Silicone breast implants and connective tissue disease: an overview

Silicone breast implants have been implicated in the possible pathogenesis of various connective tissue diseases. These findings have had a major impact not only on the medical and legal communities, but also on the community at large. In this communication, we review the history of the breast implant controversy, and examine the medical evidence regarding the possible link of silicone gel implants with connective tissue disorders such as scleroderma, rheumatoid arthritis, and lupus. Finally, we give a broad overview of the topic and offer some general suggestions regarding the care of patients who have silicone breast implants.     

Release of low molecular weight silicones and platinum from silicone breast implants

We have conducted a series of studies addressing the chemical composition of silicone gels from breast implants as well as the diffusion of low molecular weight silicones (LM-silicones) and heavy metals from intact implants into various surrounding media, namely, lipid-rich medium (soy oil), aqueous tissue culture medium (modified Dulbecco's medium, DMEM), or an emulsion consisting of DMEM plus 10% soy oil. LM-silicones in both implants and surrounding media were detected and quantitated using gas chromatography (GC) coupled with atomic emission (GC-AED) as well as mass spectrometric (GC/MS) detectors, which can detect silicones in the nanogram range. Platinum, a catalyst used in the preparation of silicone gels, was detected and quantitated using inductive argon-coupled plasma/mass spectrometry (ICP-MS), which can detect platinum in the parts per trillion range. Our results indicate that GC-detectable low molecular weight silicones contribute approximately 1-2% to the total gel mass and consist predominantly of cyclic and linear poly-(dimethylsiloxanes) ranging from 3 to 20 siloxane [(CH3)2-Si-O] units (molecular weight 200-1500). Platinum can be detected in implant gels at levels of approximately 700 micrograms/kg by ICP-MS. The major component of implant gels appears to be high molecular weight silicone polymers (HM-silicones) too large to be detected by GC. However, these HM-silicones can be converted almost quantitatively (80% by mass) to LM-silicones by heating implant gels at 150-180 degrees C for several hours. We also studied the rates at which LM-silicones and platinum leak through the intact implant outer shell into the surrounding media under a variety of conditions. Leakage of silicones was greatest when the surrounding medium was lipid-rich, and up to 10 mg/day LM-silicones was observed to diffuse into a lipid-rich medium per 250 g of implant at 37 degrees C. This rate of leakage was maintained over a 7-day experimental period. Similarly, platinum was also observed to leak through intact implants into lipid-containing media at rates of approximately 20-25 micrograms/day/250 g of implant at 37 degrees C. The rates at which both LM-silicones and platinum have been observed to leak from intact implants could lead to significant accumulation within lipid-rich tissues and should be investigated more fully in vivo.     

Fatty acid composition of breast adipose tissue in breast cancer patients and in patients with benign breast disease

In this study, we report on the cell adhesion properties of marrow stromal cells to extracellular matrix components such as collagen and noncollagenous proteins. The osteoblastic cells and their non-osteoblastic counter-parts (MBA series) from the marrow stroma differentially recognized a spectrum of extracellular matrix proteins. The osteoblastic cells, MBA-15, preferentially attached to bone matrix proteins, whereas fibroendothelial MBA-2.1 and adipocytic 14F1.1 cells did not. The MBA-15 cells demonstrated a preference in their attachment to fibronectin > mixture of collagens > bone matrix extracts > collagen type I > noncollagenous proteins. Clonal subpopulations derived from the MBA-15 cell line representing various stages along the osteogenic lineage expressed differential attachment preference. MBA-15.4, a less differentiated clonal line, was compared to MBA-15.6, a mature cell line.     

Correlation of central hemodynamics and tissue blood flow in patients with hypertensive disease

A study was made of the effect of thymectomy carried out in guinea pigs aged 1 month on the antibody-forming cell (AFC) count (cells forming antibodies against sheep erythrocytes), and also the effect of thymosin on the AFC distribution in the spleen and the lymph nodes of thymectomized animals. It was shown that as a result of thymectomy the AFC content increased in the peripheral lymphoid organs, and, particularly, in the spleen. But under the effect of thymosin the AFC count in the spleen decreased and in the lymph nodes somewhat increased; this permitted one to suggest a normalizing influence of thymosin on the AFC count in the thymectomized animals.     

The life span of silicone gel breast implants and a comparison of mammography, ultrasonography, and magnetic resonance imaging in detecting implant rupture: a meta-analysis

Because of the growing concern surrounding the integrity and life span of silicone gel breast implants and the reported variations in the diagnostic accuracy of various imaging techniques in identifying ruptured implants, the authors undertook a meta-analysis of articles in the scientific literature to examine these concerns. They were able to include reports from the literature that detailed the condition and removal of 1,099 breast implants during the past 7 years. The median life span of a silicone gel implant was estimated to be 16.4 years. Of the implants, 79.1% were intact at 10 years, falling to 48.7% by 15 years. The sensitivities and specificities of three imaging modalities used in the diagnosis of implant rupture (mammography, ultrasonography, and magnetic resonance imaging [MRI]) were also evaluated and compared statistically in an effort to discover which of the three techniques might serve as the most reliable screening tool in the diagnosis of gel implant rupture. The sensitivity of mammography for finding a ruptured implant is 28.4% with a specificity of 92.9%. Ultrasonography has a sensitivity and specificity of 59.0% and 76.8% respectively compared with MRI, which was 78.1% and 80.0% respectively. For implants in place for 10 years, one would need to image 3.3 implants by ultrasound to identify a single possible rupture. However, because of the 76.8% specificity, 8.1 implants would need to be imaged to find a confirmed intraoperative rupture. This was similar to MRI, in which 3.1 implants would need to be imaged to detect one suspected rupture, and 6.1 implants would need to be imaged to find one intraoperatively confirmed rupture. The authors do not recommend either ultrasound or MRI as a screening tool based on their meta-analysis.     

Correlation of odontogenic soft tissue infection and thermal effects with special reference to temperature sense. Statistical analysis of 2,111 patients

Many persons are exposed to preservatives/biocides based on methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), since toiletries and cosmetics, as well as products/water-based systems used occupationally, may all contain MCI/MI. In toiletries and cosmetics, the MCI/MI concentration is often below 15 ppm (0.0015%). In some industries, workers handle high concentrations of MCI/MI, which can cause chemical burns and induce sensitization if skin is exposed. Contact allergy to MCI/MI is common and reports on chemical burns have been published. Thus, there is a need for prevention of skin diseases caused by MCI/MI. The inactivation of MCI/MI by glutathione (GSH) in emollients, containing different amounts of lipids, was studied by HPLC. Various amounts of GSH were added to Fenuril, Essex, and Locobase, giving 3 preparations of each emollient containing 0.10%, 0.50% and 2.0% GSH, respectively. The inactivation of 15 ppm MCI/MI and the total inactivating capacity of GSH in these preparations, kept at room temperature and refrigerated, was studied over a period of 6 months. The inactivating capacity of GSH in the emollients was almost equivalent, regardless of the lipid contents of the emollients, type of storage and age. On the other hand, the GSH concentration in the emollients had a crucial importance on the inactivation of MCI/MI. Emollients containing 2% GSH were capable of inactivating up to 2400 ppm MCI/MI.     

The neu-oncogene product in serum and tissue of patients with breast carcinoma

Patients with non-cardiac chest pain (NCCP) (n = 387) and cardiac chest pain (CCP) (n = 93) were compared with community controls (n = 81), using a symptom questionnaire that assessed the presence of irritable bowel syndrome (IBS), functional dyspepsia, and oesophageal dysfunction and chest pain characteristics. A significantly (p < 0.05) increased prevalence of symptoms compatible with IBS occurred in NCCP patients when compared with those with CCP and with controls. Dysphagia was more frequent in both those with non-cardiac and cardiac chest pain than in controls; this was not apparent, however, when patients with concomitant IBS were excluded. The presence of oesophageal or gastrointestinal symptoms did not enable discrimination with regard to the chest pain characteristics. We conclude that unselected referred patients with documented NCCP are more likely to have IBS and that the presence of oesophageal symptoms such as dysphagia may merely reflect the spectrum of the 'irritable gut'.     

Effects of guided bone regeneration around commercially pure titanium and hydroxyapatite-coated dental implants. II. Histologic analysis

The purpose of this study was to determine which treatment of a large osseous defect adjacent to an endosseous dental implant would produce the greatest regeneration of bone and degree of osseointegration: barrier membrane therapy plus demineralized freeze-dried bone allograft (DFDBA), membrane therapy alone, or no treatment. The current study histologically assessed changes in bone within the healed peri-implant osseous defect. In a split-mouth design, 6 implants were placed in edentulous mandibular ridges of 10 mongrel dogs after preparation of 6 cylindrical mid-crestal defects, 5 mm in depth, and 9.525 mm in diameter. An implant site was then prepared in the center of each defect to a depth of 5 mm beyond the apical extent of the defect. One mandibular quadrant received three commercially pure titanium (Ti) screw implants (3.75 x 10 mm), while the contralateral side received three hydroxyapatite (HA) coated root-form implants (3.3 x 10 mm). Consequently, the coronal 5 mm of each implant was surrounded by a circumferential defect approximately 3 mm wide and 5 mm deep. The three dental implants in each quadrant received either DFDBA (canine source) and an expanded polytetrafluoroethylene membrane (ePTFE), ePTFE membrane alone, or no treatment which served as the control. Clinically, the greatest increase in ridge height and width was seen with DFDBA/ePTFE. Histologically, statistically significant differences in defect osseointegration were seen between treatment groups (P < 0.0001: DFDBA/ePTFE > ePTFE alone > control). HA-coated implants had significantly greater osseointegration within the defect than Ti implants (P < 0.0001). Average trabeculation of newly formed bone in the defect after healing was significantly greater for HA-coated implants than for titanium (P < 0.0001), while the effect on trabeculation between treatments was not significantly different (P = 0.14). Finally, there were significantly less residual allograft particles in defect areas adjacent to HA-coated implants than Ti implants (P = 0.0355). The use of HA-coated implants in large size defects with DFDBA and ePTFE membranes produced significantly more osseointegration histologically than other treatment options and more than Ti implants with the same treatment combinations. The results of this study indicate that, although the implants appeared osseointegrated clinically after 4 months of healing, histologic data suggest that selection of both the implant type and the treatment modality is important in obtaining optimum osseointegration in large size defects.     

Analysis of anti-U1 RNA antibodies in patients with connective tissue disease. Association with HLA and clinical manifestations of disease

Histatin 1 is a histidine-rich phosphoprotein present in human parotid saliva that possesses candidacidal activity and functions in mineralization by adsorbing to hydroxyapatite. The objective of the present study was to develop a system for recombinant production of histatin 1 and to examine the role of phosphorylation in the functional activities of this molecule. Native histatin 1 (containing a phosphoserine at residue 2) was purified from parotid saliva, whereas a bacterial expression system was used to produce a recombinant form of histatin 1 (re-Hst1) that lacked phosphorylated serine. Histatin 1 cDNA was inserted into the vector pGEX-3X, which expresses foreign genes as soluble fusion proteins attached to the carboxyl-terminus of glutathione S-transferase (GST). The GST/re-Hst1 fusion protein was isolated from cell lysates by affinity chromatography on glutathione (GSH)-Sepharose and digested with cyanogen bromide to separate re-Hst1 from the GST fusion partner. The digest was subjected to reversed-phase high-performance liquid chromatography on a C18 column, and re-Hst1 was eluted as a well-defined peak. The yield of re-Hst1 was 4 mg/L of bacterial culture. Amino-terminal sequencing and amino acid analysis confirmed the final product as re-Hst1. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) showed that native histatin 1 and re-Hst1 had the same apparent molecular weights, while cationic PAGE showed that re-Hst1 was more basic. Phosphate analysis indicated 1 mol phosphate/mol of native histatin 1, while re-Hst1 lacked any detectable phosphate. Re-Hst1 demonstrated candidacidal activity comparable to that of native histatin 1, but displayed substantially lower binding to hydroxyapatite. These results show that phosphorylation of histatin 1 at residue 2 contributes significantly to its ability to bind to hydroxyapatite.     

Audiological correlates of speech understanding deficits in elderly listeners with mild-to-moderate hearing loss. II. Correlation analysis

OBJECTIVE: The study was conducted to determine the relationship between measures of auditory performance in elderly individuals. Specifically, its goal was to uncover a set of measures correlated with the set of measures of speech understanding under specific conditions of interference to gain a better understanding of decline of the "cocktail party effect" in aging. DESIGN: Audiological status and auditory performance of a group of elderly (60- to 81-yr-old) individuals were determined through a test battery. When present, the hearing loss of elderly subjects was symmetrical in the two ears and, at most, moderate. The battery included tests of speech intelligibility on the word and sentence levels, with and without the presence of interfering speech. In addition pure-tone and speech reception thresholds, perception of spectrally or temporally distorted speech and auditory resolution of frequency, time, and space were tested. Two tests received special consideration: the Speech Perception In Noise Test and the Modified Rhyme Reverberation Test. RESULTS: Results indicated that, despite the nearly normal hearing levels that characterized much of the subject group, auditory sensitivity measures showed persistent correlation to all other measures, with the exception of auditory resolution regarding frequency, time, and space. As a set, sensitivity measures accounted for more than 85% of the variance. When auditory sensitivity was controlled for, other factors underlying speech processing in the presence of interfering stimuli were uncovered, factors most likely related to the ability to perceptually segregate one speech signal from another. CONCLUSIONS: The findings suggest that, to determine the relationship between audiological/auditory test results of an elderly population, it is important to remove the effects of hearing loss through appropriate statistical methods.     

Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer

PURPOSE: To evaluate the influence of cumulative dose, dose-intensity, single-dose level, and schedule of epirubicin on the risk of developing congestive heart failure (CHF) in patients with advanced breast cancer. PATIENTS AND METHODS: Four hundred sixty-nine consecutive anthracyline-naive patients with metastatic breast cancer were included. Only patients with cardiac failure according to New York Heart Association (NYHA) function class II or more were recorded as having CHF. For each patient, the following were calculated: the cumulative dose of epirubicin, mean dose-intensity (cumulative dose of epirubicin/duration of treatment), and single-dose level (cumulative dose of epirubicin/number of injections). RESULTS: Thirty-four patients (7.2%) developed CHF. The cumulative risk of cardiotoxicity was 4% at 900 mg/m2 and increased exponentially to 15% at 1,000 mg/m2. Irradiation against the mediastinum and thoracic spine increased the risk of CHF (P=.025), but dose-intensity, single-dose level, and schedule had no influence on the risk of developing CHF. Age, previous adjuvant irradiation (to the left or right hemithorax), and previous chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF]) were not risk factors. The median time to onset of CHF following the last dose of epirubicin was 57 days (range, 0 to 853). Among patients with CHF, 13 (38.2%) died of cardiac failure. The median survival time for all patients with CHF was 162 days (range, 0 to +1,957). Previous irradiation directly against the heart increased the risk of death due to cardiac failure and decreased the median survival time to 125 days (range, 0 to 336). CONCLUSION: The present large retrospective study of 469 patients substantiates previous results concerning the cardiotoxicity of epirubicin. A significantly increasing risk of CHF in patients who receive cumulative doses greater than 950 mg/m2 was established. The future recommended maximum cumulative dose of epirubicin should be 900 mg/m2 in patients with metastatic breast cancer. Previous irradiation against the heart leads to an increased risk of developing CHF with an accelerated course to death, which indicates an additive cardiotoxic effect of irradiation and epirubicin.     

Early phase II study of TAT-59 in patients with advanced or recurrent breast cancer--a multicenter dose finding study

A dose finding early phase II study of TAT-59, a new triphenylethylene derivative, was performed in patients with advanced or recurrent breast cancer. TAT-59 was given orally for over 8 weeks at a daily dose of 10 mg, 20 mg or 40 mg/day. Thirty-six, 38 and 35 patients were eligible in the group treated with 10, 20 and 40 mg of TAT-59, respectively. The proportion of patients obtaining a complete or partial response with 10 mg/day, 20 mg/day and 40 mg/day of TAT-59 was 28.6% (10/35), 28.6% (10/35) and 25.8% (8/31) in the evaluable cases, respectively. The median duration of initial response with TAT-59 was 38.5 days, 26.5 days and 25.6 days, respectively. The frequent adverse reactions observed in all dosing groups included hot flashes, anorexia, nausea and vomiting, sweating, and abnormal values in liver function tests. In these adverse reactions, the incidence of hot flashes, which might be caused by the pharmacologic function of TAT-59 was 0.0% (0 of 35), 2.9% (1 of 35) and 10.0% (3 of 30) in the evaluable cases receiving 10 mg, 20 mg and 40 mg of TAT-59, respectively. In conclusion, it was recommended that the optimal dose in terms of efficacy and adverse reactions should be 20 mg/day.     

Serum lysozyme as a marker of host resistance. II. Patients with malignant melanoma, hypernephroma or breast carcinoma

Serum lysozyme activity was measured in groups of untreated patients with malignant melanoma, hyperneophroma and breast carcinoma. Significant elevation of serum levels of the enzyme was confined to patients with localized disease. In the presence of metastatic disease such elevation was not detected. The rise in serum lysozyme activity was not due to renal damage or any infective process and in the case of malignant melanoma was shown to be associated with infiltration of the tumour mass by macrophages. In vitro studies demonstrated that the macrophages resident in a tumour mass are responsible for relasing lysozyme in large amounts. It is proposed that the elevation of serum lysozyme in these cases may be an indicator of macrophage-mediated host resistance and that the measurement of macrophage products such as lysozyme in the extracellular fluid may under well defined conditions provide useful clinical information concerning host reactions.     

Comparison of electromotive drug administration with ketorolac or with placebo in patients with pain from rheumatic disease: a double-masked study

This study was undertaken to assess the efficacy of ketorolac compared with placebo when delivered by electromotive drug administration (EMDA) in patients with pain from rheumatic disease. In EMDA, or iontophoresis, a low-intensity electric current is applied over the skin to deliver medication into body tissues. Although EMDA has been used to treat patients with various diseases, controlled studies are lacking in patients with rheumatic disease. This double-masked study included 60 patients (43 women and 17 men) aged 31 to 80 years with the following conditions: 12, epicondylitis; 30, scapulohumeral periarthritis; 10, gonalgia; and 8, metatarsalgia. They were divided randomly by a physician into 2 groups of 30 patients each for 5 sessions of active treatment (30 mg of ketorolac) or placebo (5 mL of normal saline). Treatment took place every other day for 20 minutes. Immediately before and after the five treatment sessions and 7 days after treatment ended, both patient and physician measured the degree of pain using a categoric scale (no pain, slight pain, intermediate pain, strong pain, and very strong pain) and evaluated pain intensity using the Scott and Huskisson Visual Analogue Scale (VAS). Seven days after treatment ended, both physician and patient judged the result of treatment using a second categoric scale (no improvement or intermediate, good, or very good result). Both ketorolac and placebo provided immediate, significant pain relief when delivered by EMDA, but only those patients receiving ketorolac experienced a further reduction in pain 7 days after treatment; those receiving placebo experienced a slight increase in pain. VAS values differed significantly between the two groups. Poor results (no improvement) were significantly higher in the placebo-treated group, while good results were significantly higher in the ketorolac-treated group. No patient reported any adverse effects during treatment. This study demonstrates that ketorolac relieves pain when delivered by EMDA and offers longer-lasting pain relief than does placebo.     

Rehabilitation of patients with severely resorbed maxillae by means of implants with or without bone grafts. A 1-year follow-up study

Forty-three patients with severely resorbed maxillae who had been referred for implant treatment were assigned to one of three treatment groups: bone grafting and implant placement (graft group); modified implant placement but no bone grafting (trial group); or optimized complete dentures (no-implant group). Sixteen, 20, and 7 patients, respectively, were assigned to the three groups. At the 1-year follow-up, 10% of the implants had been lost. Only a few of the failures (3/22) occurred after prosthesis placement. The cumulative success rates were 83% in the graft group and 96% in the trial group. A substantial reduction of the grafted bone, especially of the onlay grafts, occurred in many patients. During the period from prosthesis connection to the 1-year follow-up, marginal peri-implant bone loss was on average 0.5 mm. Despite the often demanding procedures involved, all but one patient in each implant group said that they would undergo the treatment again. Most patients were very satisfied with the treatment outcome and their improved masticatory ability. Those who had renounced implant treatment appeared modestly adapted to their optimized dentures, but reported retention problems and less satisfaction with mastication.     

Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease

Twenty-six patients with relapsed or refractory Hodgkin's disease (HD) were treated with an intensive salvage regimen combining ifosfamide (3000 mg/m2/d, days 1-4 through continuous intravenous infusion) and vinorelbine (25 mg/m2, i.v. days 1 and 5) with mesna uroprotection and G-CSF support. Courses were given at 3-week intervals. Ten patients achieved a complete and 10 patients a partial response, yielding an overall response rate of 77%. The main toxic effect was neutropenia and the combination was well tolerated.