If the cost comes down a lot using this for facial injections would be a great indication. How much better it is then fat grafts? That remains to be seen.

DancingBev said...

you state "I'll reiterate that the economic model and rationale of this for breast reconstruction does not work, and the pending "socialization" of US healthcare makes it even less likely to be adopted IMO."

I recently heard a presentation of them stating that the costs for the whole reconstruction procedure (doctor fee, equipment, medical personal, energy...) would not surpass 8000$ of which the stem cell product itself costs roughly 2000 $.

The company recently reported promising clinical results on the San Antonio Breast Cancer Symposium

http://biz.yahoo.com/bw/071217/20071217005216.html?.v=1

more research in europe to be done..

Anonymous said...

in respect of the procedure the abstract from SABCS gives a nice overview and a indication of time required for the therapy:

Patients: This investigator-initiated study was approved by the Institutional Review Boards of the Kyushu Central Hospital and the Kyushu University, and all patients were appropriately consented.
Twenty-one (21) female patients aged from 29 to 59 (mean 46.9) years underwent 25 stem cell
augmented reconstructions at the Department of Breast Surgery, Kyushu Central Hospital, Fukuoka,
Japan. All patients previously received BCT, for small BRCA. Subsequent to the surgical treatment, 19 patients also received radiation therapy in doses ranging between 50 - 60 Gy (mean 53 Gy). All patients
were deemed free of any local recurrence or distant metastasis for ≥ 13 months following BCT. The
volume of autologous ADRC-enhanced fat transplant for each patient was determined by clinical
evaluation including assessment of the volume defect at the time of screening, the severity of radiation damage present and an assessment of residual scarring and fibrosis in the affected breast.
Autologous ADRC-Enhanced Reconstruction Procedure: Under general anesthesia, adipose tissue
(approximately twice the estimated volume to be used for reconstruction) was harvested by
lipoaspiration using standard tumescent technique. Aspirated adipose tissue was divided into two equal portions; one portion, referred to as “Fat A”, was reserved for processing in the Celution™ Cell Processing System to extract, wash and concentrate adipose derived stem and progenitor cells (ADRCs); the other portion, “Fat B”, was used as the primary filler material. Concurrent to the processing of “Fat A”, “Fat B” was irrigated to remove any blood, and the remaining adipose tissue, which was fragmented into numerous 2 - 5 mm fragments by the lipoaspiration procedure, was enriched with concentrated ADRCs out of the Celution™ System by gentle mixing immediately prior to the ADRC-enhanced autologous ransplantation procedure.
After local anesthesia around the recipient site on the breast, three 2 mm incisions were made at
strategically selected areas, and the autologous ADRC-enhanced fat graft was injected in 0.1 – 0.2 cc
aliquots using a 2.5 cc syringe with a 14-gauge needle. Areas of BCT post operative scarring and
radiation fibrosis were incised by multiple 14-gauge needle passes. This resulted both in releasing
subcutaneous fibrotic areas and in creating physical spaces to receive the autologous ADRC-enhanced fat graft. After the best possible cosmetic result was achieved, each incision was closed with 6-0 nylon suture.
Follow-up was performed at one week, 1, 3, and 6 months after treatment. Data collected at each
follow-up visit included clinical examination of the transplantation site(s), photography for historical
comparison, a patient questionnaire to measure the outcome from the patient’s perspective, and an
assessment of breast tissue thickness using t-mode ultrasound.
The tissue thickness measurement (TTM) was done using the SSA-700A Aplio (Toshiba, Japan) ultrasound machine at 3 and 6 months post-procedure. TTM were taken at the most prominent area of the scar where the autologous ADRC-enhanced fat transplant was performed using 2-D ultrasound.
TTM represents the change in tissue thickness between the skin surface and the pectoralis major
muscle surface from baseline to follow up.
Table 1 Baseline patient characteristics and procedural data
Concentration of viable ADRCs from CelutionTM Mean 20x106 vc / 5cc Range 3x106 to 80x106 viable cells / 5cc
System
Patient follow up period Mean 11 months Range 2 to 18 months (19 patients > 8 months)
Range 13.1 to 140.1 months
[b]Total Procedural time Mean 182 minutes Range 129 to 254 minutes[/b]
Areas of adipose tissue harvest Abdomen – 15 pts, Thighs – 7 pts, Hips – 2 pts, Lower back – 1 pt
Range 46 to 152 cc
Range 124 to 500 cc
Range 29 to 56 years
Volume of Autologous ADRC-enhanced fat graft Mean 95 cc
Volume of adipose tissue harvested Mean 272 ± 94 cc
Time from BCT to Index Procedure Mean 58.3 months

So total procedure time including liposuction, processing of tissue with Celution and actual lumpectomy treatment around 3 hours. The patients could go on pursuing their business the next day. I would be surprised if any clinic (or surgeon) would feel exploited if he/she would be reimbursed with 5-6.000$ excluding the cost of the disposable required for cell extraction.

I know that Yoshimura, the frontrunner in the augmentation procedure, demands 20-25.000$ in his Cellport clinic. However he is using a manual cell isolation procedure which takes 12-16 hours, which makes quite of a difference.

Lets say, the gino rigotti´s and emmanuel delay´s of this world do things slightly more complex and therefore more expensive.