CD39 delineates chimeric antigen receptor regulatory T cell subsets with distinct cytotoxic & regulatory functions against human islets.

Human regulatory T cells (Treg) suppress other immune cells. Their dysfunction contributes to the pathophysiology of autoimmune diseases, including type 1 diabetes (T1D). Infusion of Tregs is being clinically evaluated as a novel way to prevent or treat T1D. Genetic modification of Tregs, most notably through the introduction of a chimeric antigen receptor (CAR) targeting Tregs to pancreatic islets, may improve their efficacy. We evaluated CAR targeting of human Tregs to monocytes, a human ß cell line and human islet ß cells in vitro. Targeting of HLA-A2-CAR (A2-CAR) bulk Tregs to HLA-A2+ cells resulted in dichotomous cytotoxic killing of human monocytes and islet ß cells. In exploring subsets and mechanisms that may explain this pattern, we found that CD39 expression segregated CAR Treg cytotoxicity. CAR Tregs from individuals with more CD39low/- Tregs and from individuals with genetic polymorphism associated with lower CD39 expression (rs10748643) had more cytotoxicity. Isolated CD39- CAR Tregs had elevated granzyme B expression and cytotoxicity compared to the CD39+ CAR Treg subset. Genetic overexpression of CD39 in CD39low CAR Tregs reduced their cytotoxicity. Importantly, ß cells upregulated protein surface expression of PD-L1 and PD-L2 in response to A2-CAR Tregs. Blockade of PD-L1/PD-L2 increased ß cell death in A2-CAR Treg co-cultures suggesting that the PD-1/PD-L1 pathway is important in protecting islet ß cells in the setting of CAR immunotherapy. In summary, introduction of CAR can enhance biological differences in subsets of Tregs. CD39+ Tregs represent a safer choice for CAR Treg therapies targeting tissues for tolerance induction.

Long-term efficacy of modified-release recombinant human thyrotropin augmented radioiodine therapy for benign multinodular goiter: results from a multicenter, international, randomized, placebo-controlled, dose-selection study.

BACKGROUND: Enhanced reduction of multinodular goiter (MNG) can be achieved by stimulation with recombinant human thyrotropin (rhTSH) before radioiodine ((131)I) therapy. The objective was to compare the long-term efficacy and safety of two low doses of modified release rhTSH (MRrhTSH) in combination with (131)I therapy. METHODS: In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2 ± 9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0 mL; range 31.9-242.2 mL) were randomized to receive placebo (n=32), 0.01 mg MRrhTSH (n=30), or 0.03 mg MRrhTSH (n=33) 24 hours before a calculated (131)I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by computed tomography scan) at baseline, six months, and 36 months. Thyroid function and quality of life (QoL) was evaluated at three-month and yearly intervals respectively. RESULTS: At six months, TV reduction was enhanced in the 0.03 mg MRrhTSH group (32.9% vs. 23.1% in the placebo group; p=0.03) but not in the 0.01 mg MRrhTSH group. At 36 months, the mean percent TV reduction from baseline was 44 ± 12.7% (SD) in the placebo group, 41 ± 21.0% in the 0.01 mg MRrhTSH group, and 53 ± 18.6% in the 0.03 mg MRrhTSH group, with no statistically significant differences among the groups, p=0.105. In the 0.03 mg MRrhTSH group, the subset of patients with basal (131)I uptake <20% had a 24% greater TV reduction at 36 months than the corresponding subset of patients in the placebo group (p=0.01). At 36 months, the largest relative increase in SCAT was observed in the 0.03 mg MRrhTSH group (13.4 ± 23.2%), but this was not statistically different from the increases observed in the placebo or the 0.01 mg MRrhTSH group (p=0.15). Goiter-related symptoms were reduced and QoL improved, without any enhanced benefit from using MRrhTSH. At three years, the prevalence of permanent hypothyroidism was 13%, 33%, and 45% in the placebo, 0.01 mg, and 0.03 mg MRrhTSH groups respectively. The overall safety profile of the study was favorable. CONCLUSIONS: When used as adjuvant to (131)I, enhanced MNG reduction could not be demonstrated with MRrhTSH doses ≤ 0.03 mg, indicating that the lower threshold for efficacy is around this level.

Long-term survival of proximal humerus allografts for reconstruction following resection of malignant bone tumours.

We previously reported early favourable results concerning allograft use in proximal humerus reconstruction following malignancy. We now present the long-term follow-up of patients who underwent tumour resection with massive humeral allograft reconstruction. This is a retrospective review of 8 consecutive patients who underwent massive proximal humeral allograft for primary or secondary bone tumours. The median age at first surgery was 41 years; the median followup is 11.1 years. The overall revision rate of the allografts was 75%. A total of 10 revision procedures were required in this cohort. Five-year survival for implants was 44%; at ten years no implants were intact. Five-year survival for patients was 88%; it was 60% at ten years. In our experience, proximal humerus allograft reconstruction was associated with a high complication rate and resulted in multiple revision procedures in the long-term. We no longer perform or recommend this procedure.

Implementation of evidence-based practices for surgical site infection prophylaxis: results of a pre- and postintervention study.

BACKGROUND: Although evidence-based guidelines for best practices pertaining to surgical site infection (SSI) prophylaxis exist, the feasibility of implementing such practices remains to be demonstrated outside of a controlled clinical trial. This study was designed to assess the safety and feasibility of implementing evidence-based care practices to prevent SSIs. STUDY DESIGN: A prospective, double-cohort (pre- and postintervention) trial in elective, general surgery patients was conducted. All patients undergoing elective, major colorectal or hepatobiliary operations were enrolled. Postintervention cohort patients were exposed to new strategies to improve antibiotic administration times, perioperative normothermia rates, and perioperative glucose control. They were compared with the preintervention cohort, which received standard practice at the time. Outcomes evaluated include timing of antibiotic administration, perioperative temperatures, and postoperative glucose levels. SSI rates between cohorts were also compared. RESULTS: A total of 208 patients were enrolled. The proportion of patients receiving their preoperative antibiotics within 60 minutes improved from 5.9% to 92.6% (p < 0.001); perioperative normothermia rates improved from 60.5% to 97.6% (p < 0.001) between cohorts. There was no improvement in rates of hyperglycemia. SSI rates improved but did not reach statistical significance (14.3% versus 8.7%; p = 0.21). CONCLUSIONS: Implementation of evidence-based care practices to prevent SSI is both safe and practical outside the setting of a randomized, controlled trial. Sustained compliance remains to be demonstrated, although practice audits at our institution suggest ongoing success is possible.

Mortality following hip fracture surgery in patients with recent myocardial infarction.

INTRODUCTION: In an elective setting, surgery is best avoided for at least 6 months following myocardial infarction. However, in the presence of a femoral neck fracture, this would most probably lead to significant complications in relation to prolonged immobilisation. There is no published mortality data for patients undergoing surgery for hip fracture following a recent myocardial infarction. The aim of this retrospective study was to assess the mortality of hip fracture patients with a recent myocardial infarction that have undergone surgery at our institution. PATIENTS AND METHODS: Between January 2003 and October 2005, 2270 patients were admitted to our unit with a proximal femoral fracture. Of these, 11 patients were found to have a recent myocardial infarction. RESULTS: Of these 11 patients, 8 were female. The average age was 78.2 years (range, 59-90 years). Average delay from the time of infarction to operation was 11.2 days (range, 3-23 days). Mortality at 1 and 6 months was 45.4% and 63.5%, respectively. DISCUSSION: This is much higher than the overall reported mortality following proximal femur fracture. This information may be useful when planning future peri-operative care and discussing overall prognosis with patients and their relatives.

The value of a complete blood count in predicting cancer of the colon.

Mortality from colon cancer could be reduced with routine screening, yet screening rates are low. Current screening tools are limited by expense and suboptimal acceptance. A retrospective case-control study of all cases of colon cancer diagnosed at our institution over a 5-year period was performed to determine the frequency of blood count abnormalities in these patients upon presentation. One hundred twenty-seven patients had right-sided colon cancer: 107 (84%) had an elevated red cell distribution width (RDW); 87 (69%) had anemia; and 70 (55%) had a low mean corpuscular volume (MCV). Ninety-eight patients had left-sided colon cancer: 49 (50%) had an elevated red cell distribution width; 43 (44%) had anemia; and 22 (22%) had a low mean corpuscular volume. The red cell distribution width was 84% sensitive and 88% specific for right-sided colon cancer. An elevated red cell distribution width may help better identify those patients who should be referred for full colonoscopy.