The impact of islet mass,number of transplants,and time between transplants on graft function in a national islet transplant program

The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C-peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3–8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C-peptide at 12 months (p < .01). Despite 1.9-fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291–15 417] vs. 6442 [5156–7639] IEQ/kg; p < .0001), stimulated C-peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta ?0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function.     

Exploring Penicillin G as an Intrawound Antibiotic Powder for Prevention of Postoperative Shoulder Infections: Does It Exhibit In Vitro Chondrotoxicity?

Cutibacterium acnes (C. acnes) is a significant insidious pathogen for postoperative infections in shoulder surgery. Studies have demonstrated that certain topical antibiotic powders used have the potential for chondrotoxicity. Benzylpenicillin, commonly referred to as Penicillin G (Pen G) has the lowest minimum inhibitory concentration (MIC) for C. acnes. There is no research regarding the topical application of Pen G during shoulder surgery, nor has its chondrocyte toxicity been previously investigated. This study sought to characterize the in vitro chondrocyte toxicity of Pen G. Culture-derived bovine chondrocytes were exposed to serial Pen G concentrations and compared with a positive and negative control. A negative control of growth medium and positive control of 1% Triton solution. The chondrocyte viability was assessed via spectrophotometer absorbance. The treatment groups were analyzed using one-way repeated measures analysis of variance and Pearson's correlation analysis. The chondrocyte viability was significantly higher for all Pen G concentrations as compared with the positive control (p < 0.001). All concentrations of Pen G exhibited continued chondrocyte metabolic activity over time. Analysis of variance, independent of time, demonstrated no significant decrease in chondrocyte viability for Pen G concentrations ≤6.25 mg/ml, as compared with the negative control (p > 0.05). Pen G demonstrated a significant negative correlation with its concentration and absorbance (r = 0.371, p < 0.001), however, concentrations ≤6.25 mg/ml did not demonstrate a significant decrease in chondrocyte viability (p = 0.063). Pen G in concentrations appropriate for C. acnes is not significantly chondrotoxic and may be safe for intrawound application. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:726-730, 2020     

Peripheral Blood Grafts for T Cell–Replete Haploidentical Transplantation Increase the Incidence and Severity of Cytokine Release Syndrome

T cell–replete post-transplant cyclophosphamide (PTCy)-based protocols have led to increasing use of haploidentical allogeneic hematopoietic cell transplantation (haploHCT). With this approach, bidirectional alloreactivity causing nonengraftment or severe graft-versus-host disease (GVHD) is no a longer major barrier to haploHCT. PTCy eliminates alloreactive lymphocytes but spares CD34⁺ stem cells and regulatory T lymphocytes, resulting in reliable hematopoietic recovery with relatively low incidence of GVHD. The immediate post-haploHCT course, usually before PTCy administration, is often complicated by cytokine release syndrome (CRS). The predictors of CRS and its effect on outcomes post-transplant have not been fully ascertained. We analyzed the outcomes of 66 patients who received haploHCT at our institution. Using published CRS criteria we identified 48 patients who developed CRS. In multivariate analysis peripheral blood grafts were significantly associated with grade ≥ 2 CRS, compared with bone marrow. Grade ≥ 2 CRS (compared with grade < 2) was not associated with differences in overall survival or nonrelapse mortality. Severe CRS was associated with a statistically nonsignificant trend toward higher incidences of grades III to IV acute GVHD, especially in the context of peripheral blood grafts. CRS is a common complication after T cell–replete peripheral blood haploHCT, but post-transplant survival outcomes may not be affected in those with severe CRS.     

Breast cancer risk and germline genomic profiling of women with neurofibromatosis type 1 who developed breast cancer

NF1 mutations predispose to neurofibromatosis type 1 (NF1) and women with NF1 have a moderately elevated risk for breast cancer, especially under age 50. Germline genomic analysis may better define the risk so screening and prevention can be applied to the individuals who benefit the most. Survey conducted in several neurofibromatosis clinics in the United States has demonstrated a 17.2% lifetime risk of breast cancer in women affected with NF1. Cumulated risk to age 50 is estimated to be 9.27%. For genomic profiling, fourteen women with NF1 and a history of breast cancer were recruited and underwent whole exome sequencing (WES), targeted genomic DNA based and RNA‐based analysis of the NF1 gene. Deleterious NF1 pathogenic variants were identified in each woman. Frameshift mutations because of deletion/duplication/complex rearrangement were found in 50% (7/14) of the cases, nonsense mutations in 21% (3/14), in‐frame splice mutations in 21% (3/14), and one case of missense mutation (7%, 1/14). No deleterious mutation was found in the following high/moderate‐penetrance breast cancer genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDH1, CHEK2, FANCC, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, TP53, and STK11. Twenty‐five rare or common variants in cancer related genes were discovered and may have contributed to the breast cancers in these individuals. Breast cancer predisposition modifiers in women with NF1 may involve a great variety of molecular and cellular functions.     

Neurocognitive Dysfunction in Hematopoietic Cell Transplant Recipients: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Complications and Quality of Life Working Party of the European Society for Blood and Marrow Transplantation

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and nonmalignant diseases. Despite increasing survival rates, long-term morbidity after HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction after HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction after HCT. In this review we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Finally, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae after HCT.     

Activity and Capacity Profile of Transplant Physicians and Centers in Australia and New Zealand

We conducted a study to analyze and report on indicators of hematopoietic cell transplant (HCT) physician time use and HCT center output measures. HCT centers in Australia and New Zealand (A&NZ) were invited to provide demographic and time use details for physicians participating in HCT patient care (HCT physicians). Resource details for adult and pediatric centers were included. From a total of 46 centers that were invited to participate, completed data were received from 37 centers (80%) representing 185 HCT physicians, with a median age of 48 (range, 33 to 72), of whom 31% were women. Just over half of HCT physicians cited prior work experience in large overseas HCT centers (97, 52%) and over one-third (79, 43%) possessed postgraduate qualifications other than specialist training. Total annual mean HCTs per HCT physician full-time equivalent (FTE) were 14.2 for centers performing both allogeneic and autologous HCT, 6.6 for autologous only centers, and 10.6 for all centers. For all HCT physicians surveyed the mean proportion of time spent on HCT related tasks was 31.7%. In A&NZ, for centers that perform both allografts and autografts, there was a mean of 4.0 allogeneic HCT annually per HCT bed, compared with 2.6 for the United States and 7.1 allogeneic HCT annually per HCT physician FTE (United States, 6.3). Projections of the A&NZ HCT physician workforce indicated that the numbers of HCT physicians are likely to stay within the region of 170 to 190 for the next 10 years, whereas HCT activity will likely continue to climb steadily. Healthcare and government authorities should be prepared to enable and support greater HCT activity in A&NZ in the future.     

Donor Experiences of Second Marrow or Peripheral Blood Stem Cell Collection Mirror the First,but CD34+ Yields Are Less

Little is known about the experiences of individuals donating peripheral blood stem cells (PBSCs) or marrow for a second time. To study this, unrelated donors making a second donation through the National Marrow Donor Program between 2004 and 2013 were evaluated. Experiences of second-time donors giving marrow (n?=?118: first donation was PBSC in 76 and marrow in 42) were compared with those making only 1 marrow donation (n?=?5829). Experiences of second-time donors giving PBSCs (n?=?602) (first donation was PBSCs in 362; marrow in 240) were compared to first-time PBSC donors (n?=?16,095). For donors giving a second PBSC or marrow donation there were no significant differences in maximum skeletal pain, maximum symptoms measured by an established modified toxicity criteria, and recovery time compared with those who donated only once. Notably, the yield of marrow nucleated cells and PBSC CD34⁺ cells with second donations was less. As previously noted with single first-time donations, female (PBSCs and marrow) and obese donors (PBSCs) had higher skeletal pain and/or toxicity with a second donation. PBSC donors who experienced high levels of pain or toxicity with the first donation also experienced high levels of these symptoms with their second donation and slower recovery times. In conclusion, for most donors second donation experiences were similar to first donation experiences, but CD34⁺ yields were less. Knowledge of the donor's first experience and stem cell yields may help centers decide whether second donations are appropriate and institute measures to improve donor experiences.     

Intestinal microbiota in infants at high risk for allergy: Effects of prebiotics and role in eczema development

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Analysis of time taken to discuss new patients with head and neck cancer in multidisciplinary team meetings

Multidisciplinary team (MDT) meetings have an important role in the management of head and neck cancer. Increasing incidence of the disease and a drive towards centralised meetings on large numbers of patients mean that effective discussions are pertinent. We aimed to evaluate new cases within a single high volume head and neck cancer MDT and to explore the relation between the time taken to discuss each case, the number of discussants, and type of case. A total of 105 patients with a new diagnosis of head and neck malignancy or complex benign tumour were discussed at 10 head and neck cancer MDT meetings. A single observer timed each discussion using a stopwatch, and recorded the number of discussants and the diagnosis and characteristics of each patient. Timings ranged from 15 to 480 s (8 min) with a mean of 119 s (2 min), and the duration of discussion correlated closely with the number of discussants (r_s = 0.63, p < 0.001). The longest discussions concerned patients with advanced T stage (p = 0.006) and advanced N stage (p = 0.009) disease, the elderly (p = 0.02) and male patients (p = 0.05). Tumour site and histological findings were not significant factors in the duration of discussion. Most discussions on patients with early stage tumours were short (T1: 58% less than 60 s, mean 90) and fewer people contributed. Many patients, particularly those with early stage disease, require little discussion, and their treatment might reasonably be planned according to an agreed protocol, which would leave more time and resources for those that require greater multidisciplinary input. Further studies may highlight extended discussions on patients with head and neck cancer, which may prompt a review of protocols and current evidence.     

Impaired oxygen on-kinetics in persons with human immunodeficiency virus are not due to highly active antiretroviral therapy

OBJECTIVE: To determine the effects of human immunodeficiency virus (HIV) and highly active antiretroviral therapy (HAART) on oxygen on-kinetics in HIV-positive persons. DESIGN: Quasi-experimental cross-sectional. SETTING: Infectious disease clinic and exercise laboratory. PARTICIPANTS: Referred participants (N=39) included 13 HIV-positive participants taking HAART, 13 HIV-positive participants not taking HAART, and 13 noninfected controls. INTERVENTIONS: Participants performed 1 submaximal exercise treadmill test below the ventilatory threshold, 1 above the ventilatory threshold, and 1 maximal treadmill exercise test to exhaustion. MAIN OUTCOME MEASURES: Change in oxygen consumption (Delta.VO2) and oxidative response index (Delta.VO2/mean response time). RESULTS: Delta.VO2 was significantly lower in both HIV-positive participants taking (946.5+/-68.1mL) and not taking (871.6+/-119.6mL) HAART than in controls (1265.3+/-99.8mL) during submaximal exercise above the ventilatory threshold. The oxidative response index was also significantly lower (P<.05) in HIV-positive participants both taking (15.0+/-1.3mL/s) and not taking (15.1+/-1.7mL/s) HAART than in controls (20.8+/-2.1mL/s) during exercise above the ventilatory threshold. CONCLUSION: Oxygen on-kinetics during submaximal exercise above the ventilatory threshold was impaired in HIV-positive participants compared with a control group, and it appeared that the attenuated oxygen on-kinetic response was primarily caused by HIV infection rather than HAART.