Mismatch repair protein status of non-neoplastic uterine and intestinal mucosa in patients with Lynch syndrome and double somatic mismatch repair protein mutations.

Mismatch repair (MMR) protein-deficient non-neoplastic colonic crypts and endometrial glands (dMMR crypts and glands) have been reported as a unique marker of underlying Lynch syndrome (LS). However, no large studies have directly compared the frequency of detection in cases with double somatic (DS) MMR mutations. We retrospectively analyzed 42 colonic resection specimens (24 LS and 18 DS) and 20 endometrial specimens (9 LS and 11 DS), including 19 hysterectomies and 1 biopsy for dMMR crypts and glands. All specimens were from patients with known primary cancers, including colonic adenocarcinomas and endometrial endometrioid carcinomas (including 2 mixed carcinomas). Four blocks of normal mucosa away from the tumor were selected from most cases, as available. MMR immunohistochemistry specific to the primary tumor mutations was analyzed. dMMR crypts were found in 65% of LS and 0% of DS MMR-mutated colonic adenocarcinomas (P < .001). Most dMMR crypts were detected in the colon (12 of 15) compared to the ileum (3 of 15). dMMR crypts showed single and grouped losses of MMR immunohistochemical expression. dMMR glands were found in 67% of LS and 9% (1 of 11) of DS endometrial cases (P = .017). Most dMMR glands were found in the uterine wall, with 1 LS and 1 DS case exhibiting dMMR glands in the lower uterine segment. Most cases exhibited multifocal and grouped dMMR glands. No morphologic atypia was identified in dMMR crypts or glands. Overall, we demonstrate that dMMR crypts and glands are highly associated with underlying LS, while being rarer in those with DS MMR mutations.

A novel approach to measure brain-to-brain spatial and temporal alignment during positive empathy.

Empathy is defined as the ability to vicariously experience others' suffering (vicarious pain) or feeling their joy (vicarious reward). While most neuroimaging studies have focused on vicarious pain and describe similar neural responses during the observed and the personal negative affective involvement, only initial evidence has been reported for the neural responses to others' rewards and positive empathy. Here, we propose a novel approach, based on the simultaneous recording of multi-subject EEG signals and exploiting the wavelet coherence decomposition to measure the temporal alignment between ERPs in a dyad of interacting subjects. We used the Third-Party Punishment (TPP) paradigm to elicit the personal and vicarious experiences. During a positive experience, we observed the simultaneous presence in both agents of the Late Positive Potential (LPP), an ERP component related to emotion processing, as well as the existence of an inter-subject ERPs synchronization in the related time window. Moreover, the amplitude of the LPP synchronization was modulated by the presence of a human-agent. Finally, the localized brain circuits subtending the ERP-synchronization correspond to key-regions of personal and vicarious reward. Our findings suggest that the temporal and spatial ERPs alignment might be a novel and direct proxy measure of empathy.

Pancreatic Frozen Section Guides Operative Management With Few Deferrals and Errors.

CONTEXT.­: Pancreatic adenocarcinoma is the third leading cause of cancer death in the United States. Surgery remains the mainstay of treatment, and frozen section analysis is used to confirm diagnosis and determine resectability and margin status. OBJECTIVE.­: To evaluate use and accuracy of frozen section and how diagnosis impacts surgical procedure. DESIGN.­: We reviewed patients with planned pancreatic resections between January 2014 and March 2019 with at least 1 frozen section. Pathology reports including frozen sections, preoperative cytology, and operative notes were reviewed. Frozen sections were categorized by margin, primary pancreatic diagnosis, metastasis, or vascular resectability. The deferral and error rates and surgeons' response were noted. RESULTS.­: We identified 898 planned pancreatic resections and 221 frozen sections that were performed on 152 cases for 102 margins, 94 metastatic lesions, 20 primary diagnoses, and 5 to confirm vascular resectability. The diagnosis was deferred to permanent sections in 13 of 152 cases (8.6%) on 16 of 221 frozen sections (7.2%): 6 for metastasis, 8 for margins, and 2 for primary diagnosis. Discrepancies/errors were identified in 4 of 152 cases (2.6%) and 4 of 221 frozen sections (1.8%). Surgeons' responses were different than expected in 8 of 221 frozen sections (3.6%), but their actions were explained by other intraoperative findings in 6 of 8. CONCLUSIONS.­: Frozen section remains an important diagnostic tool used primarily for evaluation of margins and metastasis during pancreatectomy. In most cases, a definitive diagnosis is rendered, with occasional deferrals and few errors. Intraoperative findings explain most cases where surgeons act differently than expected based on frozen section diagnosis.

Assessment of isochromosome 12p and 12p abnormalities in germ cell tumors using fluorescence in situ hybridization, single-nucleotide polymorphism arrays, and next-generation sequencing/mate-pair sequencing.

The identification of isochromosome 12p [i(12p)] and 12p gains have significant clinical utility in the diagnosis of germ cell tumors (GCTs). We have summarized the results of fluorescence in situ hybridization (FISH) assays to identify i(12p), performed in a Clinical Laboratory Improvement Amendments (CLIA)-validated setting for 536 specimens. In addition, the American Association for Cancer Research (AACR) Project GENIE registry and The Cancer Genome Atlas (TCGA) data sets were evaluated for chromosome 12p gains, and a limited number of cases were concurrently evaluated using FISH, single-nucleotide polymorphism (SNP) arrays and next-generation sequencing (NGS; including mate-pair sequencing). Specimens submitted for FISH testing were frequently from potential sites of metastases (male: 70.9% and female: 69.3%), and polysomy of chromosome 12 with or without concurrent i(12p) was a frequent finding, seen in 3% (16/536) and 35% (186/536) of cases, respectively. Our analysis suggests that 12p gains are likely to be present in approximately 73% of male GCT and in 32% of female GCT (AACR GENIE, n = 555). When comparing TCGA cases of testicular GCT (n = 149) to combined cases of sarcoma, colorectal, prostate, and urothelial carcinoma (n = 1754), 12p gains had a sensitivity of 77.2% and specificity of 97.3% for GCT. Some advantages of FISH over SNP arrays/NGS include relatively lower cost, rapid turnaround time, the ability to analyze biopsy material with a limited number of tumor cells (50 cells), and the ability to distinguish i(12p) from polysomy. The ability to spatially restrict the analysis to cells of interest is critical, as specimens submitted for testing often have low tumor purity. Disadvantages include false negative results due to an inability to detect segmental gains due to FISH probe design. With the availability of numerous testing modalities, including FISH, SNP arrays, and NGS-based assays, a nuanced understanding of the advantages and disadvantages of each methodology, as has been presented in this study, may inform appropriate testing strategies.

Aggression differentially modulates neural correlates of social intention attribution to benevolent, tickling and taunting laughter: An fMRI study in children and adolescents.

Human laughter is a powerful means of communicating social intention, ranging from welcoming and friendly to hostile and ridiculing. To be communicated accurately, the recipient must correctly identify the laugher's underlying social intention. Regular misattribution of the social intention of others has been associated with maladaptive psychosocial development, in particular with aggressive behavior. We investigated the relationship between self-reported aggressive behavior and the neural correlates of social intention attributions to different audiovisual laughter types in 50 healthy children and adolescents (29 female, 10-18 years, M 15.5, SD 2.2) using functional magnetic resonance imaging. Trial-by-trial associations of neural response and behavioral attributions were distinctly modulated by aggression for benevolent versus taunting and tickling laughter. With increasing aggression, hostile misattributions of benevolent laughter were associated with decreased dorsolateral prefrontal and anterior insular cortex activation. In contrast, hostile attributions of taunting and tickling laughter were associated with increased superior frontal, superior temporal, medial prefrontal, supplementary motor, and anterior and mid-cingulate cortex activation. We argue that aggression may be associated with down-regulated emotional saliency of benevolent laughter, whereas up-regulated neural responses to taunting laughter may underlie a heightened sensitivity to hostility or acceptance of taunting behavior in more aggressive individuals.

ESR1 genetic alterations and their association with clinicopathologic characteristics in advanced breast cancer: a single academic institution experience.

Estrogen receptor (ER) alpha, a ligand-dependent nuclear transcription factor encoded by the ESR1 gene, is expressed in 70% of breast carcinomas (BCs) and is used as a target for endocrine-based therapies. However, some patients develop resistance to endocrine-based therapies due to ESR1 mutation, which leads to constitutive activation in the absence of ligand. We retrospectively analyzed 223 clinically advanced BCs using the FoundationOne CDX assay and found 13.9% (31/223) of cases had ESR1 genetic alterations (26 mutations and 5 amplifications). All ESR1 mutations occurred within the ligand binding domain, with the most prevalent being Y537S (42.3%) and D538G (38.5%), and all ESR1-mutated cases had a history of aromatase inhibitor use. No significant difference in clinicopathologic features was identified between ESR1-mutated and ESR1-amplified cases except higher frequency of HER2 positivity and TP53 mutations in ESR1-amplified cases. The prevalence of ESR1 mutations in ER-positive BCs was 19.1% (26/136). In comparison to ESR1-nonmutated ER-positive cases, ESR1-mutated cases demonstrated significantly higher percentage of tumor cells with ER and progesterone receptor expression, an increased tendency for overall distant metastasis and liver metastasis, higher frequency of FGF3/4/19 mutations, lower frequency of TP53 mutation, but no difference in overall survival and metastatic/recurrent intervals. In conclusion, our findings suggest that development of ESR1 mutations are selected for under the influence of estrogen deprivation, and a positive correlation between ESR1 mutations and ER protein expression may exist.

Correction to: Retrospective Assessment of Behavioral Inhibition in Infants and Toddlers: Development of a Parent Report Questionnaire.

The original version of this article were unfortunately published with an error in "Methods" section. This has been corrected by publishing this correction article.

High tumor mutation burden is associated with DNA damage repair gene mutation in breast carcinomas.

BACKGROUND: Immunotherapy has demonstrated encouraging clinical benefits in patients with advanced breast carcinomas and Programmed death ligand 1 (PD-L1) expression has been proposed as an immunotherapy biomarker. Challenges with current PD-L1 testing exist and tumor mutation burden (TMB) is emerging as a biomarker to predict clinical response to immunotherapy in melanoma and non-small cell lung cancer patients. However, TMB has not been well characterized in breast carcinomas. METHODS: The study cohort included 62 advanced breast cancer patients (13 primary and 49 metastatic). Genetic alterations and TMB were determined by FoundationOne CDx next generation sequencing (NGS) and the association with clinicopathologic features was analyzed. RESULTS: High TMB was observed in a relatively low frequency (3/62, 4.8%). TMB levels were positively associated tumor infiltrating lymphocytes and significantly higher TMB was observed in breast carcinomas with DNA damage repair gene mutation(s). There was no significant association between TMB levels and other analyzed clinicopathologic characteristics. CONCLUSIONS: Our data indicate the importance of DNA damage repair proteins in maintaining DNA integrity and immune reaction and breast carcinoma patients with DDR mutation may benefit from immunotherapy.

Slow cortical potentials neurofeedback in children with ADHD: comorbidity, self-regulation and clinical outcomes 6 months after treatment in a multicenter randomized controlled trial.

Despite sizeable short-term effects of neurofeedback (NF) therapy on attention-deficit and hyperactivity disorder (ADHD), longer-term clinical, comorbidity and self-regulation outcomes are less systematically studied. The aim of this largest NF follow-up to date was to evaluate these outcomes 6 months after NF compared to a semi-active control to disentangle specific from unspecific sustained effects. We performed a multicenter, randomized, parallel, controlled, clinical, superiority trial in five German university outpatient departments. Participants were eligible if they fulfilled DSM-IV-TR criteria for ADHD and were aged from 7 to 9 years. Participants were randomly assigned (1:1-ratio) to 25 sessions of slow cortical potential (SCP)-NF or electromyogram biofeedback (EMG-BF). Participants were not blinded, since they received instructions according to each treatment setting. Primary outcomes were parent ratings of ADHD. The trial was registered, number ISRCTN761871859. Both groups showed improvement of ADHD symptoms compared to baseline at 6-months follow-up with large effect sizes for SCP-NF (d = 1.04) and EMG-BF (d = 0.85), but without group differences. When analyzing all assessments (pre-test, post-test-1, post-test-2 and follow-up), a group-by-time interaction emerged (p = 0.0062), with SCP-NF showing stable improvement following treatment but EMG-BF showing a relapse from post-test-1 to post-test-2, and subsequent remission at follow-up. Six months after the end of treatment, improvement after SCP-NF remained large and stable. However, the lack of group differences at follow-up suggests shared specific and unspecific effects contributing to this clinical outcome. Our correlational results indicate specificity of SCP-NF for selected subscales after training, but not at follow-up.

Aggression modulates neural correlates of hostile intention attribution to laughter in children.

The tendency to interpret nonverbal social signals as hostile in intention is associated with aggressive responding, poor social functioning and mental illness, and can already be observed in childhood. To investigate the neural correlates of such hostile attributions of social intention, we performed a functional magnetic imaging study in 10-18 year old children and adolescents. Fifty healthy participants rated videos of laughter, which they were told to imagine as being directed towards them, as friendly versus hostile in social intention. Hostile intention ratings were associated with neural response in the right temporal voice area (TVA). Moreover, self-reported trait physical aggression modulated this relationship in both the right TVA and bilateral lingual gyrus, with stronger associations between hostile intention ratings and neural activation in children with higher trait physical aggression scores. Functional connectivity results showed decreased connectivity between the right TVA and left dorsolateral prefrontal cortex with increasing trait physical aggression for making hostile social intention attributions. We conclude that children's social intention attributions are more strongly related to activation of early face and voice-processing regions with increasing trait physical aggression.

Multiple-Brain Connectivity During Third Party Punishment: an EEG Hyperscanning Study.

Compassion is a particular form of empathic reaction to harm that befalls others and is accompanied by a desire to alleviate their suffering. This altruistic behavior is often manifested through altruistic punishment, wherein individuals penalize a deprecated human's actions, even if they are directed toward strangers. By adopting a dual approach, we provide empirical evidence that compassion is a multifaceted prosocial behavior and can predict altruistic punishment. In particular, in this multiple-brain connectivity study in an EEG hyperscanning setting, compassion was examined during real-time social interactions in a third-party punishment (TPP) experiment. We observed that specific connectivity patterns were linked to behavioral and psychological intra- and interpersonal factors. Thus, our results suggest that an ecological approach based on simultaneous dual-scanning and multiple-brain connectivity is suitable for analyzing complex social phenomena.

The familial co-aggregation of ASD and ADHD: a register-based cohort study.

Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur. The presence of a genetic link between ASD and ADHD symptoms is supported by twin studies, but the genetic overlap between clinically ascertained ASD and ADHD remains largely unclear. We therefore investigated how ASD and ADHD co-aggregate in individuals and in families to test for the presence of a shared genetic liability and examined potential differences between low- and high-functioning ASD in the link with ADHD. We studied 1 899 654 individuals born in Sweden between 1987 and 2006. Logistic regression was used to estimate the association between clinically ascertained ASD and ADHD in individuals and in families. Stratified estimates were obtained for ASD with (low-functioning) and without (high-functioning) intellectual disability. Individuals with ASD were at higher risk of having ADHD compared with individuals who did not have ASD (odds ratio (OR)=22.33, 95% confidence interval (CI): 21.77-22.92). The association was stronger for high-functioning than for low-functioning ASD. Relatives of individuals with ASD were at higher risk of ADHD compared with relatives of individuals without ASD. The association was stronger in monozygotic twins (OR=17.77, 95% CI: 9.80-32.22) than in dizygotic twins (OR=4.33, 95% CI: 3.21-5.85) and full siblings (OR=4.59, 95% CI: 4.39-4.80). Individuals with ASD and their relatives are at increased risk of ADHD. The pattern of association across different types of relatives supports the existence of genetic overlap between clinically ascertained ASD and ADHD, suggesting that genomic studies might have underestimated this overlap.

[Genetic findings in autism spectrum disorders]. / Genetische Befunde bei Autismus-Spektrum-Störungen.

Autism spectrum disorders (ASD) are pervasive developmental disorders comprising problems in social interaction, communication, and stereotyped behavior and interests. They show a prevalence of around 0.8% in children, adolescents, and adults, and a skewed sex distribution (about 4:1 = male:female). ASD are predominantly genetically determined disorders. Heritability estimates from twin studies range between 64 and 91%. Recurrence risk in siblings is 20-fold elevated. De novo and inherited monogenetic disorders, mutations, sex chromosomal abnormalities, cytogenetic and imprinting disorders as well as common variants are associated with ASD. Genetic disorders implicating a specific additional intervention are of specific clinical relevance. Genetic testing and counselling should be provided for all families and individuals with ASD. This article gives an overview on current basic genetic research in ASD, its clinical relevance and genetic counselling in ASD.

BRAF V600E expression in histiocytic sarcoma associated with splenic marginal zone lymphoma: a case report.

BACKGROUND: Histiocytic sarcoma is a rare histiocytic neoplasm of unknown etiology that constitutes less than 1% of hematologic malignancies. A few cases of histiocytic sarcoma harboring the BRAF V600E mutation have been reported, but this finding has not been confirmed in all studies. CASE PRESENTATION: We report the case of a 63-year-old white woman with a history of splenic marginal zone lymphoma who presented with 2 weeks of right-sided neck swelling. Positron emission tomography revealed an intensely hypermetabolic and destructive soft tissue mass in her right skull base. A bone marrow biopsy was performed, which revealed an infiltrate of malignant cells characterized as large pleomorphic cells with frequent folded/irregular nuclei, variably prominent nucleoli, fine chromatin, and abundant amounts of eosinophilic cytoplasm. The malignant cells were positive for CD163, CD68 (granular), lysozyme (granular), CD4, and CD45 (partial). Based on the biopsy findings, she was diagnosed as having histiocytic sarcoma. The malignant cells tested positive for the BRAFV600E protein using immunohistochemistry. Before treatment of her histiocytic sarcoma could be initiated, she developed disseminated intravascular coagulation and acute hypoxemic respiratory failure secondary to non-cardiogenic pulmonary edema. She decided to pursue comfort care and died in our hospital 2 weeks following admission. CONCLUSIONS: Our case illustrates the aggressive nature of histiocytic sarcoma, and provides rare evidence that histiocytic sarcoma associated with indolent lymphomas may harbor the BRAF V600E mutation. Further research is needed to clarify the role of targeted therapies such as vemurafenib in the treatment of patients with this disorder.

Transcriptomic signatures of neuronal differentiation and their association with risk genes for autism spectrum and related neuropsychiatric disorders.

Genes for autism spectrum disorders (ASDs) are also implicated in fragile X syndrome (FXS), intellectual disabilities (ID) or schizophrenia (SCZ), and converge on neuronal function and differentiation. The SH-SY5Y neuroblastoma cell line, the most widely used system to study neurodevelopment, is currently discussed for its applicability to model cortical development. We implemented an optimal neuronal differentiation protocol of this system and evaluated neurodevelopment at the transcriptomic level using the CoNTeXT framework, a machine-learning algorithm based on human post-mortem brain data estimating developmental stage and regional identity of transcriptomic signatures. Our improved model in contrast to currently used SH-SY5Y models does capture early neurodevelopmental processes with high fidelity. We applied regression modelling, dynamic time warping analysis, parallel independent component analysis and weighted gene co-expression network analysis to identify activated gene sets and networks. Finally, we tested and compared these sets for enrichment of risk genes for neuropsychiatric disorders. We confirm a significant overlap of genes implicated in ASD with FXS, ID and SCZ. However, counterintuitive to this observation, we report that risk genes affect pathways specific for each disorder during early neurodevelopment. Genes implicated in ASD, ID, FXS and SCZ were enriched among the positive regulators, but only ID-implicated genes were also negative regulators of neuronal differentiation. ASD and ID genes were involved in dendritic branching modules, but only ASD risk genes were implicated in histone modification or axonal guidance. Only ID genes were over-represented among cell cycle modules. We conclude that the underlying signatures are disorder-specific and that the shared genetic architecture results in overlaps across disorders such as ID in ASD. Thus, adding developmental network context to genetic analyses will aid differentiating the pathophysiology of neuropsychiatric disorders.