Long-term results and GvHD after prophylactic and preemptive donor lymphocyte infusion after allogeneic stem cell transplantation for acute leukemia

We report on 318 patients with acute leukemia, receiving donor lymphocyte infusion (DLI) in complete hematologic remission (CHR) after allogeneic stem cell transplantation (alloSCT). DLI were applied preemptively (preDLI) for minimal residual disease (MRD, n = 23) or mixed chimerism (MC, n = 169), or as prophylaxis in high-risk patients with complete chimerism and molecular remission (proDLI, n = 126). Median interval from alloSCT to DLI1 was 176 days, median follow-up was 7.0 years. Five-year cumulative relapse incidence (CRI), non-relapse mortality (NRM), leukemia-free and overall survival (LFS/OS) of the entire cohort were 29.1%, 12.7%, 58.2%, and 64.3%. Cumulative incidences of acute graft-versus-host disease (aGvHD) grade II–IV°/chronic GvHD were 11.9%/31%. Nineteen patients (6%) died from DLI-induced GvHD. Age ≥60 years (p = 0.046), advanced stage at transplantation (p = 0.003), shorter interval from transplantation (p = 0.018), and prior aGvHD ≥II° (p = 0.036) were risk factors for DLI-induced GvHD. GvHD did not influence CRI, but was associated with NRM and lower LFS/OS. Efficacy of preDLI was demonstrated by decreasing MRD/increasing blood counts in 71%, and increasing chimerism in 70%. Five-year OS after preDLI for MRD/MC was 51%/68% among responders, and 37% among non-responders. The study describes response and outcome of DLI in CHR and helps to identify candidates without increased risk of severe GvHD

Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Background: Limited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease. Methods: We retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML. Results: Complete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively (p = 0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2 years was 37% for FT, 24% for TBF, and 34% for FLAMSA (p = 0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology (p = 0.01; p = 0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III–IV aGVHD (p = 0.02) and cGVHD (p = 0.006), with no influence on relapse. Conclusions: In conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk

Traces of trauma – a multivariate pattern analysis of childhood trauma, brain structure and clinical phenotypes

Background: Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods: We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results: We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions: Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research

Constant innervation despite pubertal growth of the mouse penis

The sexual characteristics of the vertebrate body change under the control of sex hormones. In mammals, genitals undergo major changes in puberty. While such bodily changes have been well documented, the associated changes in the nervous system are poorly understood. To address this issue, we studied the growth and innervation of the mouse penis throughout puberty. To this end, we measured length and thickness of the mouse penis in prepubertal (3–4 week old) and adult (8–10 week old) mice and performed fiber counts of the dorsal penile nerve. We obtained such counts with confocal imaging of proximal sections of the mouse penis after paraffin embedding and antibody staining against Protein-Gene-Product-9.5 or Neurofilament-H in combination with antigen retrieval procedures. We find that the mouse penis grows roughly 1.4 times in both thickness and length. Fiber counts in the dorsal penile nerve were not different in prepubertal (1,620 ± 165 fibers per penis) and adult (1,572 ± 383 fibers per penis) mice, however. Antibody staining along with myelin staining by Luxol-Fast-Blue suggested about 57% of penile nerve fibers were myelinated. Quantification of the area of mouse somatosensory penis cortex allowed us to compare cortical magnification of the penile cortex and the whisker-barrel-cortex systems. This comparison suggested that 2 to 4 times less cortical area is devoted to a penile-nerve-fiber than to a whisker-nerve-fiber. The constant innervation of mouse penis through puberty suggests that the pubertal increase of cortical magnification of the penis is not simply a reflection of peripheral change.Peer Reviewe

Development of rat female genital cortex and control of female puberty by sexual touch

<div><p>Rat somatosensory cortex contains a large sexually monomorphic genital representation. Genital cortex undergoes an unusual 2-fold expansion during puberty. Here, we investigate genital cortex development and female rat sexual maturation. Ovariectomies and estradiol injections suggested sex hormones cause the pubertal genital cortex expansion but not its maintenance at adult size. Genital cortex expanded by thalamic afferents invading surrounding dysgranular cortex. Genital touch was a dominant factor driving female sexual maturation. Raising female rats in contact with adult males promoted genital cortex expansion, whereas contact to adult females or nontactile (audio-visual-olfactory) male cues did not. Genital touch imposed by human experimenters powerfully advanced female genital cortex development and sexual maturation. Long-term blocking of genital cortex by tetrodotoxin in pubescent females housed with males prevented genital cortex expansion and decelerated vaginal opening. Sex hormones, sexual experience, and neural activity shape genital cortex, which contributes to the puberty promoting effects of sexual touch.</p></div

Genital cortex growth is due to the invasion of dysgranular territories.

<p>(A) Upper panel: Map of somatosensory cortex (S1) obtained from a female aged postnatal day (P) 25. Genital cortex is labeled in black. The interlimb cortex is marked in grey. The upper red lines marks the forepaw axis. The lower red line is rectangular to the forepaw axis, terminates at the anterior end of the hindpaw representation, and was used to demarcate interlimb cortex. Lower panel: Corresponding for cytchrome c stained tangential section, which shows best the clitoris area. (B) Same as (A), but for an animal aged P48. Note that the interlimb cortex area is smaller than in the young animal and that the clitoris representation is larger. (C) Absolute area of the clitoris representation in hemispheres of young (P25) and old (P42) animals. The clitoris representation almost doubles in size. (D) Same as (C), but the absolute area of the interlimb cortex is plotted. The interlimb cortex is slightly smaller in area in old animals than in young animals. (E) The ratio of the genital cortex to the interlimb cortex increases after puberty in P42 animals. See also <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001283#pbio.2001283.s004" target="_blank">S4 Fig</a> and <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001283#pbio.2001283.s007" target="_blank">S1 Data</a>.</p

Pubertal expansion of genital cortex, but not its maintenance in adults requires sex hormones.

<p>(A) Outline of a somatosensory cortex (S1) map obtained from a female, aged postnatal day (P)25. Genital cortex is labeled in black. (B) Same as (A), but for an adult female (P42). Note the remarkable size difference of the genital cortex compared to the P25 female. (C) Outline of a S1 map from the brain of an adult female (P42), in which the ovaries were removed at P20. (D) Same as (B), but for an adult female (P60), in which the ovaries were removed at P42. The area of the genital cortex is similar to a nontreated adult female (B) and is bigger than in female rats ovariectomized before puberty (C). (E) Absolute area of clitoris in hemispheres of P25, P42 females, and females which were ovariectomized at either P20 or P42. (F) Fraction of genital cortex of the entire S1 in hemispheres of P25, P42 females, and females which were ovariectomized at either P20 or P42. Note that there is a substantial growth of the genital cortex between P25 and P42 animals. Female rats ovariectomized during prepuberty had smaller genital cortices than animals ovariectomized after puberty. (G) Absolute area of S1 in hemispheres of P25, P42, in prepuberty (P20) ovariectomized, and postpuberty (P42) ovariectomized female rats. See also <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001283#pbio.2001283.s001" target="_blank">S1</a> and <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001283#pbio.2001283.s002" target="_blank">S2</a> Figs, <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001283#pbio.2001283.s006" target="_blank">S1 Table</a>, and <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001283#pbio.2001283.s007" target="_blank">S1 Data</a>.</p

Artificial genital touch drives genital cortex expansion and promotes female sexual maturation.

<p>(A) Control, prepubescent female rats (postnatal day [P]23) were placed each day 3 times for 10 minutes in a box across 7 days without further treatment. (B) Artificial genital touch; prepubescent female rats (P23) were placed each day 3 times for 10 minutes in a box across for 7 days, and their clitoris and vulva were stroked with a lubricated brush by a human (female) experimenter. (C) Outline of a somatosensory cortex (S1) map from the brain of a P30 female who received the control treatment described in A. Genital cortex is depicted in black. (D) Same as (C), but example map stems from the brain of a P30 female, whose genitals were brushed as described in (B). (E), Absolute area of clitoris representation in hemispheres of P30 females, which underwent control (A) or artificial genital touch (B) treatment. (F) Same as (E), but the fraction of genital cortex of the S1 is plotted. (G) Same as (E), but the absolute area of S1 is shown for the 2 groups. There is no difference in S1 size. (H) Mean scores for vaginal opening for P30 females, which underwent control (A) or artificial genital touch (B) treatment. (I) Picture showing the uterus of a female, which underwent control (A) or artificial genital touch (B) treatment. (J) Uterine weights of females that underwent control (A) or artificial genital touch (B) treatment. See also <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001283#pbio.2001283.s007" target="_blank">S1 Data</a>.</p

Systemic estradiol application drives genital cortex growth and advances puberty.

<p>(A) Upper panel: Control rats received daily subcutaneous injection of sesame oil for 5 days (postnatal day [P]26–P30). Lower panel: Outline of a somatosensory cortex (S1) map from the brain of a P30 female treated only with oil. The genital cortex is labeled in black. (B) Same as (A), but prepubescent rats were injected with sesame oil containing estradiol. (C) Absolute area of the clitoris representation in hemispheres of P30 females, which received daily injections (over 5 days) of either sesame oil alone or sesame oil containing estradiol. The genital cortex appears bigger in the estradiol group. (D) Same as (C), but the fraction of genital cortex of the entire S1 is plotted. (E) Absolute area of S1 in hemispheres of animals that received either daily oil or estradiol injections. There is no difference between the 2 groups. (F) Pictures of clitoris and vagina, before and after sesame oil treatment. Note that the vagina stays closed at P30 when animals were injected with sesame oil alone. (G) Same as (F), but for the vagina of estradiol treated animals. The vagina is already open at P30 (lower picture). (H) Mean scores for vaginal opening. A score of 0 represents a closed vagina, whereas a score of 1 stands for an opened vagina. The intermediate state (between open and closed vagina) has a score of 0.5. The vagina stayed closed in almost all control animals (treated with oil) whereas the majority of estradiol animals, showed an open vagina at P30. Each dot represents the score of vaginal opening for one animal. (I) Uterus weights of oil and estradiol treated animals. The uterus in estradiol treated animals is heavier, although this difference was not significant. Each dot represents the uterus weight from one animal. See also <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001283#pbio.2001283.s003" target="_blank">S3 Fig</a> and <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001283#pbio.2001283.s007" target="_blank">S1 Data</a>.</p

Genital cortex growth in prepubescent females is accelerated by tactile cues from males.

<p>(A) Prepubescent animals (postnatal day [P]21) were cohoused for 9 days with either an adult, sexually experienced female (upper panel) or a sexually experienced adult male (middle panel). Whereas tactile contact was allowed in both of these groups, the third group of prepubescent rats was only exposed to olfactory (by a daily exchange of bedding between the cage compartments), visual, and auditory cues of a sexually experienced adult male (lower panel). (B) Upper panel: Outline of a somatosensory cortex (S1) map from the brain of a P30 female cohoused with a sexually experienced adult female. Genital cortex is labeled in black. Middle panel: Map from a brain of a P30 female cohoused with a sexually experienced adult male. Lower panel: Outline of a S1 map obtained from a P30 female exposed to olfactory, visual, and auditory cues but not tactile cues from a sexually experienced adult male. (C) Absolute area of genital cortex in hemispheres of P30 females cohoused with either a female (female and contact), a male (male and contact), or with a male without having tactile contact (male and no contact). Note that the size of genital cortex in the brains of animals who were cohoused in tactile contact with a male is significantly larger compared to the other 2 groups (female and contact, and male and no contact). (D) Same as (C), but the fraction of genital cortex of the entire S1 is shown. (E) Same as (C), but the absolute area of S1 is plotted. There is no difference between the 3 groups. See also <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001283#pbio.2001283.s007" target="_blank">S1 Data</a>.</p