Silicone implant surface microtopography modulates inflammation and tissue repair in capsular fibrosis.

Excessive fibrous capsule formation around silicone mammary implants (SMI) involves immune reactions to silicone. Capsular fibrosis, a common SMI complication linked to host responses, worsens with specific implant topographies. Our study with 10 patients investigated intra- and inter-individually, reduced surface roughness effects on disease progression, wound responses, chronic inflammation, and capsular composition. The results illuminate the significant impact of surface roughness on acute inflammatory responses, fibrinogen accumulation, and the subsequent fibrotic cascade. The reduction of surface roughness to an average roughness of 4 µm emerges as a promising approach for mitigating detrimental immune reactions, promoting healthy wound healing, and curbing excessive fibrosis. The identified proteins adhering to rougher surfaces shed light on potential mediators of pro-inflammatory and pro-fibrotic processes, further emphasizing the need for meticulous consideration of surface design. The composition of the implant capsule and the discovery of intracapsular HSP60 expression highlight the intricate web of stress responses and immune activation that can impact long-term tissue outcomes.

Surface Topography, Microbial Adhesion, and Immune Responses in Silicone Mammary Implant-Associated Capsular Fibrosis.

Breast cancer is the most common cancer in women globally, often necessitating mastectomy and subsequent breast reconstruction. Silicone mammary implants (SMIs) play a pivotal role in breast reconstruction, yet their interaction with the host immune system and microbiome remains poorly understood. This study investigates the impact of SMI surface topography on host antimicrobial responses, wound proteome dynamics, and microbial colonization. Biological samples were collected from ten human patients undergoing breast reconstruction with SMIs. Mass spectrometry profiles were analyzed for acute and chronic wound proteomes, revealing a nuanced interplay between topography and antimicrobial response proteins. 16S rRNA sequencing assessed microbiome dynamics, unveiling topography-specific variations in microbial composition. Surface topography alterations influenced wound proteome composition. Microbiome analysis revealed heightened diversity around rougher SMIs, emphasizing topography-dependent microbial invasion. In vitro experiments confirmed staphylococcal adhesion, growth, and biofilm formation on SMI surfaces, with increased texture correlating positively with bacterial colonization. This comprehensive investigation highlights the intricate interplay between SMI topography, wound proteome dynamics, and microbial transmission. The findings contribute to understanding host-microbe interactions on SMI surfaces, essential for optimizing clinical applications and minimizing complications in breast reconstruction.

PRO Hair Safe Study: The Patient's Perspective on the Effects of Scalp Cooling on Hair Preservation.

Purpose: Alopecia has been reported a distressing side-effect of chemotherapy for breast cancer patients (BCP) that is highly relevant for quality of life during treatment. For the prevention of chemotherapy-induced alopecia, scalp cooling (SC) has been reported to be an effective and safe intervention. However, data on the patient's perspective on effectiveness and applicability of SC in a clinical routine setting are scarce. In this comparative study, we aimed at a longitudinal assessment of patient-reported outcome (PRO) data on the effect of SC on alopecia and its effect on symptoms and functional health when applied in clinical routine in BCP receiving taxane or anthracycline-based chemotherapy. Patients and Methods: Study participants were allocated either to the intervention group receiving SC or to the control group based on patient preference (non-randomized study). All patients completed PRO-measures on hair preservation (EORTC Item Library items on hair loss), symptom and functional health measures (EORTC QLQ-C30 and -BR23) and the Body Image Scale (BIS). Outcomes were assessed at chemotherapy start (baseline), mid-chemotherapy, last chemotherapy cycle, 3 months follow-up and 6-9 months follow-up. Results: Overall, we included 113 patients: 75 patients underwent SC (mean age = 51.3 years, 52.7% premenopausal); 38 patients standard care (mean age = 55.6 years, 39.5% premenopausal). A total of 53 patients (70.7%) discontinued SC, with 39 patients (73.5%) stating alopecia as the primary reason. On average, BCP stayed on treatment with the cooling cap for 40.2% of the duration of their chemotherapy (SD 25.3%). In an intention-to-treat analysis, we found no difference between the SC group and the control group with regard to their patient-reported hair loss (p=0.831) across the observation period, overall QOL (p=0.627), emotional functioning (p=0.737), social functioning (p=0.635) and body image (p=0.463) did not differ between groups. Conclusion: We found a high rate of SC-decliners and no beneficial effects of SC for patient-reported hair loss, symptoms and functional health. The efficacy and tolerability of SC applied in a clinical routine setting hence appeared to be limited. The further determination and up-front definition of criteria prognostic for effectiveness of SC may be helpful to identify patient subgroups that may experience a treatment benefit.

Quantitative Proteomic Characterization of Foreign Body Response towards Silicone Breast Implants Identifies Chronological Disease-Relevant Biomarker Dynamics.

The etiology of exaggerated fibrous capsule formation around silicone mammary implants (SMI) is multifactorial but primarily induced by immune mechanisms towards the foreign material silicone. The aim of this work was to understand the disease progression from implant insertion and immediate tissue damage response reflected in (a) the acute wound proteome and (b) the adsorption of chronic inflammatory wound proteins at implant surfaces. An intraindividual relative quantitation TMT-liquid chromatography-tandem mass spectrometry approach was applied to the profile wound proteome formed around SMI in the first five days post-implantation. Compared to plasma, the acute wound profile resembled a more complex composition comprising plasma-derived and locally differentially expressed proteins (DEPs). DEPs were subjected to a functional enrichment analysis, which revealed the dysregulation of signaling pathways mainly involved in immediate inflammation response and ECM turnover. Moreover, we found time-course variations in protein enrichment immediately post-implantation, which were adsorbed to SMI surfaces after 6-8 months. Characterization of the expander-adhesive proteome by a label-free approach uncovered a long-term adsorbed acute wound and the fibrosis-associated proteome. Our findings propose a wound biomarker panel for the early detection and diagnosis of excessive fibrosis that could potentially broaden insights into the characteristics of fibrotic implant encapsulation.

Is It All about Surface Topography? An Intra-Individual Clinical Outcome Analysis of Two Different Implant Surfaces in Breast Reconstruction.

The most common long-term complication of silicone breast implants (SMI) remains capsular fibrosis. The etiology of this exaggerated implant encapsulation is multifactorial but primarily induced by the host response towards the foreign material silicone. Identified risk factors include specific implant topographies. Of note, breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has only been observed in response to textured surface implants. We hypothesize that reduction of SMI surface roughness causes less host response and, hence, better cosmetic outcomes with fewer complications for the patient. A total of 7 patients received the routinely used CPX®4 breast expander (~60 µM Ra) and the novel SmoothSilk® (~4 µM Ra), fixed prepectoral with a titanized mesh pocket and randomized to the left or right breast after bilateral prophylactic NSME (nipple-sparing mastectomy). We aimed to compare the postoperative outcome regarding capsule thickness, seroma formation, rippling, implant dislocation as well as comfortability and practicability. Our analysis shows that surface roughness is an influential parameter in controlling fibrotic implant encapsulation. Compared intra-individually for the first time in patients, our data confirm an improved biocompatibility with minor capsule formation around SmoothSilk® implants with an average shell roughness of 4 µM and in addition an amplification of host response by titanized implant pockets.

Austrian treatment algorithms in HER2-positive metastatic breast cancer: a 2022 update.

In the past 12 months a plethora of relevant novel data for the treatment of metastatic HER2 positive breast cancer were published. To bring this new evidence into a clinical perspective, a group of Austrian breast cancer specialists updated their previously published treatment algorithm for those patients. For this consensus paper a total of eight scenarios were developed in which treatment strategies appropriate for specific patient profiles were evaluated. Consensus was established by detailed discussions of each scenario and by reaching full consensus.

Donor-Site Morbidity and Quality of Life after Autologous Breast Reconstruction with PAP versus TMG Flap.

The transverse myocutaneous gracilis (TMG) and the profunda artery perforator (PAP) flap are both safe choices for autologous breast reconstruction originating from the same donor region in the upper thigh. We aimed to compare the post-operative outcome regarding donor-site morbidity and quality of life. We included 18 patients who had undergone autologous breast reconstruction with a PAP flap (n = 27 flaps). Prospective evaluation of donor-site morbidity was performed by applying the same questionnaire that had already been established in a previous study evaluating TMG flap (n = 25 flaps) outcome, and results were compared. Comparison of the two patient groups showed equivalent results concerning patient-reported visibility of the donor-site scar and thigh symmetry. Still, the TMG group was significantly more satisfied with the scar (p = 0.015) and its position (p = 0.001). No difference was found regarding the ability to sit for prolonged periods. Donor-site wound complications were seen more frequently in the PAP group (29.6%) than in the TMG group (4.0%). Both groups expressed rather high satisfaction with their quality of life. Both flaps show minimal functional donor-site morbidity and high patient satisfaction. To minimize wound healing problems in PAP patients, thorough planning of the skin paddle is necessary.

A retrospective validation of CanAssist Breast in European early-stage breast cancer patient cohort.

CanAssist Breast (CAB), a prognostic test uses immunohistochemistry (IHC) approach coupled with artificial intelligence-based machine learning algorithm for prognosis of early-stage hormone-receptor positive, HER2/neu negative breast cancer patients. It was developed and validated in an Indian cohort. Here we report the first blinded validation of CAB in a multi-country European patient cohort. FFPE tumor samples from 864 patients were obtained from-Spain, Italy, Austria, and Germany. IHC was performed on these samples, followed by recurrence risk score prediction. The outcomes were obtained from medical records. The performance of CAB was analyzed by hazard ratios (HR) and Kaplan Meier curves. CAB stratified European cohort (n = 864) into distinct low- and high-risk groups for recurrence (P < 0.0001) with HR of 3.32 (1.85-5.93) like that of mixed (India, USA, and Europe) (n = 1974), 3.43 (2.34-4.93) and Indian cohort (n = 925), 3.09 (1.83-5.21). CAB provided significant prognostic information (P < 0.0001) in women aged ≤ 50 (HR: 4.42 (1.58-12.3), P < 0.0001) and >50 years (HR: 2.93 (1.44-5.96), P = 0.0002). CAB had an HR of 2.57 (1.26-5.26), P = 0.01) in women with N1 disease. CAB stratified significantly higher proportions (77%) as low-risk over IHC4 (55%) (P < 0.0001). Additionally, 82% of IHC4 intermediate-risk patients were stratified as low-risk by CAB. Accurate risk stratification of European patients by CAB coupled with its similar performance inIndian patients shows that CAB is robust and functions independent of ethnic differences. CAB can potentially prevent overtreatment in a greater number of patients compared to IHC4 demonstrating its usefulness for adjuvant systemic therapy planning in European breast cancer patients.

The impact of dexamethasone as a perineural additive to ropivacaine for PECS II blockade in patients undergoing unilateral radical mastectomy - A prospective, randomized, controlled and double-blinded trial.

STUDY OBJECTIVE: Dexamethasone is commonly used as an adjuvant to local anesthetics to prolong duration of peripheral nerve blocks with minimal side-effects. The present study investigates the efficacy of dexamethasone added to ropivacaine 0.2% as compared to ropivacaine 0.2% alone for pectoral nerves block II (PECS II) in unilateral radical mastectomy. DESIGN: A prospective, randomized, controlled and double-blinded trial. SETTING: The study was performed at Innsbruck Medical University Hospital, Austria, between January 2019 and October 2020. PATIENTS: Sixty female patients with an American Society of Anesthesiologists Score I-II (18-90 years, BMI 18-35) scheduled for unilateral radical mastectomy without one-stage immediate autologous breast reconstruction were randomly assigned to receive PECS II block with ropivacaine 0.2% with or without dexamethasone 8 mg. INTERVENTIONS: Patients were randomly assigned to receive PECS II block with ropivacaine 0.2% with or without dexamethasone 8 mg. MEASUREMENTS: Primary outcome parameter was the cumulative opioid consumption during the first 72 postoperative hours. Secondary outcome parameters were the duration of analgesia and the course of the visual analogue scale (VAS) and the area under the curve VAS (AUC-VAS). MAIN RESULTS: There was no difference in cumulative opioid consumption after 72 h between the ropivacaine 0.2% plus dexamethasone group and the ropivacaine 0.2% plus placebo group (11.89 vs 11.90 morphine milligram equivalent, respectively; p 0.831). Duration of analgesia also did not differ significantly between the ropivacaine 0.2% plus dexamethasone group and the ropivacaine 0.2% plus placebo group (12.75 versus 8.75 h, respectively; p 0.680). There also was no difference in the course of VAS and AUC-VAS. CONCLUSIONS: Dexamethasone 8 mg when added to ropivacaine 0.2% for PECS II block in unilateral radical mastectomy was not found to reduce total opioid consumption over 72 postoperative hours or to prolong duration of analgesia as compared to pure ropivacaine 0.2%.

Long-Term Outcome Analysis and Technical Refinements after Autologous Breast Reconstruction with PAP Flap: What We Have Learnt.

Introduction: The profunda artery perforator (PAP) flap represents a valuable alternative to the deep inferior epigastric artery perforator flap which, nowadays, is considered the golden standard for autologous breast reconstruction. The goal of this study was to evaluate the long-term satisfaction, functional outcomes of the donor site following PAP flap-based breast reconstruction and to present our personal learning experience along with suggestions for technique refinements. Methods: In this prospective single-center appraisal, 18 patients who underwent PAP flap-based breast reconstruction between January 2016 and November 2019 were enrolled. The Patient and Observer Scar Assessment Scale (POSAS) and the Breast-Q questionnaire were employed to evaluate the results 12 months postoperative. Data were analyzed with the Q-Score program. Complications were recorded in the medical database and classified with the Clavien-Dindo classification. Results: In the questionable time frame, 164 female patients underwent free flap breast reconstruction. Of those, 18 patients that received PAP flaps (9 bilateral) were included in this study. We recorded one flap loss because of venous failure. Most complications concerned the donor site, including hematoma, seroma, and wound healing problems. Patients' satisfaction was high at 12 months post-surgery, despite critical evaluation of the donor site scar. Conclusion: The PAP flap serves as an excellent option for breast reconstruction in patients who do not have abundant abdominal tissue. The overall clinical outcome was good and patients' evaluation showed high satisfaction after 12 months despite high complication rates. Modifications in planning and flap harvesting might improve the donor site outcome and the overall complication rate.

Long-Term Outcomes of Adjuvant Denosumab in Breast Cancer.

BACKGROUND: Adjuvant aromatase inhibitors increase osteoporosis and fractures in patients with hormone receptor­positive breast cancer. We have previously reported outcomes of the ABCSG-18 (study 18 from the Austrian Breast & Colorectal Cancer Study Group) trial showing that adjuvant anti­receptor activator of nuclear factor-κB ligand denosumab treatment counteracts these adverse effects and may improve outcomes. We report here the final long-term outcomes. METHODS: ABCSG-18 is a prospective, double-blind, placebo-controlled, phase 3 trial in which 3425 postmenopausal patients with early hormone receptor­positive breast cancer receiving aromatase inhibitor therapy were randomly assigned in 58 trial centers to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months. The primary end point was the time to first clinical fracture after randomization. Secondary disease outcome­related end points were disease-free survival (DFS), bone metastasis­free survival (BMFS), and overall survival (OS). RESULTS: For this final protocol-defined analysis, median follow-up is 8 years (interquartile range, 6 to 9.6 years). There were 309 versus 368 DFS events (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.97) in the denosumab versus the placebo group, respectively, resulting in an absolute 9-year DFS benefit of 3.5 percentage points (79.4 vs. 75.9%). Adjuvant denosumab improved BMFS by 2.5 percentage points (88.9 vs. 86.4%; hazard ratio, 0.81; 95% CI, 0.65 to 1.00) and OS by 1.0 percentage point (90.9 vs. 89.9%; hazard ratio, 0.80; 95% CI, 0.64 to 1.01). No new toxicities for this dose of adjuvant denosumab were observed. CONCLUSIONS: DFS, BMFS, and OS continued to show benefit in this final long-term analysis of ABCSG-18. There were no new toxicities. (Funded by Amgen; ClinicalTrials.gov number, NCT00556374.)

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer.

BACKGROUND: For postmenopausal women with hormone-receptor-positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear. METHODS: In this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture. RESULTS: Among the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84). CONCLUSIONS: In postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620.).

Resistance to HER2-targeted therapy: mechanisms of trastuzumab resistance and possible strategies to overcome unresponsiveness to treatment.

Trastuzumab has shown significant efficacy in HER2-overexpressing breast cancers and is approved for patients whose tumors carry this abnormality, both in the metastatic and in the adjuvant settings. However, several issues about its optimal use remain unresolved. Many breast cancer patients with HER2 overexpression do not respond to initial therapy with trastuzumab (Herceptin(®)), and a vast majority of these develop resistance to this monoclonal antibody within one year. This review discusses the molecular mechanisms leading to the development of trastuzumab resistance, including circulating HER2 extracellular domain, loss of PTEN, activation of alternative pathways (e.g. IGFR), and receptor-antibody interaction block. Additionally, the possibility of exploring these aberrations as therapeutic targets that potentially overcome resistance to trastuzumab is highlighted.