Thyroid Transcription Factor-1 Expression Research Articles

Diagnostic Value of Immunostaining for Thyroid Transcription Factor 1 (TTF1) and Paired Box 8 (PAX8) in Distinguishing Pulmonary Metastases of Mesonephric and Mesonephric-like Adenocarcinomas from Primary Lung Adenocarcinomas.

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. 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. 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. 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.

A case report of loss of thyroid transcription factor 1 expression in lung adenocarcinoma EBUS FNA.

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).

Abstract 5221: TTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading

Abstract Background: Thyroid transcription factor 1 (TTF-1) is expressed in 70% to 80% of lung adenocarcinomas (LUAD). Several papers revealed that TTF-1 expression is associated with better patient outcomes independent of the tumor stage. However, it is unknown whether the prognostic impact of TTF-1 only results from a different growth pattern (tumor grading) or is independently associated with a biologically more aggressive phenotype. Thus, we analyzed a large bi-centric cohort of LUAD to assume the true prognostic value of TTF-1 in relation to the tumor grade. Methods: We collected a large, real-life cohort of 447 patients with completely resected LUAD from two large-volume German lung cancer centers. TTF-1 status, evaluated by IHC, and tumor grading were correlated with clinical, pathologic, and molecular data, as well as patient outcomes. Kaplan-Meier curves were used for comparison of TTF-1 status and different tumor grades in terms of the DFS. The impact of TTF-1 was measured by univariate and multivariate Cox regression. Finally, a causal graph analysis was performed to identify and account for potential confounders to improve the statistical estimation of the predictive power of TTF-1 expression for DFS in comparison to the tumor grade. Results: Kaplan-Meier curves revealed that TTF-1 positivity is associated with longer DFS independent of tumor grade, whereas a strong association of DFS with the tumor grade is observed only in TTF-1-positive patients. In univariate analysis, TTF-1 positivity was associated with significantly longer DFS (median log HR -0.83 [-1.43; -0.20]; p=0.018), whereas higher tumor grade showed a non-significant association with shorter DFS (median log HR 0.30 [-0.58; 1.60]; p=0,62 for G1 to G2 and 0.68 [-0.24; 1.89]; p=0,34 for G2 to G3). In multivariate analysis, TTF-1 positivity resulted in a significantly longer DFS (median log HR -0.65 [-1.13; -0.09]; p=0.05) independent of all other parameters, including tumor grade. Applying the adjustment sets suggested by the causal graph analysis, the superiority of TTF-1 (median log HR -0.86 [-1.25; -0.41]) over tumor grade (median log HR 0.31 [-0.32; 1.30]/0.61[-0.07; 1.65]) in terms of prognostic power was confirmed. Conclusion: This study draws three important conclusions: Firstly, it indicates that the prognostic power of tumor grade is limited to TTF-1-positive patients. Secondly, it underlines the independent prognostic value of TTF-1 expression for DFS regardless of tumor grade. Finally, our analyses reveal that the effect size of TTF-1 surpasses that of tumor grade. To transfer the results directly into the clinical area, we recommend distinguishing between TTF-1-positive and TTF-1-negative LUADs in the pathological report. Tumor grading should only be applied to TTF-1-positive LUADs (TTF-1+/G1-3). TTF-1-negative LUADs should either not be graded or always be classified as high-grade (TTF-1-/G3). Citation Format: Simon Schallenberg, Gabriel Dernbach, Mihnea Dragomir, Georg Schlachtenberger, Kyrill Boschung, Corinna Friedrich, Kai Standvoss, Lukas Ruff, Philipp Anders, Christian Grohe, Winfried Randerath, Sabine Merkelbach-Bruse, Alexander Quaas, Matthias Heldwein, Ulrich Keilholz, Khosro Hekmat, Jens Rückert, Reinhard Büttner, David Horst, Frederick Klauschen, Nikolaj Frost. TTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5221.

Canine follicular cell and medullary thyroid carcinomas: Immunohistochemical characterization

Research on modulation of iodine uptake by thyroid cells could help improve radioiodine treatment of dogs with thyroid tumors. The aim of this study was to characterize the immunohistochemical expression of thyroid transcription factor-1 (TTF-1), thyroglobulin, thyrotropin receptor (TSHR), sodium iodide symporter (NIS), pendrin, thyroid peroxidase (TPO), vimentin, and Ki-67 in follicular cell thyroid carcinomas (FTCs) and medullary thyroid carcinomas (MTCs), and to compare protein expression between FTC causing hyperthyroidism and FTC of euthyroid dogs. Immunohistochemistry was performed in 25 FTCs (9 follicular, 8 follicular-compact, and 8 compact) and 8 MTCs. FTCs and MTCs were positive for TTF-1, and expression was higher in FTCs of euthyroid dogs compared with FTCs of hyperthyroid dogs ( P= .041). Immunolabeling for thyroglobulin was higher in follicular and follicular-compact FTCs compared with compact FTCs ( P = .001), while vimentin expression was higher in follicular-compact FTCs compared with follicular FTCs ( P = .011). The expression of TSHR, NIS, pendrin, and TPO was not significantly different among the different subtypes of FTCs or between FTCs causing hyperthyroidism and FTCs in euthyroid dogs. TSHR, NIS, pendrin, and TPO were also expressed in MTCs. Ki-67 labeling index was comparable between FTCs and MTCs, and between FTCs causing hyperthyroidism and FTCs in euthyroid dogs. Proteins of iodine transport were also expressed in canine MTCs, which could have implications for diagnosis and treatment. The different expression of thyroglobulin and vimentin between FTC histological subtypes could reflect variations in tumor differentiation.

Thyroid transcription factor‐1 expression in lung neuroendocrine tumours: a gender-related biomarker?

PurposeThyroid transcription factor‐1 (TTF‐1) assessed by immunohistochemistry (IHC) is a specific biomarker for lung adenocarcinoma, and is commonly used to confirm the pulmonary origin of neuroendocrine tumours (NET). The majority of the available data suggest that TTF-1 is favourable prognostic biomarker for lung adenocarcinomas, whereas its role is more conflicting for lung NET. The main aim of this multicenter retrospective study was to investigate the potentially relevant associations between TTF-1 biomarker and clinical and pathological features of the study population, as well as determine TTF-1 prognostic effect on the clinical outcome of the patients.MethodsA multicentre retrospective study was conducted on 155 surgically-removed lung NET, with available IHC TTF-1 assessment.ResultsMedian age was 59.5 years (range 13–86), 97 patients (62.6%) were females, 31 cases (20%) were atypical carcinoids, 4 (2.6%) had TNM stage IV. Mitotic count ≥2 per 10 high-power field was found in 35 (22.6%) subjects, whereas necrosis was detected in 20 patients (12.9%). TTF-1 was positive in 78 cases (50.3%). The median overall survival was 46.9 months (range 0.6–323) and the median progression-free survival was 39.1 months (range 0.6–323). Statistically significant associations were found between (1) TTF-1 positivity and female sex (p = 0.007); and among (2) TTF-1 positivity and the absence of necrosis (p = 0.018).ConclusionsThis study highlights that TTF-1 positivity differs according to sex in lung NET, with a more common TTF-1 positive staining in female. Moreover, TTF-1 positivity correlated with the absence of necrosis. These data suggest that TTF-1 could potentially represent a gender-related biomarker for lung NET.

Thyroid transcription factor-1 (TTF-1) expression and the efficacy of combination therapy with immune checkpoint inhibitors and cytotoxic chemotherapy in non-squamous non-small cell lung cancer.

Thyroid transcription factor-1 (TTF-1) is expressed in approximately 70% of lung adenocarcinomas and is one of the most reliable makers to distinguish primary lung adenocarcinoma from metastatic disease. TTF-1-negative status is a poor prognostic factor, and TTF-1-negative lung adenocarcinoma is associated with poor efficacy of immune checkpoint inhibitor (ICI) monotherapy. However, the relationship between TTF-1 expression and the efficacy of ICI plus chemotherapy is still unclear. We performed a retrospective analysis of 129 consecutive patients with advanced non-squamous non-small cell lung cancer (NS-NSCLC) treated with ICI monotherapy or ICI plus chemotherapy between January 2016 and December 2021. The expression of programmed death ligand-1 (PD-L1) and TTF-1 was also determined in cases for which no previous data were available. We then evaluated the association between TTF-1 expression status and treatment efficacy. Of the 129 cases, 33 were TTF-1-negative and 96 were positive. In the ICI monotherapy group (N=70), progression-free survival (PFS) was not significantly different between TTF-1-positive and negative patients (median 3.6 vs. 3.8 months, P=0.27); however, in patients with wild-type epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), a trend for worse PFS was observed in TTF-1-negative cases compared with those that were TTF-1-positive (median 3.8 vs. 4.5 months, P=0.088). Moreover, long-term efficacy of ICI monotherapy (>2 years) was not observed in the TTF-1-negative group. TTF-1-negative patients tended to have worse overall survival (OS) than TTF-1-positive patients (median 15.6 vs. 19.5 months, P=0.13). In the ICI plus chemotherapy group (N=59), TTF-1-negative patients tended to have better PFS and similar OS compared with TTF-1-positive patients (median 9.9 vs. 9.6 months, P=0.14; median 32.3 vs. 18.9 months, P=0.78). Long-term efficacy was generally observed in TTF-1-negative patients treated with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) (median PFS 22.5 months, median OS not reached). ICI monotherapy is generally less efficacious in TTF-1-negative NS-NSCLC patients, and clinicians should consider ICI plus chemotherapy in these cases. Our study suggests that ABCP is an optimal regimen for TTF-1-negative NS-NSCLC.

Thyroid transcription factor 1 (TTF-1) negativity as a predictor of unfavorable response to EGFR-TKI therapy in advanced lung adenocarcinoma patients with EGFR mutations.

The absence of thyroid transcription factor 1 (TTF-1) is associated with a lower frequency of epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma (LUAD). The aim of this study was to assess the impact of TTF-1 expression on the clinical response to EGFR-tyrosine kinase inhibitor (TKI) treatment in patients with advanced LUAD. The data of patients with advanced LUAD who were admitted to the Beijing Tiantan Hospital and Peking University Cancer Hospital (China) between April 2009 and May 2023 was retrospectively analyzed. A total of 227 patients diagnosed with advanced LUAD were included, of which 28.2% (64/227) had TTF-1-negative adenocarcinoma, while 54.6% (124/227) harbored EGFR mutations. Negative TTF-1 expression significantly correlated with male sex (68.8% vs. 42.3%, p < 0.001), history of heavy smoking (57.8% vs. 36.2%, p = 0.003), poorly differentiated tumors (86.5% vs. 43.2%, p < 0.001), and lower frequency of EGFR mutations (26.6% vs. 65.6%, p < 0.001) compared with TTF-1 positivity. Multivariable logistic regression showed that low prevalence of EGFR mutations (p < 0.001) and male sex (p = 0.006) were independent predictive factors for the negative expression of TTF-1. Patients lacking TTF-1 also exhibited worse overall response rate (ORR; 23.5% vs. 54.2%, p = 0.019), disease control rate (DCR; 58.8% vs. 89.7%, p = 0.003), and median progression-free survival (PFS; 2.9 vs. 11.6 months, p < 0.001) following treatment with EGFR-TKIs compared to the TTF-1-positive patients with EGFR mutations. Patients with TTF-1-negative and EGFR-mutant LUAD show a diminished response to EGFR-TKIs.

The role of thyroid transcription factor-1 in differentiating lung adenocarcinomas from non-pulmonary adenocarcinoma effusions.

Effusions, characterized by abnormal fluid accumulations in body cavities, present difficulties in identifying the primary organs of metastatic tumors through cytopathologic investigation, particularly in cancer-related complications. This retrospective cross-sectional laboratory study aimed to investigate the role of thyroid transcription factor-1 (TTF-1) in distinguishing lung adenocarcinomas from non-pulmonary adenocarcinomas in effusions. The study was conducted at Almobarak Cytopathology Laboratory, a private cytopathology laboratory. H&E was used to confirm the histological diagnosis of 58 archived cell blocks. TTF-1 immunostaining patterns were then correlated with the histological diagnosis. Statistical analysis, including numerical and graphical data summaries, was conducted using the Chi-square test in SPSS 23. TTF-1 expression was observed in 20 (34.4%) cases, while 38 (65.5%) cases showed no TTF-1 reaction. Positive TTF-1 was found in pleural fluid in 61.1 % of lung adenocarcinomas, while negative TTF-1 was found in only 3.4%. TTF-1 was not detected in the majority of peritoneal fluid samples. There was a highly significant relationship between pleural fluid, TTF-1, and lung adenocarcinoma (p=0.000). The data provided further evidence that TTF-1 is a useful marker for distinguishing pulmonary adenocarcinomas from non-pulmonary adenocarcinoma tumors.

Organoids of patient-derived medullary thyroid carcinoma: The first milestone towards a new in vitro model in dogs.

Organoid cultures could constitute a valuable in vitro model to explore new treatments for canine (c) medullary thyroid carcinoma (MTC). The study's objectives were to establish and characterize 3D organoid cultures of cMTC using histology and immunohistochemistry (IHC) and to evaluate the effect of antitumor drugs on organoids' viability. Five cMTC tissue samples were used to develop organoid cultures of which one organoid line, named cMTC N°2, could be passaged for an extended period. This cMTC N°2 organoid line was further compared to the primary tumour regarding morphology and IHC expression of thyroid transcription factor-1 (TTF-1), thyroglobulin, calcitonin, synaptophysin, vimentin, Ki-67, cyclooxygenase-2 (COX-2), P-glycoprotein and vascular endothelial growth factor (VEGF). Quality control of the cMTC N°2 organoid line was achieved by a single nucleotide polymorphism (SNP) array of the organoids, primary tumour and healthy blood cells of the same dog. The effect of carboplatin, meloxicam and toceranib phosphate (TOC) on cMTC N°2 organoids' viability was evaluated. The cMTC N°2 organoid line was cultured for 94 days and showed similar histological features with the primary tumour. Immunolabelling for TTF-1, thyroglobulin, calcitonin and VEGF was similar between the primary tumour and cMTC N°2 organoids. Compared to the primary tumour, organoids showed higher immunolabelling for vimentin and Ki-67, and lower immunolabelling for synaptophysin, COX-2 and P-glycoprotein. The SNP genotype was similar for each chromosome between healthy blood cells, primary tumour and cMTC N°2 organoids. Carboplatin, meloxicam and TOC had no effect on cMTC N°2 organoid cell viability within achievable in vivo concentration range. In conclusion, the cMTC N°2 organoid line is a promising first milestone towards an established in vitro organoid model to explore pathophysiology and new treatment modalities in cMTC.

Expression of Paired box 9 defines an aggressive subset of lung adenocarcinoma preferentially occurring in smokers.

A distinct subset of lung adenocarcinomas (LADs), arising from a series of peripheral lung cells defined as the terminal respiratory unit (TRU), is characterized by thyroid transcription factor 1 (TTF-1) expression. The clinical relevance of transcription factors (TFs) other than TTF-1 remains unknown in LAD and was explored in the present study. Seventy-one LAD samples were subjected to high-throughput transcriptome screening of LAD using cap analysis gene expression (CAGE) sequencing data; CAGE provides genome-wide expression levels of the transcription start sites (TSSs). In total, 1083 invasive LAD samples were subjected to immunohistochemical examination for paired box 9 (PAX9) and TTF-1 expression levels. PAX9 is an endoderm development-associated TF that most strongly and inversely correlates with the expression of TTF-1 TSS subsets. Immunohistochemically, PAX9 expression was restricted to the nuclei of ciliated epithelial and basal cells in the bronchi and bronchioles and the nuclei of epithelial cells of the bronchial glands; moreover, PAX9 expression was observed in 304 LADs (28%). PAX9-positive LADs were significantly associated with heavy smoking, non-lepidic subtype, EGFR wild-type tumors, and PD-L1 expression (all p < 0.0001). All these characteristics were opposite to those of TRU-type LADs with TTF-1 expression. PAX9 expression was an independent prognostic factor for decreased overall survival (p = 0.022). Our results revealed that PAX9 expression defines an aggressive subset of LADs preferentially occurring in smokers that may arise from bronchial or bronchiolar cells.

Prognostic Value of Thyroid Transcription Factor-1 Expression in Non-Small Cell Non-Squamous Lung Cancer

Prognostic Value of Thyroid Transcription Factor-1 Expression in Non-Small Cell Non-Squamous Lung Cancer

Relationship Between TTF-1 Expression and PFS of Pemetrexed-containing Chemotherapy in Non-squamous-NSCLC Patients With and Without Driver Genes.

We performed a retrospective study too clarify whether the presence or absence of driver genes affects the relationship between thyroid transcription factor-1 (TTF-1) expression and response to pemetrexed (PEM) in non-squamous non-small cell lung cancer (non-sq-NSCLC) patients. We reviewed the medical charts of patients treated with PEM-containing chemotherapy during the period from February 2016 to February 2022 at Mito Medical Center-University of Tsukuba, Ryugasaki Saiseikai General Hospital, and University of Tsukuba Hospital. During the period of the study, 185 driver gene-negative patients negative, and 65 driver gene-positive patients were evaluated. Among the 165 driver gene-negative patients, progression free survival (PFS) of TTF-1-expressing patients treated with PEM-containing chemotherapy was significantly longer compared to that of TTF-1-negative patients. In the analysis of 65 driver gene-positive patients, the PFS of TTF-1-positive patients treated with PEM-containing chemotherapy did not differ significantly from that of TTF-1-negative patients. There was no significant difference in PFS between driver gene-negative and driver gene-positive patients treated with PEM-containing chemotherapy. Comparison between four groups defined according to the presence of driver gene and TTF-1 expression indicated shorter PFS only in 'driver gene-negative and TTF-1-negative' patients. In driver gene-positive non-sq NSCLC patients, expression of TTF does not affect the survival outcome of PEM-containing-chemotherapy. In other words, in these patients, second-line or later-line PEM-containing chemotherapy after development of resistance for specific-tyrosine kinase inhibitor could be expected to have the same level of efficacy as first-line PEM containing chemotherapy in driver gene-negative, TTF-1-positive non-sq NSCLC patients.

Plasma Progastrin-Releasing Peptide and Chromogranin A Assays for Diagnosing and Monitoring Lung Well-Differentiated Neuroendocrine Tumors: A Brief Report

IntroductionThe use of chromogranin A (CGA) as a circulating biomarker in lung carcinoids (LCs) is limited by low specificity and sensitivity. This study aimed to evaluate plasma progastrin-releasing peptide (ProGRPp) as an alternative to plasma CGA (CGAp), for the diagnosis and follow-up of LC. MethodsProGRPp and CGAp concentrations were measured in 107 patients with LC and 105 patients with benign lung disease (BLD). ResultsProGRPp distinguished patients with LC with active disease in the pretreatment (n = 43) and post-treatment (n = 43) groups from those with BLD: area under the curve for both 0.864 (p < 0.0001); sensitivity 67.4% and 58.1%, respectively; specificity 96.2%; at 64 pg/mL cutoff. CGAp failed to differentiate both LC groups from those with BLD: area under the curve 0.579 and 0.526 (for both p > 0.1); sensitivity 34.9% and 25.6%, respectively; specificity 73.3%; at 104 ng/mL cutoff. Only ProGRPp correlated with the Ki67 proliferation index (r = 0.40, p < 0.001) and was associated with mitotic count (p = 0.025), stage (p = 0.018), grade (p = 0.019), and the expression of thyroid transcription factor-1 (p = 0.005). ProGRPp had a high sensitivity (92.3%) in LC with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Abnormal postoperative ProGRPp level was associated with residual disease (p = 0.029). The changes in ProGRPp level during treatment, a decrease greater than 30% and an increase greater than 8%, were associated with image-based outcomes, partial response and disease progression, respectively (p < 0.0001). CGAp did not reflect the disease course. ConclusionsProGRPp was superior to CGAp in diagnosing LC with correlations concerning proliferation, grading, staging, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia co-occurrence, and response to treatment. ProGRPp is an optimal emerging biomarker to be further evaluated.

Association of thyroid transcription factor-1 (TTF-1) expression with efficacy of PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in advanced non-squamous non-small cell lung cancer.

Thyroid transcription factor-1 (TTF-1) expression in advanced non-squamous non-small cell lung cancer (NSCLC) has been associated with the efficacy of pemetrexed plus platinum chemotherapy. However, the relation between TTF-1 expression and efficacy of the combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors plus pemetrexed and platinum chemotherapy, a standard first-line treatment regimen for advanced non-squamous NSCLC, has remained unclear. We retrospectively evaluated TTF-1 expression in tumor tissue of patients with advanced or recurrent non-squamous NSCLC treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting. Clinical characteristics and pathological data for each patient were assessed, and progression-free survival (PFS) was evaluated. Bias due to patient background was minimized by application of inverse probability of treatment weighting (IPTW) analysis. A total of 122 patients, 75 (61.5%) of whom were positive for TTF-1 immunostaining in tumor specimens, was included in this multicenter study. At the time of analysis, 89 (73.0%) patients had experienced progression events and 44 (36.1%) had died [median follow-up 14.6 months (range, 0.53-29.5 months)]. PFS was longer for TTF-1-positive patients than for TTF-1-negative patients [median, 12.2 vs. 6.0 months; hazard ratio (HR) =0.63 (95% CI: 0.37-1.06); log-rank P=0.028]. IPTW-adjusted PFS was significantly longer for TTF-1-positive than for TTF-1-negative patients [HR =0.62 (95% CI: 0.46-0.83); log-rank P=0.024]. TTF-1 expression in advanced non-squamous NSCLC can serve as a basis for prediction of PFS in patients treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting.

Prediction of TTF-1 expression in non-small-cell lung cancer using machine learning-based radiomics.

To explore the feasibility and performance of machine learning-based radiomics models in predicting thyroid transcription factor-1 (TTF-1) expression in non-small cell lung cancer (NSCLC). A total of 227 NSCLC patients were included in this retrospective study and divided into the training set and test set with a ratio of 8:2 randomly. Lung tumors on CT images were semi-automatic segmented utilizing 3D Slicer. Radiomic features quantifying tumor intensity, shape, texture, and transformed wavelet were extracted using a Python toolkit. Variance threshold (VT), principal component analysis (PCA), and least absolute shrinkage selection operator (LASSO) were used to reduce features; logistic regression (LR), random forest (RF), and support vector machine (SVM) were used to develop classifier, respectively. The performance of the models was evaluated by areas under the curves (AUC) of receiver operating characteristic (ROC) curves. Different models were compared by the Delong test to determine the optimal algorithms. Total 1968 radiomic features were extracted from the lung tumors images, and then 13, 15, and 13 stable features were selected by VT, PCA, and LASSO, respectively. Each classifier could discriminate against the TTF-1-positive groups with average AUC ranging from 0.601 to 0.784 in the training set. Among the models, three models constructed by the LASSO method showed satisfactory performance in the test set with AUC ranging from 0.715 to 0.787. The Delong test showed no significant difference between the LASSO models (P > 0.05). Machine learning-based radiomics model could predict the expression of TTF-1 in NSCLC patients.

Expression and Clinicopathological Significance of SOX11 in Small-Cell Lung Cancer.

Objective This study aims to investigate the expression of neuronal transcription factor SOX11 in small-cell lung cancer (SCLC) and compare it with the expression of CD56 (nerve cell adhesion molecule), synaptophysin (Syn), chromogranin A (CgA), and thyroid transcription factor-1 (TTF-1) to explore the application value of SOX11 in the pathological diagnosis of SCLC. Methods Immunohistochemical methods were used to detect the expression of SOX11, TTF-1, CD56, Syn, and CgA in 120 lung tumor tissues, and experimental results were analyzed using SPSS23.0 statistical software. Results Immunohistochemical results showed that in the 120 lung tumor samples, SOX11 was highly expressed in SCLC and localized to the nucleus, with low or no expression in control carcinoid/lung neuroendocrine tumors, lung adenocarcinomas, and lung squamous cell carcinomas. Statistical analysis results revealed the following points. First, the expression of SOX11 was closely related to the tumor histological type. The expression of SOX11 in SCLC (positive rate of 63.33%) was significantly higher than that in carcinoid/neuroendocrine tumors (positive rate of 12.50%), lung adenocarcinoma (positive rate of 0%), and lung squamous cell carcinoma (positive rate of 0%). Second, immunohistochemical investigation of 60 SCLC cases revealed that the highest positive rates of CD56, TTF-1, and Syn, respectively, were 93.33 percent, 95 percent, and 86.67 percent. SOX11 also exhibited high sensitivity (0.633) and specificity (0.875) in SCLC. The positive rates of SOX11 and CgA were 63.33% and 50.00%, respectively. Statistical results revealed that the positive rate of CgA had no significant difference (P > 0.05). Lastly, the combined use of antibodies SOX11, CgA, CD56, Syn, and TTF-1 was more beneficial to improving the diagnosis rate of SCLC than the single use of one or two antibodies. Conclusion The expression of SOX11 in different histological types of lung tumors differs considerably. SOX11 is highly expressed in SCLC. SOX11 can be used as a beneficial supplement to the combination of classical neuroendocrine markers and in combination with CgA, CD56, Syn, and TTF-1 to assist in the diagnosis of SCLC.

Neuroendocrine tumors (NETs) - experience of a single Center.

Introduction: Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from cells that are part of the diffuse neuroendocrine system. Patients, Materials and Methods: We conducted a retrospective study in which we included a number of 91 cases diagnosed with neuroendocrine tumors (NETs). Descriptive statistics was performed: number of cases based on location, distribution by gender (male/female), distribution by age, and we also performed a morphological and immunohistochemical (IHC) study. Results: The highest number of cases was found in lungs (60 cases). Tumors located on the skin, breast or bladder have been discovered, locations considered rare for this type of tumor. Of all cases diagnosed in the lungs, 59 were diagnosed as small cell carcinomas (SCCs) and only one case as NET. All surgical specimens were positive for chromogranin A (CgA), with a different expression for the other immunomarkers. For the lung biopsies, the most frequently IHC staining was CgA and cluster of differentiation 56 (CD56), with an increased positivity for the latter. Conclusions: CgA remains the most sensitive immunomarker in the diagnosis of NETs. CD56 is the most widely used immunomarker for diagnosing small cell lung tumors. Positive expression of thyroid transcription factor 1 (TTF1) immunomarker does not confirm pulmonary origin of SCCs.

The Extent of Expression of Thyroid Transcription Factor 1, Cytokeratin 7, and Anaplastic Lymphoma Kinase in Lung Adenocarcinoma.

Background:New forms of genetic alteration were developed giving a new era of lung adenocarcinoma (AdC) with diverse clinical and pathological features.Aim and Objectives:The aim is to investigate the ALK-rearranged gene as one of these genetic alterations in AdC. The role of TTF-1 and CK7 is to exclude the metastases.Material and Methods:Paraffin-embedded 50 AdC specimens were cut into 4-mm thick sections and stained with the primary antibody, using an anti-TTF-1 antibody, (all at a 1:200 dilution, mouse monoclonal antibody; Dako, Denmark), anti-CK 7 antibody (DAKO, Carpentaria, CA), and the rabbit monoclonal anti- ALK antibody (D5F3) (Ventana, USA). Positive reactivity was considered as brown nuclear immunostaining for TTF-1 and cytoplasmic for CK 7and both cytoplasmic and nuclear for ALK.Results:The median age was 56±2, with male to female ratio 7:3. Forty-four cases revealed a mixed pattern (88%), with focal intraluminal mucin. Forty-one cases (82%) were positive for TTF-1, of these; weak (13; %), moderate (16; %) and strong (12; %). Regarding CK7; 48 cases (96%) were positive; weak (7 cases; 14.5; %), moderate (18 cases; 37.5%) and strong (23 case; 47.9 %) of the positive cases. Regarding D5F3; five cases (10%) were positive; weak (1 case; 20 %), moderate (2 cases; 40 %) and strong (2 cases; 40%) out of the positive cases. Four ALK-positive cases were male and ALK-positive patients ranged from 42-55 years with median 48.Conclusion:Despite the incidence of ALk-AdC is uncommon, it might be suspected in lesions of lower age group especially with mucinous foci.

Impact of Quercus infectoria Galls Extract on Thyroid Gland and Testicular Functions in Diabetic Rats

Diabetes mellitus has been reported to be accompanied by thyroid and testicular dysfunctions. The objective of this study was to investigate the effect of Quercus infectoria galls (QIg) extract on the thyroid gland and testicular functions in diabetic rats. Sixteen rats were randomly divided into four equal groups, consisting of normal control, diabetic untreated control, diabetic treated with oral administration of 500 mg/kg BW and 1000 mg/kg BW, respectively for 15 days. Serum blood glucose, thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), testosterone (T), and luteinizing hormone (LH) were assessed. At the end of the experimental period, the rats were euthanized for histopathological analysis of thyroid gland and testis. Furthermore, immunohistochemistry was used to assess the expression of thyroid transcription factor-1 (TTF-1) in the thyroid gland of rats. The significant increase in serum blood glucose level in diabetic rats (DC) was markedly decreased by treatment with QIg extract (500 mg and 100 mg/kg BW) almost to the normal level. The reduced thyroid hormones, both the T3 and T4 were significantly recovered after 15 days of treatment with QIg extract (500 mg and 100 mg/kg BW). Whereas serum concentration of testosterone was significantly reduced in diabetic rats with QIg extract (500 mg and 100 mg/kg BW) treatment. Histopathological analysis of diabetic rats showed a wide range of morphological alterations in thyroid gland and testicular structures, which were almost completely, restored back to normal by treatment of rats with QIg extract. Furthermore, results showed overexpression of TTF-1 in the thyroid gland of diabetic rats, which was recovered back to normal expression after 15 days of treatment with QIg extract. These findings may provide new insights into the potential role of QIg extract as a promising therapeutic agent against diabetic complications in thyroid gland and testicular functions.

TTF-1: A Well-Favored Addition to the Immunohistochemistry Armamentarium as a Diagnostic Marker of SEGA

Subependymal giant cell astrocytoma (SEGA) is a World Health Organization grade 1 neoplasm, which, due to its dubious morphologic features, may be misdiagnosed as a high-grade tumor at times. This tumor shows binary immunoexpression including both glial and neural markers, leading to a state of diagnostic quandary. Recent evidences have surmised the diagnostic utility of thyroid transcription factor 1 (TTF-1), spurring us to study the practicality of this marker in distinguishing SEGAs from its mimics. In this study, TTF-1 immunohistochemistry using clone 8G7G3/1 (1:50) was performed in 38 cases of SEGA, 30 cases of central neurocytoma, 10 cases each of intraventricular glioblastoma and ependymoma, and 5 cases of cortical tubers. Additionally, serine/threonine-protein kinase B-Raf (BRAFV600E) mutation, a common genetic alteration in pediatric low-grade-glial tumors with neuronal-differentiation, was analyzed using Ventana immunohistochemistry platform. TTF-1 immunopositivity was seen in all 38 cases (100%) of SEGAs, with 20 cases (52.6%) showing diffuse (>50% of tumor area) expression while focal (<50%) immunopositivity was seen in 18 cases (47.3%). None of the cases demonstrated serine/threonine-protein kinase B-Raf immunolabeling. Barring 2 cases of neurocytoma (6.6%), all other cases including ependymoma, glioblastoma, and cortical tubers were immunonegative for TTF-1. The congruous finding of TTF-1 expression in SEGA and cells of the developing neuroepithelium in the medial ganglionic eminence hint toward a primogenitor cell with neoplastic potential in the presence of impelling factors.