Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation.

ABSTRACT: Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.

Cortical gyrification in women and men and the (missing) link to prenatal androgens.

Previous studies have reported sex differences in cortical gyrification. Since most cortical folding is principally defined in utero, sex chromosomes as well as gonadal hormones are likely to influence sex-specific aspects of local gyrification. Classic congenital adrenal hyperplasia (CAH) causes high levels of androgens during gestation in females, whereas levels in males are largely within the typical male range. Therefore, CAH provides an opportunity to study the possible effects of prenatal androgens on cortical gyrification. Here, we examined the vertex-wise absolute mean curvature-a common estimate for cortical gyrification-in individuals with CAH (33 women and 20 men) and pair-wise matched controls (33 women and 20 men). There was no significant main effect of CAH and no significant CAH-by-sex interaction. However, there was a significant main effect of sex in five cortical regions, where gyrification was increased in women compared to men. These regions were located on the lateral surface of the brain, specifically left middle frontal (rostral and caudal), right inferior frontal, left inferior parietal, and right occipital. There was no cortical region where gyrification was increased in men compared to women. Our findings do not only confirm prior reports of increased cortical gyrification in female brains but also suggest that cortical gyrification is not significantly affected by prenatal androgen exposure. Instead, cortical gyrification might be determined by sex chromosomes either directly or indirectly-the latter potentially by affecting the underlying architecture of the cortex or the size of the intracranial cavity, which is smaller in women.

JAK Inhibitors in Cytokine Storm Syndromes.

Cytokine storm syndromes (CSSs) comprise a group of severe and often fatal hyperinflammatory conditions driven by the overproduction of pro-inflammatory cytokines by activated cells of the immune system. Many of the CSS-associated cytokines mediate their downstream effects by signaling through the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). In addition, several of these cytokines are produced downstream of JAK/STAT pathway activation. Therefore, targeting JAK/STAT signaling using small molecule JAK inhibitors has become an increasingly appealing therapeutic option to dampen hyperinflammation in patients with CSSs. Application of JAK inhibitors in preclinical CSS models has shown improvements in multiple sequelae of hyperinflammation, and there is growing clinical evidence supporting the efficacy of JAK inhibition in patients with these conditions. Although generally well tolerated, JAK inhibitor use is not without potential for toxicity, especially in settings like CSSs where end-organ dysfunction is common. More prospective clinical trials incorporating JAK inhibitors, alone or in combination with other immunomodulatory therapies, are necessary to determine the optimal dosing, schedule, efficacy, and tolerability of these agents for patients experiencing CSSs.

The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

OBJECTIVE: Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS. METHODS: A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS. RESULTS: The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance. CONCLUSION: These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.

Androgens and child behavior: Color and toy preferences in children with congenital adrenal hyperplasia (CAH).

Human males and females show average gender/sex differences for certain psychological phenomena. Multiple factors may contribute to these differences, including sex chromosomes, exposure to gonadal hormones, and socialization or learning. This study investigated potential hormonal and socialization/learning influences on gender/sex differences in childhood preferences for color, specifically pink and red vs. blues, and for toys. Children (aged 4 to 11 years) with congenital adrenal hyperplasia (CAH, n = 43 girls and 37 boys), marked by elevated prenatal adrenal androgen exposure, and without CAH (n = 41 girls and 31 boys) were studied. Prior research indicates girls with CAH are masculinized for certain behaviors, such as toy choices, while boys with CAH generally do not differ from boys without CAH. In the current study, children indicated preferences for stereotyped hues of pink vs. blue as well as two control color pairs. They also indicated their preference between gender/sex-typed toys (doll vs. car) presented in black and white, in gender/sex-congruent colors (pink doll vs. blue car) and in gender/sex-incongruent colors (pink car vs. blue doll). Color findings: Control girls preferred stereotyped pink over blue more than boys or girls with CAH did; the latter two groups did not differ in their color preferences. No preference differences occurred for other color pairs. Toy findings: In black/white or gender/sex-congruent colors, boys preferred the car more than control girls or girls with CAH did, while girls with CAH preferred the car more than control girls did. In gender/sex-incongruent colors (pink car vs. blue doll), boys still preferred the car, while girls with CAH showed reduced and control girls showed increased preferences for the pink car compared to the car preferences in black/white. Results support learning theories of color preferences, perhaps also influenced by pre-existing toy preferences which may occur for other reasons, including early androgen exposure. Specifically, girls with CAH may have learned they do not enjoy stereotypical toys for girls, often colored pink, and pink coloring may subsequently diminish their preference for a car. Our results highlight the importance of gonadal hormones and learning in the development of childhood toy and color preferences.

Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults.

OBJECTIVE: Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome that often requires critical care support and remains difficult to diagnose. These guidelines are meant to aid in the early recognition, diagnosis, supportive care, and treatment of patients with hemophagocytic lymphohistiocytosis in ICUs. DATA SOURCES: The literature searches were performed with PubMed (MEDLINE). STUDY SELECTION: Keywords and medical subject headings terms for literature search included "macrophage activation syndrome," hemophagocytic lymphohistiocytosis," and "hemophagocytic syndrome." DATA EXTRACTION: The Histiocyte Society developed these consensus recommendations on the basis of published reports and expert opinions with level of evidence provided for each recommendation. They were endorsed by the Society of Critical Care Medicine. DATA SYNTHESIS: Testing for hemophagocytic lymphohistiocytosis should be initiated promptly in all patients admitted to ICUs with an unexplained or disproportionate inflammatory response, especially those with rapid clinical deterioration. Meeting five or more of eight hemophagocytic lymphohistiocytosis 2004 diagnostic criteria serves as a valuable diagnostic tool for hemophagocytic lymphohistiocytosis. Early aggressive critical care interventions are often required to manage the multisystem organ failure associated with hemophagocytic lymphohistiocytosis. Thorough investigation of the underlying triggers of hemophagocytic lymphohistiocytosis, including infections, malignancies, and autoimmune/autoinflammatory diseases, is essential. Early steroid treatment is indicated for patients with familial hemophagocytic lymphohistiocytosis and is often valuable in patients with acquired hemophagocytic lymphohistiocytosis (i.e., secondary hemophagocytic lymphohistiocytosis) without previous therapy, including macrophage activation syndrome (hemophagocytic lymphohistiocytosis secondary to autoimmune/autoinflammatory disease) without persistent or relapsing disease. Steroid treatment should not be delayed, particularly if organ dysfunction is present. In patients with macrophage activation syndrome, whose disease does not sufficiently respond, interleukin-1 inhibition and/or cyclosporine A is recommended. In familial hemophagocytic lymphohistiocytosis and severe, persistent, or relapsing secondary macrophage activation syndrome, the addition of prompt individualized, age-adjusted etoposide treatment is recommended. CONCLUSIONS: Further studies are needed to determine optimal treatment for patients with hemophagocytic lymphohistiocytosis in ICUs, including the use of novel and adjunct therapies.

Neuroscience and Sex/Gender: Looking Back and Forward.

Phoenix et al. (1959) reported that treating pregnant guinea pigs with testosterone had enduring effects on the sex-related behavior of their female offspring. Since then, similar enduring effects of early testosterone exposure have been found in other species, including humans, and for other behaviors that show average sex differences. In humans, the affected outcomes include gender identity, sexual orientation, and children's sex-typical play behavior. The evidence linking early testosterone exposure to sex-typed play is particularly robust, and sex-typed play is also influenced by many other factors, including socialization by parents and peers and self-socialization, based on cognitive understanding of gender. In addition to influencing behavior, testosterone and hormones produced from testosterone affect mammalian brain structure. Studies using human autopsy material have found some sex differences in the human brain similar to those seen in other species, and have reported that some brain sex differences correlate with sexual orientation or gender identity, although the causes of these brain/behavior relationships are unclear. Studies that have imaged the living human brain have found only a small number of sex differences, and these differences are generally small in magnitude. In addition, they have not been linked to robust psychological or behavioral sex differences. Future research might benefit from improved imaging technology, and attention to other brain characteristics. In addition, it might usefully explore how different types of factors, such as early testosterone exposure and parental socialization, work together in the developmental system that produces sex/gender differences in human brain and behavior.

Hemophagocytic lymphohistiocytosis-like toxicity (carHLH) after CD19-specific CAR T-cell therapy.

Chimeric antigen receptor T-cell (CAR T-cell) therapy is associated with significant toxicities secondary to immune activation, including a rare but increasingly recognised severe toxicity resembling haemophagocytic lymphohistiocytosis (carHLH). We report the development of carHLH in 14·8% of paediatric patients and young adults treated with CD19-specific CAR T-cell therapy with carHLH, occurring most commonly in those with high disease burden. The diagnosis and treatment of carHLH required a high index of suspicion and included multidrug immunomodulation with variable response to therapies. Compared to patients without carHLH, patients with carHLH had both reduced response to CAR T-cell therapy (P-value = 0·018) and overall survival (P-value = < 0·0001).

Recommendations for the management of hemophagocytic lymphohistiocytosis in adults.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.

Prenatal androgen exposure and children's gender-typed behavior and toy and playmate preferences.

We report findings from two studies investigating possible relations of prenatal androgen exposure to a broad measure of children's gender-typed behavior, as well as specifically to children's toy and playmate preferences. Study 1 investigated these outcomes for 43 girls and 38 boys, aged 4 to 11 years, with congenital adrenal hyperplasia (CAH, a genetic condition causing increased adrenal androgen production beginning prenatally) compared to similarly-aged, unaffected relatives (41 girls, 31 boys). The predicted sex differences were found for all of the outcome measures. Furthermore, girls with CAH showed increased male-typical and decreased female-typical behavior and toy and playmate preferences compared to unaffected girls. Study 2 investigated the relationship of amniotic fluid testosterone to gender-typed behavior and toy and playmate preferences in typically developing children (48 girls, 44 boys) aged 3 to 5 years. Although the predicted sex differences were found for all of the outcome measures, amniotic fluid testosterone was not a significant correlate, in the predicted direction, of any outcome measure for either sex. The results of study 1 provide additional support for an influence of prenatal androgen exposure on children's gender-typed behavior, including toy and playmate preferences. The results of study 2 do not, but amniotic fluid testosterone may be an insufficiently sensitive measure of early androgen exposure. A more sensitive and reliable measure of prenatal androgen exposure may be needed to consistently detect relations to later gender typed behavior in non-clinical populations.

No relationship between prenatal or early postnatal androgen exposure and autistic traits: evidence using anogenital distance and penile length measurements at birth and 3 months of age.

BACKGROUND: Autism is more prevalent in males than in females. Hypotheses related to the extreme male brain theory of autism suggest that heightened androgen exposure during early development contributes to autistic traits. Whilst prior research focused mostly on the prenatal period, the current study tests the influences of androgen exposure during both the prenatal and the early postnatal periods on autistic traits during childhood. METHODS: Anthropometric measures that are putative biomarkers of early androgen exposure were employed. Anogenital distance (AGD) was measured at birth and 3 months of age in boys and girls. Penile length at birth and 3 months of age was also measured in boys. When the children were 9-13 years old, a parent-reported questionnaire (the 10-item children's version of the Autism Spectrum Quotient; AQ-10 Child) was used to assess autistic traits in 97 boys and 110 girls. RESULTS: There were no significant associations between any of the AGD or penile length measures and scores on the AQ-10 Child in boys, girls or the entire sample. CONCLUSIONS: The current study provides the first test of whether early measurements of AGD and/or penile length predict subsequent autistic traits. The current findings do not support a relationship between prenatal or early postnatal androgen exposure and autistic traits. The current study augments prior research showing no consistent relationship between early androgen exposure and autistic traits.

Cultural Components of Sex Differences in Color Preference.

Preferences for pink and blue were tested in children aged 4-11 years in three small-scale societies: Shipibo villages in the Peruvian Amazon, kastom villages in the highlands of Tanna Island, Vanuatu, and BaYaka foragers in the northern Republic of Congo; and compared to children from an Australian global city (total N = 232). No sex differences were found in preference for pink in any of the three societies not influenced by global culture (ds - 0.31-0.23), in contrast to a female preference for pink in the global city (d = 1.24). Results suggest that the pairing of female and pink is a cultural phenomenon and is not driven by an essential preference for pink in girls.

Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis.

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.

No Evidence for Enhancement of Spatial Ability with Elevated Prenatal Androgen Exposure in Congenital Adrenal Hyperplasia: A Meta-Analysis.

Spatial abilities contribute to life and occupational competencies, and certain spatial skills differ, on average, between males and females, typically favoring males when differences occur. Factors contributing to spatial skills could include prenatal as well as experiential/cultural influences, with biological and social influences likely interacting and difficult to disentangle. This meta-analysis examined the potential influence of prenatal androgen exposure on spatial skill by examining studies of patients with congenital adrenal hyperplasia (CAH). CAH involves elevated adrenal androgens prenatally, with overall androgen concentrations higher for females with CAH versus same-sex controls but with little overall difference between males with CAH versus controls. We hypothesized that, if androgens contribute prenatally to neurobehavioral development in humans as in many other species, females with CAH would show spatial enhancement versus control females, but with no definitive hypothesis for males. Meta-analysis of 12 studies examining overall spatial skill and three spatial subcategories failed to support enhanced spatial performance for females with CAH; males with CAH showed lower spatial ability compared to control males, at least for the category of overall spatial skill. Although statistical logic precludes accepting the null hypothesis for females, the meta-analysis failed to support the idea that prenatal exposure to androgens explains spatial gender/sex differences in humans. Alternative explanations for average gender/sex differences in some spatial tasks could include androgen exposure at other times, such as mini-puberty, or different social factors experienced by males and females. We also discuss possible explanations for the different outcomes seen in females versus males with CAH.

How Large Are Gender Differences in Toy Preferences? A Systematic Review and Meta-Analysis of Toy Preference Research.

It is generally recognized that there are gender-related differences in children's toy preferences. However, the magnitude of these differences has not been firmly established. Furthermore, not all studies of gender-related toy preferences find significant gender differences. These inconsistent findings could result from using different toys or methods to measure toy preferences or from studying children of different ages. Our systematic review and meta-analysis combined 113 effect sizes from 75 studies to estimate the magnitude of gender-related differences in toy preferences. We also assessed the impact of using different toys or methods to assess these differences, as well as the effect of age on gender-related toy preferences. Boys preferred boy-related toys more than girls did, and girls preferred girl-related toys more than boys did. These differences were large (d ≥ 1.60). Girls also preferred toys that researchers classified as neutral more than boys did (d = 0.29). Preferences for gender-typical over gender-atypical toys were also large and significant (d ≥ 1.20), and girls and boys showed gender-related differences of similar magnitude. When only dolls and vehicles were considered, within-sex differences were even larger and of comparable size for boys and girls. Researchers sometimes misclassified toys, perhaps contributing to an apparent gender difference in preference for neutral toys. Forced choice methods produced larger gender-related differences than other methods, and gender-related differences increased with age.

The effects of oxygen-induced phase segregation on the interfacial electronic structure and quantum efficiency of Cs3Sb photocathodes.

High-performance photocathodes for many prominent particle accelerator applications, such as x-ray free-electron lasers, cannot be grown in situ. These highly reactive materials must be grown and then transported to the electron gun in an ultrahigh-vacuum (UHV) suitcase, during which time monolayer-level oxidation is unavoidable. Thin film Cs3Sb photocathodes were grown on a variety of substrates. Their performance and chemical state were measured by x-ray photoelectron spectroscopy after transport in a UHV suitcase as well as after O2-induced oxidation. The unusual chemistry of cesium oxides enabled trace amounts of oxygen to drive structural reorganization at the photocathode surface. This reorganization pulled cesium from the bulk photocathode, leading to the development of a structurally complex and O2-exposure-dependent cesium oxide layer. This oxidation-induced phase segregation led to downward band bending of at least 0.36 eV as measured from shifts in the Cs 3d5/2 binding energy. At low O2 exposures, the surface developed a low work function cesium suboxide overlayer that had little effect on quantum efficiency (QE). At somewhat higher O2 exposures, the overlayer transformed to Cs2O; no antimony or antimony oxides were observed in the near-surface region. The development of this overlayer was accompanied by a 1000-fold decrease in QE, which effectively destroyed the photocathode via the formation of a tunnel barrier. The O2 exposures necessary for degradation were quantified. As little as 100 L of O2 irreversibly damaged the photocathode. These observations are discussed in the context of the rich chemistry of alkali oxides, along with potential material strategies for photocathode improvement.

A multicenter study of patients with multisystem Langerhans cell histiocytosis who develop secondary hemophagocytic lymphohistiocytosis.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.

Gender development and the human brain.

Convincing evidence indicates that prenatal exposure to the gonadal hormone, testosterone, influences the development of children's sex-typical toy and activity interests. In addition, growing evidence shows that testosterone exposure contributes similarly to the development of other human behaviors that show sex differences, including sexual orientation, core gender identity, and some, though not all, sex-related cognitive and personality characteristics. In addition to these prenatal hormonal influences, early infancy and puberty may provide additional critical periods when hormones influence human neurobehavioral organization. Sex-linked genes could also contribute to human gender development, and most sex-related characteristics are influenced by socialization and other aspects of postnatal experience, as well. Neural mechanisms underlying the influences of gonadal hormones on human behavior are beginning to be identified. Although the neural mechanisms underlying experiential influences remain largely uninvestigated, they could involve the same neural circuitry as that affected by hormones.

Secondary hemophagocytic syndrome after autologous hematopoietic cell transplant and immune therapy for neuroblastoma.

Secondary hemophagocytic syndrome (HPS) has been described after autologous hematopoietic cell transplant (AutoHCT). We report two cases of secondary HPS after novel consolidation therapy for high-risk neuroblastoma as part of an institutional phase 2 trial incorporating immunotherapy into a "standard" AutoHCT regimen. Both patients developed liver dysfunction beyond expected course of hepatic veno-occlusive disease, coagulopathy, hyperferritinemia, and when evaluated, elevated soluble interleukin-2 receptor and hemophagocytosis. These cases highlight the need for clinicians to have a high index of suspicion for immune-related complications in patients receiving immune therapies.

Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO).

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.