CD31 defines a subpopulation of human adipose-derived regenerative cells with potent angiogenic effects.

Cellular heterogeneity represents a major challenge for regenerative treatment using freshly isolated Adipose Derived Regenerative Cells (ADRCs). Emerging data suggest superior efficacy of ADRCs as compared to the ex vivo expanded and more homogeneous ADRCs (= ASCs) for indications involving (micro)vascular deficiency, however, it remains unknown which ADRC cell subtypes account for the improvement. Surprisingly, we found regarding erectile dysfunction (ED) that the number of injected CD31+ ADRCs correlated positively with erectile function 12 months after one bolus of autologous ADRCs. Comprehensive in vitro and ex vivo analyses confirmed superior pro-angiogenic and paracrine effects of human CD31+ enriched ADRCs compared to the corresponding CD31- and parent ADRCs. When CD31+, CD31- and ADRCs were co-cultured in aortic ring- and corpus cavernous tube formation assays, the CD31+ ADRCs induced significantly higher tube development. This effect was corroborated using conditioned medium (CM), while quantitative mass spectrometric analysis suggested that this is likely explained by secretory pro-angiogenic proteins including DKK3, ANGPT2, ANAX2 and VIM, all enriched in CD31+ ADRC CM. Single-cell RNA sequencing showed that transcripts of the upregulated and secreted proteins were present in 9 endothelial ADRC subsets including endothelial progenitor cells in the heterogenous non-cultured ADRCs. Our data suggest that the vascular benefit of using ADRCs in regenerative medicine is dictated by CD31+ ADRCs.

Can prophylactic incisional negative pressure wound therapy Reduce Wound Complications After Inguinal Lymph Node Dissection for Melanoma? Results from a Randomized Controlled Trial.

Background: Inguinal lymph node dissection (ILND) is associated with a high complication rate. Retrospective studies suggest that incisional negative pressure wound therapy (iNPWT) might reduce complications, especially seroma, following ILND. Methods: This was a prospective multicenter, randomized (1:1), open-labeled, parallel-group trial. Patients with macrometastic melanoma to the inguinal lymph nodes and eligible for ILND were randomized to receive either iNPWT for 14 postoperative days or conventional wound dressing. The primary outcome was seroma incidence. Secondary outcomes included surgical-site infection, wound rupture, wound necrosis, hematoma, rehospitalization and readmission rates between groups. All outcomes were registered 3 months after ILND and analyzed according to the intention-to-treat principle. Results: The trial was terminated early due to a low recruitment rate as a consequence of a change in the national treatment protocol, and the estimated sample size was not reached. Twenty patients were included and randomized in the study. The trial showed less seroma formation between the iNPWT 6/11 (55%) and control 7/9 (78%) groups; however, this was not statistically significant (p = 0.29). Similarly, there were no differences in the rates of surgical-site infection (p = 0.63), wound rupture (p = 0.19), wound necrosis (p = 0.82), hematoma (p = 0.19), reoperation (p = 0.82) or readmission (p = 0.34) between groups. Conclusion: There was a tendency toward fewer complications in the iNPWT group, however this trial was underpowered and could not confirm the hypothesis that iNPWT reduces complications after ILND. Future randomized controlled trials are required to fully evaluate the treatment potential of iNPWT. Trial registration: The trial was prospectively registered at https://clinicaltrials.gov/ct2/show/NCT03433937.

Prepectoral Breast Reconstruction without Acellular Dermal Matrix: Have We Come Full Circle?

Breast reconstruction is an integral part of breast cancer treatment [...].

Patients Decision-Making Characteristics Affects Gynecomastia Treatment Satisfaction: A Multicenter Study Using the BODY-Q Chest Module.

BACKGROUND: Patient satisfaction is the most critical outcome in gynecomastia treatment. However, patient satisfaction may be affected by the patient's decision-making trait, such as exhaustively searching for the best outcome or being content with an outcome that satisfies a preconceived requirement. OBJECTIVE: To assess whether patient's decision-making characteristic affect their satisfaction with gynecomastia treatment. METHODS: This was a cross-sectional study including patients treated for gynecomastia between January 2009 and December 2019 at two tertiary hospitals in Denmark. Alive patients were sent the BODY-Q: Chest module, the SF-36 questionnaire, and the Maximizer/Satisficer decision-making survey. Patients were classified as Maximizers if they scored more than 40 points on the Maximizer/Satisficer survey. Percentage score differences (PDs) in quality of life scales were calculated between Maximizers and Satisficers. RESULTS: In total, 192 gynecomastia patients were included in this study and classified as Maximizers (n = 152) or Satisficers (n = 40). Maximizers were younger and more had gynecomastia following abuse of anabolic steroids than Satisficers (p < 0.05). With respect to bodily satisfaction, Maximizers showed significantly worse satisfaction with nipples (PDs: - 12.98%), psychological function (PDs: - 13.68%) and social function (PDs: - 8.77%, p < 0.05). In addition, Maximizers had significantly worse emotional role functioning (- 11.03%), vitality (PDs: - 11.72%) and mental health (PDs: - 10.00%, p < 0.05). CONCLUSION: Patients exhibiting maximizing-type decision-making characteristics have worse satisfaction with gynecomastia treatment and poorer psychosocial health. This information may facilitate patient counseling and alignment of treatment expectations. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Superomedial Reduction Mammoplasty Affects Patients' Ability to Breastfeed in a Distinct Manner: A Multicenter Study of 303 Patients.

BACKGROUND: Breast reduction by the superomedial technique can relieve symptoms related to breast hypertrophy; however, as the lateral and inferior portion of the breast parenchyma is removed and displaced, reduction mammoplasty may lead to an impaired ability to breastfeed. OBJECTIVES: The aim of this study was to assess patients' ability to breastfeed after superomedial reduction mammoplasty. METHODS: This was a cross-sectional study including patients treated with superomedial reduction mammoplasty between January 2009 and December 2018 at 2 tertiary hospitals in Denmark. Patients were stratified into 2 cohorts, depending on whether they had experienced childbirth before or after their reduction mammoplasty. Patients were sent specific questionnaires regarding maternity, breastfeeding before and after reduction mammoplasty, nipple sensitivity, and current demographic information. Operative details were retrieved from electronic medical records. RESULTS: In total, 303 patients were identified as eligible for this study (37 patients giving birth after and 266 before reduction mammoplasty). Fewer patients were able to breastfeed exclusively for the recommended 6 months after reduction mammoplasty (2/37, 5.41%) compared with before (92/266, 34.59%; P < 0.05). In addition, fewer patients were able to breastfeed at all after reduction mammoplasty (18/37, 48.64%) compared with before mammoplasty (241/266, 90.60%; P < 0.001). Patients unable to breastfeed after reduction mammoplasty had lower nipple sensitivity and more breast tissue excised (P < 0.05). CONCLUSIONS: Superomedial reduction mammoplasty seems to impair the patient's ability to breastfeed exclusively for the recommended 6 months. Patients of childbearing age considering reduction mammoplasty should be made aware that reduction mammoplasty reduces their breastfeeding capacity.

Prospective Validation of Indocyanine Green Lymphangiography Staging of Breast Cancer-Related Lymphedema.

Indocyanine green lymphangiography (ICG-L) allows real-time investigation of lymphatics. Plastic surgeons performing lymphatic reconstruction use the ICG-L for patient selection and stratification using the MD Anderson (MDA) and the Arm Dermal Backflow (ADB) grading systems. However, the applicability of ICG-L in evaluating breast cancer-related lymphedema (BCRL) is sparse and not well established. This study comprehensively examines the usability of ICG-L in the assessment of BCRL. We prospectively performed ICG-L in 237 BCRL patients between January 2019 and February 2020. The aim of this study was to assess the interrater and intrarater agreement and interscale consensus of ratings made using the MDA and ADB scales. Three independent raters performed a total of 2607 ICG-L assessments. The ICG-L stage for each grading system was correlated to the lymphedema volume to assess the agreement between the ICG-L stage and clinical severity. The interrater agreement was near perfect for the MDA scale (kappa 0.82-0.90) and the ADB scale (kappa 0.80-0.91). Similarly, we found a near-perfect intrarater agreement for the MDA scale (kappa 0.84-0.94) and the ADB scale (kappa 0.88-0.89). The agreement between the MDA and the ADB scales was substantial (kappa 0.65-0.68); however, the ADB scale systematically overestimated lower ICG-L stages compared to the MDA scale. The volume of lymphedema correlated slightly with MDA stage (Spearmans rho = 0.44, p < 0.001) and ADB stage (rs = 0.35, p < 0.001). No serious adverse events occurred. The staging of BCRL with ICG-L is reliable, safe, and provides unique disease information unobtainable with clinical measurements alone. The MDA scale seems to provide better disease stratification compared to the ADB scale.

Adipose-derived regenerative cells and lipotransfer in alleviating breast cancer-related lymphedema: An open-label phase I trial with 4 years of follow-up.

Patients with breast cancer-related lymphedema (BCRL) have reduced quality of life and arm function. Current treatments are palliative, and treatments improving lymphedema are lacking. Preclinical studies have suggested that adipose-derived regenerative cells (ADRCs) can alleviate lymphedema. We, therefore, aimed to assess whether ADRCs can alleviate lymphedema in clinical reality with long-term follow-up. We treated 10 patients with BCRL using ADRCs and a scar-releasing lipotransfer to the axillary region, and all patients were followed 1, 3, 6, 12, and 48 months after treatment. The primary endpoint was change in arm volume. Secondary endpoints were safety, change in lymphedema symptoms, quality of life, lymphedema-associated cellulitis, and conservative treatment use. There was no significant decrease in BCRL volume after treatment. However, self-reported upper extremity disability and arm heaviness and tension improved. Six patients reduced their use of conservative BCRL treatment. Five patients felt that their BCRL had improved substantially, and four of these would redo the treatment. We did not observe any cases of locoregional breast cancer recurrence. In this phase I study with 4 years of follow-up, axillary delivered ADRCs and lipotransfer were safe and feasible and improved BCRL symptoms and upper extremity function. Randomized controlled trials are needed to confirm the results of this study.

Age and Body Mass Index Affect Patient Satisfaction Following Reduction Mammoplasty: A Multicenter Study Using BREAST-Q.

BACKGROUND: Reduction mammoplasty effectively improves quality of life for women with macromastia. However, little is known whether surgical- or patient-related factors affect satisfaction. OBJECTIVE: The authors sought to investigate factors associated with altered patient satisfaction following reduction mammoplasty. METHODS: A cross-section study was performed by sending the BREAST-Q Reduction module to all patients who had undergone reduction mammoplasty between January 2009 and December 2018 at 2 tertiary Danish hospitals. Demographics and pre-, peri-, and postoperative details were gathered from electronic medical records. RESULTS: A total of 393 patients returned the questionnaire and were eligible for the study. Increasing age at the time of surgery was associated with higher satisfaction with breasts nipples, headache, psychosocial well-being, and outcome. Increased body mass index at the time of surgery negatively affected satisfaction with breasts and psychosocial well-being. Increase in body mass index after surgery was further associated with lower satisfaction with breasts, nipples, sexual well-being, and more pain in the breast area. Postoperative scar revision and wound infection was more common following inferior pedicle technique than superomedial technique and negatively affected satisfaction with outcome and pain in the breast area. CONCLUSIONS: Patients should be motivated to optimize their weight prior to reduction mammoplasty to achieve optimal satisfaction. Age was associated with improved patient satisfaction, which should considered when operating on younger patients. Postoperative complications affect patient satisfaction, and the superomedial technique seems to be a better choice than the inferior pedicle technique in medium-large breasts.

Risk of skin cancer in patients with vitiligo in Denmark: A nationwide cohort study.

BACKGROUND: Vitiligo is a depigmentation disorder associated with genetic loss of melanocytes and decreased melanin synthesis. The current literature is conflicting in regard to vitiligo patients' risk of cutaneous malignant melanoma and keratinocyte cancer. OBJECTIVE: To investigate the risk of cutaneous malignant melanoma and keratinocyte cancer in vitiligo patients. METHODS: We conducted a population-based study, including 2,339 subjects with a first-time vitiligo diagnosis between 1994 and 2017 and 23,293 age- and sex-matched (1:10) controls. To address surveillance bias, we included 12,380 subjects with a first-time diagnosis of lichen planus. RESULTS: Age was the only significant factor for cutaneous malignant melanoma in comparison of vitiligo with controls and lichen planus (hazard ratio 1.04, 95% confidence interval [CI] 1.03-1.05; and hazard ratio 1.02, 95% CI 1.01-1.04, respectively). Similarly, age was a significant factor for keratinocyte cancer in comparison of vitiligo with controls and lichen planus (hazard ratio 1.07, 95% CI 1.06-1.07; and hazard ratio 1.06, 95% CI 1.05-1.07). Male sex was an additional factor for keratinocyte cancer in comparison of vitiligo with lichen planus (hazard ratio 1.38; 95% CI 1.09-1.75). Phototherapy did not increase the risk of receiving a diagnosis of cutaneous malignant melanoma or keratinocyte cancer in the vitiligo cohort. CONCLUSION: We observed no significant difference in cutaneous malignant melanoma or keratinocyte cancer risk among vitiligo subjects. Phototherapy use was not associated with a higher skin cancer risk in vitiligo compared with other skin diseases.

Autologous versus implant-based breast reconstruction: A systematic review and meta-analysis of Breast-Q patient-reported outcomes.

OBJECTIVE: Breast reconstruction following mastectomy can increase the quality of life of patients. Reconstruction methods can broadly be divided into implant-based and autologous tissue reconstruction. Patient-reported outcomes following breast reconstruction are one of the most important success parameters. In this systematic review and meta-analysis, we aimed to compare the two methods using the recognized Breast-Q questionnaire. METHODS: We performed a systematic search in PubMed and EMBASE databases. Meta-analysis was performed on the five most commonly reported Breast-Q modules. RevMan 5.3 was used for statistical analysis. Methodological quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Form for Cohort Studies. RESULTS: The search strategy resulted in 219 studies of which nine studies were included in the analysis, yielding 2129 implant-based and 825 autologous breast reconstructions. Overall satisfaction with outcome as well as breast was significantly higher among patients with autologous breast reconstructions (mean Breast-Q difference between the two groups was 9.82 [3.09, 16.54], p = 0.004, and 10.33 [95% CI 5.93, 14.74], p<0.00001, respectively). Sexual and psychosocial well-being was higher among autologous breast reconstructions. There was no difference in the physical well-being. CONCLUSION: This is the first systematic review and meta-analysis to compare patient-reported outcomes of implant-based and autologous breast reconstruction. We found that autologous reconstruction yields a higher satisfaction with overall outcome and breast. These findings can aid clinicians when discussing breast reconstruction options with patients.

Submental Island Flap versus Free Flap Reconstruction for Complex Head and Neck Defects.

OBJECTIVE: Complex soft tissue reconstruction of the head and neck requires a viable, versatile, and dependable flap. Free flaps, such as the radial forearm and anterolateral thigh flap, have been the mainstay of complex head and neck reconstruction. However, a local pedicled flap, such as the submental island flap (SIF), could be a more effective and less demanding alternative. This systematic review and meta-analysis aim to compare free tissue transfer (FTT) with the SIF for head and neck reconstruction. DATA SOURCES: We performed a systematic search in PubMed and EMBASE databases. Meta-analysis was performed on outcomes reported in ≥3 studies. REVIEW METHODS: Candidate articles were assessed for eligibility by 2 authors. Three authors performed data extraction and methodological quality of the included studies using the Newcastle-Ottawa Quality Assessment Form for Cohort Studies. RESULTS: The search strategy resulted in 450 studies, of which 7 were included in the analysis, yielding 155 SIF and 198 FTT cases. Operating time and length of stay were significantly lower for the SIF than for FTT (P = .05 and P = .0008). There was no significant difference between the groups for complete flap loss, debulking revisions, and oncologic recurrence. CONCLUSION: These results suggest that the SIF reduces length of stay and operating time as compared with FTT in head and neck reconstruction. These findings suggest that the SIF can be considered an alternative reconstructive option to FTT when evaluating intraoral, lateral facial, skull base, and parotidectomy defects, given comparable defect size and tumor biology.

[Necrobiotic xanthogranuloma misdiagnosed as a planocellular carcinoma].

In this case report, an 89-year-old woman presented with a subcutaneous tumour in the orbital region. Fine needle aspiration showed no signs of malignancy. Following progressive tumour growth and cutaneous manifestation, an incisional biopsy was taken, which showed squamous cell carcinoma. The tumour was excised, and the patho-logical report showed necrobiotic xanthogranuloma being a rare histiocytic disease characterised by slow growth of nodules and plaques. Because it is rare, it can pose a diagnostic challenge, which is why, this report is an attempt to shed light on the disease and to aid its diagnosis.

Prophylactic incisional negative pressure wound therapy shows promising results in prevention of wound complications following inguinal lymph node dissection for Melanoma: A retrospective case-control series.

BACKGROUND: Inguinal lymphadenectomy (ILND) for melanoma is associated with a number of complications including seroma, surgical site infection (SSI), and lymphedema. Incisional negative pressure wound therapy (iNPWT) has shown promising results in preventing postoperative morbidity across a wide variety of surgical procedures, but these results are yet to be investigated in patients undergoing ILND for melanoma. METHODS: In this study, we reviewed the data of 55 melanoma patients treated with ILND between January 2015 and January 2017 at Odense University Hospital. Patients were followed up until April 2018 for the occurrence of seroma, SSI, and lymphedema. We used prophylactic iNPWT after ILND in 14 patients and compared their morbidity outcomes with the 41 patients receiving standard postoperative wound care in the same period. RESULTS: The iNPWT intervention significantly reduced seroma compared to the control group (28.6% vs. 90.3%, p < 0.001) and had a trending impact on wound infection (42.9% vs. 65.9%, p = 0.13). The effect was not significant for the prevention of lymphedema (35.7% vs. 51.2%, p = 0.33). Because the iNPWT group had relatively fewer incidences of seroma, SSI, and lymphedema, the iNPWT intervention was more cost-effective than conventional wound care (US$911.2 vs. US$2542.7, p < 0.05). CONCLUSION: The use of prophylactic iNPWT significantly reduced seroma formation following ILND. These promising results, however, need to be confirmed in a future prospective randomized trial.

Correction to: Prevention of seroma following inguinal lymph node dissection with prophylactic, incisional, negative-pressure wound therapy (SEROMA trial): study protocol for a randomized controlled trial.

Following publication of the original article [1], the authors reported that one of the authors' names is spelled incorrectly. In this Correction the incorrect and correct author name are shown. The original publication of this article has been corrected.

Prevention of seroma following inguinal lymph node dissection with prophylactic, incisional, negative-pressure wound therapy (SEROMA trial): study protocol for a randomized controlled trial.

BACKGROUND: Radical inguinal lymphadenectomy (ILND) for metastatic melanoma is associated with a high complication rate. Seroma is often the first postoperative complication, followed by prolonged wound healing sometimes requiring reoperation, infection, multiple outpatient visits and re-hospitalization. Prevention of seroma may, therefore, lead to a reduction in many of the other complications. METHODS/DESIGN: The primary aim of this randomized study is to investigate whether fewer patients require treatment for seroma by immediate prophylactic application of incisional, Negative-pressure Wound Therapy (iNPWT) following ILND, compared to standard postoperative treatment. The secondary outcomes include surgical-site infection, dehiscence, hematoma, length of hospitalization, quality of life, safety, long-term assessment of lymphedema and non-inferiority oncological outcome. Data will be registered prospectively at check-ups after 7 and 14 days, 1 and 3 months and 2 years after inguinal lymphadenectomy using case report forms and questionnaires and stored in a secure online database. DISCUSSION: To our knowledge, this trial is the first randomized study evaluating negative-pressure wound therapy as a prophylactic intervention for complications following melanoma-related ILND. The results from this trial will hopefully determine the efficacy and safety of prophylactic iNPWT treatment in prevention of the clinical relevant short- and long-term postoperative complications following ILND and may provide an evidence base for the an improved postoperative regimen. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03433937 . Prospectively registered on 15 February 2018.

A 12-Month Follow-up After a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunction Following Radical Prostatectomy: An Open-Label Phase I Clinical Trial.

OBJECTIVE: To explore safety in adipose-derived regenerative cells (ADRC) therapy, treating erectile dysfunction (ED). METHODS: Twenty-one patients with ED after radical prostatectomy, with no signs of recovery using conventional therapy, received a single intracavernous injection of autologous ADRC and were followed for 1 year. Six men were incontinent, and 15 were continent at inclusion. The primary (safety of ADRC therapy) and secondary endpoints (sexual function) were evaluated at 1, 3, 6, and 12 months after ADRC injection by registration of adverse events and validated questionnaires using the international index of erectile function-5 and erection hardness score. RESULTS: No serious adverse events occurred, but 8 reversible minor events related to the liposuction were noted. Eight out of 15 (53%) patients in the continent group reported erectile function sufficient for intercourse at 12 months. Baseline median international index of erectile function-5 scores (6.0; interquartile range [IQR] 3) were unchanged 1 month after the treatment, but significantly increased after 6 to 7 (IQR 17). This effect was sustained at 12 months (median 8; IQR 14). We did not see any improvements in erectile function in the group of incontinent men or among men with ED prior to radical prostatectomy. CONCLUSION: Intracavernous injection of ADRC is safe in this phase 1 study with a 12-month follow-up.

Adipose-derived stem cells for treatment of chronic ulcers: current status.

Chronic ulcers remain a difficult challenge in healthcare systems. While treatment options are limited, stem cells may be a novel alternative. Adipose-derived stem cells (ADSC) have become increasingly popular compared with bone marrow-derived stem cells as they are far easier to harvest. To summarize the current status of treating chronic ulcers with ADSC, this systematic review includes all clinical trials on the subject from PubMed and EmBase, as well as all registered clinical trials on ClinicalTrials.Gov. A total of nine clinical trials and fourteen registered trials were included. The studies were significantly different in terms of study design and patient population, and the overall quality of the studies was low to moderate. Despite the overall low study quality and the significant differences between the studies, some conclusions were consistent: ADSCs are safe, improve the healing of chronic ulcers, and reduce pain. As these results are consistent despite the shortcomings of the studies, they appear to highlight the efficacy of ADSCs in the treatment of chronic ulcers. Larger numbers of higher quality studies are needed to determine the precise role of ADSCs in treating chronic leg ulcers.

Human and Autologous Adipose-derived Stromal Cells Increase Flap Survival in Rats Independently of Host Immune Response.

INTRODUCTION: There is a rising interest in adipose-derived stromal cells for clinical use; however, it is unknown whether freshly isolated stromal cells (SVF) or culture-expanded cells (ASCs) are more efficacious. We therefore aimed to compare the 2 cellular therapies in an in vivo model of angiogenesis, the ischemic flap in rats, which induces acute ischemia. We also aimed to determine the importance of cell presence and the host immune response. METHODS: A total of 96 rats (n = 12 in each group) were used, and in each rat, a caudally based random flap measuring 2 × 7 cm was made. The study was conducted in 3 phases. First, each rat was treated with human SVF cells, human ASCs, or vehicle. Second, each rat was treated with human SVF, human SVF lysate, or vehicle. Finally, each rat was treated with rat (autologous) SVF cells or vehicle. Flap survival, vessel density, and stromal cell retention were evaluated after 7 days. RESULTS: The mean survival rates for SVF treatment regardless of human or autologous origin were significantly increased as compared with the control group. Adipose stem/stromal cell and SVF lysate injection did not increase flap survival. Vessel density was increased for human and rat SVF and human ASC but not for SVF lysate. Human cells were not detected in the flaps after 7 days. CONCLUSIONS: Flap survival increased with SVF treatment regardless of human or autologous origin, suggesting that increased flap survival is independent of the host immune response. All cell injections lead to increased vessel density, but it did not necessarily lead to increased flap survival. Further research should elaborate which molecular events make SVF treatment more efficacious than ASC.