The outcome of allogeneic HCT is dependent on several pre-transplant variables. We hypothesize that these pre-transplant factors may influence the donor/host chimerism post HCT, which in its turn may ...affect the outcome. We performed an analysis to study lineage specific D/H chimerism patterns of total blood leukocytes, myeloid cells/neutrophils, B-cells, NK-cells and T-cells.
All consecutive patients who underwent an allogeneic HCT between 01/2010 to 06/2015 on the Pediatric BMT Service at MSKCC were reviewed. Chimerism analyses were performed by short tandem repeat (STR) polymorphism analysis at the American Red Cross Blood Services (Philadelphia, PA). Lineage specific donor chimerism post HCT was studied including donor chimerism trend, and factors with potential impact on chimerism including: age, disease, graft source, and T-cell depletion (TCD). Preliminary analyzes performed on this cohort included Wilcoxon Rank Test and cox proportional hazard analyses.
140 patients with a median age of 11.5 years were included. They included 97 patients with hematologic malignancies, 27 patients with non-malignant hematologic disorders and 16 patients with immunologic disorders. Cytoreduction included TBI in 48 patients or chemotherapy only in 98 patients. 105 patients received T-cell depleted grafts, 28 patients unmodified marrow or peripheral blood grafts, and 7 patients unrelated cord blood grafts. No patients received donor leukocyte infusions (DLI).
Observational studies revealed that full donor chimerism of myeloid cells, B-cells and NK-cells, but not T-cells occurred early post-transplant. In Wilcoxon Rank Test, there was no difference in the percentage of total donor leukocytes at 3 months vs 12 months post HSCT (n=30), while the median of donor T-cell chimerism was 51% at 3 months and 91% at 12 months post HSCT (p<0.0001, n=42). For most grafts, full donor chimerism of T-cells occurred early, while for T-cell depleted transplants, it took up to one year to complete. Cord blood grafts were associated with high T-cell donor chimerism throughout the post-transplant period.
The studies of the impact of different factors on chimerism were performed, including age, disease, and type of graft. Loss of donor total leukocytes chimerism between 3 and 12 months post-transplant was significantly more pronounced for patients < 3 years of age (p=0.01) and for patients with nonmalignant disorders (p=0.007, n=30).
This preliminary analysis of lineage specific chimerism post-transplant showed that donor T-cells may take one year to fully recover post-transplant, mostly following T-cell depleted grafts, without intervention. Cord blood grafts were associated with high donor chimerism throughout the post-transplant period. Lastly, factors associated with loss of donor chimerism post-transplant were younger age and non-malignant disorders. More in-depth analyses are being performed.
In the premature infant, somatosensory and visual stimuli trigger an immature electroencephalographic (EEG) pattern, "delta-brushes," in the corresponding sensory cortical areas. Whether auditory ...stimuli evoke delta-brushes in the premature auditory cortex has not been reported. Here, responses to auditory stimuli were studied in 46 premature infants without neurologic risk aged 31 to 38 postmenstrual weeks (PMW) during routine EEG recording. Stimuli consisted of either low-volume technogenic "clicks" near the background noise level of the neonatal care unit, or a human voice at conversational sound level. Stimuli were administrated pseudo-randomly during quiet and active sleep. In another protocol, the cortical response to a composite stimulus ("click" and voice) was manually triggered during EEG hypoactive periods of quiet sleep. Cortical responses were analyzed by event detection, power frequency analysis and stimulus locked averaging. Before 34 PMW, both voice and "click" stimuli evoked cortical responses with similar frequency-power topographic characteristics, namely a temporal negative slow-wave and rapid oscillations similar to spontaneous delta-brushes. Responses to composite stimuli also showed a maximal frequency-power increase in temporal areas before 35 PMW. From 34 PMW the topography of responses in quiet sleep was different for "click" and voice stimuli: responses to "clicks" became diffuse but responses to voice remained limited to temporal areas. After the age of 35 PMW auditory evoked delta-brushes progressively disappeared and were replaced by a low amplitude response in the same location. Our data show that auditory stimuli mimicking ambient sounds efficiently evoke delta-brushes in temporal areas in the premature infant before 35 PMW. Along with findings in other sensory modalities (visual and somatosensory), these findings suggest that sensory driven delta-brushes represent a ubiquitous feature of the human sensory cortex during fetal stages and provide a potential test of functional cortical maturation during fetal development.
Extensions in the field of joint modeling of correlated data and dynamic predictions improve the development of prognosis research. The R package frailtypack provides estimations of various joint ...models for longitudinal data and survival events. In particular, it fits models for recurrent events and a terminal event (frailtyPenal), models for two survival outcomes for clustered data (frailtyPenal), models for two types of recurrent events and a terminal event (multivPenal), models for a longitudinal biomarker and a terminal event (longiPenal) and models for a longitudinal biomarker, recurrent events and a terminal event (trivPenal). The estimators are obtained using a standard and penalized maximum likelihood approach, each model function allows to evaluate goodness-of-fit analyses and plots of baseline hazard functions. Finally, the package provides individual dynamic predictions of the terminal event and evaluation of predictive accuracy. This paper presents theoretical models with estimation techniques, applies the methods for predictions and illustrates frailtypack functions details with examples.
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