Placental metastasis from maternal NUT carcinoma: diagnostic pitfalls and challenges.

We report a young pregnant woman with large midline thoracic mass and markedly elevated serum alpha-fetoprotein (AFP) levels. Initially suspected as a germ cell tumour (GCT) due to age, site, and high AFP levels, a biopsy unveiled a high-grade malignant tumour characterised by undifferentiated monotonous cells. Although tumour cells exhibited positive AFP, the overall immunoprofile did not provide additional evidence to support GCT. Further work-up showed positive for NUT (nuclear protein in testis) immunostaining and the presence of BRD4-NUT1 fusion, confirming the diagnosis of NUT carcinoma. On radiology, there were extensive metastases to lungs, liver, vertebrae, and placenta. Despite aggressive chemotherapy, radiotherapy and immunotherapy, she did not respond to the therapies. Fortunately, her child was not affected by the carcinoma. This is the first case highlighting that thoracic lung primary NUT carcinoma can spread to the placenta and manifest with elevated serum AFP levels, potentially leading to misdiagnosis as GCT both clinically and pathologically.

Wischnewski Spots in a Case of Hyperosmolar Hyperglycemic State.

ABSTRACT: Wischnewski spots were first described as a common finding in gastric mucosa of decedents exposed to hypothermic environmental conditions. In recent literature, they were also reported in cases of diabetic ketoacidosis, pancreatitis, and fatal burns. Although Wischnewski spots are not specific to cases of hypothermia, we present a case that further supports this contention. We report a case of a middle-aged woman with type 2 diabetes who died of complications of hyperosmolar hyperglycemic state. Although there were no features of hypothermia, she presented with Wischnewski spots in the gastric mucosa. On histology, the gastric mucosa contained brown-black pigmentations with no neutrophilic infiltration. Biochemical analysis from vitreous humor and femoral blood showed marked elevation of glucose levels, low concentration of ketone bodies, pseudohyponatremia, and prerenal azotemia. The autopsy findings in this case discussion shed light to the possible genesis and pathophysiology of Wischnewski spots and highlight an additional differential diagnosis for these lesions.

Microbe-Immune-Stress Interactions Impact Behaviour during Postnatal Development.

Decades of research have established the role of microbiota-brain communication in behaviour and brain function. Studies have shown that microbiota composition and diversity are influenced by a variety of factors including host genetics, diet, and other environmental exposures, with implications for the immunological and neurobiological development of the host organism. To further understand early-life interactions between environment, genetic factors, the microbiome and the central nervous system, we investigated the impact of postnatal stress in C57Bl/6 wild type and T-cell deficient mice on microbe-brain interactions and behaviour. Mice were exposed to immune challenge with lipopolysaccharide (LPS) at postnatal day (P) 3 and maternal separation at P9 (16 h overnight). Behavioural assessment of growth and development as well as behaviour (righting reflex, ultrasonic vocalizations in response to brief maternal separation, open field, sociability, and grooming) was conducted. Microbiota diversity and composition of fecal samples collected at P24 revealed reduced alpha diversity in T-cell-deficient mice as well as genotype- and stress-related taxa. Notably, integrated analyses of microbiota and behaviour in the context of immunocompromise revealed key behavioural related taxa that may be important to brain development. These findings are important to determining the influence of genetic and environmental factors on gut microbiota and advances our understanding microbiome-brain signaling pathways on neurodevelopment and behaviour.

A Case of Unilateral Proptosis Secondary to Prostatic Metastasis.

Prostate cancer metastases involving the orbit and/or paranasal sinuses represent a rare oncological presentation. Patients can have a myriad of symptoms such as proptosis, periorbital swelling, blurry vision, rhinorrhea, epistaxis, anosmia, or others depending on the structures involved. The differential diagnosis of paranasal sinus masses on imaging studies is broad and can include inflammatory, congenital, or neoplastic masses; leading to the requirement of biopsy for definitive diagnosis. Tissue sample is usually obtained via an endoscopic approach. The prognosis of such a presentation is not well described in the literature, but it is usually guarded due to the advanced stage of the disease and generally a poorly differentiated primary tumor. Treatments usually aim to reduce the burden of disease and debulk the tumor mass for palliative purposes. We present a case of a 71-year-old male presenting with unilateral proptosis and periorbital swelling secondary to prostatic metastasis.

Maternal anxiety, depression and vascular function during pregnancy.

OBJECTIVE: We aim to clarify whether type and timing of mental health symptoms in early pregnancy distinctly contribute to maternal-fetal vascular function, independent from the psychotropic medications given to treat these conditions. METHODS: Data from a prospective cohort study (n = 1678) were used to test whether self-reported fears about giving birth and depressive symptoms prior to 16 weeks of gestation were associated with vascular outcomes predictive of hypertensive disorders of pregnancy (HDP) i.e., systolic and diastolic blood pressure (BP); uterine artery pulsatility index (UAPI); umbilical artery resistance index (UmbARI); and urine protein creatinine ratio. Multiple linear regressions models and mediation models were used to test for associations between predictors and outcomes, controlling for previously identified risk factors for vascular dysfunction such as maternal age and history of infertility. RESULTS: Fears about giving birth in early pregnancy were inversely associated with UmbARI (ß = -0.33, p = 0.03, df = 51) mid- to late-pregnancy (≥20 weeks). Depressive symptoms in early pregnancy were also inversely associated with maternal systolic BP (ß = -0.13, p = 0.01, df = 387) and diastolic BP (ß = -0.10, p = 0.04, df = 387) during the first trimester. CONCLUSIONS: While fears about giving birth in early pregnancy were associated with lower vascular resistance in the fetal-placental unit, early depressive symptoms were associated with lower maternal vascular tone. At the very least, our results support the notion that early maternal psychological distress is unlikely to account for the development of HDP later during pregnancy and provide preliminary evidence to support distinct roles of pregnancy-related anxiety and depressive symptoms in maternal-fetal vascular function.

Metastatic Clear Renal-Cell Carcinoma Mimicking Anaplastic Thyroid Cancer: A Case Report.

Metastatic renal cell carcinoma to the thyroid is a rare yet aggressive histopathologic diagnosis, which may often be omitted from the initial clinical differential. This is in part due to the long latency period between the initial renal primary and appearance of metastatic disease, coupled with the diagnostic limitations of fine-needle aspiration biopsies. We herein present an interesting case of a metastatic clear-cell renal-cell carcinoma mimicking an aggressive primary thyroid neoplasm, 10 years after a nephrectomy for a renal primary, highlighting key diagnostic and management considerations.

Cancer registry study of malignant hepatic vascular tumors: hepatic angiosarcomas and hepatic epithelioid hemangioendotheliomas.

BACKGROUND: Malignant vascular tumors (MVTs) are rare and often misdiagnosed due to wide range of clinical presentations, varied histology, and exquisite imagining features. We aim to characterize two different types of MVTs of the liver: hepatic angiosarcomas (HA) and hepatic epithelioid hemangioendotheliomas (HEHE). METHODS: Data on HA and HEHE between 1975 and 2016 were extracted from the SEER database and analyzed. RESULTS: A total of 366 patients with HA were identified where 64.2% were male and 79% of White race. The median age at diagnosis was 64 ± 16.2 years. Distant metastasis was found in 24% of patients, regional disease in 22.1%, and localized disease in 21.3%. The median overall survival for HA was 2 months. For HEHE, 120 cases were identified, 32.5% were male and 80% of White race. The median age of diagnosis was 51 ± 16.8 years. Distant metastasis was found in 37.5% of patients, regional disease in 27.5%, and localized disease in 20%. The median overall survival was 182 months. CONCLUSION: Patients' demographics such as race, age, and gender may assist in elucidating distinct subtypes of MVTs. HA is an aggressive tumor despite intervention. Patients with HEHE tumors have significantly better survival compared to patients with HA. Further studies are needed to deepen our knowledge about the histopathology of these tumors, the outcomes of liver transplantation as a therapeutic alternative, and available molecular targets for MVTs.

Incidence Rates, Treatment, and Survival of Rectal Cancer Among Young Patients: A Nationwide Cohort Study.

BACKGROUND: The incidence of colorectal cancer is increasing among young adults in the United States. We aim to investigate the incidence rate, the effect of multimodal therapy, and survival outcomes of rectal cancer in patients under 45 years of age. PATIENTS AND METHODS: Data on young-onset (under 45 y) rectal cancer between 2000 and 2016 was extracted from the Surveillance, Epidemiology, and End Results Registry (SEER). RESULTS: A total of 10,375 patients with young-onset rectal cancer were identified where 54.7% were male. The median age at diagnosis was 40±5.7 years. The overall age-adjusted incidence of rectal cancer between 2000 and 2016 was 1.24 per 100,000 per year. Incidence increased with age, with the highest incidence occurring in the 40- to 44-year age group. Over the 16-year study period, rectal cancer increased by ∼2.29%. Most tumors on presentation were moderately differentiated (30.8%) while the most common stage at presentation was stage 4 (48.3%). One- and 5-year cause-specific survival for rectal cancer was 93% and 72%, respectively. According to Cox proportional hazard models, chemotherapy was associated with increased mortality in patients with localized cancer [hazard ratio (HR)=2.88, 95% confidence interval (CI): 2.04-4.08, P<0.001], did not significantly improve mortality outcomes in patients with regional cancer (HR=0.89, 95% CI: 0.70-1.04, P=0.116), but reduced mortality in patients with distant cancer (HR=0.62, 95% CI: 0.56-0.70, P<0.001), though this effect was largely seen in patients 35 years and older. Surgery was associated with improved survival across all cancer stages. CONCLUSIONS: The incidence of regional and distant rectal cancer is increasing in young patients. While patient age is an important prognostic indicator of survival, chemotherapy does not appear to improve survival in younger patients with localized and regional disease.

A prospective study on the course of sleep disturbances in first-time fathers during the transition to parenthood.

INTRODUCTION: This study examined sleep disturbances in first-time fathers from the third trimester of their partner's pregnancy to 2 months postpartum to determine prevalence, incidence, and persistence of sleep disturbances and identify associated determinants. METHODS: Men expecting their first child were recruited from local prenatal classes and university-affiliated obstetric clinics. During their partner's third trimester of pregnancy and 2 months postpartum, 459 men completed standardized online self-report questionnaires measuring sociodemographics, lifestyle, and psychosocial variables and sleep quality. RESULTS: Disturbed sleep (Pittsburgh Sleep Quality Index [PSQI] global score >5) increased from 29.6% during the third trimester to 44.7% at 2 months postpartum. The incidence of poor sleep at 2 months postpartum was 33.7%. Among men with disturbed sleep at the antenatal assessment, 70.6% continued to have sleep disturbances at 2 months postpartum. An increase in depressive symptoms and higher parenting stress was independently associated with onset and persistence of disturbed sleep at 2 months postpartum. CONCLUSIONS: Sleep is compromised in expectant and new fathers. Strategies aimed at improving sleep, depressed mood, and managing the challenges of parenting may be important components to include in prenatal interventions aimed at enhancing the transition to parenthood and infant development.

Fibrolamellar Hepatocellular Carcinoma: A Population-Based Observational Study.

BACKGROUND: In the USA, fibrolamellar hepatocellular carcinoma (FLC) accounts for 1-2% of all cases of hepatocellular carcinoma. FLC remains poorly understood. AIM: We aim to investigate the incidence, demographics, tumor characteristics, treatment, and prognosis of patients with FLC. METHODS: Data on FLC between 2000 and 2016 were extracted from the SEER database and analyzed. RESULTS: A total of 300 patients with FLC were identified where 126 were male. Median age at diagnosis was 27 ± 22 years. The overall age-adjusted incidence of FLC between 2000 and 2016 was 0.02 per 100,000 per year. A bimodal distribution was observed where the highest incidences occurred between 15-19 years and 70-74 years. Most tumors on presentation were moderately differentiated (20.7%), while the most common stage at presentation was stage 1 (21.7%) followed by stages 3 and 4 (20.0% and 20.3%, respectively); 50.3% of these tumors were surgically resected, while 8.0% received radiation and 45.3% received chemotherapy. One- and 5-year cause-specific survival for FLC was 72.0% and 32.9%, respectively, with a median survival of 32.9 months. HCC had a median survival time of 11.7 months. Patients who were not treated with surgical intervention had about 3 times increased risk for death (HR 2.8, 95% CI 1.68-4.72, P = 0.000). Radiation and chemotherapy did not significantly affect outcomes. CONCLUSION: FLC presents with a bimodal distribution in both early and elderly individuals. Compared to HCC, FLC has a higher recurrence rate but better survival outcome. Surgical intervention is superior to chemotherapy and radiation.

Predictors of Changes in Daily Activity in Transition-Age Autistic Youth.

Transitioning into adulthood is fraught with challenges for autistic youth. A greater understanding of the facilitators of community involvement in school and employment during this period is warranted. The current study examines changes in service need and receipt, and the stability of accessing daily structured activities, for autistic young adults over their transition period compared to adolescents and adults that did not enter the transition period. Baseline caregiver survey data were taken from the Canadian Autism Spectrum Disorders Alliance National Autism Needs Assessment Survey in 2014, and caregivers (n = 304) completed the same set of questions in 2017 about sociodemographic factors, clinical need, service receipt and typical weekday activities. Three cohorts were compared: (1) pretransition age youth, (2) transition-age youth, and (3) young adults who were past transition age. Results suggest that transition-age youth were found to have a unique set of priority service needs compared to pre transition-age adolescent and to adult groups, and both transition-age and adult groups had lower levels of priority service receipt compared to pretransition-age adolescents. The transition-age group experienced the greatest loss of structured weekday activity between time points, and were more likely than pretransition-age adolescents to not have structured weekday activities at Time 2. A recovery of structured daily activity was not observed in young adults. Our results highlight the tumultuous nature of the transition period for autistic youth, which continues into adulthood, and the urgent need for supports during this time. LAY SUMMARY: This research highlights that autistic young people who are transitioning to adulthood are at greatest risk of losing structured weekday activities, and that once in adulthood, many continue to struggle to obtain meaningful community engagement. These results can help guide the design of adolescent and young adult transition programs.

Fecal Microbiota Transplantation (FMT) with Colonoscopy Is Superior to Enema and Nasogastric Tube While Comparable to Capsule for the Treatment of Recurrent Clostridioides difficile Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: Several routes of fecal microbiota transplantation (FMT) administration are available for treating recurrent Clostridioides difficile infections (CDI), the most recent of which are capsules. AIM: To assess the efficacy of colonoscopy, capsule, enema, and nasogastric tube (NGT) FMT for the treatment of recurrent CDI. METHODS: We reported clinical outcomes of colonoscopy, capsule, enema, and NGT FMT for the treatment of recurrent CDI according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. During January 2000 to January 2018, three databases were searched: PubMed, EMBASE, and CINAHL. Primary outcome was overall cure rate which was assessed using a random effects model; secondary outcomes included adverse effects as well as subgroup analyses comparing donor relationship, sample preparation, and study design. RESULTS: Twenty-six studies (1309 patients) were included in the study. FMT was administered using colonoscopy in 16 studies (483 patients), NGT in five studies (149 patients), enema in four studies (360 patients), and capsules in four studies (301 patients). The random effects of pooled FMT cure rates were colonoscopy 94.8% (CI 92.4-96.8%; I2 15.6%), capsule 92.1% (CI 88.6-95.0%; I2 7.1%), enema 87.2% (CI 83.4-90.5%; I2 0%), and NGT/NDT 78.1% (CI 71.6-84.1%; I2 0%). On subgroup analysis of colonoscopy FMT, sample preparation methods had comparable cure rates: fresh 94.9% compared to 94.5%. Similarly, cure rates were unaffected by donor relationship: mixed 94.5% compared to unrelated donor 95.7%. CONCLUSION: CDI cure rates with FMT performed with colonoscopy are superior to enema and NGT FMT, while those with FMT with colonoscopy and capsule are comparable.

Evaluation and Management of Premalignant Conditions of the Esophagus: A Systematic Survey of International Guidelines.

Esophageal cancer represents one of the most lethal forms of malignancy. The growing incidence of esophageal adenocarcinoma represents an emerging public health concern. This review article summarizes current diagnostic, management, and therapeutic practices of premalignant conditions of the esophagus including Barrett's esophagus, tylosis, granular cell tumors, achalasia, and the ingestion of caustic substances. Our report provides clinicians and academics with a global clinical perspective regarding presentation, surveillance guidelines, and therapeutic management of these esophageal conditions.

Combined Hepatocellular Cholangiocarcinoma: A Population-Based Retrospective Study.

OBJECTIVES: Combined hepatocellular cholangiocarcinoma (CHC) is a rare form of primary liver cancer with features of hepatocellular carcinoma and cholangiocarcinoma. The objective of this study was to investigate the incidence, demographics, tumor characteristics, treatment, and survival of patients with CHC. METHODS: Data on CHC between 2004 and 2014 were extracted from the Surveillance, Epidemiology, and End Results Registry and analyzed. RESULTS: Five hundred twenty-nine patients with CHC were identified; 367 were male. Median age at diagnosis was 62.5 ± 12 years. The overall incidence of CHC between 2004 and 2014 was 0.05 per 100,000 per year. Incidence increased with age, with the highest incidence in men occurring between 60 and 64 years and 75-79 years for women. Women had a higher incidence of CHC compared to men (0.08 vs 0.03 per 100,000 per year). Most tumors were poorly differentiated (30.8%) while the most common stage at presentation was stage 4 (26.8%). 39.5% of these tumors were resected while 6.8% received radiation and 34% received chemotherapy. One- and 5-year cause-specific survival for CHC was 41.9% and 17.7%, respectively, with a median survival of 8 months. Worse outcomes were noted among patients with tumor stage 3 (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.44-2.87, P = 0.000), stage 4 (HR 1.71, 95% CI 1.06-2.75, P = 0.027), those not treated with surgery (HR 4.94, 95% CI 3.64-6.68, P = 0.000), those who did not receive radiation (HR 1.71, 95% CI 1.08-2.70, P = 0.021), those who did not receive chemotherapy (HR 1.54, 95% CI 1.20-1.99, P = 0.001), and those with increasing tumor size on chemotherapy (HR 1.00, 95% CI 1.00-1.00, P = 0.013). DISCUSSION: CHC is the combined presentation of 2 malignancies. Incidence appears to be increasing and is associated with age and male gender. While surgery, radiation, and chemotherapy are associated with improved outcomes, patients who did not undergo surgery are at highest risk for death.

Effects of exercise and enrichment on behaviour in CD-1 mice.

A host of scholarly work has characterized the positive effects of exercise and environmental enrichment on behaviour and cognition in animal studies. The purpose of this study was to investigate the uptake and longitudinal impact of exercise and enrichment on the behavioural phenotype of male and female CD-1 mice. CD-1 mice housed in standard (STD) or exercise and enrichment (EE) conditions post-weaning were tested in the 3-chamber sociability test, open field, and elevated plus maze and exercise activity was monitored throughout the enrichment protocol. Male and female EE mice both showed reduced anxiety and activity in the open field and elevated plus maze relative to sex-matched STD mice. EE altered social behaviours in a sex-specific fashion, with only female EE mice showing increased social preference relative to female STD mice and a preference for social novelty only present in male EE mice. This sexual dimorphism was not observed to be a product of exercise uptake, as CD-1 mice of both sexes demonstrated a consistent trend of wheel rotation frequencies. These findings suggest the importance of considering variables such as sex and strain on experimental design variables in future work on environmental enrichment.

Priority service needs and receipt across the lifespan for individuals with autism spectrum disorder.

Individuals with Autism Spectrum Disorder (ASD) have a range of health, community, and social support needs across the lifespan that create age-specific challenges in navigating service sectors. In this study, we set out to identify the priority needs of individuals with ASD across the lifespan, and the factors that predict receiving priority services. Participants included 3,317 individuals with ASD from a Canada-wide online caregiver survey, stratified into five age groups (preschool, elementary school age, adolescence, emerging adulthood, adulthood). Priority receipt was calculated as a ratio of current services that corresponded to individualized priority need. Age-stratified Poisson regression analyses were used to identify the sociodemographic, clinical and systemic predictors of priority receipt. Results indicate that the distribution of priority need varied by age, except for social skills programming, which was a high across all groups. The number of high and moderate priority needs diversified with age. Overall, 30% of individuals had none of their priority needs met and priority receipt decreased with age. Systemic factors were most consistently related to priority receipt across the lifespan. Understanding patterns and correlates of priority needs and use that currently exist in different age groups can inform policies to improve service access. Autism Res 2017, 10: 1436-1447. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Developmental expression of the neuroligins and neurexins in fragile X mice.

Neuroligins and neurexins are transsynaptic proteins involved in the maturation of glutamatergic and GABAergic synapses. Research has identified synaptic proteins and function as primary contributors to the development of fragile X syndrome. Fragile X mental retardation protein (FMRP), the protein that is lacking in fragile X syndrome, binds neuroligin-1 and -3 mRNA. Using in situ hybridization, we examined temporal and spatial expression patterns of neuroligin (NLGN) and neurexin (NRXN) mRNAs in the somatosensory (S1) cortex and hippocampus in wild-type (WT) and fragile X knockout (FMR1-KO) mice during the first 5 weeks of postnatal life. Genotype-based differences in expression included increased NLGN1 mRNA in CA1 and S1 cortex, decreased NLGN2 mRNA in CA1 and dentate gyrus (DG) regions of the hippocampus, and increased NRXN3 mRNA in CA1, DG, and S1 cortex between female WT and FMR1-KO mice. In male mice, decreased expression of NRXN3 mRNA was observed in CA1 and DG regions of FMR1-KO mice. Sex differences in hippocampal expression of NLGN2, NRXN1, NRXN2, and NRXN3 mRNAs and in S1 cortex expression of NRXN3 mRNAs were observed WT mice, whereas sex differences in NLGN3, NRXN1, NRXN2, and NRXN3 mRNA expression in the hippocampus and in NLGN1, NRXN2 and NRXN3 mRNA expression in S1 cortex were detected in FMR1-KO mice. These results provide a neuroanatomical map of NLGN and NRXN expression patterns over postnatal development in WT and FMR1-KO mice. The differences in developmental trajectory of these synaptic proteins could contribute to long-term differences in CNS wiring and synaptic function.

Temporal and spectral differences in the ultrasonic vocalizations of fragile X knock out mice during postnatal development.

The fmr1 knock out (KO) mouse has been a useful animal model to understand pathology and treatment of FXS, both anatomically and behaviorally. Ultrasonic vocalizations (USVs) are a behavioral tool to assess early life communication deficits in mice. Here, we report on the temporal and spectral features of USVs emitted after maternal separation in wild type (FVB/N) and fmr1 KO pups at postnatal days (P) P4, P7 and P10. The results show changes in the number and duration of calls in fmr1 KO pups and wild type pups were dependent on age and call type. Fmr1 KO pups showed an increased number of USVs at P7 but not at P4 or P10. This increase was specific to Frequency Jump calls. In addition, fmr1 KO mice showed a developmental shift in the temporal distribution of calls, with P10 mice calling in distinct bout patterns. Overall, these findings provide evidence that changes in USV outcomes were specific to certain call types and ages in fmr1 KO mice. Because early postnatal life is a window during which multiple neural systems activate and become established, behavioral measures such as using USVs as a measure of communication, may be useful as a predictor of brain changes and later developmental behavioral changes. Work is needed to better understand the functional outcomes of altered development of USVs and how these changes contribute to later emergence of autistic-like behaviors in animal models of autism.