Clinicopathological, immunohistochemical and molecular features of acinic cell carcinoma of the breast.

Breast acinic cell carcinoma (ACC) is a rare subtype of breast cancer. Accurate diagnosis of ACC using core needle biopsy (CNB) is pivotal for the use of effective treatments and patient prognosis. In the present study, a detailed analysis of the morphological, immunohistochemical and gene mutation features of 2 cases of ACC was performed. CNB was performed prior to surgical excision. The breast ACC in the present cases exhibited overt burrowing labyrinthine networks or 'hand-holding-hand' features. The tumor cells in both of the present cases expressed cytokeratin (CK)7, S100 and CK5/6, but were negative for p63, estrogen receptor and progesterone receptor. GATA binding protein 3 was positive in case 1 but negative in case 2. Fluorescence in situ hybridization indicated no ETS variant transcription factor 6 break-apart probe detection. Next-generation sequencing results revealed the same mutation and a similar abundance in exon 27 (NM_005120.2; c.3817G>T; p.A1273S) of the mediator of RNA polymerase II transcription, subunit 12 homolog (MED12) gene in both patients. To conclude, the findings of the present study suggested that recognition of this rare 'hand-holding-hand' structure could potentially be beneficial for avoiding patient misdiagnosis. In addition, it could be suggested that a mutation in the MED12 exon 27 was associated with the formation of a burrowing labyrinthine network or 'hand-holding-hand' feature.

A presumed missense variant in the U2AF2 gene causes exon skipping in neurodevelopmental diseases.

U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an indispensable pre-mRNA splicing factor in the early process of splicing. Recently, U2AF2 was reported as a novel candidate gene associated with neurodevelopmental disorders. Herein, we report a patient with a novel presumed heterozygous missense variant in the U2AF2 gene (c.603G>T), who has a similar clinical phenotype as the patient reported before, including epilepsy, intellectual disability, language delay, microcephaly, and hypoplastic corpus callosum. We reviewed the phenotypic and genetic spectrum of patients with U2AF2-related neurological diseases, both newly diagnosed and previously reported. To investigate the possible pathogenesis, EBV-immortalized lymphoblastoid cells were derived from the peripheral blood obtained from the patient and control groups. Furthermore, according to the results of WB, RT-PCR, Q-PCR, and cDNA sequencing of RT-PCR products, the presumed missense variant c.603G>T caused exon 6 skipping in the U2AF2 mRNA transcript and led to a truncated protein (p.E163_E201del). Cell Counting Kit-8 (CCK-8) and cell cycle detection demonstrated that the variant c.603G>T inhibited the proliferation of patient lymphocyte cells compared with the control group. This study is aimed at expanding the phenotypic and genetic spectrum of U2AF2-related neurodevelopmental diseases and investigating the potential effects. This is the first report of the possible pathogenesis of a U2AF2 gene pathogenic variant in a patient with neurodevelopmental diseases and shows that a novel presumed missense variant in the U2AF2 gene causes exon skipping.

Clinical and pathological studies of eight cases of lipidized fibrous histiocytoma.

Lipidized fibrous histiocytoma (FH) is a rare type of FH. The present study aimed to describe the clinical and pathological features of lipidized FH. A total of eight patients diagnosed with lipidized FH were retrospectively reviewed in the present study. The cohort included three male and five female patients (male to female ratio, 1.7:1) with a mean age of 48 years (range, 38-62 years). In total, four tumors were located on the buttock, three on the lower leg and one on the forearm. Histological, lipidized FH showed a wide spectrum. Some cases included prominent stromal hyalinization and hyalinized vessels with scant lipid-laden histiocytes. Other cases exhibited the prominent lipid-laden histiocytes and scant stromal hyalinization. Overall, lipidized FH must be differentiated from other benign and malignant tumors, taking into account the therapeutic and prognostic differences between these different entities.

[Factors influencing the efficacy of initial adrenocorticotropic hormone therapy for infantile epileptic spasms syndrome]. / é¦–æ¬¡ä¿ƒè‚¾ä¸Šè ºçš®è´¨æ¿€ç´ æ²»ç–—å©´å„¿ç™«ç—«ç—‰æŒ›ç»¼åˆå¾ç–—æ•ˆçš„å½±å“å› ç´ åˆ†æž.

OBJECTIVES: To study the factors influencing the short-term (28 days) efficacy of initial adrenocorticotropic hormone (ACTH) therapy for infantile epileptic spasms syndrome (IESS), as well as the factors influencing recurrence and prognosis. METHODS: The clinical data were collected from the children with IESS who received ACTH therapy for the first time in the Department of Pediatric Neurology, Xiangya Hospital of Central South University, from April 2008 to January 2018 and were followed up for ≥2 years. The multivariate logistic regression analysis was used to evaluate the factors influencing the short-term efficacy of ACTH therapy, recurrence, and long-term prognosis. RESULTS: ACTH therapy achieved a control rate of seizures of 55.5% (111/200) on day 28 of treatment. Of the 111 children, 75 (67.6%) had no recurrence of seizures within 12 months of follow-up. The possibility of seizure control on day 28 of ACTH therapy in the children without focal seizures was 2.463 times that in those with focal seizures (P<0.05). The possibility of seizure control on day 28 of ACTH therapy in the children without hypsarrhythmia on electroencephalography on day 14 of ACTH therapy was 2.415 times that in those with hypsarrhythmia (P<0.05). The possibility of recurrence within 12 months after treatment was increased by 11.8% for every 1-month increase in the course of the disease (P<0.05). The possibility of moderate or severe developmental retardation or death in the children without seizure control after 28 days of ACTH therapy was 8.314 times that in those with seizure control (P<0.05). The possibility of moderate or severe developmental retardation or death in the children with structural etiology was 14.448 times that in those with unknown etiology (P<0.05). CONCLUSIONS: Presence or absence of focal seizures and whether hypsarrhythmia disappears after 14 days of treatment can be used as predictors for the short-term efficacy of ACTH therapy, while the course of disease before treatment can be used as the predictor for recurrence after seizure control by ACTH therapy. The prognosis of IESS children is associated with etiology, and early control of seizures after ACTH therapy can improve long-term prognosis.

The second-tier status of fragile X syndrome testing for unexplained intellectual disability/global developmental delay in the era of next-generation sequencing.

Objective: Although many unexplained intellectual disability/global developmental delay (ID/GDD) individuals have benefited from the excellent detection yield of copy number variations and next-generation sequencing testing, many individuals still who suffer from ID/GDD of unexplained etiology. In this study, we investigated the applicability of fragile X syndrome (FXS) testing in unexplained ID/GDD individuals with negative or absent genetic testing. Methods: In this study, we used the triplet repeat primed polymerase chain reaction to evaluate the value and application of fragile X testing in unexplained ID/GDD individuals with negative or absent genetic testing (n = 681) from three hospitals. Results: Of the 681 ID/GDD individuals with negative or absent genetic testing results detected by FXS testing, 12 men and one woman were positive. This corresponded to a diagnostic yield of 1.9% for FXS testing in our cohort. All FXS individuals had either a family history of ID/GDD or suggestive clinical features. The detection yield of FXS testing in ID/GDD individuals who completed genetic testing (2.70%, 12/438) was significantly higher than in individuals without any genetic testing (0.40%, 1/243). Conclusions: This is the first report of FXS testing in ID/GDD individuals who lacked previous genetic testing, which promotes standardization of the FXS diagnostic process. These results highlight the utility of FXS testing of unexplained ID/GDD individuals with negative results from standard genetic testing. In the era of next-generation sequencing, FXS testing is more suitable as a second-tier choice and provides clinicians and geneticists with auxiliary references for tracing the etiology of ID/GDD.

Novel HCN1 Mutations Associated With Epilepsy and Impacts on Neuronal Excitability.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel plays a critical role in regulating the resting membrane potential and integrating synaptic transmission. Variants of HCN1 have been recognized as causes of epilepsy, and mutant HCN1 channels could act with loss-of-function (LOF), loss- and gain-of-function (LOF and GOF) and gain-of-function (GOF) mechanisms. However, phenotypes and pathogenesis of HCN1-related epilepsy are still poorly understood. This study enrolled five epileptic cases carrying five different HCN1 variants: two pathogenic variants (I380F and S710Rfs*71), two likely pathogenic variants (E240G and A395G), and a paternally inherited variant (V572A). Four variants were novel. Electrophysiological experiments revealed impaired biophysical properties of the identified mutants, including current densities and activation/deactivation kinetics. Moreover, three variants exerted effects on the biophysical properties of wild-type HCN1 channels in heterozygous conditions. Immunofluorescence experiments showed that two variants reduced the protein expression of HCN1channels in neurons. Neurons expressing E240G (GOF) variant showed increased input resistance. However, the variant of I380F (LOF) increased the neuronal firing rate, thus leading to neuronal hyperexcitability. In conclusion, the present study expands the genotypic and phenotypic spectrum of patients with HCN1-related epilepsy and clarifies the underlying mechanisms. We reported five new cases including four unreported likely/pathogenic variants. We provided assessments of biophysical function for each variant, which could help patients to receive individual therapy in the future. We confirmed that HCN1 variants contributed to neuronal hyperexcitability by regulating input resistance and the action potential firing rate, and we have shown that they can affect protein expression in neurons for the first time.

Functional Investigation of TUBB4A Variants Associated with Different Clinical Phenotypes.

Dominant TUBB4A variants result in different phenotypes, including hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), dystonia type 4 (DYT4), and isolated hypomyelination. Here, we report four new patients with a novel TUBB4A variant (p.K324T) and three new patients with previously reported variants (p.Q292K, p.V255I, p.E410K). The individual carrying the novel p.K324T variant exhibits epilepsy of infancy with migrating focal seizures (EIMFS), while the other three have isolated hypomyelination phenotype. We also present a study of the cellular effects of TUBB4A variants responsible for H-ABC (p.D249N), DYT4 (p.R2G), a severe combined phenotype with combination of hypomyelination and EIMFS (p.K324T), and isolated hypomyelination (p.Q292K and p.E410K) on microtubule stability and dynamics, neurite outgrowth, dendritic spine development, and kinesin binding. Cellular-based assays reveal that all variants except p.R2G increase microtubule stability, decrease microtubule polymerization rates, reduce axonal outgrowth, and alter the density and shape of dendritic spines. We also find that the p.K324T and p.E410K variants perturb the binding of TUBB4A to KIF1A, a neuron-specific kinesin required for transport of synaptic vesicle precursors. Taken together, our data suggest that impaired microtubule stability and dynamics, defected axonal growth, and dendritic spine development form the common molecular basis of TUBB4A-related leukodystrophy. Impairment of TUBB4A binding to KIF1A is more likely to be involved in the isolated hypomyelination phenotype, which suggests that alterations in kinesin binding may cause different phenotypes. In conclusion, our study extends the spectrum of TUBB4A mutations and related phenotypes and provides insight into why different TUBB4A variants cause distinct clinical phenotypes.

Hormonal Therapy for Infantile Spasms: A Systematic Review and Meta-Analysis.

OBJECTIVE: The limitations of adrenocorticotrophic hormone (ACTH) treatment for infantile spasms (ISs), such as high costs, limited availability, and adverse effects (AEs), make it necessary to explore whether corticosteroids are optimal alternatives. Many other compelling treatments have gone through trials due to the suboptimal effectiveness of hormonal therapy. A systematic review and meta-analysis were performed to evaluate the effectiveness and safety of hormonal therapy for patients with ISs. METHODS: EMBASE, Ovid MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and online registers were searched through April 2021 for randomized controlled trials (RCTs). RESULTS: A total of 19 RCTs (N = 1,279) were included. There was no significant difference in the effectiveness of oral corticosteroids and ACTH in electro-clinical response (risk ratio [RR] = 0.85, 95% CI 0.41-1.76). Low-dose ACTH had similar effectiveness in electro-clinical response compared to usual-dose group (RR = 0.94, 95% CI 0.60-1.47) but conferred a lower risk of AEs (RR = 1.71, 95% CI 1.08-2.71). ACTH was more beneficial in controlling spasms than vigabatrin (VGB) (RR = 1.31, 95% CI 1.05-1.64) for patients without tuberous sclerosis complex (TSC). All RCTs were connected through network meta-analysis, and we found that ketogenic diet (KD), zonisamide, methylprednisolone, or combined treatment of hormonal therapy with topiramate (TPM) or pyridoxine was not different in electro-clinical response compared to usual-dose ACTH. CONCLUSION: Our analysis showed that oral corticosteroids could be optional alternatives when ACTH is not applicable, and ACTH is more beneficial for patients without TSC. Moreover, low-dose ACTH is recommended due to comparative effectiveness but lower risk of AEs. However, due to the high heterogeneity of included patients and treatment protocols, these results must be interpreted with caution. RCTs with multicentric involvement and larger sample size are needed for solid evaluation of other alternative treatments.

The Effects of Two Nrf2 Activators, Bardoxolone Methyl and Omaveloxolone, on Retinal Ganglion Cell Survival during Ischemic Optic Neuropathy.

Nonarteritic anterior ischemic optic neuropathy (NAION) is one of the most common acute optic neuropathies that affect the over 55-year-old population. NAION causes the loss of visual function, and it has no safe and effective therapy. Bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate; CDDO-Me; RTA 402) is a semisynthetic triterpenoid with effects against antioxidative stress and inflammation in neurodegeneration and kidney disease that activates the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Moreover, RTA 402 is an FDA-approved compound for the treatment of solid tumors, lymphoid malignancies, melanoma, and chronic kidney disease. Omaveloxolone (RTA 408) is an activator of Nrf2 and an inhibitor of NFκB, possessing antioxidative and anti-inflammatory activities in mitochondrial bioenergetics. RTA 408 is also under clinical investigation for Friedreich ataxia (FA). In this study, a rodent anterior ischemic optic neuropathy (rAION) model induced by photothrombosis was used to examine the therapeutic effects of RTA 402 and RTA 408. Treatment with RTA402 results in antiapoptotic, antioxidative stress, anti-inflammatory, and myelin-preserving effects on retinal ganglion cell (RGC) survival and visual function via regulation of NQO1 and HO-1, reduced IL-6 and Iba1 expression in macrophages, and promoted microglial expression of TGF-ß and Ym1 + 2 in the retina and optic nerve. However, these effects were not observed after RTA 408 treatment. Our results provide explicit evidence that RTA 402 modulates the Nrf2 and NFκB signaling pathways to protect RGCs from apoptosis and maintain the visual function in an rAION model. These findings indicate that RTA 402 may a potential therapeutic agent for ischemic optic neuropathy.

Efficacy of different treatment modalities for acute and chronic phases of the febrile infection-related epilepsy syndrome: A systematic review.

BACKGROUND: Febrile infection-related epilepsy syndrome is associated with high mortality and morbidity rates. No systematic review of demographics, aetiologies, good treatment options, and causes of deaths has been performed. Thus, we aimed to focus on these factors to provide a structure for patient management and research. METHODS: A deep literature search was performed in PubMed and Embase of all years until May 2019. RESULTS: We retrieved 45 aSrticles: 3 multicentre cohort studies, 13 single-centre cohorts, 1 case series, and 28 case reports. We identified 229 cases: most were from Asia; 53% were males; 11.4% had several types of antibodies, and the most common was anti-glutamate receptor epsilon 2; 30% (69 cases) had good treatment outcomes; 12.2% died; and 56% remained with drug-resistant epilepsies. Univariate analysis revealed a statistically significant association between positive outcomes in Japan and China, the use of the ketogenic diet either acutely or chronically, and the use of steroids acutely or chronically. Taiwan showed a statistically significant association with negative outcomes. Multivariate logistic regression revealed the utilisation of the ketogenic diet in the acute phases (P = 0.008, OR = 3.613) and being in Japan (P = 0.003, OR = 3.146) as independent determinants of positive outcomes. Most of the deaths occurred because of the progress of the disease rather than complications of the drugs. CONCLUSIONS: Asians are more affected and several cases have antibodies. Positive outcomes are associated with being in Japan and the utilisation of the ketogenic diet in the acute phase.

Mixed Germ Cell Tumor of the Endometrium: A Case Report and Literature Review.

Germ cell tumors (GCTs) localized extragonadally are rare, with only 14 reported cases of a yolk sac tumor in the endometrium. Here we report a case of mixed endometrium GCTs in a 65-year-old postmenopausal woman with abnormal vaginal bleeding. An ultrasound examination showed an oval-shaped mass in the patient's uterine cavity. Biochemical examination revealed elevated serum α-fetoprotein (AFP) at 359 ng/mL, whereas the tumor markers CA-125, CA-199, and CEA were all within normal range. Total hysterectomy and bilateral salpingo-oophorectomy were performed;. a histological examination revealed that the malignant components contained a yolk sac tumor, embryonal carcinoma, and focal immature teratoma. Immunohistochemical staining showed that AFPs were diffusively distributed in both the yolk sac tumor and embryonal carcinoma. The stem cell marker OCT3/4 was positive in the embryonal carcinoma component and that the pan-cytokeratin AE1/AE3 staining was positive in glandular areas. GFAPs (Glial Fibrillary Acidic Proteins) were positive in neuroectodermal tubules; the Ki-67 protein was positive in 90% of the tumor cells, whereas CD117 and placental alkaline phosphatase (PLAP) were negative. The cumulative evidence indicated mixed GCTs of endometrium as the final histopathological diagnosis. The patient received three courses of adjunct chemotherapy that provided good therapeutic efficacy as evidenced by the decreased serum AFP level. Our report on this rare case of mixed GCTs of the endometrium, supported by associated histological patterns and immunophenotypes and successful adjunct chemotherapy after surgery, could provide insight on future treatment of this rare but lethal disease.

Efficacy of the ketogenic diet in Chinese children with Dravet syndrome: A focus on neuropsychological development.

OBJECTIVES: In this retrospective study, we evaluated the efficacy of the ketogenic diet (KD) treatment in Chinese children with Dravet syndrome (DS) as well as its effect on neuropsychological development. METHODS: Twenty-six children (14 male) living with DS and being treated with KD at our department between July 2014 and December 2017 were enrolled in the study. The efficacy of KD was measured by seizure frequency before and after the diet. Additionally, children's neuropsychological development, as evaluated by the Gesell developmental schedule, was compared between the KD and a non-KD group. RESULTS: After 3, 6, 12, 18, 24, and 30 months, 92.3%, 84.6%, 46.2%, 30.8%, 19.2%, and 19.2% remained on the KD, while 38.4%, 34.6%, 38.4%, 23.0%, 15.4%, and 15.4% showed >50% reduction in seizure. The development age (DA) subscores of 12 children, as measured by the Gesell developmental schedule, increased after commencement of KD. However, children's development quotient (DQ) subscores (age-adjusted) decreased after KD. In the non-KD group (40 participants), an increase of DA subscores and decrease of DQ subscores were also observed. Results found no difference in changes of DQ subscores over time between the two groups. The DQ subscores after the diet in the KD group (20 participants) did not differ significantly when compared to the DQ subscores at same age in the non-KD group (20 patients) (t-test). CONCLUSIONS: The DA subscores of 12 children in KD group increased after KD; when compared with that of the non-KD group, no significant difference was observed in respect to the changes of DQ subscore over time. Effects on cognitive and other neuropsychological development outcomes of KD for children living with DS require further study.