The evolving art of hematopoietic stem cell transplantation: translational research in post-transplant immune reconstitution and immunosuppression

Immunologic Research - Allogeneic hematopoietic stem cell transplantation (SCT) offers the best chance for cure and/or long-term survival for a broad range of diseases, including many high-risk...     

Double-chimaerism after transplantation of two human leucocyte antigen mismatched,unrelated cord blood units

The small number of progenitor cells is the major limitation to the use of umbilical cord blood (UCB) for the transplantation of adults. We tested the hypothesis that two units transplanted simultaneously could each contribute to haematopoietic reconstitution. A patient with advanced acute lymphocytic leukaemia received a mismatched, unrelated UCB transplant using units from two donors after conditioning. The recipient achieved a complete remission without graft-versus-host disease. Double chimaerism was documented in several leucocyte subpopulations; both units contributed to haematopoiesis until relapse. Triple chimaerism was present from relapse until death due to leukaemia. This approach may potentially improve UCB transplantation outcome for adults lacking a histocompatible donor.     

The influence of a bupivacaine and fentanyl epidural infusion after epidural fentanyl in patients allowed to ambulate in early labor

Epidural fentanyl after a lidocaine and epinephrine test dose provides adequate analgesia and allows for ambulation during early labor. This study was designed to determine the influence of an epidural infusion of bupivacaine plus fentanyl administered after initiation of epidural labor analgesia with fentanyl. Specifically, we evaluated whether there is an increase in motor block or an increased time to request for further analgesic medication. Fifty-one laboring primigravid women at <5 cm cervical dilation who requested epidural analgesia were enrolled. After a 3-mL epidural test dose of 1.5% lidocaine with epinephrine (5 microg/mL), patients received fentanyl 100 microg via the epidural catheter. They then randomly received either an infusion (10 mL/h) of 0.0625% bupivacaine with fentanyl (3 microg/mL) or an infusion of preservative-free saline. After the administration of the initial analgesic, pain scores and side effects were recorded for each patient at 10, 20, and 30 min, every 30 min thereafter, and at the time of request for additional analgesic medication, by an observer blinded to the technique used. There were no demographic differences between the two groups. The mean duration of analgesia (time from initial dose to request for additional analgesia) was increased in the group that received a continuous infusion of bupivacaine and fentanyl compared with the Saline group (198 +/- 86 vs 145 +/- 50 min; P < 0.009). Side effects were similar between the two groups. No patient in either group experienced any detectable motor block. Fourteen patients chose to ambulate in the Saline group, and 12 patients chose to ambulate in the Infusion group. In early laboring patients, a continuous infusion of 0.0625% bupivacaine infusion with fentanyl (3 microg/mL) prolonged the duration until top-up was required, after epidural fentanyl 100 microg after a lidocaine and epinephrine test dose, and did not cause any clinically detectable motor block. IMPLICATIONS: A 0.0625% bupivacaine and fentanyl (3 microg/mL) infusion, when added to epidural fentanyl (100 microg), prolongs the analgesic duration without increasing motor block in women in early labor.     

Percutaneous Management of Renal Hydatidosis: A Minimally Invasive Therapeutic Option

We report 2 cases of percutaneous drainage and alcohol instillation of renal hydatid cysts. The feasibility of percutaneous management of renal hydatidosis, emphasizing its safety, efficacy and obvious advantages, is discussed.     

Impact of Cytomegalovirus Viral Load on Probability of Spontaneous Clearance and Response to Preemptive Therapy in Allogeneic Stem Cell Transplantation Recipients

The optimal viral load threshold at which to initiate preemptive cytomegalovirus (CMV) therapy in hematopoietic cell transplantation (HCT) recipients remains to be defined. In an effort to address this question, we conducted a retrospective study of 174 allogeneic HCT recipients who underwent transplantation at a single center between August 2012 and April 2016. During this period, preemptive therapy was initiated at the discretion of the treating clinician. A total of 109 patients (63%) developed CMV viremia. The median time to reactivation was 17 days (interquartile range, IQR, 7-30 days) post-HCT. A peak viremia ≥150?IU/mL was strongly associated with a reduced probability of spontaneous clearance (relative risk, .16; 95% confidence interval, .1-.27), independent of established clinical risk factors, including CMV donor serostatus, exposure to antithymocyte globulin, and underlying lymphoid malignancy. The median time to clearance of viremia was significantly shorter in those who started therapy at CMV <350?IU/mL (19 days; IQR, 11-35 days) compared with those who started antiviral therapy at higher viremia thresholds (33 days; IQR, 21-42 days; P?=?.02). The occurrence of treatment-associated cytopenias was frequent but similar in patients who started preemptive therapy at CMV <350?IU/mL and those who started at CMV >350?IU/mL (44% versus 57%; P?=?.42). Unresolved CMV viremia by treatment day 35 was associated with increased risk of therapeutic failure (32% versus 0%; P?=?.001). Achieving eradication of CMV viremia by treatment day 35 was associated with a 74% reduction in 1-year nonrelapse mortality (NRM) (adjusted hazard ratio [HR], .26; 95% confidence interval [CI], .1-.8; P?=?.02), whereas therapeutic failure was associated with a significant increase in the probability of 1-year NRM (adjusted HR, 26; 95% CI, 8-87; P?<.0001). We conclude that among allogeneic HCT patients, a peak CMV viremia ≥150?IU/mL is associated with a >80% reduction in the probability of spontaneous clearance independent of ATG administration, CMV donor serostatus, and lymphoid malignancy, and is a reasonable cutoff for preemptive therapy. Delaying initiation of therapy until a CMV value ≥350?IU/mL is associated with more protracted CMV viremia, and unresolved viremia by treatment day 35 is associated with a significant increase in NRM.     

Increases in free radicals and cytoskeletal protein oxidation and nitration in the colon of patients with inflammatory bowel disease

BACKGROUND: Overproduction of colonic oxidants contributes to mucosal injury in inflammatory bowel disease (IBD) but the mechanisms are unclear. Our recent findings using monolayers of intestinal cells suggest that the mechanism could be oxidant induced damage to cytoskeletal proteins. However, oxidants and oxidative damage have not been well characterised in IBD mucosa. AIMS: To determine whether there are increases in oxidants and in tissue and cytoskeletal protein oxidation in IBD mucosa. METHODS: We measured nitric oxide (NO) and markers of oxidative injury (carbonylation and nitrotyrosination) to tissue and cytoskeletal proteins in colonic mucosa from IBD patients (ulcerative colitis, Crohn's disease, specific colitis) and controls. Outcomes were correlated with IBD severity score. RESULTS: Inflamed mucosa showed the greatest increases in oxidants and oxidative damage. Smaller but still significant increases were seen in normal appearing mucosa of patients with active and inactive IBD. Tissue NO levels correlated with oxidative damage. Actin was markedly (>50%) carbonylated and nitrated in inflamed tissues of active IBD, less so in normal appearing tissues. Tubulin carbonylation occurred in parallel; tubulin nitration was not observed. NO and all measures of oxidative damage in tissue and cytoskeletal proteins in the mucosa correlated with IBD severity. Disruption of the actin cytoarchitecture was primarily within the epithelial cells and paracellular area. CONCLUSIONS: Oxidant levels increase in IBD along with oxidation of tissue and cytoskeletal proteins. Oxidative injury correlated with disease severity but is also present in substantial amounts in normal appearing mucosa of IBD patients, suggesting that oxidative injury does not necessarily lead to tissue injury and is not entirely a consequence of tissue injury. Marked actin oxidation (>50%)-which appears to result from cumulative oxidative damage-was only seen in inflamed mucosa, suggesting that oxidant induced cytoskeletal disruption is required for tissue injury, mucosal disruption, and IBD flare up.     

Focal rectal capillaritis: microscopic polyangiitis presenting as painless rectal bleeding

Microscopic polyangiitis is a pauci-immune, necrotizing, small-vessel vasculitis without evidence of granulomatous inflammation. Gastrointestinal involvement is rare and is predominantly limited to abdominal pain. Until now, the gold standard for diagnosis has been an invasive lung or kidney biopsy. We report the case of a 59-year-old woman with microscopic polyangiitis presenting as painless rectal bleeding, which was diagnosed by rectal mucosal biopsy. This is the first reported case of microscopic polyangiitis with initial presentation of rectal bleeding and diagnosis made by rectal mucosal biopsy.