[Autologous Breast Reconstruction and Radiotherapy: Consensus Report of the German-Speaking Society for Reconstructive Microsurgery (GSRM)]. / Autologe Brustrekonstruktion und Bestrahlung: Konsensus-Bericht der Deutschsprachigen Arbeitsgemeinschaft für Mikrochirurgie (DAM).

Autologous postmastectomy breast reconstruction is associated with favourable long-term clinical outcomes and superior patient-reported outcomes (PROMs) compared with implant-based reconstruction. However, adjuvant radiotherapy has traditionally been considered a relative contraindication to immediate flap-based reconstruction due to its unpredictable effects on the reconstructive outcome. While modern adjuvant postmastectomy radiotherapy (PMRT) has been able to significantly reduce acute and chronic radiation-induced complications, plastic surgeons still hesitate to offer immediate autologous reconstruction to patients expected to undergo adjuvant radiotherapy. More recently, evidence has emerged suggesting a paradigm shift in favour of immediate autologous reconstruction despite subsequent radiotherapy. At the 44th Annual Meeting of the German-speaking Society for Reconstructive Microsurgery (GSRM) in Bern, Switzerland, a workshop discussed the literature on PMRT and autologous breast reconstruction, aiming to establish consensus among the participants. Several areas of agreement were identified, including the goals of postmastectomy reconstruction, specifically the creation of a soft and sensitive breast symmetrical in shape and size to the unaffected breast via the safest procedure possible. The importance of preserving the maximum amount of native breast skin envelope through skin- and nipple-sparing approaches was emphasised. Finally, a consensus was reached that PMRT should no longer be considered a contraindication to immediate autologous breast reconstruction.

Characterization of Immune Cell Infiltration and Collagen Type III Disorganization in Human Secondary Lymphedema: A Case-control Study.

Background: Secondary lymphedema (SL) affects 120 million people globally, posing a lifelong burden for up to 37% of cancer survivors. Chronic inflammation and progressive fibrosis are key drivers of SL, yet detailed characterization of immune cell subpopulations across lymphedema stages is lacking. This study aimed to investigate the immunologic profile of lymphedematous skin and its association with extracellular matrix changes, which could serve as clinical biomarkers or therapeutic targets. Methods: This case-control study analyzed the skin from 36 patients with and without SL, using immunofluorescence to quantify T cells, B cells, macrophages, and their subpopulations. Collagen quantity and composition were examined using picrosirius red staining, and mast cell infiltration was assessed with toluidine blue staining. Early and late SL stages were compared to identify histomorphological and immunologic correlates of stage progression. Results: We found a predominance of CD4+ T cells and mast cells in SL skin (1.4/mm² versus 1.0/mm², P < 0.01; 1.2/mm² versus 0.2/mm², P < 0.0001) and a higher ratio of collagen III to collagen I fibers (51.6% versus 75.0%, P < 0.001). M2 macrophages were more abundant in late-stage than in early-stage lymphedema (1.7/mm² versus 1.0/mm², P = 0.02). Conclusions: This study demonstrated a shift toward CD4+ T cell and mast cell infiltration in SL skin, correlating with extracellular matrix disorganization and an altered collagen III/I ratio. These findings enhance our understanding of the cellular and morphological changes in SL, potentially guiding future diagnostic and therapeutic strategies.

[Evidence of modern diagnostic, conservative, and surgical therapy of secondary lymphoedema]. / Evidenz der modernen Diagnostik, der konservativen und chirurgischen Therapie des sekundären Lymphödems.

BACKGROUND: Secondary lymphoedema (SL) is one of the most common and, at the same time, most significant consequences and complications of modern oncological therapy. Although a thorough patient history and physical examination are sufficient to substantiate a suspicion, it is essential to perform functional imaging of the lymphatic system for a targeted diagnosis and determination of severity. For this purpose, techniques such as MR and ICG lymphography as well as ultra-high-frequency ultrasound examinations have been developed and validated in recent years. The selective use of these techniques has allowed for individualized indications and successful stage-dependent treatment using (super)microsurgical techniques to restore regional lymphatic drainage in the context of intensified conservative therapy. METHOD: Systematic review of the literature on the diagnosis and treatment of SL with subsequent analysis and classification of the results into evidence levels according to the Oxford Centre for Evidence-Based Medicine and the GRADE Scale. RESULTS: The established and validated diagnosis of SL includes imaging (ICG fluorescence lymphography, MR lymphography and Tc-99 functional lymphoscintigraphy) in case of a clinical suspicion and in high-risk patients. Complex physical decongestion therapy (CPE) is superior to physical therapy or compression alone. (Super)microsurgery of SL allows for a postoperative reduction in the frequency of CPE, a reduction of erysipelas rates, a volume reduction of the lymphomatous extremity and, if carried out prophylactically, a lower incidence of SL. Suction-assited lipectomy can produce long-term, stable reductions in circumference and an improvement in quality of life. CONCLUSION: Patients with SL benefit from conservative therapy with regular re-evaluation. Patients with a high risk for SL or with clinical deterioration or persistent symptoms under guideline-based conservative therapy can benefit from (super)microsurgical therapy after an individualized functional diagnostic evaluation of the lymphatic system. Excisional dermolipectomies or lympholiposuctions are available and effective for advanced and refractory stages.

Patient-level indirect treatment comparison of lanadelumab versus pdC1-INH i.v. in hereditary angioedema patients: PATCH study.

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant inherited disease in which patients suffer from local attacks primarily affecting skin and gastrointestinal tract, and sometimes even the upper respiratory tract leading to asphyxiation. Since head-to-head trials between authorized treatments are lacking, this study compares efficacy and safety of lanadelumab and intravenous plasma-derived C1-esterase inhibitor (pdC1-INH i.v.) in HAE patients on long-term prophylaxis by means of an indirect treatment comparison. METHODS: Efficacy and safety of lanadelumab against pdC1-INH i.v. were analyzed in a fully prespecified indirect comparison based on individual patient data (n = 231) from the HELP and CHANGE clinical trials. Primary and secondary efficacy endpoints were compared using a generalized linear model for count data. Confounding variables were identified a priori via systematic literature research and validated by clinical experts. Adjustment of confounders was implemented using a conditional regression model. RESULTS: Lanadelumab showed a statistically significant improvement in reduction of HAE attack rates compared to pdC1-INH i.v. across multiple endpoints: Monthly attack rate of patients treated with lanadelumab was less than half compared to pdC1-INH i.v. (Rate ratio: 0.486; 95% CI: 0.253, 0.932). Monthly rate of laryngeal attacks was found to be five times lower for lanadelumab (Rate ratio: 0.2; 95% CI: 0.044, 0.915) and monthly rate of acute treated HAE attacks among lanadelumab patients was about one third of the attack rate of pdC1-INH i.v. patients (Rate ratio: 0.366; 95% CI: 0.185, 0.727). CONCLUSION: This study contributes to current knowledge in the treatment of HAE by indicating a statistically significant reduction of HAE attacks under lanadelumab compared to pdC1-INH i.v.

Epidemiology and treatment of children with hereditary angioedema in Germany: A retrospective database study.

BACKGROUND: Hereditary angioedema (HAE) is a potentially life-threatening inherited disease that causes recurrent, serious, and debilitating episodes of swelling. While evidence has improved in adult patients, data on the epidemiology and treatment of pediatric patients with HAE remain very limited. The aim of this study was to determine the incidence and prevalence of pediatric patients with HAE aged <12 years, as well as treatment patterns, co-medication, and specialties involved. METHODS: In this retrospective study (2016-2021), the German IQVIATM pharmacy claims (LRx) database was used to analyze prescriptions of HAE-specific treatments and co-medications. RESULTS: We found an HAE prevalence in pediatric patients aged <12 years of 2.51:100,000 and a 12-month prevalence of up to 1.02:100,000 between 2016 and 2021. Most HAE treatments were prescribed by outpatient clinics and pediatricians, with an increasing proportion of icatibant as an on-demand treatment and low rates of long-term prophylaxis (LTP). The prescription rate of analgesics as the most common co-medication decreased notably after HAE diagnosis. CONCLUSION: Our findings provide insights into the epidemiology and current pediatric HAE treatment landscape in Germany. The obtained HAE prevalence in pediatric patients aged <12 years was even higher than the previously reported average of overall cohorts, whereas the LTP rate was low, which might indicate an unmet need for newer LTP treatment options in pediatric patients.

Lymphedema-associated fibroblasts are a TGF-ß1 activated myofibroblast subpopulation related to fibrosis and stage progression in patients and a murine microsurgical model.

BACKGROUND: The driver of secondary lymphedema (SL) progression is chronic inflammation, which promotes fibrosis. Despite advances in preclinical research, a specific effector cell subpopulation as a biomarker for therapy response or stage progression is still missing for SL. METHODS: Whole skin samples of 35 murine subjects of a microsurgical-induced SL model and 12 patients with SL were collected and their fibroblasts were isolated. These lymphedema-derived fibroblasts (LAF) were cultured in a collagen I-poly-D-Lysine 3D hydrogel to mimic skin conditions. Fibroblasts from non-lymphedema skin were used as negative control and TGF-ß-stimulated fibroblasts were used to recreate profibrotic myofibroblasts. Quantitative immunocytofluorescence confocal microscopy analysis and invasion functional assays were performed in all subpopulations and statistically compared. RESULTS: In contrast to normal skin fibroblasts, LAF exhibit α-SMA-positive stress fibers and a reduced number of tight junctions in 3D hydrogel conditions. The switch from normal E-cadherin high phenotype to an N-cadherin high-E-cadherin low morphology suggests epithelial to mesenchymal transition for expansion and proliferation. This pathological behavior of LAF was confirmed by live cell imaging analysis of invasion assays. The significant activation of markers of the TGFBR2-Smad pathway and collagen synthesis (HSP-47) in LAF supports EMT phenotypic changes and previous findings relating to TGF-ß1 and fibrosis with lymphedema. CONCLUSIONS: A characteristic SL myofibroblast subpopulation was identified and translationally related to fibrosis and TGF-ß1-associated stage progression. This SL-related subpopulation was termed lymphedema-associated fibroblasts. A comprehensive stage-related characterization is required to validate LAF as a reliable biomarker for SL disease progression.

The Impact of Facial Burns on Short- and Long-Term Quality of Life and Psychological Distress-A Prospective Matched Cohort Study.

Burn injuries are a major healthcare challenge worldwide, with up to 50% of all minor burns located on the head and neck. With this study, we sought to describe the effect of facial burns (FB) on health-related quality of life through a prospective and matched cohort study design. Patients completed the 36 Item Short Form (SF-36) and the Hospital Anxiety and Depression Scale (HADS). Results were analyzed based on the distribution of datasets. In total, 55 patients with FB and 55 age-and sex-matched candidates were recruited. The most common mechanism of thermal injury was burns from flames. The FB group scored lower in physical and psychological dimensions than the control group, both acutely and one year after injury. An analysis of each domain showed that subjects in the FB group trended toward improvements in their score after one-year post-burn in physical functioning (acute: 71.0 ± 29.2; one-year: 83.7 ± 23.9; p = 0.02) and bodily pain (acute: 58.5 ± 30.3; one-year: 77.9 ± 30.5; p = 0.01) domains. Additionally, the FB group had significanlyt higher scores for anxiety (FB: 4.8 ± 3.2; control: 2.5 ± 2.8; p = <0.002) and depression (FB: 3.9 ± 3.5; control: 2.1 ± 2.7; p = 0.01) compared to the control. In conclusion, facial burns are associated with physical and psychosocial deficits, as well as elevated levels of psychological distress.

Ultimate Limits for Quickest Quantum Change-Point Detection.

Detecting abrupt changes in data streams is crucial because they are often triggered by events that have important consequences if left unattended. Quickest change-point detection has become a vital sequential analysis primitive that aims at designing procedures that minimize the expected detection delay of a change subject to a bounded expected false alarm time. We put forward the quantum counterpart of this fundamental primitive on streams of quantum data. We give a lower bound on the mean minimum delay when the expected time of a false alarm is asymptotically large, under the most general quantum detection strategy, which is given by a sequence of adaptive collective (potentially weak) measurements on the growing string of quantum data. In addition, we give particular strategies based on repeated measurements on independent blocks of samples that asymptotically attain the lower bound and thereby establish the ultimate quantum limit for quickest change-point detection. Finally, we discuss online change-point detection in quantum channels.

A Retrospective Matched-Pair Analysis of Long-term Outcomes after Successful Lower Extremity Free Flap Salvage.

BACKGROUND: Pedicle occlusion with total free flap loss after microvascular lower extremity reconstruction is a considerably rare yet devastating complication. Fortunately, in the majority of cases, emergency salvage takebacks of compromised free flaps are initiated in a timely manner. In this report, we present our analysis of long-term outcomes following transient vascular compromise mitigated through successful free flap salvage in the lower extremity. METHODS: We performed a single-center retrospective matched-pair analysis of 46 patients with lower extremity free flap reconstructions. Cases underwent successful revisions of microvascular compromise (n = 23), whereas controls had uneventful postoperative courses (n = 23). Patient-reported outcome questionnaires and physical evaluations were used to assess general quality of life, functional outcomes, and cosmesis (Lower Extremity Functional Scale [LEFS], Lower Limb Outcomes Questionnaire [LLOQ], Short Form 36 (SF-36), Vancouver Scar Scale [VSS]). The mean follow-up time was 4.4 years. RESULTS: The health-related quality of life assessed by the SF-36 did not differ significantly between both groups in any of the subscales (p ≥ 0.15 for all subscales). Functional outcomes did not show significant differences between both groups according to the LEFS (p = 0.78) and LLOQ (p = 0.45). The overall scar appearance assessed by the VSS showed significantly poorer cosmesis in the re-exploration group (p = 0.014). CONCLUSION: Salvage of compromised free flaps in the lower extremity yields similar long-term outcomes compared to noncompromised free flaps with regard to function and quality of life. However, free flap revisions may lead to impaired scar formation. This study provides further evidence that the opportunity for urgent re-exploration is indispensable.

Intraoperative Heparin Bolus and Postoperative Anticoagulation with Low Molecular Weight Heparin Increase Reliability of Microsurgical Free Flaps for Upper Extremity Reconstruction.

BACKGROUND: Microsurgery is an indispensable tool of upper extremity reconstruction addressing defect coverage and the restoration of function. Perioperative anticoagulation and antiplatelet therapy are controversially discussed with impact on microsurgical outcome, but without clear evidence. This study aims to evaluate the impact of perioperative anticoagulation and antiplatelet therapy in microsurgical upper extremity reconstruction. METHODS: All eligible patients treated with microsurgical upper extremity reconstruction between January 2000 and July 2014 were included in a comparative analysis to define a superior anticoagulation and antiplatelet regime in a retrospective study. Endpoints were all major complications (e.g., total flap loss, arterial and venous thrombosis) as well as minor complication. RESULTS: A total of 183 eligible free flaps to the upper extremity were transferred in 169 patients. Altogether, 11 arterial (6.0%) and 9 venous (4.9%) thromboses, 11 total flap losses (6.0%), and 16 cases with hematoma (8.7%) were detected. In the subgroup analysis, patients who did not receive any heparin intraoperatively (n = 21; 11.5%) had a higher rate of major complications (p = 0.001), with total flap loss being the most frequent event (p = 0.004). A trend was shown for intraoperative bolus administration of 501 to 1,000 units unfractionated heparin (UFH) intravenously to have the lowest rate of major complications (p = 0.058). Intraoperative administration of acetylsalicylic acid (n = 13; 8.1%) did not have any influence on the rate of major complications. Postoperative anticoagulation with continuous UFH intravenously (n = 68; 37.2%) resulted in more frequent complications (p = 0.012), for example, an increased rate of total flap loss (p = 0.02) and arterial thrombosis (p = 0.02). CONCLUSION: The results of the present study favor administration of 501 to 1,000 units UFH intravenously as an intraoperative bolus (e.g., 750 units UFH intravenously). Postoperative low molecular weight heparin subcutaneous application in a prophylactic dose given once or twice a day was associated with less complications compared with continuous infusion of UFH, although continuously applied UFH may reflect an increased risk profile.

From Esthetic Medicine to Optimizing Reconstructive Outcome: A Feasibility Trial on Secondary Refinement of Fasciocutaneous Anterolateral Thigh Flaps with Cryolipolysis.

BACKGROUND: Free adipocutaneous anterolateral thigh (ALT) flaps have evolved as workhorse flaps to reconstruct complex, multicompound defects. While coverage is safely achieved, flaps may remain bulky. As a standard of care, flaps are refined with liposuction, partial excision, or combination of both. Cryolipolysis is widely used for fat reduction in esthetic medicine. This pilot comparative study analyses whether cryolipolysis may serve as a safe alternative method to effectively reduce volume in fasciocutaneous flaps. Moreover, patients' satisfaction with the procedure is evaluated. METHODS: In this single-center, retrospective, interventional comparative cohort study, 10 patients with free subfascial ALT flaps for distal extremity reconstruction underwent cryolipolysis (60 minutes, -9°C). Circumference of the extremities and subcutaneous fat thickness were determined before (T1) and 12 weeks (T2) after cryolipolysis. Patient satisfaction was evaluated with a questionnaire of Likert's scale questions. Duration of hospital stay, intervention time, costs, and possible complications were analyzed and compared with surgical flap contouring (n = 12). RESULTS: All patients undergoing cryolipolysis were male, with a median age of 52 years without arterial disease-like state or deep vein thrombosis (DVT). At T2, a significant reduction of circumference of 1.8 ± 0.9 cm (p < 0.001) and subcutaneous fat layer of 7.7 ± 3.0 mm (p < 0.0001) was recorded. Overall, 90% of the patients were satisfied with the result. Cryolipolysis was well tolerated. One patient developed a second-degree frostbite which healed without further intervention. Cryolipolysis proofed to be as safe as surgical flap contouring. Hospital stay was significantly shorter (p < 0.01) and personal resources were spared when flap contouring was performed with cryolipolysis. CONCLUSION: This is a novel application of evolving body-contouring cryolipolysis from esthetic medicine into optimizing outcomes in reconstructive surgery. Cryolipolysis has been shown to be relatively safe and effective to reduce ALT's volume with high patients' satisfaction. This successful pilot study encourages further investigation with a prospective randomized control trial.

Short- and long term hyposmia, hypogeusia, dysphagia and dysphonia after facial burn injury - A prospective matched cohort study.

BACKGROUND: Facial burns frequently occur in occupational or household accidents. While dysphagia and dysphonia are known sequelae, little is known about impaired smell and taste after facial burns. METHODS: In a prospective observational controlled study, we evaluated hyposmia via the Sniffin' Stick Test (SnS), hypogeusia via a taste strip test, and dysphonia and dysphagia via validated questionnaires acutely and one-year after burn, respectively. A matched control group consisting of a convenience sample of healthy volunteers underwent the same assessments. RESULTS: Fifty-five facial burn patients (FB) and 55 healthy controls (CTR) were enrolled. Mean burn size was 11 (IQR: 29) % total body surface area (TBSA); CTR and FB were comparable regarding age, sex and smoking status. Acutely, hyposmia was present in 29% of the FB group (CTR: 9%, p = 0.014) and burn patients scored worse on the SnS than CTR (FB: 10; CTR: 11; IQR: 2; p = 0.013). Hyposmia per SnS correlated with subjective self-assessment. Hyposmia and SnS scores improved over time (FB acute: 10.5 IQR: 2; FB one year: 11; IQR: 2; p = 0.042) and returned to normal at one-year post burn in most patients who completed the study (lost to follow-up: 21 patients). Taste strip scores were comparable between FB and CTR, as was the acute prevalence of dysphagia and dysphonia. CONCLUSION: Hyposmia acutely after facial thermal trauma appeared frequently in this study, especially when complicated by inhalation trauma or large TBSA involvement. Of all complete assessments, a fraction of burn patients retained hyposmia after one year while most improved over time to normal. Prevalence of dysphonia, dysphagia and hypogeusia was comparable to healthy controls in this study, perhaps due to overall minor burn severity.

Microsurgical Strategies after Free Flap Failure in Soft Tissue Reconstruction of the Lower Extremity: A 17-Year Single-Center Experience.

Background: There is no clear consensus on the optimal surgical strategy for providing safe coverage in salvage free flap surgery after total free flap failure. Methods: A retrospective study was conducted to evaluate patients with total failure of the primary free flap in lower extremity reconstruction between 2000 and 2017. Results: In a cohort of 1.016 patients, we identified 43 cases of total flap failure (4.2%). A total of 30 patients received a salvage free flap with a success rate of 83.3% (25/30). One patient received a secondary salvage free flap. Overall limb salvage after primary free flap loss was 83.7% (36/43). Conclusions: Microsurgical management of free flap loss in the lower extremity is challenging and requires a decisive re-evaluation of risk factors and alternative strategies. This should include reconsidering the flap choice with a tendency towards traditional and safe workhorse flaps, a low-threshold switch to different recipient vessels, including arteriovenous (AV) loops, bypasses (especially in case of venous insufficiency) and back-up procedures, such as negative pressure wound therapy or dermal regeneration templates with skin grafting in cases of lower demand and critically ill patients. We derived one suggestion from our previous practice: replacing perforator flaps with axial pattern flaps ("safe workhorses").

[Autologous Breast Reconstruction in Conjuction with Lymphatic Microsurgery in Breast Cancer-Related Lymphedema]. / Autologe Brustrekonstruktion und lymphorekonstruktive Chirurgie nach Mastektomie bei Mammakarzinom-assoziiertem LymphödemAutologe Brustrekonstruktion in Kombination mit lymphorekonstruktiver ChirurgieCombined Surgical Treatment of Breast Cancer-Related Lymphedema and Autologous Breast Reconstruction After Mastectomy.

Breast cancer-related lymphedema of the upper extremity is the most significant non-oncological complication of tumour therapy, leading to functional impairment and impacting patients' quality of life. Autologous breast reconstruction per se effectively reduces incidence and stage of lymphedema after breast cancer treatment by surgical angiogenesis. In addition, modern surgical techniques for treating lymphedema are effective in reducing limb volume, circumference and functional impairment, and improving patients' quality of life, body image, integrity and local immunocompetence. Reconstructive surgery, including lymphovenous anastomoses (LVA) and vascularised lymph node transfer (VLNT), have been shown to rearrange or restore lymphatic flow and prevent stage progression. For patients with breast cancer-related lymphedema after mastectomy, autologous breast reconstruction in conjunction with lymphatic microsurgery using VLNT, LVA or a combination of these procedures offers the option of holistic and single-stage restoration in modern senology. Extensive scar release in the axilla is a crucial component of the surgical technique, aiming to prepare the recipient bed for the VLN transplant and to allow for the functional recruitment of remaining lymph vessels of the upper extremity. This article presents the indications, preoperative diagnostic evaluation, surgical techniques and precautions, complications and results of combined lymphatic and breast restoration.

The impact of previous surgery on scaphoid nonunion reconstruction: a retrospective study of 95 cases.

We retrospectively compared 64 scaphoid reconstructions in cases that had not undergone previous surgery with 31 cases in which previous surgery had been performed. The characteristics of the groups were similar except that there were more smokers in the group without previous surgery and a more frequent use of vascularized bone grafts in the group with previous surgery. At final follow-up, 66 and 65 months, respectively, after reconstruction, union incidence was 89% and 90%. In patients with previous surgery, grip strength was higher but not when expressed in percent of the contralateral hand. There were no differences in pinch strength, active wrist motion, functional scores, carpal height or scapholunate angle. We conclude that repeat surgery to the scaphoid did not seem to be a major risk factor for the overall outcomes, keeping in mind that a vascularized bone graft was more frequently used for secondary reconstructions.Level of evidence: III.

Antigen presentation safeguards the integrity of the hematopoietic stem cell pool.

Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of blood and immune cells. Throughout life, HSPCs acquire oncogenic aberrations that can cause hematological cancers. Although molecular programs maintaining stem cell integrity have been identified, safety mechanisms eliminating malignant HSPCs from the stem cell pool remain poorly characterized. Here, we show that HSPCs constitutively present antigens via major histocompatibility complex class II. The presentation of immunogenic antigens, as occurring during malignant transformation, triggers bidirectional interactions between HSPCs and antigen-specific CD4+ T cells, causing stem cell proliferation, differentiation, and specific exhaustion of aberrant HSPCs. This immunosurveillance mechanism effectively eliminates transformed HSPCs from the hematopoietic system, thereby preventing leukemia onset. Together, our data reveal a bidirectional interaction between HSPCs and CD4+ T cells, demonstrating that HSPCs are not only passive receivers of immunological signals but also actively engage in adaptive immune responses to safeguard the integrity of the stem cell pool.