Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.

BACKGROUND AND PURPOSE: Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi-allelic mutations in NKX6-2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. METHODS: Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6-2 mutations in a multicentre setting is described. Then, all reported NKX6-2 mutations and those identified in this study were combined and an in-depth analysis of NKX6-2-related disease spectrum was provided. RESULTS: Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6-2 were identified, evidencing a high NKX6-2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6-2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. CONCLUSIONS: NKX6-2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6-2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels.

Outcomes by treatment modality in elderly patients with localized gastric and esophageal cancer.

Background: We aimed to assess current treatment patterns and outcomes in elderly patients with localized gastric and esophageal (ge) cancers. Methods: This retrospective analysis considered patients 75 years of age or older with ge cancers treated during 2012-2014. Patient demographics and tumour characteristics were collected. Overall survival (os) and disease-free survival were assessed by univariable and multivariable Cox proportional hazards regression, adjusting for demographics. Logistic regression analyses were used to examine factors affecting treatment choices. Results: The 110 patients in the study cohort had a median age of 81 years (range: 75-99 years). Primary disease sites were esophageal (55%) and gastric (45%). Treatment received included radiation therapy alone (29%), surgery alone (26%), surgery plus perioperative therapy (14%), chemoradiation alone (10%), and supportive care alone (14%). In multivariable analyses, surgery (hazard ratio: 0.48; 95% confidence interval: 0.26 to 0.90; p = 0.02) was the only independent predictor for improved os. Patients with a good Eastern Cooperative Oncology Group performance status (p = 0.008), gastric disease site (p = 0.02), and adenocarcinoma histology (p = 0.01) were more likely to undergo surgery. Conclusions: At our institution, few patients 75 years of age and older received multimodality therapy for localized ge cancers. Outcomes were better for patients who underwent surgery than for those who did not. To ensure optimal treatment selection, comprehensive geriatric assessment should be considered for patients 75 years of age and older with localized ge cancers.

Prevalence of oral lichen planus in Iranian children and adolescents: a 12-year retrospective study.

AIM: To investigate the prevalence of oral lichen planus in patients younger than 18 years, referred to a dermatology centre in Iran during 2002-2014. Lichen planus is a chronic inflammatory, immune-mediated disease that could affect the oral mucosa and is a pre-cancerous condition. The disease usually develops in middle age with female predominance and is rare in children. METHODS: In this retrospective study, cases with definitive histopathologic diagnosis of lichen planus, over a 12-year period from 2002 to 2014 from a dermatologic hospital archive were evaluated. The prevalence of both cutaneous and oral lichen planus, the male:female ratio and site of involvement were calculated using SPSS version 21. RESULTS: Thirty-six of 564 patients younger than 18 years old diagnosed with lichen planus. Two females (0.4%) had oral lichen planus. One patient had erosive, and one had bullous, oral lichen planus. CONCLUSION: Oral lichen planus had a very low frequency in Iranian population younger than 18 years old, identifying these patients is recommended for long-term follow-up.

2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

High frequency of microsatellite instability in sporadic colorectal cancer patients in Iran.

Microsatellite instability in sporadic colorectal cancer patients was assessed, and the clinicopathological associations were evaluated in northeastern Iran, which is a high-risk region for gastrointestinal malignancies. Microsatellite instability (MSI) status of tumoral tissue, compared to normal tissue, was assessed with a standard panel of MSI markers on paraffin-embedded surgically resected tissues from 67 consecutive sporadic colorectal cancer patients. Eleven of the patients were under 40 years old. Female patients were significantly younger than male patients (mean age 54.2 vs 62.1 years, P = 0.020). MSI analysis revealed 18 cases of MSI-H (26.9%), 11 MSI-L (16.4%) and 38 MSS (microsatellite stable tumors; 56.7%). While a greater proportion of patients consisted of males, 56.7 vs 43.3% females, MSI-H was more frequent in females (34.5 vs 21.5%). MSI was associated with proximal location of tumor (P = 0.003) and lower stages of tumor (P = 0.002), while MSS tumors were associated with node metastasis. MSI has a higher frequency in sporadic colorectal cancer patients, suggesting that molecular epidemiology of the genetic alterations involved in colorectal cancer carcinogenesis has a different pattern in the Iranian population, which deserves further epidemiological attention. The high frequency of MSI-H in this population suggests that we should look at microsatellite instability prior to chemotherapy to determine the most appropriate chemotherapeutic strategy in our population.

Bypassing the maturation arrest in myeloid cell line U937 by over-expression of microRNA-424.

Micro RNAs are a class of small non-coding RNAs which has been recently shown to play a crucial role in major cellular processes such as development and differentiation through post-transcriptional regulation. The role of these epigenetic elements has also been demonstrated in hematopoietic lineage differentiation and there is a large body of evidence that miR-424 is responsible for monocyte differentiation. Our goal was to examine the effect of miR-424 over-expression on defeating the maturation blockage in monoblastic cell line U937. The permanent over-expression of miR-424 was established using a retroviral vector construct containing the precursor of miR-424 sequence. Induction of differentiation process was monitored by assaying changes in cell morphology, and expression of cell surface markers using light microscopy, quantitative RT-PCR, and flow cytometry for monocyte markers such as CD11b and CD14. The cells showed monocytic characteristics 14 days after transduction, and CD11b and CD14 expression were significantly increased, confirmed by flow cytometry QRT-PCR and RT-PCR results. In conclusion, miR-424 over-expression is an effective factor in maturation of the monoblastic U937 cells and it has the ability of directing them into cells, expressing monocyte/macrophage characteristics.