The Mandatory German Breast Implant Registry Law: A Model for Sustainable Implant Registries.

BACKGROUND: Recurrent scandals involving breast implants have revealed that scientific evidence on the performance of these devices is lacking, and passive monitoring systems are not capable of detecting problems at an early stage. The German health authorities therefore decided to implement a prospective, mandatory registry. OBJECTIVES: The aim of this article was to provide information about the advantages of implementing a mandatory registry, the potential hurdles involved, and to establish structural requirements that future registries can use. METHODS: Since 2018, the authors have assisted the German Ministry of Health in refining the Implant Law and its implementation. They adapted an internationally consented dataset, promoted international data amplification and conducted monthly trial inputs for over 2 years. By identifying several key issues they were able to assist in developing solutions. RESULTS: The cooperation with the authorities was characterized by appreciation of the authors' expertise and previous international work. Challenges included data privacy issues, federal competence, longitudinal follow-up, and contact data; as well as associated costs and technical solutions for data inclusion and the use of information technology to communicate with stakeholders. Addressing these challenges required considerable interference with personal rights and complementary measures for all stakeholders. Extensive structural precautions were taken to safeguard personal data privacy as far as possible. CONCLUSIONS: The authors' experience and lessons learned can guide registries seeking to engage in high levels of evidence data. The authors describe their approach, the obstacles they encountered, and the strategies employed to overcome the setbacks of other registries.

Genotyping of circulating cell-free DNA enables noninvasive tumor detection in myxoid liposarcomas.

Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin. About 50% of patients with STS experience relapse and more than 30% will die within 10 years after diagnosis. In this study we investigated circulating free DNA (cfDNA) and tumor-specific genetic alterations therein (circulating tumor DNA, ctDNA) as diagnostic biomarkers. Plasma concentrations and fragmentation of cfDNA was analyzed with quantitative PCR. Patients with STS (n = 64) had significantly higher plasma concentrations and increased fragmentation of cfDNA when compared to patients in complete remission (n = 19) and healthy controls (n = 41) (p < 0.01 and p < 0.001). Due to overlapping values between patients with STS and controls, the sensitivity and specificity of these assays is limited. Sensitive assays to detect genomic alterations in cfDNA of synovial sarcomas (t(X;18)), myxoid liposarcomas (t(12;16) and TERT C228T promoter mutation) and well-differentiated/de-differentiated liposarcomas (MDM2 amplifications) were established. ctDNA was quantified in nine liposarcoma patients during the course of their treatment. Levels of breakpoint t(12;16) and TERT C228T ctDNA correlated with the clinical course and tumor burden in patients with myxoid liposarcomas (n = 4). ctDNA could detect minimal residual disease and tumor recurrence. In contrast, detection of MDM2 amplifications was not sensitive enough to detect tumors in patients with well-differentiated/de-differentiated liposarcomas (n = 5). Genotyping of cfDNA for tumor specific genetic alterations is a feasible and promising approach for monitoring tumor activity in patients with myxoid liposarcomas. Detection of ctDNA during follow-up examinations despite negative standard imaging studies might warrant more sensitive imaging (e.g. PET-CT) or closer follow-up intervals to timely localize and treat recurrences.

Identification of a blood-borne miRNA signature of synovial sarcoma.

BACKGROUND: Synovial sarcoma account for approximately 10 % of all soft-tissue tumors and occur most frequently in young adults. A specific translocation in this sarcoma induces fusion of the SYT gene on chromosome 18 to the SSX genes on chromosome X, leading to proliferation of the tumor cells. The need for non-invasive biomarkers indicating recurrence and activity of this disease has sparked research into short non-coding RNA known as microRNA (miRNA). METHODS: Blood samples of patients with active synovial sarcoma and of synovial sarcoma patients in complete remission as well as of healthy donors and patients with active leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma were collected. Whole blood RNA was extracted and samples of patients with active synovial sarcoma and of healthy donors were analyzed using an Affymetrix GeneChip miRNA Array v. 4.0. qRT-PCR was carried out to confirm a panel of miRNAs which where differentially expressed in the miRNA array. This miRNA-panel was further evaluated in patients with synovial sarcoma in complete remission and patients with active leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma as well as in an independent cohort of synovial sarcoma patients. RESULTS: Unsupervised hierarchical clustering of the miRNA arrays separated patients with active synovial sarcoma from healthy controls. A panel of seven miRNAs (miR-99a-5p, miR-146b-5p, miR-148b-3p, miR-195-5p, miR-223-3p, miR-500b-3p and miR-505-3p) was further validated by qRT-PCR to be significantly upregulated in synovial sarcoma patients. Moreover, most of the analyzed miRNAs were shown to be significantly upregulated in synovial sarcoma patients compared to leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma patients. Validation of the miRNA panel in an independent cohort of synovial sarcoma patients confirmed higher expression levels compared to healthy controls and patients in complete remission. CONCLUSION: Our results have identified a specific whole blood miRNA signature that may serve as an independent biomarker for the diagnosis of local recurrence or distant metastasis of synovial sarcoma. It even distinguishes synovial sarcoma from other sarcoma subtypes, thus potentially serving as a specific biomarker for synovial sarcoma.

Sensitivity after Clitoral Reconstruction in Patients with Female Genital Mutilation.

Background: In the past decades, reconstructive choices after female genital mutilation extended beyond de-infibulation and scar release. The current trend to expand techniques addressing sexual and aesthetic aspects by reconstructing the clitoris and prepuce, and dissecting the clitoral nerves raises concern, as there is a paucity of evidence on the functional outcomes and suspected iatrogenic lacerations. Methods: A total of 128 female genital mutilation patients were included in the study. To evaluate clitoral sensitivity after elevation, the Semmes-Weinstein-monofilament test was performed before and after genital reconstruction. Results: Preoperatively, patients with a visually intact clitoris showed significantly better sensitivity compared with patients with a mutilated clitoris or infibulation (P < 0.0001). Surgery was performed in 84 patients. After clitoral reconstruction (CR), 70 of 73 patients were able to perceive 2.83 monofilaments (95.9%), whereas three perceived 3.61. Patients with a visually intact clitoris served as control, and 95.0% perceived 2.83 monofilaments. We showed a significant improvement of clitoral sensitivity (P = 0.0020) in the subgroup consisting of patients with a mutilated clitoris in whom the test was performed before and after reconstruction. Conclusions: Clitoral sensitivity improves significantly after CR. Seventy of 73 patients attained the same sensitivity as unharmed women. No patient showed a decreased sensitivity compared with their preoperative findings. Therefore, our study supports the argument that CR offers sufficient improvement of objective clitoral sensitivity without additionally addressing clitoral nerves.

Breast Implant-Associated Tumors.

In addition to anaplastic large T-cell lymphomas (BIA-ALCL), other implant-related tumors have been described for some years. Squamous cell carcinoma (SSC) and B-cell lymphomas occurred in very rare cases. The unexplained pathogenesis as well as the unclear individual risk profile is an ongoing source of uncertainty for patients and physicians. The pathogenesis of the tumors is still largely not understood. While BIA-ALCL occurs more frequently with textured breast implants, other tumors were also observed with smooth implants and at other implant sites. Multiple potential mechanisms are discussed. It is suspected that the etiology of a chronic inflammatory response and subsequently immunostimulation is multifactorial and appears to play a key role in the malignant transformation. Since there are currently no sufficiently valid data for a specific risk assessment, this must be done with caution. This article presents the incidence, pathogenesis, as well as the level of evidence according to the current state of knowledge, and evaluates and discusses the current literature.

Postoperative Course of Reconstructive Procedures in FGM Type III-Proposal for a Modified Classification of Type III Female Genital Mutilation.

BACKGROUND: Reconstruction after female genital mutilation (FGM) has developed from being merely a therapy for complications to addressing body perception and sexuality. However, evidence regarding a direct correlation between FGM and sexual dysfunction is scarce. The present WHO classification provides an imprecise grading system, which makes it difficult to compare present studies with treatment outcomes. The aim of this study was to develop a new grading system based on a retrospective study of Type III FGM, evaluating operative time and postoperative results. METHODS: The extent of clitoral involvement, operative time of prepuce reconstruction and lack of prepuce reconstruction, and postoperative complications of 85 patients with FGM-Type III were retrospectively analyzed at the Desert Flower Center (Waldfriede Hospital, Berlin). RESULTS: Even though universally graded by the WHO, large differences in the degree of damage were found after deinfibulation. In only 42% of patients, a partly resected clitoral glans was found after deinfibulation. There was no significant difference in operative time when comparing patients who required prepuce reconstruction and patients who did not (p = 0.1693). However, we found significantly longer operative time in patients who presented with a completely or partly resected clitoral glans when compared to patients with an intact clitoral glans underneath the infibulating scar (p < 0.0001). Two of the 34 patients (5.9%) who had a partly resected clitoris required revision surgery, while none of the patients in whom an intact clitoris was discovered under the infibulation required revision. However, these differences in the complication rates between patients with and without a partly resected clitoris were not statistically significant (p = 0.1571). CONCLUSIONS: A significantly longer operative time was found in patients who presented with a completely or partly resected clitoral glans when compared with patients with an intact clitoral glans underneath the infibulating scar. Furthermore, we found a higher, though not significantly significant, complication rate in patients with a mutilated clitoral glans. In contrast to Type I and II mutilations, the presence of an intact or mutilated clitoral glans underneath the infibulation scar is not addressed in the present WHO classification. We have developed a more precise classification, which may serve as a useful tool when conducting and comparing research studies.

P2Y12 receptor blockers are anti-inflammatory drugs inhibiting both circulating monocytes and macrophages including THP-1 cells.

P2Y12 blockade improves patient outcomes after myocardial infarction. As well as antithrombotic effects, anti-inflammatory effects may contribute to this beneficial clinical outcome. Here we aimed to identify potential anti-inflammatory effects of P2Y12 receptor blockers on monocytes and macrophages. Using flow cytometry, migration assays, flow chambers and RNA microarrays, we investigated the effects of adenosine diphosphate (ADP) and P2Y12 receptor blockers on blood monocytes, THP-1 monocytes and THP-1 monocytes after differentiation to macrophages. P2Y12 -expressing platelets can form aggregates with monocytes in circulating blood. Mediated by platelets, ADP results in activation of the integrin receptor Mac-1 on blood monocytes, as detected by the conformation-specific single-chain antibody MAN-1. Via the same association with platelets, THP-1 monocyte adhesion to the endothelial intercellular adhesion molecule 1 (ICAM-1) is induced by ADP. P2Y12 receptor blockers prevent these ADP effects on monocytes. Interestingly, in contrast to THP-1 monocytes, THP-1 monocytes, after differentiation to macrophages, directly expressed the P2Y12 receptor and consequently ADP was found to be a potent chemoattractant. Again, P2Y12 receptor blockers antagonised this effect. Accordingly, stimulation of THP-1 macrophages with ADP caused a substantial change in gene expression pattern and upregulation of several genes associated with inflammation and atherogenesis. These data establish novel anti-inflammatory effects of P2Y12 receptor blockers on monocytes and macrophages, which are expected to contribute to cardiovascular risk reduction.

Gynecomastia: histological appearance in different age groups.

OBJECTIVE: Gynecomastia is a common finding in the male population which is mostly idiopathic. The aim of our study was to analyze the histological differences in young and old patient groups and its association with recurrence rates. METHODS: Three hundred and five gynecomastia patients (555 breasts) undergoing surgical treatment from 1997 to 2015 were divided into four groups: Group 1: 13-17 years, Group 2: 18-30 years, Group 3: 31-49 years and Group 4: 50-83 years. They were evaluated concerning clinical classification, histological differences and association with antiandrogen or steroids/immunosuppressive therapy. RESULTS: We found that the rate of florid gynecomastia was higher in older patient groups, while fibrous gynecomastia was more common in adolescents and young adults (p = .0180). Glandular gynecomastia was more frequent in younger patients, while in the older patient groups, lipomatous gynecomastia was more common (p = .0006). Patients presenting with florid gynecomastia showed a higher rate of recurrence than patients with the fibrous type of gynecomastia (12.5 and 4.7%, respectively). Of note, 18.75% of florid gynecomastia was associated with antiandrogen agents or steroid/immunosuppressive therapy, while only 4.69% of fibrous gynecomastia was associated with antiandrogenic or immunosuppressive therapy. However, there was no increase of recurrence rates in patients using antiandrogen agents or undergoing steroid/immunosuppressive therapy. CONCLUSIONS: Fibrous gynecomastia was found to be more common in adolescents and young adults, while the florid type was more frequent in older patients. Patients presenting with florid gynecomastia showed a higher rate of recurrence than patients with the fibrous type of gynecomastia.

Pedicled and free flaps for intrathoracic fistula management.

OBJECTIVES: Intrathoracic fistulae are among the potential sequelae of radiation therapy, empyema and abscess clearance and surgical tumour resections. Interdisciplinary plastic-reconstructive flap surgery is a helpful tool for the successful treatment of intrathoracic fistulae. METHODS: From February 2006 to April 2016, 13 patients (3 females and 10 males) underwent flap surgery for bronchial (n = 5), tracheal (n = 2), oesophageal (n = 2), post-pneumonectomy bronchopleural fistula (n = 2), tracheo-oesophageal (n = 1), gastrobronchial (n = 1) and oesophagobronchial (n = 1) fistulae. Patient characteristics, identified pathogenic micro-organisms, treatment and decision criteria, long-term outcome and postoperative complications were evaluated by analysing patient charts and surgical reports. RESULTS: The mean age of the 13 patients who underwent reconstructive surgery was 55.5 years (range: 42-66 years). The median follow-up time was 31.4 months (range: 2-96 months). American Society of Anaesthesiologists classification was II for 1 patient, III for 8 patients and IV for 4 patients. In total, 18 flaps were performed (7 latissimus dorsi pedicled flaps, 7 pectoralis major pedicled flaps, 2 rectus abdominis myocutaneous flaps, 1 free temporo-parietal fascia flap and 1 intercostal muscle flap). A second flap was indicated in 5 cases (38.5%) due to fistula recurrence; of these, 1 patient developed a bronchial fistula after successful reconstruction of a gastrobronchial fistula. Eight of the 13 patients (61.5%) were evaluated postoperatively at regular intervals for at least 1 year and showed no signs of fistula recurrence. CONCLUSIONS: Our study showed that plastic-reconstructive flap surgery, although associated with significant morbidity and mortality, can be a life-saving tool for intrathoracic fistula reconstruction. CLINICAL TRIAL REGISTRATION: DRKS00010447.

Microparticles: major transport vehicles for distinct microRNAs in circulation.

AIMS: Circulating microRNAs (miRNAs) have attracted major interest as biomarkers for cardiovascular diseases. Since RNases are abundant in circulating blood, there needs to be a mechanism protecting miRNAs from degradation. We hypothesized that microparticles (MP) represent protective transport vehicles for miRNAs and that these are specifically packaged by their maternal cells. METHODS AND RESULTS: Conventional plasma preparations, such as the ones used for biomarker detection, are shown to contain substantial numbers of platelet-, leucocyte-, and endothelial cell-derived MP. To analyse the widest spectrum of miRNAs, Next Generation Sequencing was used to assess miRNA profiles of MP and their corresponding stimulated and non-stimulated cells of origin. THP-1 (monocytic origin) and human umbilical vein endothelial cell (HUVEC) MP were used for representing circulating MP at a high purity. miRNA profiles of MP differed significantly from those of stimulated and non-stimulated maternal THP-1 cells and HUVECs, respectively. Quantitative reverse transcription-polymerase chain reaction of miRNAs which have been associated with cardiovascular diseases also demonstrated significant differences in miRNA profiles between platelets and their MP. Notably, the main fraction of miRNA in plasma was localized in MP. Furthermore, miRNA profiles of MP differed significantly between patients with stable and unstable coronary artery disease. CONCLUSION: Circulating MP represent transport vehicles for large numbers of specific miRNAs, which have been associated with cardiovascular diseases. miRNA profiles of MP are significantly different from their maternal cells, indicating an active mechanism of selective 'packaging' from cells into MP. These findings describe an interesting mechanism for transferring gene-regulatory function from MP-releasing cells to target cells via MP circulating in blood.