Navid Mohamadpour Toyserkani

Safety and Potential Effect of 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

Background Prostate cancer is the most common cancer in men, and radical prostatectomy (RP) often results in erectile dysfunction (ED) and a substantially reduced quality of life. The efficacy of current interventions, principal treatment with PDE-5 inhibitors, is not satisfactory and this condition presents an unmet medical need. Preclinical studies using adipose-derived stem cells to treat ED have shown promising results. Herein, we report the results of a human phase 1 trial with autologous adipose-derived regenerative cells (ADRCs) freshly isolated after a liposuction. Methods Seventeen men suffering from post RP ED, with no recovery using conventional therapy, were enrolled in a prospective phase 1 open-label and single-arm study. All subjects had RP performed 5–18 months before enrolment, and were followed for 6 months after intracavernosal transplantation. ADRCs were analyzed for the presence of stem cell surface markers, viability and ability to differentiate. Primary endpoint was the safety and tolerance of the cell therapy while the secondary outcome was improvement of erectile function. Any adverse events were reported and erectile function was assessed by IIEF-5 scores. The study is registered with ClinicalTrials.gov, NCT02240823. Findings Intracavernous injection of ADRCs was well-tolerated and only minor events related to the liposuction and cell injections were reported at the one-month evaluation, but none at later time points. Overall during the study period, 8 of 17 men recovered their erectile function and were able to accomplish sexual intercourse. Post-hoc stratification according to urinary continence status was performed. Accordingly, for continent men (median IIEFinclusion = 7 (95% CI 5–12), 8 out of 11 men recovered erectile function (IIEF6months = 17 (6–23)), corresponding to a mean difference of 0.57 (0.38–0.85; p = 0.0069), versus inclusion. In contrast, incontinent men did not regain erectile function (median IIEF1/3/6 months = 5 (95% CI 5–6); mean difference 1 (95% CI 0.85–1.18), p > 0.9999). Interpretation In this phase I trial a single intracavernosal injection of freshly isolated autologous ADRCs was a safe procedure. A potential efficacy is suggested by a significant improvement in IIEF-5 scores and erectile function. We suggest that ADRCs represent a promising interventional therapy of ED following prostatectomy. Funding Danish Medical Research Council, Odense University Hospital and the Danish Cancer Society.

Cell-Assisted Lipotransfer: A Systematic Review of Its Efficacy.

AbstractIntroduction Autologous lipotransfer is seen as an ideal filler for soft tissue reconstruction. The main limitation of this procedure is the unpredictable resorption and volume loss of the fat graft. In the recent decade, an increasing amount of research has focused on the use of adipose tissue-derived stromal cells (ASCs) to enrich the fat graft, a procedure termed cell-assisted lipotransfer (CAL). The aim of this review was to systematically review the current preclinical and clinical evidence for the efficacy of CAL compared with conventional lipotransfer.Materials and MethodsA systematic search was performed on PubMed and other databases to identify all preclinical and clinical studies where CAL with ASCs was compared with conventional lipotransfer. A total of 20 preclinical studies and seven clinical studies were included in the review.ResultsThe preclinical studies consisted of 15 studies using immunodeficient animal models and five studies using immunocompetent studies. Seventeen studies examined weight/volume retention of which 15 studies favored CAL over conventional lipotransfer. One clinical study did not find any efficacy of CAL and the remaining six studies favored CAL.ConclusionsThe present evidence suggests that there is a big potential for CAL in reconstructive surgery; however, the present studies are so far still of low quality with inherent weaknesses. Several aspects regarding CAL still remain unknown such as the optimal degree of cell enrichment and also its safety. Further high-quality studies are needed to establish if CAL can live up to its potential.Level of Evidence VThis 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.

Adipose-Derived Stem Cells: New Treatment for Wound Healing?

AbstractEmerging evidence has shown that adipose tissue is the richest and most accessible source of mesenchymal stem cells. Many different therapies for chronic wounds exist with varying success rates. The capacity of adipose-derived stem cells (ASCs) to promote angiogenesis, secrete growth factors, regulate the inflammatory process, and differentiate into multiple cell types makes them a potential ideal therapy for chronic wounds. The aim of this article was to review all preclinical trials using ASCs in problem wound models. A systematic search was performed and 12 studies were found where different chronic wound models across different animals were treated with ASCs. Different ASC sources and delivery methods were used in the described studies. Studies demonstrated improved wound healing with utilization of ASC, and this treatment modality has so far shown great potential. However, more preclinical studies and large-scale clinical trials are needed to show if the emerging therapy can satisfy expectations.

Concise Review: A Safety Assessment of Adipose-Derived Cell Therapy in Clinical Trials: A Systematic Review of Reported Adverse Events

The popularity of adipose‐derived cell therapy has increased over the last decade, and the number of studies published annually is growing. However, concerns regarding safety in the setting of previous malignancy or the use of allogeneic cells have been raised. We therefore aimed to systematically review all clinical studies using adipose‐derived cell therapy to identify reported adverse events with a special focus on risk of thromboembolic, immunological, and oncological safety concerns. Our systematic search resulted in 70 included studies involving more than 1,400 patients that were treated with adipose‐derived cell therapy. Safety assessment method was not described in 32 of the included studies. For studies involving systemic or cardiac administration, one case of pulmonary thromboembolism and cases of both myocardial and cerebral infarctions were described. In the setting of allogeneic cell therapy studies, where the production of specific antibodies toward donor cells was examined, it was noted that 19%–34% of patients develop antibodies, but the consequence of this is unknown. With regard to oncological safety, only one case of breast cancer recurrence was identified out of 121 patients. Adipose‐derived cell therapy has so far shown a favorable safety profile, but safety assessment description has, in general, been of poor quality, and only adverse events that are looked for will be found. We encourage future studies to maintain a strong focus on the safety profile of cell therapy, so its safeness can be confirmed. Stem Cells Translational Medicine 2017;6:1786–1794

Seroma indicates increased risk of lymphedema following breast cancer treatment: A retrospective cohort study

INTRODUCTION Lymphedema is one of the most serious complications following breast cancer treatment. While many risk factors are well described the role of seroma formation has recently produced mixed results. Therefore, we aimed to evaluate if seroma is a risk factor for development of lymphedema in one of the largest retrospective cohort studies. MATERIAL AND METHODS We included all patients with unilateral breast cancer treated in the period of 2008-2014. Data regarding treatment and breast cancer characteristics were retrieved from the national breast cancer registry. Data regarding lymphedema treatment and seroma aspirations were retrieved from local treatment codes. RESULTS In total 1822 patients were included of which 291 developed lymphedema. Multivariate cox regression analysis showed that seroma was an independent risk factor (HR 1.92 CI 1.30-2.85, p= 0.001). Other independent risk factors were lymphadenectomy, radiation therapy, chemotherapy, BMI above 30, total lymph nodes removed above 15 and higher number of metastatic lymph nodes. CONCLUSIONS Postoperative seroma doubles the risk of developing lymphedema. Future studies should examine if seroma reducing measures will lead to lower risk of lymphedema.

The effect of prophylactic lymphovenous anastomosis and shunts for preventing cancer-related lymphedema: a systematic review and meta-analysis

Lymphedema is one of the most dreaded side effects to any cancer treatment involving lymphadenectomy. Progressed lymphedema is adversely complex and currently there is no widely acknowledged curative treatment. Therefore recent focus has shifted to risk reduction and prevention. It has been hypothesized that bypassing lymphatic vessels to veins prophylactically, could minimize the lymphatic dysfunction seen following lymphadenectomy.

Stem cells show promising results for lymphoedema treatment – A literature review

Abstract Lymphoedema is a debilitating condition, manifesting in excess lymphatic fluid and swelling of subcutaneous tissues. Lymphoedema is as of yet still an incurable condition and current treatment modalities are not satisfactory. The capacity of mesenchymal stem cells to promote angiogenesis, secrete growth factors, regulate the inflammatory process, and differentiate into multiple cell types make them a potential ideal therapy for lymphoedema. Adipose tissue is the richest and most accessible source of mesenchymal stem cells and they can be harvested, isolated, and used for therapy in a single stage procedure as an autologous treatment. The aim of this paper was to review all studies using mesenchymal stem cells for lymphoedema treatment with a special focus on the potential use of adipose-derived stem cells. A systematic search was performed and five preclinical and two clinical studies were found. Different stem cell sources and lymphoedema models were used in the described studies. Most studies showed a decrease in lymphoedema and an increased lymphangiogenesis when treated with stem cells and this treatment modality has so far shown great potential. The present studies are, however, subject to bias and more preclinical studies and large-scale high quality clinical trials are needed to show if this emerging therapy can satisfy expectations.

Cell-Assisted Lipotransfer Using Autologous Adipose-Derived Stromal Cells for Alleviation of Breast Cancer-Related Lymphedema

Lymphedema is one of the most frequent side effects following cancer treatment, and treatment opportunities for it are currently lacking. Stem cell therapy has been proposed as a possible novel treatment modality. This study was the first case in which freshly isolated adipose‐derived stromal cells were used to treat lymphedema. Treatment was given as a cell‐assisted lipotransfer in which 4.07 × 107 cells were injected with 10 ml of lipoaspirate in the axillary region. Four months after treatment, the patient reported a great improvement in daily symptoms, reduction in need for compression therapy, and volume reduction of her affected arm. There were no adverse events. The outcome for this patient provides support for the potential use of cellular therapy for lymphedema treatment. We have begun a larger study to further test the feasibility and safety of this procedure (ClinicalTrials.gov Identifier NCT02592213).

Treatment of Breast Cancer-Related Lymphedema with Adipose-Derived Regenerative Cells and Fat Grafts: A Feasibility and Safety Study

Breast cancer‐related lymphedema (BCRL) is a debilitating late complication with a lack of treatment opportunities. Recent studies have suggested that mesenchymal stromal cells can alleviate lymphedema. Herein, we report the results from the first human pilot study with freshly isolated adipose‐derived regenerative cells (ADRC) for treating lymphedema with 6 months follow‐up. Ten BCRL patients were included. ADRC was injected directly into the axillary region, which was combined with a scar‐releasing fat graft procedure. Primary endpoints were change in arm volume. Secondary endpoints were change in patient reported outcome and safety. The study is registered with ClinicalTrials.gov (NCT02592213). During follow‐up, a small volume reduction was noted but was not significant. Five patients reduced their use of conservative management. Patient‐reported outcomes improved significantly over time. ADRCs were well tolerated and only minor transient adverse events related to liposuction were noted. In this pilot study, a single injection of ADRC improved lymphedema based on patient‐reported outcome measures, and there were no serious adverse events in the 6 months follow‐up period. In addition, half of the patients reduced their use of conservative management. ADRC therapy is a promising interventional therapy for alleviating lymphedema, but results need to be confirmed in randomized clinical trials. Stem Cells Translational Medicine 2017;6:1666–1672

Tc-99m-Human Serum Albumin Transit Time as a Measure of Arm Breast Cancer-Related Lymphedema

Background: Lymphoscintigraphy has often been used for evaluating arm lymphatic dysfunction, but no optimal approach for quantification has so far emerged. We propose a quantifiable measure of lymphatic function that we applied in patients treated for breast cancer. Methods: Eleven patients, aged 34–68 years, with unilateral arm lymphedema following breast cancer treatment underwent bilateral lymphoscintigraphy using intradermal injection in both hands of technetium-99m–labeled human serum albumin and sequential 5 min imaging for 5 hours. The mean transit time (MTT) in the arms was calculated based on time activity curves generated from injection site and arm regions. Visual lymphedema scoring was performed based on dermal backflow and lymph node presence. Excess arm volume was calculated from circumference measurements. Results: The MTT (mean ± SD) was significantly longer in the lymphedema arm than in the normal arm: 60.1 ± 27.7 versus 5.4 ± 2.5 minutes (mean difference, 54.7 minutes; 95% confidence interval, 36.5–72.9 minutes; P < 0.0001). Patients with previous erysipelas infection had significantly longer MTT than other patients (mean difference, 43.7 minutes; 95% confidence interval, 18.6–68.7 minutes; P < 0.001). There was a positive correlation between MTT and excess arm volume (r = 0.64; P = 0.04) and number of lymph nodes removed (r = 0.65; P = 0.03) but no correlation between visual score and MTT. Conclusion: Measurements of MTT were able to discriminate lymphedema from healthy arm and MTT correlated with relevant markers for lymphedema severity. We encourage further research using the MTT approach for monitoring lymphedema and evaluation of treatment response.