Orismilast in moderate-to-severe psoriasis: Efficacy and safety from a 16-week, randomized, double-blinded, placebo-controlled, dose-finding, and phase 2b trial (IASOS).

BACKGROUND: Orismilast is a novel oral phosphodiesterase-4 (PDE4) B/D inhibitor being investigated as a potential treatment for moderate-to-severe psoriasis. OBJECTIVE: To evaluate efficacy and safety of orismilast modified-release formulation in moderate-to-severe psoriasis. METHODS: This multicenter, randomized (1:1:1:1 to 20, 30, 40 mg orismilast or placebo, twice daily), double-blinded, placebo-controlled, parallel-group, phase 2b, 16-week, dose-ranging study evaluated orismilast in adults with moderate-to-severe plaque psoriasis (NCT05190419). Efficacy end points were analyzed using multiple imputation. RESULTS: Of 202 randomized patients, baseline characteristics were balanced across arms, except greater severe disease proportions for orismilast vs placebo. Orismilast showed significant improvements in the primary end point, percentage change in Psoriasis Area and Severity Index (PASI), from baseline to week 16 (orismilast -52.6% to -63.7% and placebo, -17.3%; all P <.001). Greater proportions receiving orismilast achieved PASI75 (39.5%-49.0%; P <.05) and PASI90 (22.0%-28.3%; P <.05 for 20 and 40 mg) vs placebo (PASI75, 16.5% and PASI90, 8.3%) at week 16. Safety findings were as expected with PDE4 inhibition; dose-dependent tolerability effects observed. LIMITATIONS: Small sample size, disease severity imbalance between groups, limited duration and diversity in study population. CONCLUSION: Orismilast demonstrated greater efficacy vs placebo and a safety profile in line with PDE4 inhibition.

Pharmacology of orismilast, a potent and selective PDE4 inhibitor.

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.

Oral orismilast: Efficacy and safety in moderate-to-severe psoriasis and development of modified release tablets.

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.

Psychological characteristics of Danish women with cosmetic breast implants.

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.

Delayed breast reconstruction with implants after invasive breast cancer does not impair prognosis.

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.

A nationwide study of connective tissue disease and other rheumatic conditions among Danish women with long-term cosmetic breast implantation.

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.

Reconstructive breast implantation after mastectomy for breast cancer: clinical outcomes in a nationwide prospective cohort study.

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.

Mortality and suicide among Danish women with cosmetic breast implants.

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.

A feasibility study of magnetic resonance imaging of silicone breast implants in Finland.

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.

Incidence of silicone breast implant rupture.

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.

Self-reported diseases and symptoms by rupture status among unselected Danish women with cosmetic silicone breast implants.

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.

Long-term health status of Danish women with silicone breast implants.

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.

Untreated silicone breast implant rupture.

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.

The Danish Registry for Plastic Surgery of the Breast: establishment of a nationwide registry for prospective follow-up, quality assessment, and investigation of breast surgery.

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.

Adverse health outcomes in offspring of mothers with cosmetic breast implants: a review.

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.

Long-term cosmetic outcome after breast implantation.

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.

Cancer risk among Danish women with cosmetic breast implants.

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.

The diagnosis of silicone breast-implant rupture: clinical findings compared with findings at magnetic resonance imaging.

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.

Surgical intervention and capsular contracture after breast augmentation: a prospective study of risk factors.

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.

Health outcomes in offspring of Danish mothers with cosmetic breast implants.

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.