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...     

A rare case of cellular schwannoma in the pharynx

Cellular schwannomas in pharyngeal region are rare. These tumors histologically mimic malignant peripheral nerve sheath tumors because of their growth pattern, high cellularity and mitotic activity, but they are relatively benign tumors with a tendency to recur but do not metastasize.     

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.     

Influence of breast cancer on thymic function in mice

The thymus is the major site of T cell maturation; extensive proliferation, differentiation, and apoptosis occur in this organ. During mammary tumorigenesis, there is a profound involution of the thymus associated with a severe depletion of the most abundant subset of thymocytes, CD4⁺8⁺ immature cells. Experiments to investigate the mechanism of loss of the CD4⁺8⁺ population indicated that there was no increase in the systemic levels of glucocorticoids, no loss of bone marrow precursors, and no decrease in precursor seeding of the thymus. Likewise, no enhanced emigration of thymocytes from the thymus to the periphery was observed in tumor-bearing mice. A slight increase in apoptosis was found in tumor bearers' thymi, but there was no apparent decrease in the proliferation of early thymic precursors CD4^–8^– cells. Importantly, severely altered levels of subpopulations of the CD4^–8^– precursors, consistent with an arrest in differentiation at an early stage of development, were detected. Moreover, thymic stromal cell function appeared to become impaired during tumorigenesis, possibly due to the action of tumor-derived factors. Thus, downregulation of cell-mediated immune functions occurring at late stages of the disease may be causally related to the thymic involution occurring during mammary tumorigenesis.     

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.     

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.