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Objective: To increase the knowledge of the long-term effects of artificial hip and knee joint implants. Methods: The study groups consisted of 24,636 patients with osteoarthritis who underwent hip implant surgery and 5,221 who received knee implants during 1977-89. The post-implant rate of hospitalization for connective tissue disease (CTD) was compared with the rate in the general population of Denmark and with that among osteoarthritis patients without implant surgery. Results: The rates of hospitalization for CTD were higher than the background level among both hip and knee implant patients with osteoarthritis, whereas the comparison with non-implanted osteoarthritis patients revealed that the hospitalization rate for CTD was reduced after hip implant surgery, but increased after knee implant surgery. Conclusion: Since the materials used in hip and knee implants in Denmark are not substantially different, these results are unlikely to reflect an implant effect but rather the selection criteria of referral for implant surgery. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by eczematous skin lesions and pruritus. There is an unmet need for effective first-line systemic therapies with good safety profiles, particularly oral medications. Orismilast is a novel first-in-class oral phosphodiesterase-4 (PDE4) B/D inhibitor under investigation for the treatment of moderate-to-severe AD., Objectives: To evaluate the optimal dose, efficacy and safety of orismilast twice-daily (BID) in patients with moderate-to-severe AD., Methods: This 16-week, multicenter, randomized, placebo-controlled, phase 2b dose-ranging study (NCT05469464) included patients from 48 centers in Europe and the United States. Adults with moderate-to-severe AD were given (1:1:1:1) BID orismilast 20, 30, or 40 mg, or placebo. The primary endpoint was percentage change in Eczema Area and Severity Index (EASI); secondary: achievement of a score of Clear (0) or Almost Clear (1) with ≥2-point improvement by Investigator Global Assessment (IGA 0/1); achievement of peak pruritus numerical rating scale (PPNRS) reduction of ≥4 points; and achievement of a reduction in EASI of 75%, 90%, and 100% (EASI75, EASI90, EASI100, respectively) from baseline; all week 16., Results: Overall, 233 patients were randomly assigned to orismilast 20 mg (n=58), 30 mg (n=61), 40 mg (n=59), or placebo (n=55). At week 16, Reductions in EASI (%-point) from baseline to week 16 were seen across orismilast groups and placebo (p>0.05 for orismilast versus placebo). Significantly more patients achieved IGA 0/1 with a ≥2-point improvement with orismilast 20 mg and 40 mg versus placebo (p<0.05). Significantly greater proportions of patients achieving a ≥4-point reduction in PPNRS were demonstrated with orismilast at week 2. The safety profile was consistent with that of the PDE4 class, with no major safety concerns reported., Conclusions: These data support the clinical relevance of selective PDE4B/D inhibition with orismilast, potentially offering a convenient, novel, oral therapy for the treatment of AD., (© The Author(s) 2025. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: There remains an unmet need for oral medications that are safe and efficacious for long-term management of chronic inflammatory skin diseases (CISD). Inhibition of phosphodiesterase 4 (PDE4) can modulate a broad range of pro-inflammatory cytokines that play a major role in CISD pathogenesis. Orismilast is a second generation PDE4 inhibitor in clinical development for CISD treatment., Objectives: The objective of this study was to examine the PDE4 enzymatic activity and anti-inflammatory effects of orismilast in vitro, ex vivo, and in vivo., Methods: The PDE1-11 enzymatic activity of orismilast was tested in vitro using a single concentration of 308 nM orismilast. The PDE4 selectivity and inhibitory potency was further examined in a radiometric assay. Orismilast was tested on human whole blood and human peripheral blood mononuclear cells (PBMC) to determine effects on its cytokine secretion and inhibition profile ex vivo. Orismilast was orally administered in a murine model of chronic oxazolone-induced ear skin inflammation. Ear thickness, a marker of inflammation, and inflammatory cytokines were analysed., Results: Orismilast selectively inhibited PDE4 and demonstrated potent inhibition of PDE4B and PDE4D subtype splice variants in vitro. Orismilast inhibited whole blood and PBMC production of tumour necrosis factor α (TNFα), and the secretion of T-helper (Th)1 (TNFα and IFNγ), Th17 (IL-22 and IL-23), and Th2 (IL-4, IL-5, and IL-13) related cytokines in PBMC. In vivo, 10 and 30 mg/kg doses of orismilast significantly reduced ear thickness and inflammation markers (p < 0.0001, respectively)., Conclusion: Orismilast displayed selective and potent PDE4 inhibition and broad-spectrum anti-inflammatory activity in several pre-clinical models. The results of the study support clinical development of oral orismilast as a novel treatment option for CISD including psoriasis, atopic dermatitis, and hidradenitis suppurativa., (© 2022 UNION therapeutics. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Orismilast is a high-potency phosphodiesterase 4 (PDE4) inhibitor with enhanced selectivity for the PDE4B and PDE4D subtypes., Objectives: The objective of this phase 2a trial was to examine the efficacy and safety of orismilast for psoriasis using a first-generation immediate-release (IR) formulation. The objective of the subsequent phase 1 trial was to test new formulations designed to minimize the gastrointestinal (GI)-related adverse events (AEs) observed with the first-generation IR formulation. We examined the following: (1) pharmacokinetic (PK) properties of orismilast modified release (MR) and IR, (2) food effects on PK properties of orismilast MR or IR, (3) safety of orismilast MR compared to placebo., Methods: In a phase 2a prospective, randomized, double-blind, placebo-controlled trial, patients with moderate-to-severe psoriasis were randomized to receive 30 mg oral orismilast IR or placebo over 16 weeks. The single-site phase 1 trial consisted of three parts: (1) participants received a single 30 mg dose of orismilast MR and IR (open-label), (2) participants received 30 mg orismilast MR or IR under either fasting condition, following a high-fat meal or low-fat meal (open-label) and (3) participants received up to 60 mg orismilast MR twice-daily or a placebo for 17 days (double-blind)., Results: In the phase 2a trial, treatment with orismilast IR significantly improved the mean Psoriasis Area Severity Index score at week 16 compared to placebo. The phase 1 trial revealed comparable PK properties of the orismilast MR and IR formulations, with participants in the orismilast MR group experiencing fewer GI-related AEs than those receiving orismilast IR (16.7% vs. 33.3%)., Conclusion: Orismilast IR displayed higher efficacy compared to placebo in patients with moderate-to-severe psoriasis at week 16. Orismilast MR had similar PK properties and fewer GI disorders compared to the IR formulation in healthy participants. Future development of orismilast will be based on the MR formulation., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

An excess of suicide among women with cosmetic breast implants compared with controls has consistently been reported in epidemiologic studies. We have evaluated psychological characteristics among 423 Danish women with cosmetic breast implants, compared with 414 controls. Odds ratios (OR) with 95% confidence intervals (CI) for self-reported psychological symptoms were calculated using multiple logistic regression. Substantial excesses of all studied symptoms before implant surgery were reported among women with breast implants compared with women with other cosmetic surgery, whereas ORs for virtually all symptoms occurring after surgery were close to or below 1.0. In particular, ORs for treatment for depression, cognitive/depressive symptoms, and depression/low spirit before surgery were 4.6 (95% CI = 2.1-10.0), 3.9 (95% CI = 1.9-7.8), and 2.5 (95% CI = 1.1-5.5), respectively. In contrast, the corresponding ORs for these 3 psychological symptoms after surgery were 0.9 (95% CI = 0.6-1.4), 1.0 (95% CI = 0.7-1.5), and 1.0 (95% CI = 0.6-1.5), respectively. In conclusion, women with cosmetic breast implants reported preoperative psychological symptoms indicative of depressive disorders substantially more frequently than women with other cosmetic surgery. Future studies using standardized, validated psychiatric assessment tools are needed to determine whether this can explain the higher risk for suicide among a subset of women seeking cosmetic breast implants.

We investigated if delayed breast implant reconstruction after breast cancer impairs prognosis. Using data from the Danish Breast Cancer Cooperative Group register, we identified all women <70 years who underwent breast reconstruction with implants after mastectomy after invasive breast cancer during 1978 to 1992, on average 2.2 years (range, 3 days-9.4 years) after mastectomy. The reconstructed women were closely matched to breast cancer patients without reconstruction on age and calendar time of diagnosis, tumor size, regional lymph node involvement, and adjuvant radiation therapy. Overall, 580 reconstructed women and 1158 individually matched controls were followed-up for disease-free survival within the first 10 years and for overall survival for an average of 20.1 year (range, 12.8-27.5 years). Disease-free survival was significantly improved hazard ratio 0.78; 95% confidence interval 0.64-0.95 and overall survival was nonsignificantly improved (hazard ratio, 0.90; 95% confidence interval 0.76-1.06) among the breast reconstructed women. This is likely because of differences in socioeconomic and health factors.

Background: To assess whether maternal cosmetic breast implants are associated with adverse health outcomes among offspring, the authors examined published findings of epidemiologic studies that addressed this hypothesis., Methods: Four epidemiologic studies, all from Scandinavia, were identified. Women with breast implants were identified from existing public and private registers of patients, and their offspring were traced through nationwide population and birth registers. The studies included a total of 11,445 women with breast implants and 3248 children born after the mothers' implantation procedures. Comparison was made with children born to mothers who had undergone other cosmetic surgery or general population controls. Outcomes under study were congenital malformations, hospitalization for esophageal and rheumatic disorders, and perinatal mortality., Results: Overall, the studied outcomes were similar between children born to mothers with breast implants and children of controls, and between children born before and after maternal breast implantation. In the Danish studies, significantly elevated rates of esophageal disorders were observed for children born before (observed-to-expected ratio, 2.0; 95 percent confidence interval, 1.3 to 2.8) but not after (observed-to-expected ratio, 1.3; 95 percent confidence interval, 0.5 to 2.9) the mother's breast implant surgery. Similar excesses were observed among control children born before and after maternal breast reduction. In the Swedish and Finnish studies, all risk estimates for malformations and perinatal health were close to unity., Conclusion: Rates of esophageal and rheumatic disorders, congenital malformations, and perinatal mortality and hospitalization were comparable between children born to mothers with breast implants and children born to mothers who had undergone other cosmetic surgery.

All women who underwent breast augmentation at 1 public and 1 private clinic in Denmark from 1973 to 1988, and available for follow-up, were invited to participate in a clinical study including a self-administered questionnaire, medical record abstraction, and a clinical examination. One hundred ninety (52%) out of 368 eligible women participated. Mean time with implants in situ was 19 years (range, 5-35). Sixty-one percent of the women had 1 implantation, 23% had 2 implantations, 16% had 3 or more implantations. Nineteen women (10%) had no implants at the time of examination. A large proportion of the women (62%) had clinically significant capsular contracture, and only half of the study women were found to have satisfactory overall breast appearance at examination. In contrast, the majority of women reported satisfaction with their implant surgery (60%). The women tended to grade themselves more positively than the examining physicians.

Purpose: Numerous epidemiologic studies have demonstrated that breast implants are not associated with connective tissue diseases (CTDs). However, many CTDs are rare, and continued follow-up of women with breast implants is warranted., Methods: We extended by 5 years the follow-up of our earlier population-based cohort study of Danish women with cosmetic breast implants (n = 2761) and comparison groups of women with other types of cosmetic surgery (n = 8807). All women were followed from January 1977 through December 2001. Hospitalization and outpatient data for CTD and ill-defined and other rheumatic conditions in the implant and comparison groups were compared with those in the general Danish population. Additionally, CTDs and fibromyalgia were confirmed through medical chart review, and direct comparisons of the breast implant cohort with the comparison cohort were performed., Results: When compared with general population rates, CTDs were not statistically significantly elevated in either the implant or the comparison cohorts. However, unspecified rheumatism was similarly increased in the implant (standardized rate ratio = 1.9; 95% confidence interval = 1.6 to 2.2) and comparison (standardized rate ratio = 1.5; 95% confidence interval = 1.4 to 1.7) cohorts. In analyses of diagnoses validated by chart review, women with cosmetic breast implants compared with those having other types of plastic surgery or consultation for plastic surgery had no statistically significant excess for any specific confirmed CTD or combined CTDs (hazard ratio = 1.3; 95% CI = 0.9 to 1.9). In addition, there was no relation between breast implants and confirmed fibromyalgia (hazard ratio = 1.2; 95% CI = 0.6 to 2.1)., Conclusions: This extension of our earlier cohort study further supports the consensus of epidemiologic research that breast implants are unrelated to the development of CTD.

The available epidemiologic evidence does not support a carcinogenic effect of silicone breast implants on breast or other cancers. Data on cancer risk other than breast cancer are limited and few studies have assessed cancer risk beyond 10-15 years after breast implantation. We extended follow-up of our earlier cohort study of Danish women with cosmetic breast implants by 7 years, yielding 30 years of follow-up for women with longest implant duration. The study population consisted of women who underwent cosmetic breast implant surgery at private clinics of plastic surgery (n = 1,653) or public hospitals (n = 1,110), and a control group of women who attended private clinics for other plastic surgery (n = 1,736), between 1973-95. Cancer incidence through 2002 was ascertained using the Danish Cancer Registry. Risk evaluation was based on computation of standardized incidence ratios (SIR) and Cox proportional hazards models, adjusting for age, calendar period and reproductive history. We observed 163 cancers among women with breast implants compared to 136.7 expected based on general population rates (SIR = 1.2; 95% confidence interval [CI] = 1.0-1.4), during a mean follow-up period of 14.4 years (range = 0-30 years). Women with breast implants experienced a reduced risk of breast cancer (SIR = 0.7; 95% CI = 0.5-1.0), and an increased risk of non-melanoma skin cancer (SIR = 2.1; 95% CI = 1.5-2.7). Stratification by age at implantation, calendar year at implantation and time since implantation showed no clear trends, however, the statistical precision was limited in these analyses. When excluding non-melanoma skin cancer, the SIR for cancer overall was 1.0 (95% CI = 0.8-1.2). With respect to other site-specific cancers, no significantly increased or decreased SIR were observed. Similar results were found when directly comparing women who had implants at private clinics with women who attended private clinics for other plastic surgery, with rate ratios for cancer overall, breast cancer and non-melanoma skin cancer of 1.1 (95% CI = 0.8-1.6), 0.7 (95% CI = 0.4-1.3) and 1.5 (95% CI = 0.8-2.7), respectively. In conclusion, our study lends further support to the accumulating evidence that silicone breast implants are not carcinogenic. Reasons for the consistently reported deficit of breast cancer among women with breast implants remain unclear, whereas increased exposure to sunlight may explain the excess occurrence of non-melanoma skin cancer. We found no indication of delayed diagnosis of breast cancer due to the presence of breast implants.

Background: Clinical reports have raised concern about local complications following breast implantation used in reconstructive or cosmetic surgery, but there is a shortage of epidemiological studies in this area., Objective: To assess in a prospective epidemiological manner the occurrence of short-term local complications in a nationwide implantation registry., Design, Setting, and Participants: The Danish Registry for Plastic Surgery of the Breast prospectively collects preoperative, perioperative, and postoperative information on Danish women undergoing breast augmentation. Through the registry, we collected data on short-term local complications among 574 women who underwent postmastectomy reconstruction with breast implants from June 1, 1999, through July 24, 2003., Main Outcome Measures: Complication incidence rates., Results: Thirty-one percent of the women who underwent initial implantation developed at least 1 adverse event. Forty-nine percent of the adverse events occurred within 3 months after implantation and 67% within 6 months. Surgical intervention was required after initial implantation among 21% of women, most frequently because of capsular contracture, asymmetry, or displacement of the implant. Thirty-six percent of women who underwent subsequent implantation experienced at least 1 adverse event, and 21% underwent surgical intervention to treat definitive complications or to optimize cosmetic result., Conclusions: Women who undergo postmastectomy breast implantation frequently experience short-term local complications. Surgical or medical intervention is commonly required during the reconstructive course, but reconstruction failure (loss of implant) is rare. However, when weighing benefits and risks associated with reconstruction, the patient should consider that breast reconstruction is a process involving planned and unplanned supplementary surgical correction to achieve the desired result.

The objective was to evaluate the usefulness of clinical examination in the evaluation of breast-implant integrity, using the diagnosis at magnetic resonance imaging (MRI) as the "gold standard." Fifty-five women with 109 implants underwent a breast examination either just before or shortly after an MRI examination. Twenty-four of 109 implants were clinically diagnosed with possible rupture or rupture. Eighteen of the 24 implants were ruptured according to the MRI examination (75%). Eighty-five implants were clinically classified as intact, and 43 of these were actually ruptured at MRI (51%). The sensitivity of the clinical examination for diagnosing rupture was thus 30% and the specificity 88%. The positive predictive value of a clinical diagnosis of rupture was 75%, and the negative predictive value was 49%. In this study, we found that when a clinical examination is used as the sole diagnostic tool to identify implant rupture, neither the sensitivity nor the specificity is acceptable.

Epidemiologic data on local complications after breast augmentation are scarce. In particular, few prospectively collected data are available on modern breast implants on this issue. Using data from the Danish Registry for Plastic Surgery of the Breast, the authors examined determinants of surgery-requiring complications and capsular contracture grades III to IV among 2277 women who underwent cosmetic breast implantation from June 1999 through April 2003. During an average follow-up period of 1.6 years after implantation, 4.3% of these women (3% of implants) required secondary surgery as a result of short-term complications. The most frequent clinical indications for surgery were displacement of the implant (38%), capsular contracture grades III to IV (16%), ptosis (13%), and hematoma (11%). Overall, the authors found that inframammary incision and subglandular placement were associated with decreased risks of developing complications requiring surgical intervention, whereas implants larger than 350 mL increased the risk of such complications (relative risk [RR], 2.3; 95% confidence interval [CI], 1.3-4.0). Thirty-nine Baker III to IV capsular contractures were identified, of which 22 were treated surgically within the study period. Submuscular placement of the implant decreased the risk of capsular contracture grades III to IV (RR, 0.3; 95% CI, 0.2-0.8), whereas surgical routes other than inframammary and drainage of implant cavity were associated with increased risk of capsular contracture. Current surgical practices and modern implants used for breast augmentation produce fewer short-term complications than procedures and devices of the past. This prospective study indicates that surgical procedures are more important predictors for local (short-term) complications than implant or patient characteristics.

Cosmetic breast implants have become increasingly popular throughout the world. However, there is insufficient knowledge about the frequency and severity of local complications such as rupture and capsular contracture. A pilot study of 25 Finnish women with 50 cosmetic breast implants was organized to determine the feasibility of conducting a magnetic resonance imaging (MRI)-based study of rupture incidence. The pilot investigation included a clinical examination by a plastic surgeon, MRI scan, and self-administered questionnaire. The participation rate was 100%. Implants in our study represented a cross-section of the different generations of implants in Finland, with implant ages varying from 4 months to 20 years. The average implant size was 215 mL, typical in Finnish cosmetic surgery. MR images were evaluated by two independent readers. The first reader diagnosed six implants with intracapsular rupture, while the other diagnosed all implants as intact. The procedures of the feasibility study proved successful, and the results demonstrate the importance of a rigid image evaluation protocol with employment of well-defined rupture criteria, as well as the benefits of several image readers.

Background: Epidemiologic studies indicate that women with cosmetic breast implants have a significantly increased risk of suicide. Our objectives were to examine mortality among Danish women who underwent cosmetic breast implant surgery and to evaluate the baseline prevalence of psychopathological disorders as measured by admission to a psychiatric hospital among women seeking cosmetic surgery., Methods: Cohort study of 2761 women who underwent cosmetic breast implant surgery at private clinics of plastic surgery or public hospitals, 7071 women who underwent breast reduction surgery at public hospitals, and 1736 women who attended private clinics for cosmetic surgery other than breast implantation, between 1973 and 1995. Causes of death through 1999 were identified through the Danish Mortality Files. Information on admission to psychiatric hospitals prior to cosmetic surgery was obtained from the Danish Psychiatric Central Register., Results: Women with cosmetic breast implants had significantly elevated standardized mortality ratios (SMRs) for death overall (SMR, 1.4; 95% confidence interval [CI], 1.1-1.7), nonmalignant lung disease (3.4; 95% CI, 1.4-6.9), and suicide (SMR, 3.1; 95% CI, 1.7-5.2). Women who underwent breast reduction exhibited low SMRs for death overall (0.7; 95% CI, 0.7-0.8) and several specific causes, including breast cancer (0.4; 95% CI, 0.2-0.6), whereas death from suicide was moderately above expectation (SMR, 1.6; 95% CI, 1.0-2.5). The prevalence of psychiatric admission prior to cosmetic surgery was higher among women who underwent cosmetic breast implant surgery (8.0%; 95% CI, 7.0%-9.0%) than among women who underwent breast reduction (4.7%; 95% CI, 4.2%-5.2%) or other cosmetic procedures (5.5%; 95% CI, 4.5%-6.7%). When compared with all control groups, women with cosmetic implants had an odds ratio for prior psychiatric admission of 1.7 (95% CI, 1.4-2.0)., Conclusions: Danish women with cosmetic breast implants experienced higher overall mortality compared with women in the general population owing in part to a 3-fold increase in suicide. Women with breast reduction had a low total and cause-specific mortality but a moderate excess risk of suicide. For the first time, to our knowledge, we found evidence of an increased prevalence of mental illness as measured by admission to a psychiatric hospital prior to implant surgery among women receiving cosmetic breast implants. Studies are needed to clarify the underlying reasons for the consistently reported 2- to 3-fold excess of suicide among women with cosmetic breast implants.

Implant rupture is a well-known complication of breast implant surgery that can pass unnoticed by both patient and physician. To date, no prospective study has addressed the possible health implications of silicone breast implant rupture. The aim of the present study was to evaluate whether untreated ruptures are associated with changes over time in magnetic resonance imaging findings, serologic markers, or self-reported breast symptoms. A baseline magnetic resonance imaging examination was performed in 1999 on 271 women who were randomly chosen from a larger cohort of women having cosmetic breast implants for a median period of 12 years (range, 3 to 25 years). A follow-up magnetic resonance imaging examination was carried out in 2001, excluding women who underwent explantation in the period between the two magnetic resonance imaging examinations (n = 44). On the basis of these examinations, the authors identified 64 women who had at least one ruptured implant at the first magnetic resonance imaging examination and, for comparison, all women who had intact implants at both examinations (n = 98). Magnetic resonance images from the two examinations were compared and changes in rupture configuration were evaluated. Comparisons were also made for self-reported breast symptoms occurring during the study period and for changes in serum values of antinuclear antibodies, rheumatoid factor, and cardiolipin antibodies immunoglobulin G and immunoglobulin M. The majority of the women with implant rupture had no visible magnetic resonance imaging changes of their ruptured implants. For 11 implants (11 percent) in 10 women, the authors observed progression of silicone seepage, either as a conversion from intracapsular into extracapsular rupture (n = 7), as progression of extra-capsular silicone (n = 3), or as increasing herniation of the silicone within the fibrous capsule (n = 1); however, in most cases, these changes were minor. Some changes could be ascribed to trauma, but others seemed spontaneous. There was no increase in levels of autoantibodies during the study period in either study group. Women with untreated implant ruptures reported a significant increase in nonspecific breast changes (odds ratio, 2.1; 95 percent confidence interval, 1.2 to 3.8) compared with women without ruptures. On the basis of this first study of women with untreated silicone breast implant rupture, the authors conclude that implant rupture is a relatively harmless condition, which only rarely progresses and gives rise to notable symptoms. Even so, because of a small risk of silicone spread, the authors suggest that women with implant ruptures be followed clinically, if not operated on. Because implant ruptures often occur asymptomatically, any woman with silicone implants, regardless of rupture status, should be evaluated at regular intervals.

Long-term safety data are important in the evaluation of possible adverse health outcomes related to silicone breast implants. The authors evaluated long-term symptoms and conditions and medication use among 190 Danish women with cosmetic silicone breast implants compared with 186 women who had undergone breast reduction surgery and with 149 women from the general population. Breast implant and reduction surgeries were performed from 1973 to 1988 at one public hospital and one private plastic surgery clinic. Among women with breast implants, the average implantation time was 19 years, 60 percent (n = 114) had only one implantation, and 10 percent (n = 19) had undergone explantation before the time of study (1997 to 1998). The authors found no material differences in self-reported diseases or symptoms among study groups, except for breast pain, which was reported nearly three times as often by women with implants than by women with breast reduction (odds ratio, 2.8; 95 percent confidence interval, 1.4 to 5.3). Approximately 80 percent of women in each study group reported at least one symptom. No consistent differences were observed in the seroprevalences of antinuclear antibodies or other autoantibodies. Self-reported use of psychotropic drugs was higher among women with breast implants than among either control group. The authors conclude that long-term cosmetic breast implantation may cause capsular contracture and breast pain but does not appear to be associated with other symptoms, diseases, or autoimmune reactivity. The authors' finding of excess use of drugs for treatment of depression and anxiety among women with breast implants may warrant further investigation.

Background: No epidemiological evidence of an association between silicone breast implants and connective tissue disease has been found. Based on case reports, it has been hypothesized that silicone breast implants may be associated with a unique rheumatic symptom cluster termed "atypical connective tissue disease.", Material and Methods: We have evaluated self-reported rheumatic symptoms among women who received breast implants between 1977 and 1997 at 2 private plastic surgery clinics in Denmark. Women with other cosmetic surgery, including breast reduction, as well as women from the general population, were identified as controls., Results: No statistically significant differences in mild (odds ratio [OR] = 0.9; 95% confidence interval [CI] = 0.6-1.3), moderate (OR = 0.7; 95% CI = 0.4-1.2), or severe (OR = 1.1; 95% CI = 0.6-2.1) musculoskeletal symptoms were observed when women with breast implants were compared with women with other cosmetic surgery. Compared with women from the general population, women with breast implants were statistically significantly less likely to have mild or moderate musculoskeletal symptoms (OR = 0.5; 95% CI = 0.3-0.7 and OR = 0.3; 95% CI = 0.2-0.5, respectively); for severe symptoms the deficit was not statistically significant (OR = 0.7; 95% CI = 0.3-1.3). For individual symptom groups, there was no consistent pattern of reporting among women with implants., Conclusion: We did not find an excess of rheumatic symptoms or symptom clusters among women with breast implants. In fact, the occurrence of mild, moderate, and severe musculoskeletal symptoms was generally lower among women with implants compared with women with other cosmetic surgery and women in the general population.

The frequency and severity of local complications remain the primary safety issues with silicone breast implants. The Danish Registry for Plastic Surgery of the Breast (DPB), established in 1999, prospectively collects pre-, peri- and postoperative information regarding Danish women undergoing breast augmentation. Through DPB, we conducted a prospective follow-up study of short-term local complications among 1090 women who underwent cosmetic breast implantation from June 1999 through October 2002. Nineteen percent of women who underwent initial implantation developed at least 1 adverse effect. Forty percent of the adverse effects occurred within 3 months of implantation; 79%, within 6 months. Capsular contracture grade II-IV was observed among 4.1% of women in the 2-year follow-up period. Overall, 97 (29%) of the 344 adverse effects among 55 (6%) of the 971 women required surgical intervention. A higher incidence of adverse effects typically occurred after subsequent implantations. According to the DPB experience, we conclude that most short-term postoperative adverse effects following cosmetic implantation are clinically insignificant and do not require treatment and that short-term complications requiring adjuvant treatment are rare.

Hypothesis: The incidence of silicone breast implant rupture varies with implantation time and type of implant., Objective: To measure the incidence of implant rupture by repeated magnetic resonance imaging (MRI) among women with silicone breast implants., Design, Setting, and Participants: In 1999, 271 women who had received breast implants at least 3 years before, and who were randomly chosen from a larger cohort of women with cosmetic breast implants, underwent a baseline MRI. A second MRI was performed in 2001; 317 silicone implants (in 186 women) that were intact at the baseline MRI (n = 280) or were intact at baseline but removed before the second MRI (n = 37) were included in the rupture incidence analyses., Main Outcome Measures: Implants were diagnosed with definite or possible rupture. Crude and implant age-adjusted incidence rates were calculated, and implant survival was estimated based on the observed rupture rates., Results: We found 33 definite ruptures (10%) and 23 possible ruptures (7%) during the 2-year period. The overall rupture incidence rate for definite ruptures was 5.3 ruptures/100 implants per year (95% confidence interval, 4.0-7.0). The rupture rate increased significantly with increasing implant age. Double-lumen implants were associated with substantially lower rupture risk than single-lumen implants. For modern implants intact 3 years after implantation, we estimated rupture-free survival of 98% at 5 years and 83% to 85% at 10 years., Conclusions: The risk of implant rupture increases with implant age. A minimum of 15% of modern implants can be expected to rupture between the third and tenth year after implantation.

Although numerous epidemiologic studies have examined the long-term safety of silicone breast implants during the past decade, there is a relative lack of surveillance data on short-term health effects and complications following cosmetic surgery of the breast. The Danish Registry for Plastic Surgery of the Breast, established in May of 1999, provides plastic surgeons with a nationwide system for the collection of preoperative, perioperative, and postoperative data on women undergoing breast implantation, breast reduction, or mastopexy. The purpose of the Registry is to examine short-term and, eventually, long-term local complications and possible health effects, and to contribute to an ongoing evaluation of surgical results and surveillance of the products. Furthermore, the Registry will allow the identification of new areas for research into cosmetic and reconstructive breast surgery. Women accepting registration in the Danish Registry for Plastic Surgery of the Breast complete a self-administered questionnaire focusing on medical history and demographic and behavioral factors. Preoperative blood samples are drawn for storage. Surgical data, postoperative results, and complications are registered following surgery and at postoperative visits. Currently, registration has been initiated at 24 private and public clinics, representing more than 80 percent of the plastic surgery clinics in Denmark. As of November of 2001, a total of 1472 women with breast implants and 560 women with breast reduction were included in the Registry. These figures are expected to increase annually by 1000 women undergoing breast implantation and 500 women undergoing breast reduction or mastopexy. The authors present their experience of establishing the first nationwide comprehensive clinical-epidemiologic database and biological bank for cosmetic and reconstructive surgery procedures.

Epidemiologic evidence does not support an association between silicone breast implants and connective tissue or other rheumatic diseases. However, a recent study has suggested that women with ruptured implants may be at increased risk of developing fibromyalgia. An analysis of adverse health outcomes according to breast implant rupture status was conducted in 238 unselected Danish women with cosmetic silicone breast implants. Ninety-two of the women had definite implant rupture, and 146 had intact implants as determined by magnetic resonance imaging. Before undergoing imaging, the women provided blood samples and completed a self-administered questionnaire. Women with ruptured implants overall, and the subgroup with extracapsular ruptures (n = 23), were compared with women with intact implants regarding a number of self-reported diseases and symptoms and the presence of specific autoantibodies, such as antinuclear antibodies, rheumatoid factor, and cardiolipin immunoglobulin G and M antibodies. Overall, there were no differences in the occurrence of self-reported diseases or symptoms or in the presence of autoantibodies between women with intact implants and women with ruptured implants, including extracapsular rupture. The only exception was capsular contracture, which was reported six times more frequently by women with extracapsular ruptures than by women with intact implants (OR, 6.3; 95 percent CI, 1.7 to 23.5). In conclusion, this study of unselected women with silicone breast implants could establish no association between silicone implant rupture and specific diseases or symptoms related to connective tissue disease or other rheumatic conditions, except for an excess of capsular contracture among women with extracapsular rupture.

Herein the authors describe characteristics of women with breast implants compared with women with other types of cosmetic surgery as well as population controls. All women who acquired breast implants from 1977 to 1997 were identified from the files of two private plastic surgery clinics in Denmark. Patient characteristics were obtained through a self-administered questionnaire. The magnitude of differences between patient and control groups was estimated using odds ratios and 95% confidence intervals. Women with breast implants had a significantly lower body mass index and reported a two-fold greater incidence of current smoking compared with women from the general population and compared with women with other cosmetic surgery. Women with implants reported a greater number of full-term pregnancies and were less likely than controls to have had their first birth at age 30 years or older. Women with implants were not more likely than women in either control group to report a history of diseases, including connective tissue diseases, cancer, or depression before their implant surgery. Women with cosmetic breast implants differ from women with other forms of cosmetic surgery and from general population controls with respect to characteristics that may importantly influence health outcomes and that need to be addressed in future breast implant studies.

Concern has been raised recently regarding the absence of information on the occurrence and severity of local complications after cosmetic breast implantation. The authors evaluated the occurrence of local complications in a large epidemiological retrospective cohort study of women with cosmetic breast implants in Denmark. All women with breast implants were identified from the files of two private clinics of plastic surgery in Denmark. Information on implant characteristics, surgical procedure, as well as short- and long-term complications was obtained through medical record review. Patient characteristics were obtained through a self-administered questionnaire. A total of 754 women (1,572 implants) had at least one cosmetic implantation performed at the study clinics. Average age at implantation was 32 years. Implant types included silicone double lumen with textured surface, 31.2%; silicone single lumen with textured surface, 27.8%; silicone single lumen with smooth surface, 24.5%; silicone double lumen with smooth surface, 0.8%; and other or missing information, 15.7%. Average implant size was 247 ml (range, 110-630 ml). Placement was submuscular for 91.3% of implants, subglandular for 2.6%, and 6.1% had no available information. Overall, 77.8% of implantations were not followed by complications, 17.8% were followed by one complication, 3.6% were followed by two complications, and 0.8% were followed by three or more complications. In 94.6% of implantations, no additional hospitalizations were recorded as a result of complications. Forty-seven of 57 explantations/reimplantations were secondary to postoperative complications. General complications such as hematoma and infection were rare, occurring in 2.3% and 2.0% of implantations respectively. Capsular contracture remains the most common complication, occurring in 11.4% of implantations. In this investigation, among the first epidemiological studies of local complications, the authors found cosmetic breast implant surgery to be associated with a low frequency of normal surgical complications such as infection, hematoma, and wound dehiscence. Most complications were mild and did not lead to additional hospitalization. The complication that led most frequently to the need for additional surgery/hospitalization was capsular contracture. Kjøller K, Hölmich LR, Jacobsen PH, Friis S, Fryzek J, McLaughlin JK, Lipworth L, Henriksen TF, Jørgensen S, Bittmann S, Olsen JH. Epidemiological investigation of local complications after cosmetic breast implant surgery in Denmark.

To assess whether maternal breast implants are related to adverse health outcomes in offspring, the authors conducted a retrospective cohort study of esophageal disorders, rheumatic disease, and congenital malformations among 2,854 children born to women with breast implants and among 5,805 children born to a comparison group of women who underwent breast reduction or other plastic surgery. Rates were calculated using both hospitalization and outpatient data. Significantly higher rates of esophageal disorders were observed (O) than were expected (E) for children born before (O/E, 2.0; 95% CI, 1.3-2.8) but not after (O/E, 1.3; 95% CI, 0.5-2.9) maternal breast implant surgery. Risk of rheumatic disease was similar among children born before (O/E, 1.4; 95% CI, 0.7-2.6) and after (O/E, 1.4; 95% CI, 0.2-5.0) maternal breast implant surgery. A marginally significant excess of congenital malformations of the digestive organs was observed among children born after maternal implant surgery (O/E, 1.8; 95% CI, 1.0-3.1), with a similar finding among children born to women in the comparison group (O/E, 1.9; 95% CI, 1.4-2.4). The risk of malformations overall was not statistically significantly higher than expected among children born after maternal breast implant surgery. The elevated risks of adverse health outcomes appear unrelated to breast implants per se, because similar findings were observed among children born both before and after the mother's implant surgery, as well as among children born to mothers in the comparison cohort.

The authors investigated the association between the occurrence of capsular contracture and implant and patient characteristics. All women with breast implants from 1977 to 1997 were identified from the files of two private plastic surgery clinics in Denmark. Information on implant and patient characteristics, surgical procedure, and complications was obtained through medical records and self-administered questionnaires. Of 754 women (1,572 implants), average age at implantation was 32 years. Implant types were silicone double lumen, textured, 31.2%; silicone single lumen, textured, 27.8%; silicone single lumen, smooth, 24.5%; silicone double lumen, smooth, 0.8%; and other or missing, 15.7%. Placement was submuscular for more than 90% of implants. Capsular contracture occurred in 7.9% of implanted breasts, on an average of 621 days postoperatively, with 51.6% being bilateral. Overall, 66.1% of capsular contractures were recorded within the first 12 months postoperatively, and 79.0% were recorded within 24 months. Double-lumen implants were associated with a significantly (p < 0.01) reduced occurrence of capsular contracture. In summary, capsular contracture typically occurs within the first 2 years of implantation. Host factors may be important because more than half the capsular contractures in the current study were bilateral. Occurrence of capsular contracture did not appear to be associated with implant surface or placement, occurrence of local complications, or patient characteristics, although these findings should be interpreted cautiously.

The durability of silicone gel-filled breast implants is of concern, but there are few epidemiological studies on this issue. To date, most of the relevant findings are derived from studies of explantation, which suffer from bias by including women with symptoms or concerns about their implants. As part of a long-term magnetic resonance imaging study of the incidence of rupture, this study involved 271 women with 533 cosmetic breast implants who were randomly selected from among women who underwent cosmetic breast implantation from 1973 through 1997 at one public and three private plastic-surgery clinics in Denmark. The prevalence of rupture was determined from the first magnetic resonance screening. The images were evaluated by four independent readers, using a standardized, validated form. The outcomes under study were rupture, possible rupture, and intact implant. Ruptures were categorized as intracapsular or extracapsular. Overall, 26 percent of implants in 36 percent of the women examined were found to be ruptured, and an additional 6 percent were possibly ruptured. Of the ruptured implants, 22 percent were extracapsular. In multiple regression analyses, age of implant was significantly associated with rupture among second- and third-generation implants, with a 12-fold increased prevalence odds ratio for rupture of implants that were between 16 and 20 years of age, compared with implants between 3 and 5 years of age. Surgitek implants (Medical Engineering Corporation, Racine, Wis.) had a significantly increased prevalence odds ratio of 2.6 for rupture, compared with the reference implants. No significant association was found with the position (subglandular or submuscular) or the type of implant (single- or double-lumen). Extracapsular ruptures were significantly associated with a history of closed capsulotomy (p = 0.001). In the future, the authors plan to examine the women in their cohort with a second magnetic resonance imaging scan to establish the incidence of rupture, a parameter unknown to date in the literature, and to further characterize those factors associated with the actual risk of rupture.

Objective: To examine the occurrence of connective tissue diseases (CTDs) as well as ill-defined and other rheumatic conditions among Danish women with cosmetic silicone breast implants., Patients and Methods: A total of 2761 women with breast implants and 8807 control subjects were identified from plastic surgery private clinics and from public hospital plastic surgery departments. Women operated on at plastic surgery private clinics were identified through the files of each clinic, while women operated on at public hospitals were identified using the nationwide Danish National Registry of Patients. The control group consisted of women who underwent cosmetic surgery other than breast implantation or who only had a consultation. All women were followed up from January 1, 1977, through December 31, 1996, through the Danish National Registry of Patients for the occurrence of CTD as well as ill-defined and other rheumatic conditions. For the study period January 1, 1977, through December 31, 1994, the Danish National Registry of Patients contains information on hospitalization only, whereas data on outpatient visits are included from 1995 on, thus improving the sensitivity of the data. The implant and control groups were compared with the Danish population rates for CTD and ill-defined and other rheumatic conditions, and a direct comparison between the implant and control groups was also performed., Results: When compared with rates from the general population, no excess of definite CTD was observed in the implant cohorts. For ill-defined and other rheumatic conditions, statistically significant excesses of unspecified rheumatism were observed in both the implant and control cohorts when compared with national rates. A direct comparison between the implant and control cohorts found no material differences between the groups., Conclusions: The findings of this study support previous investigations and independent review panel conclusions that an association between silicone breast implants and definite CTDs is unlikely. The observation of an excess of unspecified rheumatism among women with implants and among control women suggests that women undergoing cosmetic plastic surgery have hospitalization rates for this condition in excess of those from the general population.

Most studies on cancer incidence after breast implantation have focused on breast cancer, while the risk of cancers at other sites has been less well investigated. We examined cancer incidence among 1,653 women who underwent cosmetic breast implant surgery at private clinics of plastic surgery in Denmark and 1,736 women attending the same clinics for other reasons during the period 1973-1995. Furthermore, we updated previously reported results among 1,114 women who received implants for cosmetic indications at public hospitals. All women were followed for cancer through the Danish Cancer Registry. In comparison with the general female population, the overall standardized incidence ratio (SIR) for cancer among women who received implants in private clinics was 1.65 [95% confidence interval (CI) = 1.17-2.27]. This elevated SIR reflected increased incidence ratios for almost all major cancer sites; however, only for non-melanoma skin cancer was there an excess of more than 2 cases. No significant excess of cancer was observed among women who received implants in public hospitals (SIR = 1.10, 95% CI = 0.76-1.52) or among women attending the private clinics for other problems (SIR = 1.10, 95% CI = 0.78-1.52). The SIRs for breast cancer after breast implantation were 1.1 (95% CI = 0.5-2.2) among private clinic patients and 0.9 (95% CI = 0.4-1.7) among public hospital patients. The overall findings of these 2 implant cohorts and results from other investigations suggest that cancer risk is probably not increased among women receiving cosmetic breast implants. The inconsistent results for private clinics and public hospitals are likely related to selection bias and confounding among the private clinic patients, but our data did not permit exploration of these possibilities. Further research into the determinants of these inconsistencies is warranted., (Copyright 2000 Wiley-Liss, Inc.)

Objective: To examine the occurrence of esophageal disorders, connective tissue diseases, and congenital malformations in children of mothers with breast implants., Methods: Nationwide register-based follow-up study of all offspring born during 1977 to 1992 to a cohort of 1135 women with breast implants for cosmetic reasons and to a comparison cohort of 7071 women who underwent breast reduction surgery. Cause-specific hospi-talization rates among offspring, relative to those of the general population, were calculated from the Danish National Registry of Patients., Results: Among the 939 children of mothers with breast implants, higher rates of esophageal disorders were observed, but the excess was similar for those born before versus after the implant surgery. Higher than expected hospitalization rates for these conditions were also observed among 3906 children of women who underwent breast reduction surgery. No significant increases in connective tissue diseases or congenital malformations were observed in either the breast implant or breast reduction cohorts., Conclusions: This first epidemiologic cohort study provides no evidence that silicone breast implants affect risks of esophageal or other disorders in children of the implantees. Rather, the observed risk pattern suggests that a lower threshold exists among both groups of women who have undergone cosmetic breast surgery in seeking professional medical care for problems normally solved outside the hospital.

Although millions of women worldwide have received breast implants for cosmetic or medical reasons, possible late effects (in particular cancer) have not been well studied. To provide quantitative information on cancer occurrence among women undergoing breast implant surgery, 1,135 women treated for cosmetic reasons in Denmark were evaluated. Patients were identified using the nationwide Hospital Discharge Registry with linkage to the nationwide Danish Cancer Registry to determine subsequent cancer incidence. The average age of the women at implant surgery was 31 years, and the average follow-up was 8.4 years, up to a maximum of 17 years. Overall, 27 cancers developed after implant surgery compared with 24.7 expected based on incidence rates from the general population (standardized incidence ratio [SIR] = 1.1; 95% CI: 0.7-1.6). Eight breast cancers were observed vs. 7.8 expected (SIR = 1.0; 95% CI: 0.4-2.0). No evidence was found to link breast implants with increased cancer risk in the decade after surgery. While the results are encouraging, longer follow-up into later life will be necessary to assess fully any possible adverse effects.

Sarcomas have been shown to develop next to foreign body implants, silicone included, in animal experiments. However, this carcinogenesis is not believed to have any human relevance. A review of the existing epidemiological studies suggests that women with silicone breast implants have a reduced risk for developing breast cancer. However, the presence of breast implants does obscure mammographic visualization as well as palpation of mammary tissue. This has led to the assumption that breast cancer detection could be compromised in women with breast implants. In the few studies that have dealt with this issue, women with breast implants were diagnosed with the same stage of disease as women without implants. However, the percentage of false negative mammographies was increased in one study. In conclusion, there is currently no evidence of an association between breast implants and cancer or postponed breast cancer detection.

The American Food and Drug Administration recently restricted the use of silicone gel-filled mammary implants for breast augmentations and reconstructions because a number of case reports had suggested that there was an association between silicone and connective tissue disease. We have found 36 such case reports published since 1982. Systemic sclerosis is the most common reported diagnosis (n = 15). Implants were removed from 15 patients, in nine of whom symptoms improved. The mechanism behind the postulated relationship is obscure, and most authors focused on an auto-immune-like response to silicone, which acts directly as a hapten or as an adjuvant. We found no conclusive evidence to implicate silicone mammary implants in connective tissue diseases. We do, however, recommend removal of implants from patients with severe connective tissue diseases. Patients with symptoms or active connective tissue disease should not be considered for silicone implants.

The American Food and Drug Administration (FDA) recently introduced a temporary stop for silicone breast prosthesis implants. The reason is a suspected connection between silicone implants and the development of autoimmune disease. The present authors have reviewed the 32 cases of connective tissue disease which have hitherto been reported in the literature, of these 13 were cases of systemic sclerodermia. On the basis of approximately 2 million silicone prosthesis implants which were introduced in USA alone during the past 20 years, approximately 200 cases of systemic sclerodermia would be anticipated. Nevertheless, the fact that several patients had spontaneous remission of their chronic disease after removal of the silicone implant speaks in favour of a possible connection. It is concluded that on account of the limited number of cases of connective tissue disease which have been reported in patients with silicone implants, insufficient evidence is present to stop implantation of these. Implantation of prostheses filled with saline are recommended for patients with connective tissue disease.

The authors present the case of a body-builder who sustained a spiral fracture of the humerus during arm wrestling (Indian wrestling). The cause of the fracture and the underlying mechanism are discussed and it is concluded that it appears appropriate to warn body-builders and weight-lifters against arm wrestling.