Transplantation of a New Biological Product in Rare Diseases, Such as Epidermolysis Bullosa: Response and Clinical Outcome.

BACKGROUND: Epidermolysis bullosa (EB) is a phenotypically diverse group of hereditary blistering disorders involving mutations in 20 different genes. Those debilitating disorders are currently incurable; however, there are a number of promising preclinical trials, where some treatments already approach the stage of early clinical trial. In this paper we introduce a novel surgical approach to the treatment of EB-induced ulcerations. The purpose of our study was to evaluate the safety and efficacy of a new biological dressing in the form of an allogenic human skin equivalent graft before using multipotent stem cells, classified as an advanced therapy medicinal product. METHODS: Implanted human acellular dermal matrices were prepared from the superficial layers of donated human skin. Scaffold sterilization was conducted via irradiation with the use of a linear electron accelerator. Following water-knife debridement, wounds were surgically covered with accordingly prepared grafts and dressed in burn-injury fashion. Subsequently, the wounds were monitored for infection and viability. RESULTS: Our data indicate that grafting as a potential new medicinal product was safe and effective in patients with rare diseases, such as EB, and may be used for stem cells to create new Advanced Therapy Medicinal Products. During a 200-day follow-up, we proved the safety of using human scaffolds (allogeneic graft) by observing no apparent infection or necrosis. Instead, we noted fewer required dressing changes, promoted wound healing, pain reduction, and an overall improvement in the quality of life in patients with EB. CONCLUSION: The protocol for grafting allogenic acellular epidermal sheets is the most promising treatment for severely affected skin areas in EB patients to date.

New Treatment of Wound Healing With Allogenic Acellular Human Skin Graft: Preclinical Assessment and In Vitro Study.

BACKGROUND: Nonhealing wounds can be a major clinical problem. Impaired wound healing is often related to massive tissue injury, concomitant wound healing deficiencies (chronic wounds), burn injury, or congenital conditions. We propose a novel biological dressing as an alternative surgical approach. The dressing is a form of an allogenic human skin graft equivalent with further use of allogeneic stem cells classified as an advanced therapy medicinal product. This new allogenic acellular human skin graft has been specifically developed to address the clinical indications for dressing wound lesions and promoting tissue repair in specific rare genetic diseases. METHODS: This case report illustrates the use of an acellular human skin allograft seeded with multipotent stem cells in the treatment of tissue injuries (burns), congenital conditions, and chronic wounds. Donor-tissue processing yields an acellular dermal matrix with integral collagen bundling and organization, as well as an intact basement membrane complex. RESULTS: Preclinical observations show prolonged viability of acellular human skin grafts with multipotent stem cells. This was confirmed with histological and electron-microscopic evaluation of biopsies, which demonstrated host-cell infiltration and neovascularization of the biological dressing. Moreover, the dressings were characterized by low immunogenicity, as confirmed by histology exam and T-cell proliferation assays in vitro. CONCLUSION: Our data confirmed the safety and efficacy of the evaluated acellular human skin grafts, which may be used in patients with rare diseases, such as epidermolysis bullosa, burn injuries, and chronic wounds.

Results of Renal Transplant From Deceased Anti-hepatitis C Virus Donors, Poland 1998-2012.

Kidney transplant (KTx) is the best method of renal insufficiency treatment. In dialyzed patients, mortality rises with the time on dialysis. There is a continuing shortage of organs for transplantation, hence a propensity to expand the donor pool with expanded-criteria donors, anti-hepatitis C virus-positive included. In the above case a transmission of hepatitis C virus (HCV) genotype to recipient is present. It has been proven that contamination with more than 1 HCV genotype did not worsen KTx outcomes. There are 2.6% anti-HCV(+) donors in Poland. Use is only possible in cases of anti-HCV(+) and anti-HCV RNA(+) recipients. METHODS: Retrospective analysis covered 8675 deceased donors (1998-2012 Polish data from Poltransplant). The early (after 12 months) and late (after 60 months) graft and patient survival was assessed in KTx recipients, with documented recipient and donor data spanning at least 1 year after KTx. In comprehensive analysis, 7016 KTx recipients with known anti-HCV status were included according to anti-HCV profile of recipient and donor. The results are in absolute and percentage values and P < .05 assessed with χ2 test. RESULTS: Twelve-month survival: recipient (R) (95%), graft (G) (89%), total; R (95% vs 89%, P < .001), G (88 vs 79, P < .001) in HCV(-) to HCV(+/-) vs HCV(+) to HCV(+); R (95 vs 94, P = .2), G (88 vs 83, P < .001), HCV(-) to HCV(-) vs HCV(-) to HCV(+); R (93 vs 95, P = .004), G (82 vs 89, P < .001) in HCV(+/-) to HCV(+) vs HCV(-) to HCV(-); R (95 vs 89, P < .001), G (88 vs 79, P < .001) in HCV(-) to HCV(-) vs HCV(+) vs HCV (+). Sixty-month survival: R (86%), G (75%), total; R (84 vs 88, P = .01), G (63 vs 71, P = .001) in HCV(+/-) to HCV(+) vs HCV(-) to HCV(-); R (88 vs 80, P = .003) in HCV(-) to HCV(-) vs HCV(+) to HCV(+). CONCLUSIONS: The worst anti-HCV serological profile was HCV(+) to HCV(+), although transplanting HCV(+) to HCV(+) did not worsen outcomes in that group. Worse KTx outcomes of HCV(+) over HCV(-) donors can be attributed to HCV(+) status of the recipient.

Better actual 10-year renal transplant outcomes of 80% reduced cyclosporine exposure with sirolimus base therapy compared with full cyclosporine exposure without or with concomittant sirolimus treatment.

OBJECTIVE: Retrospective analysis of 10-year outcomes of sirolimus (SRL) plus varying exposure to cyclosporine (CsA) in combination therapy for renal transplantation. METHODS: Univariate, multivariate, and receiver operating characteristic (ROC) analyses of 10-year outcomes of 167 subjects treated with full exposures to CsA/SRL/steroid versus 233 with CsA/no SRL/steroid who were generally enrolled in randomized trials versus 192 patients prescribed 80% reduced CsA exposure adjunctive to SRL baseline therapy with steroid withdrawal (groups 1, 2, and 3, respectively). RESULTS: Groups 1 and 3 showed greater 1-year graft survivals (GS) than group 2 (93% and 94% vs 86%; P=.05, particularly when mean SRL C0≥10.5; P=.02); fewer acute rejection episodes (11% and 19% vs 40%; P<.001) and more frequent success of steroid withdrawal (47% and 66% vs 27%; P<.0001). Group 3 versus 1 displayed a higher mean glomerular filtration rate using the Modification of Diet in Renal Disease (MDRD) formula: 56 versus 49 (P=.02) and 53 versus 41 mL/min per 1.73 m2 (P<.001) at 5 and 10 years, respectively. The 10-year GS among group 1 subjects was predicted by a ≥59 mL/min per 1.73 m2 at 1 year using ROC. Multivariate analysis showed factors predictive of 10-year GS among group 1 to include living donor source (P=.004), younger recipient age (P=.02), and fewer HLA-mismatches (P=.02). For group 3, the adverse factors were lower MDRD (P=.01); hypercholesterolemia (P=.01), and advanced donor age (P=.02). Group 3 versus 1 subjects displayed fewer skin tumors (2.6% vs 7.1%; P=.04), sepsis bouts (3.6% vs 9%; P=.04), and herpes virus infection (10% vs. 23%; P=.002), but more urinary tract infections (64% vs 53%; P=.04) and wound problems (43.7% vs 25.1%; P<.0001). CONCLUSION: An 80% reduction of de novo CsA exposure in combination with SRL engendered improved renal function as well as better graft survival at 10 years compared with patients treated with full CsA exposures with or without SRL co-therapy.

36-month follow-up of 75 renal allograft recipients treated with steroids, tacrolimus, and azathioprine or mycophenolate mofetil.

OBJECTIVES: The aim of this retrospective study was to assess the incidence of acute rejection episodes (AR), diabetes mellitus (DM), and serum creatinine (SCr) among renal transplant recipients treated with tacrolimus (Tac), steroids (S), and mycophenolate mofetil (MMF) or azathioprine (Aza). METHODS: Seventy-five renal allograft recipients enrolled in the COSTAMP study were followed for a period of 3 years. Patients were randomized to receive either Tac and MMF (n = 41) or Tac and Aza (n = 34) concomitantly with steroids. Follow-up assessments were performed at 3, 6, 12, 24, and 36 months. RESULTS: Patient survival at month 36 was 91.18% in the Tac/Aza/S group and 97.56% in the Tac/MMF/S group. Graft survival at month 36 was 82.35% and 85.37%, respectively. During the study period, 22 cases of biopsy-proven AR were diagnosed in 17 patients (22.6%). After 36 months the total number of AR was 11 in the Aza-treated group (32.4%) and 11 in the MMF-treated group (26.8%). DM was diagnosed de novo in 17 individuals (22.6%). During 36 months, 10 patients from Aza-treated group (29.4%) and seven from MMF-treated group developed DM (17.1%). Serum creatinine values were not significantly different in both arms of the study. Comparison of arterial blood pressure and total cholesterol revealed no significant changes in any of the studied groups. CONCLUSIONS: We conclude that combinations of steroids, tacrolimus, and azathioprine or MMF provide good results with regard to renal function.

Perioperative single high dose ATG-Fresenius S administration as induction immunosuppressive therapy in cadaveric renal transplantation--preliminary results.

Monoclonal and polyclonal antilymphocyte antibodies have been used successfully in organ transplantation as induction therapy and in the treatment of acute graft rejection. Used for induction the medication is generally given for the first 7-10 days. The aim of this study was to assess the safety and efficacy of single high dose (9 mg/kg) ATG Fresenius S given perioperatively, before revascularization, to kidney allograft recipients. During last twelve months seventy six, first cadaveric kidney adult recipients were included into the study in two centers (center A-64, center B-12). All patients received triple drug immunosuppression (Neoral, steroids and Cellcept which was replaced by azathioprine after 4 months), and were randomized to receive ATG or not. The follow-up period ranged from 1 month up to 1 year. The preliminary results are very promising, the rejection rate in bolus group was significantly lower than in control. No significant side effects or serious adverse events in both groups were observed.