SIRG minutes - 9 March 2000

Silicone Gel Breast Implants: Independent Review Group Meeting

9 March, Hannibal House, Elephant and Castle

Present:
Professor R Sturrock (Chairman)
Mr T Milward
Professor J Sloane

Secretariat:
Dr A Austin
Dr D M Gott
Dr S Ludgate
Mr J Tinkler

Apologies:
Mrs V Harpwood
Professor A Silman
Professor R Batchelor
Professor D London
Ms C Rayner

1. Introduction
The Chairman welcomed all members of the Group present. Apologies from those unable to attend were noted.

2. Minutes of the last meeting
The minutes of the previous meeting held on the 14 October (SIRG(99)44) were confirmed. These had been agreed by IRG members by correspondence before their publication on the IRG Website.

3. Matters arising
All matters arising from the minutes of the last meeting were covered by the Agenda.

4. Membership of Group
It was noted that Dr Judy Evans will not be participating in the work of the IRG meantime.

5. Update on the recommendations
5.1 Recommendations 1,3,4 - Patient information leaflet (SIRG(00)35)
The secretariat reminded the IRG that they had commented on an earlier draft of the patient information leaflet and noted that the document was in the final drafting stage. 100,000 copies were expected to be available at the end of March. It was agreed that the IRG should receive a copy of the document before it was released.

The feasibility of a specific consent form for women having breast implant operations was discussed and it was agreed that this was a matter for the group set up by the Royal College of Surgeons to address Good Practice Guidelines (GMG) in breast implant surgery. The Chair of the IRG agreed to write to the Chair of the GPG group regarding specific consent, MDA’s adverse incident system and the need to report explant operations to the National Breast Implant Registry.

5.2 Recommendation 5 - Private Sector
The IRG noted that recommendation 5 is being addressed as part of the wider issue of standards within the private sector. The Care standards Bill is at the report stage and is expected to be completed during this parliamentary session.

In addition it was noted that guidelines for best clinical practice are being drafted. These will be issued to all plastic surgeons and will apply to practice in both the public and private sector.

5.3 Recommendation 6 - NBIR Steering Group, Actions and Proposals
The Chair informed the IRG that Professor McRae is temporarily taking on the chair of the NBIR Steering Group and taking forward the plans to perform a pilot study. This study aims to determine the feasibility of obtaining information from the patient’s notes or whether interviews with patients would be necessary to obtain relevant information.

It was noted that discussions with the Research and Development Department are underway.

5.4 Recommendation 8 - Research SIRG(00)02
As agreed at the last meeting the Chair wrote to Ministers regarding the slow progress in this area. In the absence of Professor Batchelor, Mr Tinkler was asked to give feedback on the second meeting of the research steering group.

The research steering group had reviewed the anti-polymer antibody study carried out in Holland. The study suggested that there was no association between the polymer binding antibodies and the degree of functional disability, although few subjects with moderate or severe functional disablement were included in the population investigated. He noted that the Dutch group were in the process of carrying out a confirmatory study with the same subjects. The Group agreed that this was important work and looked forward to receiving details of the results of the follow up study. Once more was known the IRG would consider whether further work with UK cohorts was indicated. Funding of this would need to be considered in line with research priorities. At this time they will also consider the need to issue advice on the appropriateness of this test.

6. Adjournment Debate on Silicone Gel breast Implants (SIRG(00)30)
The IRG noted that Tom Brake MP had led a debate in the House of Commons relating to the safety of breast implants. Tom Brake discussed the case of a constituent of his who had experienced problems and ill health which she associated with her breast implants. The secretariat pointed out that this lady's case was known to the Group and correspondence from her was included in SIRG(00)29. Her case was also being investigated under MDA's adverse incident system. Tom Brake MP raised several issues and requested that the whole issue of breast implants should be looked at again. The reply by Gisela Stuart MP, Parliamentary Undersecretary of State for Health, informed the House of the progress being made on the IRG’s recommendations and other government related action in this area.

7. Scientific Papers: Discussion and Update (SIRG(00)03-21 & SIRG(00)33 and SIRG(00)34)
The Chair reminded members that they should submit their comments on scientific papers to the Secretariat for compilation [Note: The IRG’s comments on the papers reviewed can be found in an annex to these minutes].

Members present agreed that these papers did not alter the IRG's original conclusions, but one or two papers had identified areas that required continued monitoring. It was agreed that members of the IRG should indicate in their comments on scientific papers which articles were of particular note, so that they can be highlighted.

8. Correspondence concerning the IRG
8.1 Letters between the Department of Health and the IRG (SIRG(00)22)
As agreed at the last meeting the Chair wrote to Ministers regarding the slow progress in taking forward recommendation 8 and inquiring whether Ministers envisage the IRG continuing to meet. Minister and the Chief Medical Officer both wrote to the IRG indicating an appreciation of work performed by the IRG and the request that they continue to meet in order to evaluate new evidence.

8.2 Letters to Claire Rayner (SIRG(00)23)
Claire Rayner had forwarded correspondence which she had received from one of the silicone support groups. She had requested that the Group give consideration to extending the IRG’s membership to include someone with direct experience of problems following breast implantation. MDA had also received letters from a second support group suggesting that a representative of their group would be most appropriate for such a role. The IRG discussed this in detail and it was decided that it would not be appropriate to increase the membership of the group at this time.

The Group felt that it would be more appropriate to hold an open meeting to obtain new evidence from all interested parties. The chair asked the secretariat to establish the views of the absent members on this and, in the event of support for the suggestion, to make arrangements for such a meeting within a year.

Claire Rayner had also forwarded correspondence received from Dr James from the University of Dundee. The IRG noted that he had been asked by the group to submit evidence during their initial review but that this had not been forthcoming. It was agreed that Dr James should be informed of the proposed open meeting which would give him an opportunity to submit new evidence.

8.3 Letter from Tim Milward (SIRG(00)24)
Tim Milward raised the issue of the ownership of breast implants which have been removed. The IRG noted that the Department of Health’s solicitors had indicated that following implantation, the implants would be treated as part of the patient’s body.

He also asked for clarification on what should be done with explanted breast implants, in particular those that had ruptured within 10 years. The secretariat was able to clarify this and noted that the details of the adverse incident system had been provided to the Royal College of Surgeons for incorporation into their the Good Practice Guidelines for breast implant surgery.

8.4 Letter regarding European Parliament Report (SIRG(00)25)
The IRG noted that the European Parliament has asked a group of Spanish public health professionals to review the safety of silicone in medical devices. This Group asked MDA for information which has been supplied. It is understood that their report is due to be presented to the European Parliament in April.

8.5. Letters From Members of the Public relating to:
Remploy (SIRG(00)26)
Further correspondence relating to Remploy has been received. The IRG noted that the position was unchanged since the discussion at the last meeting (see minutes SIRG(99)44 for details).

NBIR (SIRG(00)27)
Several letters had been received regarding the format and use of the National Breast Implant Registry. These did not raise any new issues but their contents were noted by the IRG.

US Settlement (SIRG(00)28)
An MP had raised the issue of the amounts of monies paid to British women under the US manufacturer’s settlement. He had also expressed his opinion that women with breast implants who are unwell might not be treated on the NHS. The IRG noted that neither the cause of the disease nor the availability of funds from a legal settlement had any bearing on the availability of treatment within the NHS.

Safety of Silicone Gel Breast Implants (SIRG(00)29)
Several letters from members of the public and their MPs were received which related to individuals’ experiences following breast implant surgery. The IRG commented that the letters often contained very detailed descriptions of distressing personal problems and ill heath but they did not contain any information to alter the conclusions it had drawn in 1998.

9. Date of next meeting
The date of the next meeting has still to be arranged.

Annex 1 : Recently published literature : Summaries provided by IRG members

Clinical response
SIRG (00)18 Javaid M and Shibu M. Breast Implant Infection Following Nipple Piercing; British Journal Of Plastic Surgery 94:676-677 (1999)

This is a case report of cellulitis and mastitis following nipple piercing in a woman with a previous silicone breast implant. The case highlights the risk of retrograde spread of infection from the nipple and emphasises the importance of avoiding this kind of procedure by women who have had a breast implant.

SIRG (00)19 Von Eiff C, Heilmann C and Peters G. Staphylococcus Epidermis: Why Is It So Successful? Clin. Microbiology Infection 4:297-299 (1998)

This is a review of the biological properties of Staphylococcus epidermidis describing its ability to colonise polymers and to form biofilms thus leading to chronicity of infection. It is known that capsular contraction after silicone breast implantation may be caused by chronic infection and the review supports the IRG's concern that low grade infection with an organism such as Staph. Epidermidis could cause chronic ill health in some women who have had a breast implant.

SIRG (00)20 Adler G K, Kinsley B, Hurwitz S, Mossey C J & Goldenberg D L.

Reduced Hypothalamic-Pituitary and Sympathoadrenal Responses to Hypoglycemia in Women with Fibromyalgia Syndrome; American Journal of Medicine 109:534-543 (1999)

This paper examines Hypothalamic - pituitary adrenal responses in women with the Fibromyalgia syndrome. The only abnormality observed was a decreased response to hypoglycaemia in 30% of the patients tested. However there were no appropriate controls for other chronic pain syndromes and therefore the findings may not be disease specific.

Immunology
SIRG (00)05 Shanklin D R & Smalley D L. Dynamics of Wound Healing after Silicone Device Implantation. Experimental & Molecular Pathology 67:26-39 (1999)

This paper covers 3 topics

a) T lymphocyte responses of women, with various types of silicone implants, co-cultured with colloidal silicon dioxide;
b) Patterns and thickness of the fibrous capsules surrounding the implants;
c) Large wounds and formation of capsules surrounding the implants.

Topic a) is dealt with by assessing data from work carried out in 1995. T lymphocyte proliferative responses to colloidal silicon dioxide of 520 patients with different types of implants are summarized. As in previous papers by these authors, the responses are reported as Stimulation Indices (SI). Two tables of data are shown. In the first, the mean SI of different groups of women (gel filled implants; polyurethane cover with gel filling; double lumen implants - one gel, the other saline; and saline filled only ) are tabulated. Data are shown for women with the device in place, and for women after explantation of the device. Student's T test is used to calculate probability values. There were no significant differences between the mean SI of women with the device in place and after explantation, except in the case of the group of women with an implant containing saline only. However, in that instance, there were just 10 women in the post-explantation group. The second table gives similar data for women who had received more than one implant. No significant difference was observed in mean SI between the women with an implant in place and those in whom the implant had been removed.

Comments: The criticisms made in the immunological section of the full report of the Independent Review Group about the studies of Smalley et al. are still relevant to the current paper. They include such questions as

a) where is the evidence that silicon dioxide acts as an antigen in individuals with implants consisting of siloxanes, which are chemically distinct ?

b) where is the rigorous evidence that the stimulation indices recorded in the cultures represent T cell responses to an antigen ?

The remaining parts of the paper give details on the mean thickness of capsules surrounding implants, and the presence of lymphocytes and plasma cells. This is duscussed below under Toxicology and Pathology

SIRG (00)06 Abbondanzo SL, Young V L, Wei M Q & Miller F W. Silicone Gel-Filled Breast and Testicular Implant Capsules: A Histologic and Immunophenotypic Study. Modern Pathology 12:706-713 (1999)

The title of this paper adequately describes its contents. Each of the women providing tissue in this study had undergone removal of unilateral or bilateral silicone get-filled implants because of suspected implant rupture. Seventeen tissue sections from 9 breast implant and I testicular implant recipients were studied for their histologic appearance. The authors characterised the leucocytic infiltrate around silicone implants using immunohistochemistry. Infiltrating inflammatory cells were stained for expression of CD20, CD45 RO, b FI, CD68, CD44, immunoglobulin light chains, and bcl- XL. The most common histological features seen included prominent T cell and foamy macrophage reactions with foreign body giant cells and granulomas in dense fibrovascular connective tissue. The Majority of T cells observed expressed CD45 RO - often referred to as a marker for "memory" T cells, but it may be that this merely reflects the ability of this sub-population of T cells to migrate from blood into tissues. Refractile strands of non-polarizable material consistent with silicone were also seen in some cases. T lymphocytes reacting with antibodies to CD45RO and beta Fl are interpreted as "anamestically responding". While reactivity with these antibodies may identify T cells which have previously responded to antigens, it cannot be inferred that the antigens in question are actually present in the breast.

Comments: This paper does not provide any evidence for an immune response to silicone implants. However, it confirms previous observations on the histologic appearances of tissues adjacent to silicone breast implants. The presence of infiltrating inflammatory cells has also been noted in earlier studies, and it is likely that the amount of inflammation present was related to the fact that the sections were prepared from women with suspected rupture of their implants.

SIRG (00)17 Powell J J, Van de Water J & Gershwin M E. Evidence for the Role of Environmental Agents in the Initiation or Progression of Autoimmune Conditions. Environ Health Perspect 107:667-672 (1999)

This review discusses the broad issue that non-protein chemicals can initiate the autoimmune process, often after a long latency. The antigenic potential of such agents (referred to as xenobionic) is determined, not only by its characteristics, but also by certain host features such as genetic background. The paper discusses a number of models whereby such exposures can cause autoimmune disease in man.

Of relevance to silicone (which is not considered in any detail in this report) is the quote of a paper by Naim that different silicone formulations, such as used in implants, have different adjuvant effects in inducing delayed type hypersensitivity in rats. Silica exposure is well recognised as being related to scleroderma (amongst other autoimmune disorders) thought the mechanism of the autoimmune response is unclear, although upregulation of soluble F as one pathway.

The paper also reviews the data linking organic solvents to scleroderma and suggests that Sel-70 autoantibodies, seen in diffuse disease, are more frequent in those with a history of solvent exposure (based on a recent publication).

The nature of the relationship between vinyl chloride exposure and disease is discussed with the conclusion that vinyl chloride may indeed initiate an autoimmune response.

The relevance to silicone breast implants is that autoimmune disease may develop from exposure to a variety of non-biological environmental agents and a number of immune processes can be involved. There are however, no new data in this publication on an explanation as to why silicone exposure can lead to autoimmunity.

SIRG (00)12 Schaefer C J and Wooley P H. The Influence of Silicone Implantation on Murine Lupus in MRL Lpr/Lpr Mice. The Journal of Rheumatology, 26: 2215-2221 (1999). This paper describes the immunological effects of implanting silicone oil or silicone gel into mice of the MRL lpr (lupus prone) or MRL +/+ (control) strains. The former mice develop a syndrome similar to systemic lupus erythematosus (SLE). The latter strain are genetically similar but lack the lpr gene, do not develop the SLE-like syndrome, but do develop glomerulonephritis.

In brief, the implants of oil or gel had no effect upon the appearance time, or severity of signs of the SLE-like syndrome in the lpr mice, judged from palpable lymph nodes, or levels of protein in the urine. In contrast, both oil and get implanted lpr mice developed significantly higher titres of antibodies to double stranded DNA than were found in control mice. Similarly, higher titres of rheumatoid factor were found in lpr mice that had been implanted with silicone oil.

Studies on a number of cytokines were also carried out. Serum IL-1 levels were significantly raised at termination of the experiments in lpr mice given silicone oil or gel, and IL-2 levels were significantly raised in mice given silicone oil.

Finally, silicone gel that had not dispersed by the end of the experiments was dissected out, washed, and analysed for bound proteins. There was increased total protein recovered from the gel in the case of the lpr mice. Three bands of self-proteins which reacted with autologous serum from the implanted mouse were detected by Western blots.

Comments: This is a careful study carried out by a group with an excellent scientific reputation. As in the case of a previous, similar study on collagen-induced arthropathy in DBA /1 mice, implantation of silicone oil or gel in these genetically susceptible mice did not give rise to more rapid or aggressive signs of disease. Nevertheless, the experiments confirm that some self proteins have a tendency to adhere to silcone gel, and this may be related to the higher titres of auto-antibodies (anti- DS DNA, & RF) found in the mice. It thus remains theoretically possible that in women that are genetically susceptible, implantation with silicone gel might have the same effect.

However, as discussed at some length in the Independent Review Group's original report (Immunology section, pages 7- 9), the present evidence is insufficient to sustain this hypothesis. As the epidemiological evidence shows that there is no significant increase of autoimmune disorders in unselected populations of women with silicone breast implants, it would be necessary to identify the hypothesized genetically susceptible group, and the target antigen.

Toxicology and pathology
SIRG(00)03 Pasteris JD, Wopenka B, Freeman JJ, Leroy Young V & Brandon H J.

Medical Mineralogy as a New Challenge to The Geologist: Silicates in Human Mammary

Tissue? American Mineralogist, 84:997-1008 (1999).

Raman spectroscopy was used to analyse sections of breast tissue from six women who had received silicone implants and three who had undergone reduction mammoplasty. Silicone was identified in the implanted women but not in the non-implanted controls. Neither crystalline nor amorphous silica was identified in any of the subjects. This is an important point as Shanklin has assumed that some of the particulate material identified in implanted breasts is silica. Furthermore, silica is used by Shanklin and Smalley in their T cell stimulation test (see SIRG(00)05). The research described in this paper was funded by an unrestricted gift from the Dow Corning Corporation.

SIRG(00)04 Klykken P C, Galbraith T W, Kolesar, G .B, Jean P A, Woolhiser M R-, Elwell M R, Burns-Naas, L A, Mast R-W, McCay J A, White K L & Munson A E. Toxicology and Humoral Immunity Assessment of Octamethylcyclotetrasiloxane (D4) Following a 28-Day Whole Body Vapour Inhalation Exposure in Fischer 344 Rats. Drug and Chemical Toxicology 22:655-677 (1999)

Fischer rats were made to inhale octamethylcyclotetrasiloxane (D4) at doses between 7 and 540ppm for 6 hours/day, 5 days/week for 28 days. An increase in liver weight was detected unaccompanied by any histological change. No other abnormalities were detected in these animals.

SIRG(00)05 Shanklin D R, and Smalley D L. Dynamics of Wound Healing after Silicone Device Implantation. Experimental and Molecular Pathology 67:26-39 (1999)

This paper covers 3 topics

a) T lymphocyte responses of women, with various types of silicone implants, co-cultured with colloidal silicon dioxide;
b) Patterns and thickness of the fibrous capsules surrounding the implants;
c) Large wounds and formation of capsules surrounding the implants.

Immunology studies described in this paper are discussed in the Immunology section.

Implant capsule thickness was studied and found to be especially great around implants coated with polyurethane. Lymphocytic and lympho-plasmacytic vasculitis was found to correlate with thicker capsules. The authors state that these types of vasculitis are markers of delayed hypersensitivity but they provide no illustrations of the processes. The IRG has disagreed with Shanklin's interpretations of histological sections said to show vasculitis. In the Group's opinion Dr. Shanklin's histological photographs merely exhibit perivascular lymphocyte and plasma cell infiltration. There is no evidence in this paper that his diagnostic criteria have changed.

A further finding in this paper is a significant decrease in mean "T cell stimulation indexes" after explantation of saline filled devices but not those containing gel or gel and saline. It is not made clear in Table 1 whether the "indexes" were calculated after stimulation of T cells by concanavalin A or silica and the relevance of the latter is questionable given the failure to find, to date, evidence of silica deposition around capsules (see SIRG(00)03). No nominal controls are included.

In short, this paper contains no new data of any significance and does not contribute to the debate on whether or not there is an immune response to silicone implants.

SIRG(00)07 Peters W, Smith D & Lugowski S. Silicon Assays in Women with and without Silicone Gel Breast Implants - A Review. Annals of Plastic Surgery 43:324-330 (1999)

This is an article reviewing silicon assays in women with silicone implants. The authors' conclusion is that silicon measurements in blood, serum, breast milk- or implant capsule tissue are so variable that they have no effective role in the clinical monitoring of implant leakage in women with silicone breast implants.

SIRG(00)08 Garrido L & Young V.L. Analysis of Periprosthetic Capsular Tissue from Women with Silicone Breast Implants by Magic-Angle Spinning NMR. Magnetic Resonance in Medicine 42:436-441 (1999).

The amount of PDMS in capsular tissue surgically removed from women with breast implants was measured using 29Si and 'H magic-angle spinning solid-state NA4R spectroscopy. Levels of PDMS ranging from 0.05 to 9.8% silicon were detected in wet tissue. No silicon-containing compound other than PDMS was detected. No relationship was found between the amount of PDMS and the degree of capsular contracture.

SIRG(00)09 Santos-Briz A, Lopez-Rios F & De Agustin P P. Granulomatous Reaction To Silicone In Axillary Lymph Nodes. A Case Report with Cytologic Findings. Acta Cytologica 43: 1163-1165 (1999).

A case is reported describing identification of a granulomatous reaction in the axillary lymph nodes of a patient with silicone breast implants. The report demonstrates the usefulness of FNAC in this context in diagnosing implant rupture and distinguishing the consequent reactive changes in nodes from malignant to neoplasia

Surgical technique and imaging
SIRG(00)10 Ikeda D M, Borofsky H B, Herfkens R J, Sawyer-Glover A M, Birdwell R L & Glover G H. Silicone Breast Implant Rupture: Pitfalls of Magnetic Resonance Imaging and Relative Efficacies of Magnetic Resonance, Mammography, and Ultrasound. Plastic and Reconstructive Surgery 104:2054-62 (1999)

This paper surveys 30 patients referred to Stanford University Medical School with suspected ruptures. In only 16 patients were they able to confirm the imaging opinion with surgical findings. Though all 30 cases of rupture were diagnosed by MRI there were 6 false positive MRI findings, 4 of which was due to wrong interpretation of the "rat tail sign".

One message from this paper is the unreliability of the "rat tail sign".

Ultrasonography and mammography were less reliable than MRI scan.

SIRG(00)11 Feng L-J & Amini S B. Analysis of Risk Factors Associated with Rupture of Silicone Gel Breast Implants. Plastic and Reconstructive Surgery 104:955-63 (1999)

This paper analyses 842 patients who had 1619 implants removed, all carried out by a single surgeon between 1990 and 1996. This massive series was analysed to see if there were any factors that would predict implants that were ruptured rather than those that were not. The following factors were associated with an increased chance of rupture.

1. Increasing age.
2. Retroglandular location.
3. Baker contracture grades III and IV.
4. Presence of local symptoms.
5. McGhan implants had a significantly lower rupture rate than other manufacturers. Double-lumen implants and polyurethane- covered implants had a lower rupture rate than smooth surface gel implants.

It could be that using these pointers when the MRI diagnosis of possible rupture was equivocal could give the surgeon some guidance as to which patients to explant.

SIRG(00)13 Caner B, Ozgur F, Bor D, Ulutucel N, Aydin M & Oktay S. Effect of Silicone Breast Implants on Myocardial Imaging. Annals of Plastic Surgery 43:471-75 (1999)

This article confirms that silicone gel implants can block the read out from the myocardium on thallium-201 myocardial perfusion scintigraphy in a similar way to just bulky breast tissue. This article is helpful to nuclear medicine specialists when allowing for breast implants in modifying the myocardial read out.

SIRG(00)14 Eppley, B L Alloplastic Implantation Plastic and Reconstructive Surgery 104:1761-85 (1999)

This is an historical article talking about various things used for breast implantation prior to the introduction of the medical grade silicone bag prosthesis in the early 1960’s. It makes the point that whatever may be thought of silicone implants now they are vastly superior to anything that came before.

SIRG (00)16 Rohrich R J, Radhakrishnan R, Robinson J B & Griffin J R. Factors Predictive of Quality of Life after Silicone Implant Explantation. Plastic & Reconstructive Surgery 104:1334-1337 (1999)

This methodologically weak report, which should not have survived the peer review process, nonetheless addresses an important issue. The alleviation of symptoms following explantation is frequently seen as an indication of a cause/effect relationship.

In this report, 50 responders (of 180 patients circulated) answered a questionnaire on improvement in quality of life post explantation. It is assumed, though not stated, that it was the occurrence of post implant medical problems that resulted in the request for an explant.

Only half the responders reported an improvement in quality of life, in the remainder symptoms were either stable or deteriorated. The greater the number of symptoms, prior to explant, the lesser the likelihood of improvement.

Clearly in this large series, explantation did not achieve a substantial improvement in quality of life in those with multiple symptoms. One explanation is that the symptoms were actually unrelated to the implant. Other explanations include the measuring instrument being insensitive and response bias.