Pre-pectoral Immediate Breast Reconstruction Following Conservative Mastectomy Using Acellular Dermal Matrix and Semi-smooth Implants.

BACKGROUND/AIM: Improvements in acellular dermal matrix (ADM) and surgical techniques have facilitated pre-pectoral immediate breast reconstruction (IBR). Outer shell texturing is a key risk factor for anaplastic large cell lymphoma, prompting this evaluation of reconstruction with nano-textured rounded implants. PATIENTS AND METHODS: Fifty-one consecutive patients underwent 72 pre-pectoral ADM-assisted (fenestrated SurgiMend™) IBRs using nano-textured implants (Sebbin™). Patients were invited to complete a satisfaction questionnaire, including aesthetic outcome (linear scale 0-10) during follow-up. RESULTS: Average mastectomy weight was 300 g (range=83-1,018 g). After a mean follow-up of 18.3 month, 2 patients (2.8%) had minor wound complications. One patient suffered nipple necrosis. Capsular contracture occurred in 5 cases (6.9%) and significant rippling in one case. No implants were lost. Patient-reported aesthetic outcomes had a mean score of 9.3 (range=3-10; N=71). CONCLUSION: Pre-pectoral ADM-assisted IBR using semi-smooth implants following NSM is reliable and safe, with a low incidence of complications and high patient satisfaction.

BIA-ALCL and Textured Breast Implants: A Systematic Review of Evidence Supporting Surgical Risk Management Strategies.

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a significant public health concern for women with breast implants. The increase in incidence rates underscores the need for improved methods for risk reduction and risk management. The purpose of this study was to perform a systematic review to assess surgical risk reduction techniques and analyze communication/informed consent practices in patients with textured implants. METHODS: A systematic review of the literature was conducted in PubMed (legacy), Embase (Embase.com), and Scopus with four search strategies including key terms centered around breast reconstruction and BIA-ALCL. RESULTS: A total of 571 articles were identified, of which 276 were included in the final review after duplicates were removed. After review, no articles were determined to fit the inclusion criteria of demonstrating data-driven evidence of BIA-ALCL risk reduction through surgical measures, demonstrating a significant lack of data on risk reduction for BIA-ALCL. CONCLUSIONS: Risk management for BIA-ALCL is an evolving area requiring additional investigation. Although removal of textured devices in asymptomatic patients is not currently recommended by the Food and Drug Administration, variability in estimates of risk has led many patients to electively replace these implants in an effort to decrease their risk of developing BIA-ALCL. To date, however, there is no evidence supporting the concept that replacing textured implants with smooth implants reduces risk for this disease. This information should be used to aid in the informed consent process for patients presenting to discuss management of textured breast implants.

Applying Principles of Breast Revision to Managing Aesthetic Patients with Textured Implants.

SUMMARY: Textured breast implants have garnered increased attention recently because of their risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), an uncommon and treatable type of T-cell lymphoma. Treatment involves bilateral en bloc capsulectomy, which is curative in the majority of cases. At present, there is no defined management approach for aesthetic patients asymptomatic for BIA-ALCL requesting the removal of their textured implants, particularly as it relates to the management of the capsule. It is unclear if en bloc capsulectomy is necessary in these patients as it is in patients with BIA-ALCL. In the absence of clear guidance on the management of the capsule in asymptomatic patients, the basic principles of breast revision surgery can be applied to these patients.

The Capsule Question: How Much Should Be Removed with Explantation of a Textured Device?

SUMMARY: Current controversies surrounding breast implants are focused not only on the implant but also on the capsule. There has been tremendous discussion regarding how much of the capsule, if any, should be removed during explantation for benign conditions. The appearance of benign capsules is highly variable ranging from a thin membrane to densely fibrotic with calcifications. The options for capsulectomy include none, partial, complete, complete-intact, and en bloc. Some patients are requesting en bloc capsulectomy even in the absence of anaplastic large cell lymphoma; however, the scientific evidence only supports this for patients with capsular malignancies. The purpose of this article is to review the old and new evidence to answer the question regarding how much capsule should be removed during explantation for benign conditions.

"You Helped Create This, Help Me Now": A Qualitative Analysis of Patients' Concerns about Breast Implants and a Proposed Strategy for Moving Forward.

BACKGROUND: Some women with breast implants express concern about the safety of implants, fearing the possibility of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) and breast implant-related illness. METHODS: A qualitative analysis was performed to examine the perceived challenges, barriers, and worries experienced by these women. Convenience sampling was used to elicit responses from members of Canadian BIA-ALCL Facebook advocacy groups. Three independent coders read and reread the transcripts, using thematic analysis to identify emerging themes. RESULTS: Sixty-four women answered questions posed by the president of the Canadian Society of Plastic Surgeons regarding concerns about their breast implants. Five themes were identified: informing, listening, acknowledging, clarifying, and moving forward. Patients desire improved communication about possible risks before implantation and as new information becomes available (informing), sincere listening to their concerns (listening), acknowledgement that these disease entities may be real and have psychosocial/physical impact on patients (acknowledging), clarification of implant-related problems and their treatment (clarifying), and improved processes for monitoring and treatment of patients with identified problems (moving forward). Consideration of these themes in the context of the five domains of trust theory (i.e., fidelity, competence, honesty, confidentiality, and global trust) suggests significant breakdown in the doctor-patient relationship for a subset of concerned women. CONCLUSIONS: Concerns related to BIA-ALCL and breast implant-related illnesses have undermined some women's trust in plastic surgeons. Consideration of these five themes and their impact on the five domains of trust can guide strategies for reestablishing patients' trust in the plastic surgery community.

Is Breast Implant-Associated Anaplastic Large Cell Lymphoma Better Classified as a Lymphoproliferative Disorder and How Surgeons Reduce Risk?

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a complex topic with evolving classification and etiology. Commonalities between BIA-ALCL and lymphoproliferative disorders exist, suggesting that BIA-ALCL may be better represented on a spectrum of disease from benign effusion to malignant metastatic lymphoma. Meticulous sterile surgical technique, involving the use of betadine-containing irrigation, should be used to decrease the biological burden introduced into the surgical field and possibly prevent future incidences of BIA-ALCL.

Is Banning Texturized Implants to Prevent Breast Implant-Associated Anaplastic Large Cell Lymphoma a Rational Decision? A Meta-Analysis and Cost-Effectiveness Study.

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an emergent disease that threatens patients with texturized breast implants. Major concerns about the safety of these implants are leading to global changes to restrict the utilization of this product. The principal alternative is to perform breast augmentation utilizing smooth implants, given the lack of association with BIA-ALCL. The implications and costs of this intervention are unknown. OBJECTIVES: The authors of this study determined the cost-effectiveness of smooth implants compared with texturized implants for breast augmentation surgery. METHODS: A tree decision model was utilized to analyze the cost-effectiveness. Model input parameters were derived from published sources. The capsular contracture (CC) rate was calculated from a meta-analysis. Effectiveness measures were life years, avoided BIA-ALCL, avoided deaths, and avoided reoperations. A sensitivity analysis was performed to test the robustness of the model. RESULTS: For avoided BIA-ALCL, the incremental cost was $18,562,003 for smooth implants over texturized implants. The incremental cost-effectiveness ratio was negative for life years, and avoided death and avoided reoperations were negative. The sensitivity analysis revealed that to avoid 1 case of BIA-ALCL, the utilization of smooth implants would be cost-effective for a risk of developing BIA-ALCL equal to or greater than 1:196, and there is a probability of CC with smooth implants equal to or less than 0.096. CONCLUSIONS: The utilization of smooth implants to prevent BIA-ALCL is not cost-effective. Banning texturized implants to prevent BIA-ALCL may involve additional consequences, which should be considered in light of higher CC rates and more reoperations associated with smooth implants than with texturized implants.

A Prospective Approach to Inform and Treat 1340 Patients at Risk for BIA-ALCL.

BACKGROUND: The increasing incidence and associated mortality of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has become alarming. However, many patients remain unaware of their risk for BIA-ALCL and may overlook early warning signs of the cancer. The authors aim to contact all breast implant patients at a single institution to educate them on the disease and provide screening and treatment as indicated. METHODS: All patients who had breast implants placed at Penn State Hershey Medical Center from 1979 to November of 2017 were mailed a letter to describe BIA-ALCL and to encourage a follow-up visit. Patient information regarding demographics, implant type, the number of calls and follow-up visits, physical examination findings, and patient decisions after being informed of the disease were recorded prospectively. RESULTS: One thousand two hundred eighty-four letters were mailed to 1020 patients (79.4 percent) with smooth implants and 264 patients (20.6 percent) with textured implants. Seventy-six calls were received and 100 patients (84 smooth and 16 textured) were evaluated within the first 2 months. Of the 16 patients with textured implants, nine are undergoing secondary surgery to remove or replace their textured device. CONCLUSIONS: Informing patients at risk for BIA-ALCL is an important endeavor. Patients educated on the disease will likely be diagnosed and treated earlier, which can prevent the need for adjuvant chemotherapy and/or radiation therapy and decrease mortality. The authors provide a method, supporting documents, and preliminary data to help other institutions contact their breast implant patients at risk for BIA-ALCL.

Modern Primary Breast Augmentation: Best Recommendations for Best Results.

LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Develop a practical method for preoperative implant size selection. 2. List characteristics and examples of fourth- and fifth-generation silicone implants. 3. Recognize the differences in "profile" designations across implant manufacturers. 4. Recall updated statistics on breast implant-associated anaplastic large cell lymphoma and describe current guidelines on disease diagnosis and treatment. 5. Apply atraumatic and aseptic surgical techniques in primary breast augmentation. SUMMARY: Modern primary breast augmentation requires an intimate knowledge of the expanding breast implant market, including characteristics of current generation silicone implants and "profile" types. Optimal implant size selection requires balancing patient desires with tissue qualities. Evidence and awareness of breast implant-associated anaplastic large cell lymphoma continue to grow, and patients and surgeons alike should be informed on the most updated facts of the disease entity. Atraumatic surgical technique and aseptic adjuncts are critical in reducing periprosthetic inflammation and contamination, both of which are known instigators of capsular contracture and potentially breast implant-associated anaplastic large cell lymphoma.

Current Approaches Including Novel Nano/Microtechniques to Reduce Silicone Implant-Induced Contracture with Adverse Immune Responses.

Capsular contracture, which is the pathologic development of fibrous capsules around implants, is a major complication of reconstructive and aesthetic breast surgeries. Capsular contracture can cause implant failure with breast hardening, deformity, and severe pain. The exact mechanisms underlying this complication remain unclear. In addition, anaplastic large cell lymphoma is now widely recognized as a very rare disease associated with breast implants. Foreign body reactions are an inevitable common denominator of capsular contracture. A number of studies have focused on the associated immune responses and their regulation. The present article provides an overview of the currently available techniques, including novel nano/microtechniques, to reduce silicone implant-induced contracture and associated foreign body responses.

Betadine and Breast Implants.

In the fourth quarter of 2017, the US FDA reviewed and approved a request by one of the breast implant manufacturers for a change in the Directions for Use (DFU) that removed warnings regarding the use of Betadine (povidone-iodine [PI] 10% solution, 1% available iodine [Purdue Frederick Company, Stamford, CT], also available in generic formulations [Aplicare, Inc., Meriden, CT]). Previously, in 2000, there were concerns by the FDA that PI would degrade the silicone elastomer shell. This change in the DFU represents an important advance that will benefit patients through the permitted use of PI to reduce the risk of bacterial contamination of implant surfaces. What was formerly an off-label practice can be openly practiced by plastic surgeons as an anti-infective and biofilm-mitigation strategy. PI has an ideal spectrum effect for gram-positive and gram-negative organisms. Gram-positive organisms have been linked to capsular contracture and gram-negative Ralstonia picketti to breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). R picketti is resistant to aminoglycoside antibiotics, but it is susceptible to at least a 50% solution of PI. We believe that the strategy of antisepsis and biofilm mitigation is an integral part of a contemporary approach for breast augmentation. This is beneficial regarding reduction of the risk of surgical infection, capsular contracture, and BIA-ALCL. Outcome data so far indicate that antibiotics/anti-infectives seem to reduce the incidence of these adverse events that lead to reoperation and increased costs. It behooves plastic surgeons to take all actionable steps that enhance the quality of breast implant outcomes and reduce the rate of reoperation.

The dichloromethane extract of the ethnomedicinal plant Neurolaena lobata inhibits NPM/ALK expression which is causal for anaplastic large cell lymphomagenesis.

The present study investigates extracts of Neuolaena lobata, an anti-protozoan ethnomedicinal plant of the Maya, regarding its anti-neoplastic properties. Firstly, extracts of increasing polarity were tested in HL-60 cells analyzing inhibition of cell proliferation and apoptosis induction. Secondly, the most active extract was further tested in anaplastic large cell lymphoma (ALCL) cell lines of human and mouse origin. The dichloromethane extract inhibited proliferation of HL-60, human and mouse ALCL cells with an IC50 of ~2.5, 3.7 and 2.4 µg/ml, respectively and arrested cells in the G2/M phase. The extract induced the checkpoint kinases Chk1 and Chk2 and perturbed the orchestrated expression of the Cdc25 family of cell cycle phosphatases which was paralleled by the activation of p53, p21 and downregulation of c-Myc. Importantly, the expression of NPM/ALK and its effector JunB were drastically decreased, which correlated with the activation of caspase 3. Subsequently also platelet derived growth factor receptor ß was downregulated, which was recently shown to be transcriptionally controlled by JunB synergizing with ALK in ALCL development. We show that a traditional healing plant extract downregulates various oncogenes, induces tumor suppressors, inhibits cell proliferation and triggers apoptosis of malignant cells. The discovery of the 'Active Principle(s)' is warranted.

miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma.

Many transformed lymphoma cells show immune-phenotypes resembling the corresponding normal lymphocytes; thus, they provide a guide for proper diagnosis and present promising routes to improve their pathophysiologic understanding and to identify novel therapeutic targets. However, the underlying molecular mechanism(s) of these aberrant immune-phenotypes is largely unknown. Here, we report that microRNA-135b (miR-135b) mediates nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-driven oncogenicity and empowers IL-17-producing immunophenotype in anaplastic large cell lymphoma (ALCL). NPM-ALK oncogene strongly promoted the expression of miR-135b and its host gene LEMD1 through activation of signal transducer and activator of transcription (STAT) 3. In turn, elevated miR-135b targeted FOXO1 in ALCL cells. miR-135b introduction also decreased chemosensitivity in Jurkat cells, suggesting its contribution to oncogenic activities of NPM-ALK. Interestingly, miR-135b suppressed T-helper (Th) 2 master regulators STAT6 and GATA3, and miR-135b blockade attenuated IL-17 production and paracrine inflammatory response by ALCL cells, indicating that miR-135b-mediated Th2 suppression may lead to the skewing to ALCL immunophenotype overlapping with Th17 cells. Furthermore, antisense-based miR-135b inhibition reduced tumor angiogenesis and growth in vivo, demonstrating significance of this "Th17 mimic" pathway as a therapeutic target. These results collectively illuminated unique contribution of oncogenic kinase-linked microRNA to tumorigenesis through modulation of tumor immune-phenotype and microenvironment.

In vitro and in vivo antitumor effect of the anti-CD26 monoclonal antibody 1F7 on human CD30+ anaplastic large cell T-cell lymphoma Karpas 299.

CD26 is a M(r) 110,000 surface glycoprotein with diverse functional properties, including having a potentially significant role in tumor development, and antibodies to CD26 mediate pleomorphic cellular functions. In this report, we show that binding of soluble anti-CD26 monoclonal Ab 1F7 inhibits the growth of the human CD30+ anaplastic large cell T-cell lymphoma cell line Karpas 299 in both in vitro and in vivo experiments. In vitro experiments show that 1F7 induces cell cycle arrest at the G1-S checkpoint, associated with enhanced p21 expression that is dependent on de novo protein synthesis. Furthermore, experiments with a severe combined immunodeficient mouse tumor model demonstrate that 1F7 treatment significantly enhances survival of tumor-bearing mice by inhibiting tumor formation. Our data therefore suggest that anti-CD26 treatment may have potential clinical use for CD26+ hematological malignancies.