Marie‐Christine Vantyghem

OBJECTIVE: To 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 METHODS: A 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. RESULTS: Insulin 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 HbA(1c) 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). CONCLUSIONS: The 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.

Currently, the major indications for solitary islet transplantation are recurrent severe hypoglycemia and labile glucose control. Quantifying these problems remains subjective. We have developed a scoring system for both hypoglycemia and glycemic lability, established normative data, and used them in patients who have undergone islet transplantation. A composite hypoglycemic score (HYPO score) was devised based on the frequency, severity, and degree of unawareness of the hypoglycemia. In addition, using 4 weeks of glucose records, a lability index (LI) was calculated based on the change in glucose levels over time and compared with a clinical assessment of glycemic lability. A mean amplitude of glycemic excursions (MAGE) was also calculated based on 2 consecutive days of seven readings each day. These scores were determined in 100 randomly selected subjects with type 1 diabetes from our general clinic to serve as a control group and in patients before and after islet transplantation. The mean age of the control diabetic subjects was 38.4 +/- 1.3 years (+/-SE), with a duration of diabetes of 21.5 +/- 1.1 years. The median HYPO score in the control subjects was 143 (25th to 75th interquartile range: 46-423). The LI in the diabetic control subjects was 223 (25th to 75th interquartile range: 130-329 mmol/l(2)/h.week(-1)). The LI correlated much more closely than the MAGE with the clinical assessment of lability. A HYPO score of > or = 1,047 (90th percentile) or an LI > or = 433 mmol/l(2)/h.week(-1) (90th percentile) indicated serious problems with hypoglycemia or glycemic lability, respectively. The islet transplant patients (n = 51) were 42.1 +/- 1.4 years old, with a duration of diabetes of 25.7 +/- 1.4 years. Islet transplant patients had a mean HYPO score of 1,234 +/- 184 pretransplant, which was significantly higher than that of the control subjects (P < 0.001), which became negligible posttransplantation with the elimination of hypoglycemia. The median LI pretransplant was 497 mmol/l(2)/h.week(-1) (25th to 75th interquartile range: 330-692), significantly higher than that of control subjects (P < 0.001), and fell to 40 (25th to 75th interquartile range: 14-83) within a month after the final transplant. In those who had lost graft function, the LI rose again. The HYPO score and LI provide measures of the extent of problems with hypoglycemia and glycemic lability, respectively, complement the clinical assessment of the problems with glucose control before islet transplantation, and will allow comparison of selection of subjects for transplants between centers.

BACKGROUND: The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate. PATIENTS AND METHODS: We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance. RESULTS: Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/d. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (<5N, inferior to 5-fold normal values) and major (>5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. No fatal hepatitis was observed. CONCLUSIONS: Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolves after drug withdrawal.

BACKGROUND: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. METHODS: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. RESULTS: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. CONCLUSIONS: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.

Gitelman's syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCC). Because 18 to 40% of suspected GS patients carry only one SLC12A3 mutant allele, large genomic rearrangements may account for unidentified mutations. Here, we directly sequenced genomic DNA from a large cohort of 448 unrelated patients suspected of having GS. We found 172 distinct mutations, of which 100 were unreported previously. In 315 patients (70%), we identified two mutations; in 81 patients (18%), we identified one; and in 52 patients (12%), we did not detect a mutation. In 88 patients, we performed a search for large rearrangements by multiplex ligation-dependent probe amplification (MLPA) and found nine deletions and two duplications in 24 of the 51 heterozygous patients. A second technique confirmed each rearrangement. Based on the breakpoints of seven deletions, nonallelic homologous recombination by Alu sequences and nonhomologous end-joining probably favor these intragenic deletions. In summary, missense mutations account for approximately 59% of the mutations in Gitelman's syndrome, and there is a predisposition to large rearrangements (6% of our cases) caused by the presence of repeated sequences within the SLC12A3 gene.