OBJECTIVE: To carry out clinical and genetic analysis for a child featuring Brain-Lung-Thyroid syndrome (BLTS).
METHODS: A child who had presented at the Children\'s Hospital Affiliated to Shandong University on May 27, 2022 was selected as the study subject. Clinical data was collected. Trio-whole exome sequencing (Trio-WES) was carried out for the child and his parents, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The child was given individualized treatment following the diagnosis.
RESULTS: The child, a two-year-and-seven-month-old boy, had presented with global developmental delay, ataxia and hypothyroidism. WES revealed that he has harbored a heterozygous c.674C>T variant of the NKX2-1 gene, based on which he was diagnosed with BLTS. CT scan revealed interstitial and parenchymal inflammation in his lungs, which was reduced by budesonide aerosol inhalation.
CONCLUSIONS: Discovery of the novel c.674C>T variant has enriched the mutational spectrum of the NKX2-1 gene. Budesonide aerosol may be used to treat lung inflammation associated with BLTS.

UNASSIGNED: Several studies explored the association between thyroid transcription factor-1 (TTF-1) and the therapeutic efficacy of immunotherapy. However, the effect of TTF-1 on the therapeutic efficacy of programmed death-1 (PD-1) inhibitor/chemoimmunotherapy in patients with non-squamous non-small cell lung cancer (non-Sq NSCLC) with a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or more who are highly susceptible to immunotherapy remains unresolved. Therefore, we evaluated whether TTF-1 has a clinical impact on this population.
UNASSIGNED: Patients with non-Sq NSCLC and high PD-L1 expression who received PD-1 inhibitor monotherapy or chemoimmunotherapy between May 2017 and December 2020 were retrospectively enrolled. Treatment efficacy was compared after adjusting for baseline differences using propensity score matching.
UNASSIGNED: Among the 446 patients with NSCLC with high PD-L1 expression, 266 patients with non-Sq NSCLC were analyzed. No significant differences in therapeutic efficacy were observed between the TTF-1-positive and -negative groups in the overall and propensity score-matched populations. Of chemoimmunotherapy, pemetrexed containing regimen significantly prolonged progression-free survival compared to chemoimmunotherapy without pemetrexed, regardless of TTF-1 expression (TTF1 positive; HR: 0.46 (95% Confidence interval: 0.26-0.81), p<0.01, TTF-1 negative; HR: 0.29 (95% Confidence interval: 0.09-0.93), p=0.02).
UNASSIGNED: TTF-1 expression did not affect the efficacy of PD-1 inhibitor monotherapy or chemoimmunotherapy in patients with non-Sq NSCLC with high PD-L1 expression. In this population, pemetrexed-containing chemoimmunotherapy demonstrated superior anti-tumor efficacy, irrespective of TTF-1 expression.

BACKGROUND: NKX2-1-related disorders (NKX2-1-RD) are rare conditions affecting lung, thyroid, and brain development, primarily caused by pathogenic variants or deletions in the NKX2-1 gene. Congenital hypothyroidism (CH) is a common endocrine manifestation, leading to irreversible intellectual disability if left untreated.
OBJECTIVE: The aim was to evaluate the current evidence for the use of screening and diagnostic techniques for endocrine alterations in patients with NKX2-1-RD.
METHODS: This systematic review was reported following the PRISMA guidelines. Two separate research questions in PICO format were addressed to cover initial screening and diagnosis procedures for endocrine diseases in patients with NKX2-1-RD. Eligibility criteria focused on patients with genetic confirmation of the disease and hypothyroidism. Various databases were searched, and data were extracted and assessed independently by two reviewers.
RESULTS: Out of 1012 potentially relevant studies, 46 were included, for a total of 113 patients. CH was the most frequent endocrine alteration (45% of patients). Neonatal screening was reported in only 21% of patients based on blood TSH measurements. TSH thresholds varied widely across studies, making hypothyroidism detection ranges difficult to establish. Diagnostic tests using serum TSH were used to diagnose hypothyroidism or confirm its presence. 35% of patients were diagnosed at neonatal age, and 42% at adult age. Other hormonal dysfunctions identified due to clinical signs, such as anterior pituitary deficiencies, were detected later in life. Thyroid scintigraphy and ultrasonography allowed for the description of the thyroid gland in 30% of cases of hypothyroidism. Phenotypic variability was observed in individuals with the same variants, making genotype-phenotype correlations challenging.
CONCLUSIONS: This review highlights the need for standardized protocols in endocrine screening for NKX2-1-RD, emphasizing the importance of consistent methodology and hormone threshold levels. Variability in NKX2-1 gene variants further complicates diagnostic efforts. Future research should concentrate on optimizing early screening protocols and diagnostic strategies.

It is known that V-set and immunoglobulin domain containing 1 (VSIG1) is a cell-cell adhesion molecule that can serve as an indicator of better survival in patients with gastric cancer. Its interaction with cytoplasmic thyroid transcription factor 1 (TTF-1) has been hypothesized to characterize gastric-type HCC, but its clinical importance is far from understood. As VSIG1 has also been supposed to be involved in the epithelial-mesenchymal transition (EMT) phenomenon, we checked for the first time in the literature the supposed interaction between VSIG1, TTF-1, and Vimentin (VIM) in HCCs. Immunohistochemical (IHC) stains were performed on 217 paraffin-embedded tissue samples that included tumor cells and normal hepatocytes, which served as positive internal controls. VSIG1 positivity was seen in 113 cases (52.07%). In 71 out of 217 HCCs (32.71%), simultaneous positivity for VSIG1 and TTF-1 was seen, being more specific for G1/G2 carcinomas with a trabecular architecture and a longer OS (p = 0.004). A negative association with VIM was revealed (p < 0.0001). Scirrhous-type HCC proved negative for all three examined markers. The present paper validates the hypothesis of the existence of a gastric-type HCC, which shows a glandular-like architecture and is characterized by double positivity for VSIG1 and TTF-1, vimentin negativity, and a significant OS.

BACKGROUND: NKX2-1-related disorder (NKX2-1-RD) is a rare disease characterized by a triad of primary hypothyroidism, neonatal respiratory distress, and neurological features, including chorea.
OBJECTIVE: This study aimed to identify discrepancies in the management of NKX2-1-RD among European Union (EU) specialists.
METHODS: The ERN-RND Chorea & Huntington disease group designed a survey to conduct a cross-sectional multicenter study on the management of NKX2-1-RD. Descriptive analysis was performed, and total responses are presented for each item.
RESULTS: The study involved 23 experts from 13 EU countries with experience in evaluating hyperkinetic patients with NKX2-1-RD: 11 were adult specialists, and 12 were pediatric specialists. NKX2-1-RD diagnosis was made at different ages, with the most common initial symptoms being hypotonia and/or motor developmental delay (reported by 11 experts) and chorea (reported by 8 experts). Chorea involved various body parts and showed improvement as reported by 9 experts, stabilization by 12 experts, and worsening by 2 experts with age. The pharmacological treatment of chorea varied widely among the experts. Misdiagnosis was reported by 14 experts. NKX2-1 pathogenic variants or deletions were confirmed in >75 % of patients (reported by 12 experts). Pulmonary and endocrinology evaluations were requested by 7 and 12 experts, respectively. The management of psychiatric comorbidities also varied among the different experts.
CONCLUSIONS: This study highlights the need for a clinical practice guideline for the management of NKX2-1-RD to ensure that patients across the EU receive consistent and appropriate care. Such a guideline would benefit both doctors and healthcare practitioners.

Background: Brain-lung-thyroid syndrome (BLTS) is caused by NKX2-1 haploinsufficiency, resulting in chorea/choreoathetosis, respiratory problems, and hypothyroidism. Genes interacting with NKX2-1 mutants influence its phenotypic variability. We report a novel NKX2-1 missense variant and the modifier function of TAZ/WWTR1 in BLTS. Methods: A child with BLTS underwent next-generation sequencing panel testing for thyroid disorders. His family was genotyped for NKX2-1 variants and screened for germline mosaicism. Mutant NKX2-1 was generated, and transactivation assays were performed on three NKX2-1 target gene promoters. DNA binding capacity and protein-protein interaction were analyzed. Results: The patient had severe BLTS and carried a novel missense variant c.632A>G (p.N211S) in NKX2-1, which failed to bind to specific DNA promoters, reducing their transactivation. TAZ cotransfection did not significantly increase transcription of these genes, although the variant retained its ability to bind to TAZ. Conclusions: We identify a novel pathogenic NKX2-1 variant that causes severe BLTS and is inherited through germline mosaicism. The mutant lacks DNA-binding capacity, impairing transactivation and suggesting that NKX2-1 binding to DNA is essential for TAZ-mediated transcriptional rescue.

Cell plasticity theoretically extends to all possible cell types, but naturally decreases as cells differentiate, whereas injury-repair re-engages the developmental plasticity. Here we show that the lung alveolar type 2 (AT2)-specific transcription factor (TF), CEBPA, restricts AT2 cell plasticity in the mouse lung. AT2 cells undergo transcriptional and epigenetic maturation postnatally. Without CEBPA, both neonatal and mature AT2 cells reduce the AT2 program, but only the former reactivate the SOX9 progenitor program. Sendai virus infection bestows mature AT2 cells with neonatal plasticity where Cebpa mutant, but not wild type, AT2 cells express SOX9, as well as more readily proliferate and form KRT8/CLDN4+ transitional cells. CEBPA promotes the AT2 program by recruiting the lung lineage TF NKX2-1. The temporal change in CEBPA-dependent plasticity reflects AT2 cell developmental history. The ontogeny of AT2 cell plasticity and its transcriptional and epigenetic mechanisms have implications in lung regeneration and cancer.

UNASSIGNED: This study was performed to determine the biological processes in which NKX2-1 is involved and thus its role in the development of lung squamous cell carcinoma (LUSC) toward improving the prognosis and treatment of LUSC.
UNASSIGNED: Raw RNA sequencing (RNA-seq) data of LUSC from The Cancer Genome Atlas (TCGA) were used in bioinformatics analysis to characterize NKX2-1 expression levels in tumor and normal tissues. Survival analysis of Kaplan-Meier curve, the time-dependent receiver operating characteristic (ROC) curve, and a nomogram were used to analyze the prognosis value of NKX2-1 for LUSC in terms of overall survival (OS) and progression-free survival (PFS). Then, differentially expressed genes (DEGs) were identified, and Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) were used to clarify the biological mechanisms potentially involved in the development of LUSC. Moreover, the correlation between the NKX2-1 expression level and tumor mutation burden (TMB), tumor microenvironment (TME), and immune cell infiltration revealed that NKX2-1 participates in the development of LUSC. Finally, we studied the effects of NKX2-1 on drug therapy. To validate the protein and gene expression levels of NKX2-1 in LUSC, we employed immunohistochemistry(IHC) datasets, The Gene Expression Omnibus (GEO) database, and qRT-PCR analysis.
UNASSIGNED: NKX2-1 expression levels were significantly lower in LUSC than in normal lung tissue. It significantly differed in gender, stage and N classification. The survival analysis revealed that high expression of NKX2-1 had shorter OS and PFS in LUSC. The multivariate Cox regression hazard model showed the NKX2-1 expression as an independent prognostic factor. Then, the nomogram predicted LUSC prognosis. There are 51 upregulated DEGs and 49 downregulated DEGs in the NKX2-1 high-level groups. GO, KEGG and GSEA analysis revealed that DEGs were enriched in cell cycle and DNA replication.The TME results show that NKX2-1 expression was positively associated with mast cells resting, neutrophils, monocytes, T cells CD4 memory resting, and M2 macrophages but negatively associated with M1 macrophages. The TMB correlated negatively with NKX2-1 expression. The pharmacotherapy had great sensitivity in the NKX2-1 low-level group, the immunotherapy is no significant difference in the NKX2-1 low-level and high-level groups. The analysis of GEO data demonstrated concurrence with TCGA results. IHC revealed NKX2-1 protein expression in tumor tissues of both LUAD and LUSC. Meanwhile qRT-PCR analysis indicated a significantly lower NKX2-1 expression level in LUSC compared to LUAD. These qRT-PCR findings were consistent with co-expression analysis of NKX2-1.
UNASSIGNED: We conclude that NKX2-1 is a potential biomarker for prognosis and treatment LUSC. A new insights of NKX2-1 in LUSC is still needed further research.

OBJECTIVE: Both mesonephric adenocarcinoma (MA) and mesonephric-like adenocarcinoma (MLA) express thyroid transcription factor 1 (TTF1). TTF1 is also considered a highly sensitive and specific diagnostic marker for primary lung adenocarcinoma (PLA). However, distinguishing PLA from pulmonary metastatic MA/MLA (PMM) based on the expression of TTF1 alone can be difficult. This study aimed to investigate the expression of TTF1 and paired box 8 (PAX8) and assess their value in distinguishing PMM from PLA.
METHODS: We reviewed the electronic medical records and pathology slides of eight PMM cases. We conducted immunostaining for TTF1 and PAX8 in 6, 8, and 21 cases of primary MA/MLA, PMM, and PLA, respectively.
RESULTS: Two patients with stage IB uterine MLA developed lung metastases at 5 and 57 months after hysterectomy. Solitary pulmonary nodules were suspected to be primary lung cancer in two patients. Compared to primary tumors, all matched PMMs exhibited reduced TTF1 immunoreactivity. In contrast, the majority of PLAs showed uniform and intense TTF1 expression. All except one PMM exhibited diffuse and strong PAX8 expression, while only one PLA showed focal and weak PAX8 expression.
CONCLUSIONS: Immunostaining for TTF1 and PAX8 can help in distinguishing PMM from PLA in the diagnosis of pulmonary lesions detected in patients with a history of MA/MLA.

We present a case report of a 76-year-old male with a histologically confirmed KRAS mutated, thyroid transcription factor 1 (TTF1) positive, grade 1, mucinous adenocarcinoma with cytologically difficult to interpret lymph node metastasis showing loss of TTF1 expression and overlapping features with goblet cell hyperplasia. The case highlights the importance of molecular testing in aiding diagnosis and guiding treatment of non-small cell lung carcinomas (NSCLC).