IL-9 is a Biomarker of BIA-ALCL Detected Rapidly By Lateral Flow Assay.

BACKGROUND: A delayed seroma around breast implants is the most common clinical presentation of BIA-ALCL. However, most seromas are due to benign causes. Therefore, it is essential to distinguish benign seromas from seromas due to BIA-ALCL. In a prior study mean concentrations of IL-9, IL-10 and IL-13 were found to be significantly higher in BIA-ALCL than in benign seromas. OBJECTIVES: The aim of this research was to test the ability to detect high concentrations of IL-9 rapidly with a lateral flow assay (LFA). Because we previously reported that a LFA for CD30 detected BIA-ALCL in seromas we compared CD30 and IL-9 LFAs in distinguishing BIA-ALCL from benign seromas. METHODS: Thirty microliter samples of 26 seromas (15 benign, 11 malignant) were tested on in-house prepared strips for IL-9 and CD30. Nanoparticle-conjugated antibodies specific to IL-9 and CD30 were used for detection. IL-9 was analyzed in undiluted samples and CD30 samples were optimized at 1:3 dilution. The dynamic range of detection was determined by spiking recombinant IL-9 into a benign seroma. Image analysis measured intensity of both test line (TL) and control line (CL) and a TL/CL ratio was calculated. IL-9 protein and IL-9 transcription factor PU.1 were stained in BIA-ALCL lines and clinical samples. RESULTS: The IL-9 LFA was reliable in distinguishing BIA-ALCL from benign seromas when the concentration of IL-9 was greater than 10 ng/ml. The CD30 LFA was positive in all 11 malignant cases. In one case with only faint CD30 and IL-10 test lines, the IL-9 LFA was clearly positive. Immunohistochemistry showed IL-9 and its essential transcription factor PU.1 were present in tumor cells in BIA-ALCL lines and clinical samples. CONCLUSIONS: IL-9 is a tumor cell biomarker of BIA-ALCL that can be detected by lateral flow assay and immunohistochemistry. Concentrations of IL-9 greater than 10 ng/ml reliably distinguished BIA-ALCL from benign seromas. Moreover, IL-9 LFA could detect BIA-ALCL when CD30 LFA was not definitive and IL-10 was of low concentration with a faint IL-10 TL, suggesting a multiplex LFA including IL-9, CD30 and IL-10 might be more effective in detecting BIA-ALCL in selected cases.

Symptom Improvement After Explantation With No Capsulectomy for Systemic Symptoms Associated With Breast Implants.

BACKGROUND: The previously published Aesthetic Foundation (ASERF) biospecimen study documented systemic symptom improvement after implant removal regardless of the type of capsulectomy performed. A limitation of that study was that all subjects had at least some capsule removed for biospecimen analysis of heavy metals, microbes, and capsule histology. OBJECTIVES: Systemic symptoms associated with breast implants (SSBI) describes a group of patients who attribute a variety of symptoms to their implants. Previous studies have shown symptom improvement after implant removal in these patients which is independent of whether part or all the implant capsule has been removed. This study evaluates implant removal with no capsule removed in symptomatic and control subjects. METHODS: Eligible study subjects were sequentially enrolled at five investigator sites. The SSBI Cohort included patients with systemic symptoms they attributed to their implants requesting explantation. The non-SSBI Cohort included subjects without systemic symptoms attributed to their implants, requesting explantation with or without replacement. All subjects agreed to undergo explantation without removal of any capsule. RESULTS: Systemic symptom improvement was noted in SSBI subjects without removal of the implant capsule, comparable to the results of our previously published study. SSBI patients showed a 74% reduction in self-reported symptoms at six months with no capsulectomy which was not statistically different from partial or total capsulectomies (p = 0.23). CONCLUSIONS: Explantation with or without capsulectomy provides symptom improvement in patients with systemic symptoms they associate with their implants.

CD30 Lateral Flow and Enzyme-Linked Immunosorbent Assays for Detection of BIA-ALCL: A Pilot Study.

INTRODUCTION: Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) commonly presents as a peri-implant effusion (seroma). CD30 (TNFRSF8) is a consistent marker of tumor cells but also can be expressed by activated lymphocytes in benign seromas. Diagnosis of BIA-ALCL currently includes cytology and detection of CD30 by immunohistochemistry or flow cytometry, but these studies require specialized equipment and pathologists' interpretation. We hypothesized that a CD30 lateral flow assay (LFA) could provide a less costly rapid test for soluble CD30 that eventually could be used by non-specialized personnel for point-of-care diagnosis of BIA-ALCL. METHODS: We performed LFA for CD30 and enzyme-linked immunosorbent assay (ELISA) for 15 patients with pathologically confirmed BIA-ALCL and 10 patients with benign seromas. To determine the dynamic range of CD30 detection by LFA, we added recombinant CD30 protein to universal buffer at seven different concentrations ranging from 125 pg/mL to 10,000 pg/mL. We then performed LFA for CD30 on cryopreserved seromas of 10 patients with pathologically confirmed BIA-ALCL and 10 patients with benign seromas. RESULTS: Recombinant CD30 protein added to universal buffer produced a distinct test line at concentrations higher than 1000 pg/mL and faint test lines at 250-500 pg/mL. LFA produced a positive test line for all BIA-ALCL seromas undiluted and for 8 of 10 malignant seromas at 1:10 dilution, whereas 3 of 10 benign seromas were positive undiluted but all were negative at 1:10 dilution. Undiluted CD30 LFA had a sensitivity of 100.00%, specificity of 70.00%, positive predictive value of 76.92%, and negative predictive value of 100.00% for BIA-ALCL. When specimens were diluted 1:10, sensitivity was reduced to 80.00% but specificity and positive predictive values increased to 100.00%, while negative predictive value was reduced to 88.33%. When measured by ELISA, CD30 was below 1200 pg/mL in each of six benign seromas, whereas seven BIA-ALCL seromas contained CD30 levels > 2300 pg/mL, in all but one case calculated from dilutions of 1:10 or 1:50. CONCLUSIONS: BIA-ALCL seromas can be distinguished from benign seromas by CD30 ELISA and LFA, but LFA requires less time (<20 min) and can be performed without special equipment by non-specialized personnel, suggesting future point-of-care testing for BIA-ALCL may be feasible.

Longevity of Post-Explantation Systemic Symptom Improvement and Potential Etiologies: Findings From the ASERF Systemic Symptoms in Women-Biospecimen Analysis Study: Part 4.

BACKGROUND: Breast Implant Illness (BII) describes a variety of symptoms reported by patients with breast implants. Biospecimens data revealed minimal statistical differences between BII and non-BII cohorts. Baseline analysis of PROMIS data demonstrated significant differences between the BII cohort and the 2 control cohorts. OBJECTIVES: This study was designed to determine if patients in the BII cohort obtained any symptom improvement after explantation, whether symptom improvement was related to the type of capsulectomy, and which symptoms improved. METHODS: A prospective blinded study enrolled 150 consecutive patients divided equally into 3 cohorts. Baseline demographic data and a systemic symptoms survey, including PROMIS validated questionnaires, were obtained at baseline, 3 to 6 weeks, 6 months, and 1 year. RESULTS: A total of 150 patients were enrolled between 2019 and 2021. Follow-up at 1 year included 94% of the BII cohort and 77% of non-BII and mastopexy cohorts. At 1 year, 88% of patients showed at least partial symptom improvement, with a reduction of 2 to 20 symptoms. The PROMIS score in the BII cohort decreased at 1 year for anxiety, sleep disturbances, and fatigue. Systemic symptom improvement was noted out to 1 year in the BII cohort regardless of the type of capsulectomy performed. CONCLUSIONS: Parts 1-3 in this series concluded that there were no consistent differences in biospecimen results between the cohorts. Unlike the data observed in the biospecimen analysis, BII patients had heightened symptoms and poorer PROMIS scores at baseline compared to the control cohorts. The reduction of negative expectations and a potential nocebo effect could contribute to this improvement.

Separating Myth from Reality in Breast Implants: An Overview of 30 Years of Experience.

SUMMARY: The purpose of this article is to review the pivotal events in the history of breast implants in the United States, including the events leading to the U.S. Food and Drug Administration moratorium on the use of silicone gel implants and subsequent approval; the emergence of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL); and persistent concerns about an association between breast implants, autoimmune disease, and systemic symptoms. This article reviews the medical literature to outline our current knowledge on BIA-ALCL; offers recommendations for diagnosis and management of symptomatic and asymptomatic patients with textured implants; and reviews the science of potential associations of implants with autoimmune and systemic symptoms. The authors hope to help patients separate myths from reality and make educated decisions on having breast implants placed or removed.

The Efficacy and Associated Learning Curve of Office-Based High-Resolution Ultrasound to Detect Shell Failure in Breast Implants.

BACKGROUND: High-resolution ultrasound (HRUS) is widely employed in plastic surgery practices to detect implant rupture prior to revisional surgery. Published research has found a good overall accuracy of shell failure detection. The literature often references a learning curve associated with incorporating this imaging technique into a medical practice, but it has yet to be visualized or defined. OBJECTIVE: This study was undertaken to calculate current testing statistics for use of HRUS to detect shell failure and to define the learning curve associated with the predicted improvement reflected by statistics of test and surgeon proficiency. METHODS: A retrospective review of sequential in-office HRUSs on patients with breast implants was conducted across 2 plastic surgery practices. Preoperative ultrasound reports and intraoperative findings were compared. Test statistics were calculated for each group of 10 subsequent patients, and a regression analysis was performed to define the learning curve. RESULTS: A total of 480 implants were examined and averages for all test statistics were calculated. All were higher than most of the previously reported literature standards. The regression analysis showed a linear improvement for both sensitivity and specificity over time, with significant improvement in sensitivity. CONCLUSION: Results show that HRUS is highly effective in detecting shell failure in breast implants. There is also a calculable linear improvement for all test values of the HRUS over time. Surgeons were able to remain above the literature standard for sensitivity after their 60th HRUS reading. This improvement shows that continued use and practice of the imaging technique allow for more accurate findings.

US FDA Patient Decision Checklist for Breast Implants: Results of a Survey to Members of The Aesthetic Society, April 2022.

The US Food and Drug Administration (FDA), in response to concerns that patients undergoing breast implant surgery were not adequately informed about the risks of receiving an implanted medical device, mandated a Patient Decision Checklist (PDC) in October 2021. Breast implant manufactures communicated with plastic surgeons in 2022 regarding the use of the PDC as a condition for the sale of breast implants. Plastic surgeons voiced concerns over the accuracy of the content in the PDC and its confusing statements about the risk of adverse events associated with breast surgery. In April 2022, The Aesthetic Society developed a survey that was sent to its members regarding their experiences with the PDC. This was a 5-question survey, with 1 additional place for comments. The purpose of this survey was to develop data based on the 6-month experience of plastic surgeons with the PDC. A total of 206 Aesthetic Society members (9%) participated in the survey (1849 total active members in the United States). Patients deserve appropriate information prior to breast implant surgery to make an informed decision after reviewing the potential risks and benefits. The authors believe that there is still more work to be done to create an ideal PDC that is fair and balanced, scientifically describes risk incidence in a way that patients understand, and can be updated.

Microbes, Histology, Blood Analysis, Enterotoxins, and Cytokines: Findings From the ASERF Systemic Symptoms in Women-Biospecimen Analysis Study: Part 3.

BACKGROUND: There has been an increasing need to acquire rigorous scientific data to answer the concerns of physicians, patients, and the FDA regarding the self-reported illness identified as breast implant illness (BII). There are no diagnostic tests or specific laboratory values to explain the reported systemic symptoms described by these patients. OBJECTIVES: The aim of this study was to determine if there are quantifiable laboratory findings that can be identified in blood, capsule tissue pathology, or microbes that differentiate women with systemic symptoms they attribute to their implants from 2 control groups. METHODS: A prospective blinded study enrolled 150 subjects into 3 cohorts: (A) women with systemic symptoms they attribute to implants who requested implant removal; (B) women with breast implants requesting removal or exchange who did not have symptoms attributed to implants; and (C) women undergoing cosmetic mastopexy who have never had any implanted medical device. Capsule tissue underwent detailed analysis and blood was sent from all 3 cohorts to evaluate for markers of inflammation. RESULTS: No significant histologic differences were identified between the cohorts, except there were more capsules with synovial metaplasia in the non-BII cohort. There was no statistical difference in thyroid-stimulating hormone, vitamin D levels, or complete blood count with differential between the cohorts. Next-generation sequencing revealed no statistically significant difference in positivity between Cohort A and B. Of the 12 cytokines measured, 3 cytokines, interleukin (IL)-17A, IL-13, and IL-22, were found to be significantly more often elevated in sera of subjects in Cohort A than in Cohorts B or C. The enterotoxin data demonstrated an elevation in immunoglobulin G (IgG) anti-Staphylococcus aureus enterotoxin A in Cohort A. There was no correlation between the presence of IgE or IgG anti-Staphylococcal antibody and a positive next-generation sequencing result. CONCLUSIONS: This study adds to the current literature by demonstrating few identifiable biomedical markers to explain the systemic symptoms self-reported by patients with BII.

Defining Internal Tissue Closure: High-Resolution Ultrasound Evaluation of Interi-A Novel Internal Tissue Closure System.

Background: Seroma remains a leading postsurgical complication in plastic surgery. Conventional drains are ineffective in clearing blood and fluid and closing down surgical spaces. The Interi (Internal Closure System, IC Surgical, Grand Rapids, MI) is comprised of a novel branching internal manifold attached to a self-contained portable pump with a higher, consistent, continuous negative pressure, may reduce this long-standing issue. In addition, high-resolution ultrasound (HRUS) has emerged as an ideal tool to visualize structures, fluid collections, and seromas internally. Objectives: This study evaluates Interi in full abdominoplasty patients utilizing HRUS to evaluate Interi's ability to evacuate blood and fluid, hold internal tissues together and document, for the first time, what internal tissue healing actually looks like radiographically. Methods: An IRB approved, Contract Research Organization reviewed retrospective study evaluated consecutive patients undergoing full abdominoplasty utilizing Interi from July 2020 through March 2021 by three plastic surgeons. HRUS visualized and confirmed the presence or absence of fluid collections and healing tissue planes during the postoperative process. Study data and all adverse events were recorded, with HRUS images reviewed by investigators and confirmed by an independent radiologist. Results: Seventy-one Interi patients were enrolled. Mean age was 43 (range: 21-74) and BMI was 28. Seroma was confirmed clinically and through HRUS in 3/71 patients, and was associated with either clot (2) or failure to activate system (1). Interi's ability to eliminate fluid and approximate/hold surgical tissue planes together was confirmed with HRUS. No other major complications, including abscess, hematomas, or flap necrosis were observed. Conclusions: This novel Internal Tissue Closure System effectively evacuated blood and fluid, approximated and maintained closure of internal tissue planes in abdominoplasty patients, allowing for primary tissue healing and internal wound closure to occur. Healing tissue planes and any fluid present are easily identified on HRUS visualizing actual internal tissue healing with a simple, widely available radiographic scan.

Heavy Metals in Breast Implant Capsules and Breast Tissue: Findings from the Systemic Symptoms in Women-Biospecimen Analysis Study: Part 2.

BACKGROUND: Breast Implant Illness (BII), as described in recent medical literature and by social media, describes a range of symptoms in patients with breast implants for which there are no physical findings or laboratory results that explain their symptoms. OBJECTIVES: Part 2 of this study aims to determine whether heavy metals are present in the capsules around saline and silicone implants and if there are statistical differences in the type or level of these metals between women with or without symptoms. Demographic data was collected to investigate potential alternate sources of metals: inhaled, absorbed, or ingested. METHODS: A prospective, blinded study enrolled 150 consecutive subjects divided equally into in three cohorts: (A) women with systemic symptoms they attribute to their implants who requested implant removal, (B) women with breast implants requesting removal or exchange who do not have symptoms they attribute to their implants, and (C) women undergoing cosmetic mastopexy who have never had any implanted medical device. Capsule tissue was removed from Cohort A and B for analysis of 22 heavy metals. Additionally, breast tissue was obtained from a control group with no previous exposure to any implanted medical device. RESULTS: The study was performed between 2019-2021. Heavy metal content was compared between the capsule tissue from Cohort A and B. The only statistically significant differences identified in Cohort A were higher levels of arsenic and zinc, and lower levels of cobalt, manganese, silver, and tin. There were no elevated levels or statistically significant differences in the other metals tested between Cohorts A and B. CONCLUSIONS: This study analyzes the metal content in capsules surrounding both saline and silicone breast implants. Heavy metals were also detected in the non-implant control group breast tissue, with some metals at numerically higher levels than either breast implant cohort. Smoking, gluten free diets, dietary supplements, and the presence of tattoos were all identified as statistically significant sources of arsenic and zinc in Cohort A. The risk of heavy metal toxicity should not be used as an indication for total capsulectomy if patients elect to remove their breast implants.

A Practical Guide to Managing Patients With Systemic Symptoms and Breast Implants.

Numerous studies have explored the possibility of an association between breast implants and systemic symptoms potentially linked to exposure to silicone. Some studies show no direct association whereas others provide insufficient scientific evidence to prove or disprove an association. Nonetheless, some patients with breast implants remain concerned about the possible role of their implants in systemic symptoms they may be experiencing. This paper provides a practical approach for plastic surgeons in managing patients with breast implants who present with systemic symptoms, including recommendations for patient counseling, clinical and laboratory assessment of symptoms, and/or referral. Integral components of patient counseling include listening attentively, providing unbiased information, and discussing the risks and benefits of options for evaluation and treatment. A thorough history and assessment of symptoms, including appropriate laboratory tests, may identify underlying conditions to expeditiously address patients' health issues through a specialist referral. Diagnosing and treating disorders that are causing a patient's symptoms, if unrelated to their implant, would avoid a potentially unnecessary surgery. Ultimately, better information is needed to reliably guide patients in an evidence-based fashion. Long-term follow-up of patients who are explanted to see what symptoms may or may not improve could be useful in educating patients. Control groups in studies prospectively following women with implants for development of systemic symptoms would also be useful because the symptoms reported are common in women without implants. Cases are presented to illustrate the recommendations for a practical approach toward management of women reporting systemic symptoms with breast implants.