What proportion of the brain structural and functional abnormalities observed among children with fetal alcohol spectrum disorder is explained by their prenatal alcohol exposure and their other prenatal and postnatal risks?

BACKGROUND: Individuals with prenatal alcohol exposure (PAE) often present with a myriad of other prenatal (e.g. exposure to tobacco and other illicit drugs, poor prenatal care) and postnatal risk factors (e.g. multiple home placements, physical/sexual abuse, low socio-economic status)-all of which are likely contributing to their adverse outcomes. METHODS: A comprehensive neuropsychological battery, coupled with magnetic resonance imaging, was administered to children with fetal alcohol spectrum disorders (FASD) in 2009. Study participants diagnosed with FASD by the University of Washington using the FASD 4-Digit Code were compared to typically-developing peers with no PAE. Data from this MRI study were used to explore the proportion of variance in brain structural and functional abnormalities explained by PAE and 14 other prenatal and postnatal risk factors. RESULTS: PAE was the dominant risk factor explaining the largest proportion of variance in regional brain size (total brain, frontal lobe, caudate, hippocampus and corpus callosum) and brain function (intellect, achievement, memory, language, executive-function, motor, adaptation, behavior-attention and mental health symptoms). Other prenatal and postnatal risk factors were 3 to 7-fold more prevalent than in the general population. Individually, each risk factor explained a statistically significant, but smaller proportion of variance in brain outcome compared to PAE. In combination, the proportion of variance explained by the presence of multiple prenatal and postnatal risks rivaled that of PAE. CONCLUSION: A better understanding of the impact other prenatal and postnatal risk factors have on the neurodevelopmental outcomes of individuals with FASD can inform more effective prevention and intervention strategies.

Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero.

Importance: The developmental origins of mental illness are incompletely understood. Although the development of autism and schizophrenia are linked to infections during fetal life, it is unknown whether more common psychiatric conditions such as depression might begin in utero. Objective: To estimate the risk of psychopathologic conditions imparted from fetal exposure to any maternal infection while hospitalized during pregnancy. Design, Setting, and Participants: A total of 1 791 520 Swedish children born between January 1, 1973, and December 31, 2014, were observed for up to 41 years using linked population-based registries. Children were excluded if they were born too late to contribute person-time, died before being at risk for the outcome, or were missing particular model data. Infection and psychiatric diagnoses were derived using codes from hospitalizations. Directed acyclic graphs were developed from a systematic literature review to determine Cox proportional hazards regression models for risk of psychopathologic conditions in the children. Results were evaluated using probabilistic and simple bias analyses. Statistical analysis was conducted from February 10 to October 17, 2018. Exposures: Hospitalization during pregnancy with any maternal infection, severe maternal infection, and urinary tract infection. Main Outcomes and Measures: Inpatient diagnosis of autism, depression, bipolar disorder, or psychosis among offspring. Results: A total of 1 791 520 Swedish-born children (48.6% females and 51.4% males) were observed from birth up to age 41 years, with a total of 32 125 813 person-years. Within the directed acyclic graph framework of assumptions, fetal exposure to any maternal infection increased the risk of an inpatient diagnosis in the child of autism (hazard ratio [HR], 1.79; 95% CI, 1.34-2.40) or depression (HR, 1.24; 95% CI, 1.08-1.42). Effect estimates for autism and depression were similar following a severe maternal infection (autism: HR, 1.81; 95% CI, 1.18-2.78; depression: HR, 1.24; 95% CI, 0.88-1.73) or urinary tract infection (autism: HR, 1.89; 95% CI, 1.23-2.90; depression: HR, 1.30; 95% CI, 1.04-1.61) and were robust to moderate unknown confounding. Within the directed acyclic graph framework of assumptions, the relationship between infection and depression was vulnerable to bias from loss to follow-up, but separate data from the Swedish Death Registry demonstrated increased risk of suicide among individuals exposed to pregnancy infection. No evidence was found for increased risk of bipolar disorder or psychosis among children exposed to infection in utero. Conclusions and Relevance: These findings suggest that fetal exposure to a maternal infection while hospitalized increased the risk for autism and depression, but not bipolar or psychosis, during the child's life. These results emphasize the importance of avoiding infections during pregnancy, which may impart subtle fetal brain injuries contributing to development of autism and depression.

The Aftermath of Zika: Need for Long-Term Monitoring of Exposed Children.

Pregnancy infections with Zika virus are associated with a spectrum of fetal brain injuries beyond microcephaly. Nonmicrocephalic children exposed to Zika virus in utero or early life should undergo neurodevelopmental testing to identify deficits and allow for early intervention. Additionally, long-term monitoring for higher order neurocognitive deficits should be implemented.

Twin study confirms virtually identical prenatal alcohol exposures can lead to markedly different fetal alcohol spectrum disorder outcomes-fetal genetics influences fetal vulnerability.

BACKGROUND: Risk of fetal alcohol spectrum disorder (FASD) is not based solely on the timing and level of prenatal alcohol exposure (PAE). The effects of teratogens can be modified by genetic differences in fetal susceptibility and resistance. This is best illustrated in twins. OBJECTIVE: To compare the prevalence and magnitude of pairwise discordance in FASD diagnoses across monozygotic twins, dizygotic twins, full-siblings, and half-siblings sharing a common birth mother. METHODS: Data from the Fetal Alcohol Syndrome Diagnostic & Prevention Network clinical database was used. Sibling pairs were matched on age and PAE, raised together, and diagnosed by the same University of Washington interdisciplinary team using the FASD 4-Digit Code. This design sought to assess and isolate the role of genetics on fetal vulnerability/resistance to the teratogenic effects of PAE by eliminating or minimizing pairwise discordance in PAE and other prenatal/postnatal risk factors. RESULTS: As genetic relatedness between siblings decreased from 100% to 50% to 50% to 25% across the four groups (9 monozygotic, 39 dizygotic, 27 full-sibling and 9 half-sibling pairs, respectively), the prevalence of pairwise discordance in FASD diagnoses increased from 0% to 44% to 59% to 78%. Despite virtually identical PAE, 4 pairs of dizygotic twins had FASD diagnoses at opposite ends of the fetal alcohol spectrum-Partial Fetal Alcohol Syndrome versus Neurobehavioral Disorder/Alcohol-Exposed. CONCLUSION: Despite virtually identical PAE, fetuses can experience vastly different FASD outcomes. Thus, to protect all fetuses, especially the most genetically vulnerable, the only safe amount to drink is none at all.

Spontaneous tumor lysis syndrome in acute myeloid leukemia: two cases and a review of the literature.

Spontaneous tumor lysis syndrome (TLS) is a constellation of electrolyte abnormalities and acute renal failure, which occurs in the setting of rapid cell turnover prior to the administration of cytotoxic chemotherapy. While spontaneous TLS is well described in patients with Burkitt's lymphoma, it is thought to occur less commonly in other hematologic malignancies. We present two cases of spontaneous TLS in patients with newly diagnosed acute myeloid leukemia (AML) followed by a review of the literature in this field.

Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era.

BACKGROUND: Trastuzumab is associated with improvements in overall survival (OS) among patients with HER2-positive metastatic breast cancer (MBC); however disease course and patterns of care in individual patients are highly variable. METHODS: 113 HER2-positive patients diagnosed with MBC from 1999 to 2005 who received trastuzumab-based therapy were retrospectively identified to allow for a minimum of 5 years of follow-up time. Median OS and median duration of therapy were determined using Kaplan-Meier methodology and group comparisons were based on the log-rank test. Hazard ratios (HR) were obtained using a Cox proportional hazards model. RESULTS: Median OS was 3.5 years (95% CI 3.0-4.4) from time of initiation of first therapy in the metastatic setting. On univariate analysis, central nervous system (CNS) disease at first recurrence was associated with a shorter OS compared with liver and/or lung metastases or other sites (CNS: 1.9 years CI 0.1-5.9, liver/lung: 3.2 years CI 2.5-4.2, other: 4.6 years CI 2.7-8.0; p = 0.05), however, this was not predictive of survival outcome in multivariate analysis. CNS metastases developed in 62 (55%) patients by the time of death or last follow-up. Median duration of therapy was similar up to 6 lines of treatment, and ranged from 5.2 months to 7.2 months. CONCLUSIONS: The natural history of HER2-positive MBC has evolved with trastuzumab-based therapy with median OS now exceeding 3 years. CNS disease is a major problem with continued risk of CNS progression over time. Patients demonstrate clinical benefit to multiple lines of HER2-directed therapy.

Clinicopathological features among patients with advanced human epidermal growth factor-2-positive breast cancer with prolonged clinical benefit to first-line trastuzumab-based therapy: a retrospective cohort study.

BACKGROUND: The magnitude of benefit of trastuzumab for the treatment of advanced HER2-positive breast cancer varies widely. In this retrospective study, we investigated the clinicopathological features associated with prolonged first-line trastuzumab-based treatment duration. PATIENTS AND METHODS: A total of 164 patients diagnosed with advanced HER2-positive breast cancer and treated with first-line trastuzumab-based therapy from 1999 to 2009 were identified. Duration of treatment was classified according to tertiles. Different logistic regression models including age, disease-free interval, number of metastatic sites, visceral disease, hormone receptor, and adjuvant trastuzumab were fitted to investigate associations with benefit of prolonged trastuzumab-based therapies. The predictive value of each model was assessed using C-statistics. RESULTS: At a median follow-up of 5.8 years (range, 0.7-22.1 years), patients in the short-, intermediate-, and long-term treatment duration groups were given first-line trastuzumab-based therapy for < 7.2 months, 7.2 to 14 months, and > 14 months, respectively. In the multivariate analysis, patients with long-term clinical benefit had a higher likelihood of having hormone receptor-positive tumors (odds ratio [OR]positive vs. negative = 2.39 [95% confidence interval (CI), 1.08-5.31]; P = .032); and a lower likelihood of having received adjuvant trastuzumab (ORadjuvant trastuzumab vs. no adjuvant trastuzumab = 0.30 [95% CI, 0.10-0.96]; P = .043]. C-statistics varied between 0.634 and 0.699. CONCLUSION: Long-term benefit of trastuzumab-based therapy is associated with hormone receptor positivity and the absence of previous adjuvant trastuzumab. Nevertheless, clinicopathological features had a low predictive value for prolonged treatment duration. The validation of the current findings and the identification of molecular features associated the magnitude of trastuzumab benefit should be encouraged.

Targeting the human epidermal growth factor receptor 2 pathway in breast cancer.

The discovery of amplification of human epidermal growth factor receptor 2 (HER2), a member of the epidermal growth factor receptor family, was an important milestone in our understanding of the biology of breast cancers. This heralded the discovery of trastuzumab, a humanized monoclonal antibody targeting HER2. Trastuzumab is the foundation of treatment of HER2-positive breast cancers, demonstrating dramatic responses in patients with metastatic disease. Unfortunately, most tumors will inevitably develop resistance to trastuzumab, necessitating the need for alternate HER2-directed therapeutic approaches. Recent advances in our understanding of the interaction between HER2 and other members of the epidermal growth factor receptor family have led to identification of newer agents, resulting in the expansion of the clinical armamentarium of available agents for the treatment of HER2-positive tumors. In this article, we review the molecular biology of the ERbb receptor family, the use of HER2-targeted agents in early and advanced breast cancer, and the next-generation anti-HER2 agents that are currently in clinical evaluation.

The ethical use of mandatory research biopsies.

Increasingly, clinical trials incorporate translational research questions aimed at identifying biomarkers of response or resistance to agents under investigation. Biomarker assays can require tissue samples to be collected through a research biopsy before therapy, during treatment, or at the time of tumor progression. Such biopsy samples will generally not provide a direct benefit to the patient and, given the risks associated with any surgical procedure, ethical concerns have been raised when the participant's enrollment on a clinical trial depends on their consent to undergo a research biopsy. In this Perspectives article, we present the rationale for mandatory research biopsies and offer suggestions for standardization to ensure that high-quality, patient-centered, clinical trials continue to be designed with scientific and ethical rigor.

Utility of the systemic inflammatory response syndrome (SIRS) criteria in predicting the onset of septic shock in hospitalized patients with hematologic malignancies.

BACKGROUND: The systemic inflammatory response syndrome (SIRS) criteria have not been validated in patients with hematologic malignancies (HM). OBJECTIVE: To determine whether daily assessment of SIRS criteria allows early identification of HM patients who will develop septic shock (SS). DESIGN: Observational, single-center,nested case-control study. SETTING: Oncology unit of a tertiary care center. PATIENTS: 547 consecutive, hospitalized, HM subject were enrolled. Using incidence-density sampling, 184 controls were matched to 46 SS cases. MEASUREMENTS: The study exposure was the SIRS score. The study outcome was the development of SS during the hospitalization. MAIN RESULTS: 8.4% of subjects developed SS. SIRS scores measured 24 hours prior to SS were significantly higher in cases than in controls (2.1 vs. 1.4,p<0.0001). Using standard SIRS cutpoints, fever, tachypnea and tachycardia were each associated with the onset of SS. Population-specific SIRS criteria were empirically derived. LIMITATIONS: Single-center study. Further validation is warranted. CONCLUSIONS: SIRS can identify HM patients at risk for SS at least 24 hours before SS onset. These data may lead to evidence-based guidelines using routine vital signs to risk-stratify HM patients for SS.