original articleT h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 355;13 www.nejm

OBJECTIVETo describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010.RESEARCH DESIGN AND METHODSA total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999–2002), mid (2003–2006), or recent (2007–2010) transplant era based on annual follow-up to 5 years.RESULTSInsulin independence at 3 years after transplant improved from 27% in the early era (1999–2002, n = 214) to 37% in the mid (2003–2006, n = 255) and to 44% in the most recent era (2007–2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001).CONCLUSIONSThe CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007–2010 compared with those in 1999–2006, with fewer islet infusions and adverse events per recipient.

OBJECTIVEImpaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50–80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment.RESEARCH DESIGN AND METHODSThis multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant.RESULTSThe primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients.CONCLUSIONSTransplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

The treatment of diabetes mellitus by transplantation of isolated pancreatic islets is an approach that remains the subject of research by a large number of investigators throughout the world. A crucial requirement for the success of this enterprise is the ability to prepare viable isolated islets in adequate quantity. Over the years numerous descriptions of procedures for islet isolation from the pancreas of experimental animals and of man have been advanced; each claiming to be an improvement on previous methods. Indeed, there certainly have been advances, although few techniques live up to the claims that are made in their support Part of the problem is the generally poor methodology

Acute respiratory distress syndrome (ARDS) in COVID‐19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti‐inflammatory effects and could yield beneficial effects in COVID‐19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC‐MSC) infusions in subjects with COVID‐19 ARDS. A double‐blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty‐four subjects were randomized 1:1 to either UC‐MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC‐MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC‐MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion‐associated AEs. No serious adverse events (SAEs) were observed related to UC‐MSC infusions. UC‐MSC infusions in COVID‐19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC‐MSC‐treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE‐free survival (P = .008), and time to recovery (P = .03). UC‐MSC infusions are safe and could be beneficial in treating subjects with COVID‐19 ARDS.