MENTOR’S SILICONE GEL-FILLED BREAST IMPLANTS (P030053)

 

SUMMARY OF CERTAIN CLINICAL ISSUES PRESENTED TO FDA’S GENERAL AND PLASTIC SURGERY DEVICES ADVISORY PANEL

Based on communications with the Food and Drug Administration (“FDA”), Mentor is submitting this summary overview of certain key clinical issues concerning its silicone gel-filled breast implants, to facilitate the Panel’s evaluation of these products.  This summary supplements, and is not intended to replace, the more detailed package of PMA information previously provided by Mentor in CD format.

I.                   CLINICAL RELEVANCE OF SILICONE BREAST IMPLANT GENERATIONS

The literature recognizes three distinct generations of implants:[1]/ 


The relevance and value of the silicone gel-filled breast implant literature, as it relates to generations, are as follows: 

A.                 Potential Health Consequences

Information concerning the biological effects of silicone may be validly gleaned from the extensive universe of medical literature on all generations of implants.  Health consequences literature on earlier generations of silicone gel-filled implants in fact provides us with a measure of the worst case over a longer period of time of use, given the higher rates of exposure (e.g., from rupture) associated with those implants. 

B.                 Mechanical Characteristics

In contrast to potential health consequences, literature relating to the mechanical characteristics (e.g., rupture and migration) should be evaluated on a generation-by‑generation basis.  Mentor’s implants are third generation (i.e., they have a low-bleed elastomeric shell with a barrier layer and thick gel).  All literature pertaining to third generation implants is directly applicable to the performance of Mentor’s PMA products, given the similarity in design and chemical composition of all third generation implants. 

Reliance on prior generation literature would not be appropriate to evaluate rupture and related mechanical performance characteristics, given the substantially different design profiles of the prior generations.  Marked differences in rupture rate and related mechanical performance between generations have been clearly demonstrated in a number of studies.[2]/

II.                EXTENT OF MENTOR’S FOLLOW-UP IN ITS CORE STUDY

Mentor obtained 3-year follow-up on a majority of the patients (n=665) prior to Mentor’s August 2004 submission.  Among those patients eligible for follow-up at time of database closure, 94% had returned for the 3-year follow-up visit.   Follow-up rates also were consistently high for all enrolled patients in the study at the 1- and 2-year visits (94% overall).  As of 2005 (i.e., post-submission), 3-year follow-up has been obtained for 812 enrolled patients.  Data from this latest follow-up shows no statistical difference in Kaplan-Meier complications from the August 2004 submission. 

 

III.             THE WEIGHT OF EVIDENCE SUPPORTING NO ASSOCIATION BETWEEN CONNECTIVE TISSUE DISEASE (CTD) AND RELATED SYMPTOMS, AND SILICONE BREAST IMPLANTS

It is well-established that the issue of CTD is best addressed by well-designed, controlled epidemiological studies.  These studies examined the potential association between both ruptured and intact silicone breast implants and CTD and/or related symptoms. 

As noted below,[3]/ the weight of the evidence from the literature evaluating silicone implants generally (i.e., irrespective of rupture), shows no association between these products and CTD and related symptoms.  The sum total of patients with breast implants in these studies exceeds 34,000 (patients from the same cohort reported in multiple studies were counted only once).

Berner et al. 2002

Brinton et al. 2004

Breiting et al. 2004

Burns et al. 1996

Edworthy et al. 1998

Englert et al. 1996

Englert et al. 2001

Friis et al. 1997

Fryzek et al. 2001

Gabriel et al. 1994

Gaubitz et al. 2002

Giltay et al. 1994

Goldman et al. 1995

Hennekens et al. 1996

Hochberg et al. 1996

Hölmich et al. 2003

Janowsky et al. 2000 (meta-analysis)

Jensen et al. 2001

Kjøller et al. 2001

Kjøller et al. 2004

Laing et al. 2001

Lipworth et al. 2004 (meta-analysis)

Nyrén et al. 1998

Park et al. 1998

Sánchez-Guerrero et al. 1995

Schusterman et al. 1993

Strom et al. 1994

Weisman et al. 1988

Wells et al. 1994

Williams et al. 1997

 

 

Likewise, the weight of the evidence from the following studies support no association between ruptured implants and CTD and related symptoms:

Citation

N

Average Follow-up (Years)

Hölmich et al. 2003[4]/

238

14

Berner et al. 2002[5]/

32

7

Gaubitz et al. 2002[6]/

90

9.1

Brown et al. 2001[7]/

344

16.5

Fryzek et al. 2001[8]/

1,280

13

Wolfe and Anderson 1999[9]/

508

Not Applicable (Case Control Study)

 

Importantly, these epidemiologic studies reflect worst-case exposure -- that is, they included patients with prior generation implants associated with higher rupture rates and exposure than has been demonstrated for the current third generation implants. 

Although patients in the Core study were monitored for CTD and related symptoms, as noted above, it is well-established that the issue of CTD is best addressed by well-designed, controlled epidemiological studies.  Nevertheless, the occurrence of CTD in the Core Study was well below the published rates for the individual diseases in the general population.

CTD Diagnosis

Core Gel Study Incidence

Published Rates in General Population

Hashimoto thyroiditis/ autoimmune hypothyroidism

2 patients (0.2%)

0.8% (including Hashimoto and other) (Jacobson et al. 1997)[10]/

Fibromyalgia

2 patients (0.2%)

3.4% (Wolfe et al. 1995)[11]/

Pyoderma gangrensosum

1 patient (0.1%)

0.6% (Mancini et al. 2002)[12]/

Rheumatoid arthritis

1 patient (0.1%)

0.9% (Jacobson et al. 1997)[13]/

 

Two very common symptoms experienced by the general population are fatigue and joint pain.  The appropriate method to investigate whether there is a causal relationship between these symptoms and silicone breast implants is well-designed, controlled epidemiological studies. As summarized below, it is well established through such studies that joint pain and fatigue are no more common in women with breast implants than in the general population.  Also as summarized below, it is well established that joint pain and fatigue are no different in women with ruptured versus intact implants and women with intracapsular versus extracapsular ruptures.

Joint Pain and Women with Breast Implants:

Epidemiology Studies

 

 

Findings

Citation

Design

Relative Risks

Odds Ratios (95% CI)

Kjøller et al. (2004)[14]/

Cohort

1.1

0.7–1.8

Hölmich et al. (2003)[15]/

Cohort

1.0

 

1.4

0.5–1.8: patients w/ ruptured vs. intact implants
 0.4–4.7: patients w/ extracapsular rupture
vs. intact implants

Brown et al. (2002)[16]/

Cohort

1.4

0.8-2.4: patients w/  extracapsular
vs. intracapsular rupture

Berner et al. (2002)[17]/

Matched Pair Analysis

No significant difference

62.5% in cancer patients with implants

60.9% in cancer patients without implants

Gaubitz et al. (2002)[18]/

Cohort

No significant difference

79.2% in patients with ruptured implants (by MRI)

74.2% in patients with intact implants

Fryzek (2001)[19]/

Cohort

1.1 (not significant) patients with implant leakage
vs. patients with no local complications

Park et al. (1998)[20]/

Cohort

1.07

 

1.01

0.49-2.32: augmentation patients
0.56-1.84:  reconstruction patients

Giltay et al. (1994)[21]/

Cohort

2.28

1.37-3.81

Wells et al. (1994)[22]/

Cohort

1.929

0.521-7.142

 

Fatigue and Women with Breast Implants:

Epidemiology Studies

 

 

Findings

Citation

Design

Relative Risks

 Odds Ratios (95% CI)

Kjøller et al. (2004)[23]/

Cohort

1.6

0.9–2.8

Hölmich et al. (2003)[24]/

Cohort

0.7

 

 

1.9

0.3–1.6:  patients w/ extracapsular rupture vs. intact implants

0.7–5.2: patients w/ extracapsular rupture vs. intact implants

Brown et al. (2002)[25]/

 

1.1

0.5-2.1: patients w/  extracapsular
vs. intracapsular rupture

Berner et al. (2002)[26]/

Matched Pair Analysis

No significant difference

40.6% in cancer patients with implants

34.4% in cancer patients without implants

 

Gaubitz et al. (2002)[27]/

Cohort

No significant difference

45.8% in patients with ruptured implants (by MRI)

47.0% in patients with intact implants

 

Fryzek (2001)[28]/

Cohort

1.0 (not significant)

Patients with implant leakage
vs. patients with no local complications

Park et al. (1998)[29]/

Cohort

2.01

0.76

0.74-5.56: augmentation patients

0.37-1.60: reconstruction patients

Wells et al. (1994)[30]/

Cohort

1.379

1.379 (95% CI 0.547-3.310)

 

IV.              RUPTURE RATE AND HEALTH CONSEQUENCES    

Any evaluation of rupture (e.g., rates, intracapsular versus extracapsular, asymptomatic versus symptomatic, issues of progression, and change over time) must be reviewed first and foremost in light of what is known regarding the potential health consequences resulting from ruptures.  As noted above, findings from a number of well-designed, controlled epidemiology studies, taken together, do not support an association between ruptured silicone breast implants and systemic disease or symptoms.  These epidemiological findings of no systemic health consequences should guide and override any perceived limitations with respect to individual evaluations of rupture rate and progression.

The Core data provide meaningful information concerning the expected rupture rate through three years.  These findings are consistent with literature evaluating overt (i.e., patient and/or physician-recognized) ruptures in third generation devices for a similar or longer period of time (Henrickson et al. 2003 and third generation subset analysis of Kjøller).[31]/  In Henrickson et al. (2003), 971 women (85% augmentation, 15% reconstruction) were followed up to two years post surgery with no overt ruptures reported.  In an unpublished third generation subanalysis of Kjøller et al. (2002) involving augmentation patients (mean implantation time of 5 years; range of up to 9 years), only 2 of 509 implants ruptured (0.4%).

The Core findings are supported and extended by Mentor’s PMA longer-term data which evaluated overt and silent (i.e., asymptomatic) ruptures of Mentor’s third generation PMA implants out to 12 years (Sharpe and Collis).  The long-term rupture study conducted by Drs. Sharpe and Collis evaluated by MRI the integrity of subglandular textured Mentor implants up to 12 years in 101 augmentation patients. Patients with Baker III/IV capsular contracture (considered by some to be at higher risk for rupture[32]) were included, as were patients with prior surgical procedures (e.g., mastopexy).  The inframammary incision that was used in the Sharpe and Collis study also was used in the majority of Augmentation patients in Mentor’s Core Study.  The study’s use of subglandular placement, which is associated with a higher rate of capsular contracture (see Kulmala et al. 2004),[33]/ provides a worst case evaluation of rupture risk.  Mentor’s textured implants are representative of all implants used in the Core Study, given the lack of an association between surface type and complications reported both in the Core Study (Cox analysis) and in the literature (Kulmala et al. 2004; mean follow-up 10.9 years).[34]/ 

The objective of the statistical methodology used for the Sharpe and Collis study was to provide a valid approach to estimate the cumulative incidence of rupture based on these data.  Mentor recognizes that estimation of cumulative incidence over time is almost always estimated based on longitudinal data, often using survival analysis methodology.  The Sharpe and Collis data, however, are cross-sectional.  Specifically, the data consisted of two elements for each implant:  the age of the implant (in years) and whether or not the MRI for the implant is called a silent rupture.  Standard methods to use such cross-sectional data to estimate a cumulative incidence (or, equivalently, a survival curve) were not available and, thus, an alternative statistical method was employed. 

The approach used, while not standard, was derived using standard mathematical estimation methods, and is fully valid.  Thus, it is possible to estimate the cumulative incidence of rupture based on a cross-sectional sample of implants.  The approach employed standard mathematical statistical methods, specifically maximum likelihood estimation, to derive an appropriate estimate of the survival curve.  A jackknife method was then used to estimate the variance from which 95% confidence intervals were obtained using the normal approximation.

This study provides several important findings concerning long-term silent  and overt rupture rates.  There were no overt ruptures identified among this population, and silent ruptures were not observed until approximately 7 years after implantation. The rupture rate slowly increased thereafter until, at 12 years, it was 15% (by patient) and 9% (by implant).  There were no confirmed extracapsular ruptures, and the average age of implant at time of confirmed rupture was 9.6±1.6 years.   

Like the Core findings, the Sharpe and Collis findings are consistent with literature -- specifically, a multi-site Danish study that evaluated silent and overt third generation device ruptures for a similar period of time (Hölmich et al. 2003).[35]/   (The findings of the Hölmich et al. 2003 study fall within the Sharpe and Collis study confidence intervals.)  Approximately 62% of the implants evaluated in the Hölmich et al. 2003 study were third generation implants, which are representative of Mentor’s PMA products.  Because third generation implants have essentially equivalent materials and design, literature assessing third generation implant rupture is directly relevant to assessing product performance characteristics of Mentor’s devices.  As with the Sharpe and Collis findings of no rupture through 7 years, the authors of this study note that “third generation implants currently in use are relatively durable for the first six to eight years in situ, after which the rupture rate increases.”[36]/

 

In the Hölmich et al. (2003) study, two MRIs were performed on each study implant, approximately 2 years apart.  Third generation implants ranged in age from approximately 3 to 12 years.  Based on the MRI results, 2-year cumulative incidence of implant rupture was estimated by implant age category (e.g., 3-5, 6-7, 8-9, and 10-11 years).  These estimates by age category were then combined (assuming a piecewise exponential distribution within age category) to estimate a cumulative rupture-free implant survival.  Subtracting from one, this provides an estimate of the cumulative incidence of implant rupture by implant age. 

Based on these cumulative estimates, and consistent with the Sharpe and Collis study, the authors conclude “for modern [third generation] implants intact 3 years after implantation, we estimated rupture-free survival of 98% at 5 years and 83% to 85% at 10 years”[37]/  (i.e., 15% rupture, by implant).  Other rates not specific to third generation implants or not cumulative in nature are not appropriate for estimating cumulative rupture incidence rates.  For example, the 3.6% rupture rate per year cited in this study for third generation implants is not itself a cumulative rupture incidence rate, and should not be used to calculate cumulative rupture incidence rate because it does not take implant age into account.  Likewise, the rate of 8.9% ruptures per year cited in the publication for all generations, is not representative of third generation rates.

 

The Hölmich study evaluated patients who entered the study with implants intact three years after implantation.  This should not, however, impact overall rupture rates based on the findings from other third generation studies because, as noted above, other studies establish that third generation implants do in fact remain intact through 3 years.[38]/

·                    Only one confirmed patient with ruptures among 1,007 patients in Mentor’s Core Study after three years of follow-up;

·                    No ruptures among 971 women in the first two years of follow-up in Henrickson et al. (2003): and

·                    Two ruptures among the subset of 509 (0.4%) patients with third generation implants and a mean follow-up of 5 years in Kjøller et al. (2002) (based on a subanalysis of the original study).

In addition to information on silent rupture over time, the Danish data (e.g., Hölmich et al.) are important and informative in helping to define progression of ruptures and extracapsular rupture rates as well. 

·                    Progression: Hölmich et al. (2004)[39]/ directly addressed progression of ruptures using MRI evaluations.  Because a third generation subanalysis was not available for this aspect of the study, the findings on progression likely represent worst case.  In this study, 90% of intracapsular ruptures showed no change at second MRI (i.e., two years later), and 84% of extracapsular ruptures remained stationary at second MRI. 

·                    Extracapsular ruptures: The extracapsular rupture rate for third generation devices was assessed in an unpublished subanalysis by the authors of the Hölmich publications, and found to be extremely low (0.8%).

V.                 EFFECTIVENESS DATA AND SUPPORTING LITERATURE

A.                 Core Study Findings

Primary effectiveness measures were met for each cohort in the Core Study, i.e., increase in cup size for Augmentation and Revision patients; restoration of the breast mound for the Reconstruction patients; and an increase in chest circumference in all cohorts. 

The following secondary effectiveness/quality of life measures also were evaluated consistent with FDA guidance.

Instrument

Augmentation

Reconstruction

Revision

Body Esteem

ü

ü

ü

Rosenberg Body Esteem

ü

ü

ü

SF-36

ü

ü

ü

Tennessee Self-Concept Scale

ü

ü

ü

FLIC (Cancer)

 

ü

 

 

A number of these scales focused on issues that are unrelated to breast image and satisfaction with surgical outcome.  For example, the Tennessee Self-Concept Scale requires that the patient indicate the extent to which she agrees with the following statements: “I am a moral failure;” “Once in a while, I laugh at a dirty joke;” “I often act like I am ‘all thumbs;’” “I would rather win than lose in a game;” “At times I feel like swearing;” “I should love my family more;” and “I do not like everyone I know.”  Consequently, it is important to review the specific subscales of each assessment tool to understand their relevance to satisfaction in this population. 

In the Augmentation cohort, an increase in self esteem was noted on the Rosenberg Self Esteem Scale.  There was no change on the overall score of the Body Esteem Scale.  However, the Sexual Attractiveness subscale and the Chest Score of the Body Esteem Scale, which are more relevant to this population, increase.  Although there was a small decrease on the SF-36, it does not appear to be clinically significant. 

No change among Reconstruction patients can be viewed as positive due to the body image concerns and physical challenges facing these patients.  Nonetheless, a significant improvement in functioning was observed in the Core Reconstruction cohort, as measured by the Functional Living Index of Cancer.  No change was observed on the Body Esteem Scale, Rosenberg Self Esteem Scale, or the Mental and Physical Components of the SF‑36.

The Revision patients represent a uniquely difficult population from both a medical and psychological perspective; therefore, greater difficulties, while unfortunate, are not unexpected.  Nonetheless, an increase in the Body Esteem Scale Chest score was observed in the Core Revision cohort.  Many of the other Body Esteem Scale questions are not relevant for patients with breast implants (e.g., satisfaction with feet is one such question).  There was no change on the Rosenberg Self Esteem Scale.  Decreases were seen on the SF-36; however, scores remained high. 

The final secondary measure of effectiveness was Global Patient Satisfaction.  Global Patient Satisfaction ratings are frequently used and widely accepted in outcomes assessments generally, and in plastic surgery specifically.  The satisfaction ratings are compellingly high for all cohorts and have been maintained throughout the course of the study.

Cohort

Two Years

Three Years

Augmentation

99%

97%

Reconstruction

98%

98%

Revision

95%

96%

 

These high global satisfaction rates are consistently substantiated in the literature. 

B.                 Correlation Between Satisfaction and Clinical Benefits, As Reported in the Literature

A review of the benefits literature, to be relevant, must focus on more recent publications, which are more reflective of current cultural norms.  Earlier cultural biases against plastic and reconstructive surgery are no longer representative of today’s implant population. 

Self-improvement represents the driving reason for seeking aesthetic breast augmentation, and women today have highly personal and varied motives to do so, including: improved body image; improved psychosocial outcomes (which encompass mental health and well-being generally, and improved self-esteem, relationships, and sexuality, specifically).[40]/

With respect to augmentation benefits, satisfaction results are consistently high in the literature, and correlate to psychological and physical well-being.  

·                      In an online survey conducted by Young et al. (2004),[41]/ of 2,273 women who underwent breast augmentation, 98% of the respondents reported that the surgery met expectation; 92% reported that they were happy with their decision to get implants; 93% reported they would recommend the procedure to friends or family; and 92% thought that breast augmentation improved their overall appearance. 

·                      The interrelationship of patient satisfaction with improved mental and physical well-being was evaluated by Cash et al. (2002), in their multicenter, prospective, two-year study in 360 women who underwent breast augmentation.  They found that overall surgical satisfaction with outcome was high, and this satisfaction was highly related to improved body image satisfaction (p<0.001), improved self-image (p<0.001), and improved sexual satisfaction (p<0.001).[42]/ 

·                      In an editorial response to the Cash et al. (2002) article, Sarwer noted that: “[s]tudies will help correct the public perception that cosmetic surgery is simply trivial vanity and will help reassure the individual patient that improving one’s appearance can result in psychological improvements.”[43]/

As with the literature, the FDA has acknowledged that “the potential psychological benefits” offered by silicone gel-filled breast implants “are an important part of the device’s efficacy.”[44]/

In addition to psychological benefits of breast augmentation, there are also functional (i.e., restorative) benefits to breast implants.  To better understand these functional/restorative benefits, the population of cosmetic breast implant recipients must first be understood.  Women seeking breast implants for cosmetic purposes are predominantly married (64%) and in their 20s, 30s, and 40s; 64% percent of the married women have children.[45]/  In this population, some level of breast involution and/or sagging can result from pregnancy, lactation, and/or significant weight change caused by these events.  For these women, physiological replacement of the involuted/sagging breast -- that is, regaining the breast size/shape these women had before pregnancy, lactation, or weight changes -- also factors into decisions for seeking cosmetic breast augmentation.[46]/  Women who have augmentation for this reason report high levels of satisfaction with the results of their surgery.[47]/  Thus, there are clearly identifiable functional (i.e., restorative) as well as psychological benefits to these women.

With respect to breast reconstruction, women seek this procedure for a variety of reasons related to improved mental health.  For example, in a review of the literature conducted by Harcourt and Rumsey (2001),[48]/ it was noted that the motivation for breast reconstruction includes: maintained feelings of  femininity, restored symmetry, improved self-confidence, and  avoidance of the need for external prosthesis. 

The clinical benefits of breast implants to women undergoing reconstruction following mastectomy, are virtually self evident.  The FDA has acknowledged these benefits for over a decade, when it formally recognized the public health need for these products in the reconstruction population.[49]/   Clinical benefits of breast implants in these women also have been reported by several investigators.

·                    Significant improvements in all psychosocial variables, including emotional well-being, vitality, general mental health, and body image were reported by Wilkins et al. (2000) in a large prospective, multicenter study that employed validated assessments (Medical Outcome Study Short Form-36 (SF-36); Functional Assessment of Cancer Therapy-Breast (FACT-B)) to measure these endpoints.[50]/ 

·                    Girotto et al. (2003) conducted a prospective study in which they found that older patients (i.e., >65 years of age) who elected breast reconstruction, had better outcomes than age-matched general population patients and previously reported mastectomy-only patients in all surveyed areas (i.e., physical and emotional well-being, social functioning, vitality, and general health).[51]/

In conclusion, regardless of study design, the composite of recent literature consistently demonstrates that satisfaction correlates to psychological and physical well-being -- i.e., clinical benefits.  Importantly: (1) in a number of the studies, sample sizes ranged from several hundred to over two thousand; (2) the studies measuring pre- and postoperative status used the same assessment instruments; (3) patients served as their own control and were evaluated using pre- and postoperative assessments; (4) a number of the studies were multicenter; (5) the majority of studies did not exclude participants with adverse outcomes; (6) most of the survey instruments are generally accepted and validated outcome measures; (7) the duration of studies are representative of social sciences literature; and (8) satisfaction results are consistent among cited studies and with the Core Study. 

Given these findings, patient and literature reports of clinical benefits should be factored into the risk/benefit evaluation of Mentor’s silicone gel-filled breast implants

VI.              CLARIFICATIONS OF FDA QUESTIONS PRESENTED TO PANEL

FDA notes in its question #5 concerning whether there is reasonable assurance of safety for these devices that “revision patients [are] a continuum for patients originally undergoing breast augmentation or reconstruction.”   In Mentor’s Core Study, only 3% of augmentation patients and 7% of reconstruction patients underwent explantation with replacement.  The decision of whether or not to undergo a revision procedure with implant replacement is a new decision that is ultimately the patient’s choice.  At the point of this decision, the patient and her physician can evaluate the risk/benefit profile for the various revision options (that may include other alternatives), and determine which, if any, option to pursue.  The decision to pursue revision with implant replacement is by no means automatic and thus revision patients should not be viewed as a continuum for all augmentation and reconstruction patients.



[1]/             Peters, W., 2000.  Current status of breast implant survival properties and the management of the woman with silicone breast implants.  Can. J. Plast. Surg.  8(2):54-67.

[2]/             Peters, W.J., et al.  1996.  Failure properties of 352 explanted silicone gel-filled breast implants.  Can. J. Plastic Surg.  4(1): 55-8; Peters, W., 2000.  Current status of breast implant survival properties and the management of the woman with silicone breast implants.  Can. J. Plast. Surg.  8(2):54-67; Collis, N. and D.T. Sharpe.  2000.  Silicone gel-filled breast implant integrity: A retrospective review of 478 consecutively explanted implants.  Plast. Reconstr. Surg.  105:1979-1985; Brown, S.L., et al.  2002.  An association of silicone-gel breast implant rupture and fibromyalgia.  Curr. Rheumatol. Rep. 4:293-8; Hölmich, L.R., et al.  2001.  Prevalence of silicone breast implant rupture among Danish women.  Plast. Reconstr. Surg.  108:848-58; Hölmich, L.R., et al.  2003.  2003.  Incidence of silicone breast implant rupture.  Arch. Surg.138:801-6.

[3]/             Berner, I., M. et al.  2002.  Comparative examination of complaints of patients with breast-cancer with and without silicone implants.  Eur. J Obstet. Gynecol. Reprod. Biol.  102:61-6; Brinton, L.A., et al.  2004.  Risk of connective tissue disorders among breast implant patients.  Am. J. Epidemiol.  160(7):619-27; Breiting, V.B., et al.  2004.  Long-term health status of Danish women with silicone breast implants.  Plast. Reconstr. Surg.  114:217-26; Burns, C.J., et al.  1996.  The epidemiology of scleroderma among women: Assessment of risk from exposure to silicone and silica.  J. Rheumatol.  23(11):1904-11; Edworthy, S.M., et al.  1998.  A clinical study of the relationship between silicone breast implants and connective tissue disease.  J. Rheumatol.  25(2): 254-60; Englert, H.J., et al.  1996.  Scleroderma and silicone gel breast prostheses -- The Sydney study revisited.  Australia and New Zeal. J. Med.  26:349-55; Englert, H., et al.  2001.  Women’s health after plastic surgery. Intern Med J. 31(2):77-89; Friis, S., et al.  1997.  Breast implants and cancer risk in Denmark.  Int. J. Cancer  71(6):956-8; Fryzek, J.P., et al.  2001.  Self-reported symptoms among women after cosmetic breast implant and breast reduction surgery. Plast. Reconstr. Surg. 107:206-13; Gabriel, S.E., et al.  1994.  Risk of connective-tissue diseases and other disorders after breast implantation.  NEJM 330(24):1697-1702; Gaubitz, M., et al.  2002. Silicone breast implants: correlation between implant ruptures, magnetic resonance spectroscopically estimated silicone presence in the liver, antibody status and clinical symptoms.  Rheumatology 41(2):129-35; Giltay, E.J., et al.  1994.  Silicone breast prostheses and rheumatic symptoms: A retrospective follow-up study.  Ann. Rheum. Dis.  53:194-6; Goldman, J.A., et al.  1995.  Breast implants, rheumatoid arthritis, and connective tissue diseases in a clinical practice.  J. Clin. Epidemiol.  48(4):571-82; Hennekens, C.H., et al.  1996.  Self-reported breast implants and connective tissue diseases in female health professionals.  J. Amer. Med. Assoc.  275(8):616-21; Hochberg, M.C., et al.  1996.  Lack of association between augmentation mammoplasty and systemic sclerosis (scleroderma).  Arthritis and Rheumatism 39(7):1125-31; Hölmich, L.R., et al. 2003. Self-reported diseases and symptoms by rupture status among unselected Danish women with cosmetic silicone breast implants. Plast. Reconstr. Surg. 111:723-32; Janowsky, E.C., et al.  2000.  Meta-Analyses of the Relation Between Silicone Breast Implants and the Risk of Connective-Tissue Diseases.  N. Engl. J. Med. 342(11):781-90; Jensen, B., et al. 2001.  Rheumatic manifestations in Danish women with silicone breast implants.  Clin. Rheumatol.20(5):345-52; Kjøller, K., et al.  2001. Connective tissue disease and other rheumatic conditions following cosmetic breast implantation in Denmark.
Arch Intern Med. 2161(7):973-9; Kjøller, K., et al.  2004.  Self-reported musculoskeletal symptoms among Danish women with cosmetic breast implants.  Ann Plast Surg. 52(1):1-7; Laing, T.J., et al.  2001.  Potential risk factors for undifferentiated connective tissue disease among women: implanted medical devices.  Am. J. Epidemiol.  154:610-617; Lipworth, L., et al.  2004.  Silicone breast implants and connective tissue disease.  An updated review of the epidemiologic evidence.  Ann. Plast. Surg.  52(60:598-601; Nyren, O., 1998.  Risk of connective tissue disease and related disorders among women with breast implants: A nation-wide retrospective cohort study in Sweden.  Br. Med. J.  31(7129):417-21; Park, A.J., et al. 1998.  Silicone gel-filled breast implants and connective tissue disease.  Plast. Reconstr. Surg.  191(20:261-7; Sanchez-Guerrero, J., et al.  1995.  Silicone breast implants and the risk of connective-tissue diseases and symptoms.  NEJM.  332(25):1666-70; Schusterman, M.A., et al.  1993.  Incidence of autoimmune disease in patients after breast reconstruction with silicone gel implants versus autogenous tissue: A preliminary report.  Ann. Plast. Surg.  31(1):1-6; Strom, B.L., et al.  1994.  Breast silicone implants and risk of systemic lupus erythematosis.  J. Clin. Epidemiol.  47(10):1211-14; Weisman, M.H., et al.  1988.  Connective-tissue disease following breast augmentation: A preliminary test of the human adjuvant tissue hypothesis.  Plast. Reconstr. Surg.  82(4):626-30; Williams, H.J., et al.  1997.  Breast implants in patients with differentiated and undifferentiated connective tissue disease.  Arthritis and Rheumatism 40(3):437-40.

[4]/             Hölmich, L.R., et al. 2003. Self-reported diseases and symptoms by rupture status among unselected Danish women with cosmetic silicone breast implants. Plast. Reconstr. Surg. 111:723-32.

[5]/             Berner, I., M. et al.  2002.  Comparative examination of complaints of patients with breast-cancer with and without silicone implants.  Eur. J Obstet. Gynecol. Reprod. Biol.  102:61-6.

[6]/             Gaubitz, M., C., et al.  2002. Silicone breast implants: correlation between implant ruptures, magnetic resonance spectroscopically estimated silicone presence in the liver, antibody status and clinical symptoms.  Rheumatology 41(2):129-35.

[7]/             Brown, S.L., et al. 2001. Silicone gel breast implant rupture, extracapsular silicone, and health status in a population of women. J. Rheumatol. 28:996-1003.

[8]/             Fryzek, J.P., et al.  2001.  Self-reported symptoms among women after cosmetic breast implant and breast reduction surgery. Plast. Reconstr. Surg. 107:206-13.

[9]/             Wolfe, F. and J. Anderson.  1999.  Silicone filled breast implants and the risk of fibromyalgia and rheumatoid arthritis.  J. Rheumatol.  26:2025-8.

[10]/           Jacobson, D.L., et al.  1997.  Epidemiology and estimate population burden of selected autoimmune diseases in the United States.  Clin. Immunol. Immunopathol.  84(3):223-13.

[11]/           Wolfe, F., et al.  1995.  The prevalence and characteristics of fibromyalgia in the general population.  Arthritis Rheum.  38(1): 19-28.

[12]/           Mancini, G.J., et al.  2002.  Parastomal pyoderma gangrenosum: a case report and literature review.  Am. Surg.  68(9):824-6.

[13]/           Jacobson, D.L., et al.  1997.  Epidemiology and estimate population burden of selected autoimmune diseases in the United States.  Clin. Immunol. Immunopathol.  84(3):223-13.

[14]/           Kjøller, K., et al., 2004.  Self-reported musculoskeletal symptoms among Danish women with cosmetic breast implants. Ann. Plast. Surg. 52:1-7.

[15]/           Hölmich, L.R., et al. 2003. Self-reported diseases and symptoms by rupture status among unselected Danish women with cosmetic silicone breast implants. Plast. Reconstr. Surg. 111:723-32.

[16]/           Brown, S.L., et al.  2002.  An association of silicone-gel breast implant rupture and fibromyalgia.  Curr. Rheumatol. Rep. 4:293-8.

[17]/           Berner, I., 2002.  Comparative examination of complaints of patients with breast-cancer with and without silicone implants.  Eur. J Obstet. Gynecol. Reprod. Biol.  102:61-66.

[18]/           Gaubitz, M.,.  2002. Silicone breast implants: correlation between implant ruptures, magnetic resonance spectroscopically estimated silicone presence in the liver, antibody status and clinical symptoms.  Rheumatology 41(2):129-35.

[19]/           Fryzek, J.P., et al.  2001.  Self-reported symptoms among women after cosmetic breast implant and breast reduction surgery.  Plast. Reconstr. Surg.  107:206-13.

[20]/           Park, A.J., et al.  1998. Silicone gel-filled breast implants and connective tissue disease.  Plast. Reconstr. Surg.  101:262-267.

[21]/           Gilatay, E.J., et al.  1994.  Silicone breast prostheses and rheumatic symptoms - a retrospective follow-up-study.  Ann. Rheumatol. Dis.  53:194-6.

[22]/           Wells, K.E., et al.  1994.  The health status of women following cosmetic surgery.  Plast. Reconstr. Surg.  93:907-12.

[23]/           Kjøller, K., et al., 2004.  Self-reported musculoskeletal symptoms among Danish women with cosmetic breast implants. Ann. Plast. Surg. 52:1-7.

[24]/           Hölmich, L.R., et al. 2003. Self-reported diseases and symptoms by rupture status among unselected Danish women with cosmetic silicone breast implants. Plast. Reconstr. Surg. 111:723-32.

[25]/           Brown, S.L., et al.  2002.  An association of silicone-gel breast implant rupture and fibromyalgia.  Curr. Rheumatol. Rep. 4:293-8.

[26]/           Berner, I., 2002.  Comparative examination of complaints of patients with breast-cancer with and without silicone implants.  Eur. J Obstet. Gynecol. Reprod. Biol.  102:61-66.

[27]/           Gaubitz, M.,.  2002. Silicone breast implants: correlation between implant ruptures, magnetic resonance spectroscopically estimated silicone presence in the liver, antibody status and clinical symptoms.  Rheumatology 41(2):129-35.

[28]/           Fryzek, J.P., et al.  2001.  Self-reported symptoms among women after cosmetic breast implant and breast reduction surgery.  Plast. Reconstr. Surg.  107:206-13.

[29]/           Park, A.J., et al.  1998. Silicone gel-filled breast implants and connective tissue disease.  Plast. Reconstr. Surg.  101:262-267.

[30]/           Wells, K.E., et al.  1994.  The health status of women following cosmetic surgery.  Plast. Reconstr. Surg.  93:907-12.

[31]/           Henriksen, T.F., et al.  2003.  Incidence and severity of short-term complications after breast augmentation.  Ann. Plast. Surg. 51(6):531-539; Unpublished subanalysis of Kjøller et al. 2002 cohort).

[32]/           Bondurant, S., V.L. Ernster and R. Herdman, Eds.  2000.  Safety of silicone breast implants. Committee on the Safety of Silicone Breast Implants, Division of Health Promotion and Disease Prevention, Institute of Medicine.  Washington, D.C.: National Academy Press.

[33]/           Kulmala, I., et al.  2004.  Local complications after cosmetic breast implant surgery in Finland.  Ann. Plast. Surg.  53(50:413-9.

[34]/           Id.

[35]/           Hölmich, L.R., et al. 2003. Self-reported diseases and symptoms by rupture status among unselected Danish women with cosmetic silicone breast implants. Plast. Reconstr. Surg. 111:723-32.

[36]/           Id.

[37]/           Id. 

[38]/           Henriksen, T.F., et al.  2003.  Incidence and severity of short-term complications after breast augmentation.  Ann. Plast. Surg. 51(6):531-539; Unpublished subanalysis of Kjøller et al. 2002 cohort).

[39]/           Hölmich, L.R., et al.  2004.  Untreated silicone breast implant rupture.  Plast. Reconstr. Surg.  114:204-14.

[40]/           Cash, T.F., et al.  2002.  Women’s psychosocial outcomes of breast augmentation with silicone gel-filled implants: A 2-year prospective study.  Plast. Reconstr. Surg.  109(6):2112-23; Young, V.L., et al.  2004. Initial results from an online breast augmentation survey.  Aesthetic Surgery Journal 24(2):117-35; Kaslow, F., and Becker, H.  1992.  Breast augmentation: psychological and plastic surgery considerations.  Psychotherapy 29:467-73; Anderson, R.C.  1996.  Aesthetic surgery and psychosexual issues.  Aesthet. Surg. Q. 16:227-9; Anderson, R.C.  The Augmentation Mammaplasty Patient.  Psychological Issues.  In: Surgery of the Breast. LippincottWilliams * Wilkin.  In Press.

[41]/           Young, V.L., et al.  2004. Initial results from an online breast augmentation survey.  Aesthetic Surgery Journal  24(2):117-35.

[42]/           Cash, T.F., et al.  2002.  Women’s psychosocial outcomes of breast augmentation with silicone gel-filled implants: a 2-year prospective study.  Plast. Reconstr. Surg.  109(6):2112-21.

[43]/           Sarwer, D.B.,  2002.  Women’s psychosocial outcomes of breast augmentation with silicone gel-filled implants: a 2-year prospective study.  Plast. Reconstr. Surg.  109(6):2122-3.

[44]/           64 Fed. Reg. 45155 at 45159 (Aug. 19, 1999) (final rule calling for PMA review of silicone gel-filled breast implants, emphasizing in particular, the potential psychological benefits offered by these devices).

[45]/           Young, V.L., et al.  2004. Initial results from an online breast augmentation survey.  Aesthetic Surgery Journal 24(2):117-35.

[46]/           See, e.g., Goin, J.M., and Goin, M.K.  1981.  Changing the Body: Psychological Effects of Plastic Surgery.  Baltimore, MD: Williams & Wilkin; Young, V.L., et al.  2004. Initial results from an online breast augmentation survey.  Aesthetic Surgery Journal 24(2):117-35.

[47]/           Id.

[48]/           Harcourt, D., and Rumsey, N.  2001.  Psychological aspects of breast reconstruction: a review of the literature.  J. Advanced Nursing 35(4):477-87.

[49]/           See 1992 Adjunct Study Agreement between Mentor Corporation and the Food And Drug Administration to Extend Review Period for PMAs . . . for Use of the Device in Women with Breast Reconstruction, stating “[t]he agency has determined that, for women seeking breast reconstruction, continued availability of silicone gel-filled breast prostheses is necessary for the public health” (at 3).

[50]/           Wilkins, E.G., et al.  2000.   Prospective analysis of psychosocial outcomes in breast reconstruction: one-year postoperative results from the Michigan breast reconstruction outcome study.  Plast. Reconstr. Surg.  106:1014-25.

[51]/           Girotto, J.A., et al.  2003.  Breast reconstruction in the elderly: preserving excellent quality of life.  Ann. Plast. Surg.  50:572-8.