Thyroid Transcription Factor-1 Expression Research Articles

Thyroid Transcription Factor-1 Amplification and Expressions in Lung Adenocarcinoma Tissues and Pleural Effusions Predict Patient Survival and Prognosis

Thyroid transcription factor-1 (TTF1) plays a role in lung adenocarcinoma development. We investigated the significance of TTF1 in primary lung adenocarcinomas, lymph node metastases, and malignant pleural effusions (MPEs). We studied TTF1 in 175 primary lung adenocarcinomas, 52 lymph node metastases, and 46 MPE using microarray-based fluorescence in situ hybridization, immunohistochemistry, and messenger RNA (mRNA) in situ hybridization. Real-time reverse transcription polymerase chain reaction was used to investigate correlations between TTF1 amplification and mRNA expression. Correlations between clinicopathologic characteristics, TTF1 amplification, TTF1 expressions, overall survival, and prognosis were analyzed. TTF1 was amplified in 7% of primary lung adenocarcinomas, 4% of lymph node metastases, and 4% of MPE. TTF1 amplification in lung adenocarcinomas was associated with pathologic subtypes (p = 0.029). Patients with positive TTF1 protein and mRNA expressions had improved overall survival if TTF1 was unamplified compared with those with TTF1 amplification (p = 0.068). A multivariate model did not show patients with positive TTF1 expressions tended to have better prognoses if TTF1 was unamplified compared with those with TTF1 amplification (p = 0.068). Survival time was longer for patients with TTF1 expressions in both primary lung tissues (p < 0.001) and MPE (p = 0.045). A multivariate model confirmed the prognostic value of TTF1 expressions in lung adenocarcinoma (p < 0.001). A multivariate model confirmed the prognostic value of TTF1 expressions in lung adenocarcinoma tissues (p < 0.001) while not in MPE (p = 0.058). TTF1 mRNA level was higher in cases with TTF1 amplification compared with those without TTF1 amplification. Patients with lung adenocarcinoma without TTF1 amplification tend to have better prognoses than those with TTF1 amplification in cases with positive TTF1 expressions. Positive TTF1 expressions in lung adenocarcinoma tissues are favorable prognostic parameters in patients with lung adenocarcinoma.

The effect of TTF-1 expression on ipsilateral mediastinal nodal (N2) metastases in primary adenocarcinoma of the lung

Aim of the studyTo study the effect of thyroid transcription factor-1 (TTF-1) expression on ipsilateral mediastinal nodal (N2) metastases in primary adenocarcinoma of the lung.Material and methodsThe patients operated on with a diagnosis of primary adenocarcinoma of the lung were retrospectively analyzed and divided into two groups according to their TTF-1 expression. The relationship between TTF-1 expression and N2 metastases was evaluated.ResultsThere were 73 patients (58 male, 15 female) with a mean age of 58.4 ±10.2 in the study group. Sixty-six lobectomies or pneumonectomies and mediastinal lymph node dissection, and seven mediastinoscopies were performed. Positivity of the TTF-1 protein expression detected by the immunohistochemical staining of the specimens was present in 33 patients (45.2%); these patients were classified as group A and the rest of the patients as group B. Eleven patients had N2 disease in group A versus five patients in group B and the difference between the two groups was statistically significant.ConclusionsPatients with primary adenocarcinoma of the lung having TTF-1 expression are more likely to have N2 disease. They might be considered as candidates for adjuvant therapy.

Molecular characterization and functional analysis of sheep thyroid transcription factor-1

Thyroid transcription factor-1 (TTF-1), a member of the Nkx2 family of homeodomain-containing proteins, is involved in binding to and in activating the promoters of several important genes in the thyroid, lungs, and brain, and in regulating expression of these tissue-specific genes. We investigated potential roles of sheep (Ovis aries) TTF-1 in regulating cell fate and organ morphogenesis and in controlling puberty and reproductive capability of females. We amplified and cloned the sheep TTF-1 full-length DNA for the first time, analyzed its functional domains and regions, predicted molecular structure of its homeodomain and DNA-binding sites, and examined its expression in pituitary, brain, thyroid gland, ovary, and hypothalamus. We found that sheep TTF-1 has a high degree of homologous identity with that of other mammals, and it has several important domains including domain N, DNA-binding domain, domain C, TN-domain, domain I, and NK2-SD. The DNA-binding domain of sheep TTF-1 has 10 potential DNA-binding sites and is a novel mammalian homeodomain that shows considerable sequence homology with the corresponding rat homeodomain. Several functional regions in sheep TTF-1 share high sequence identity with rat TTF-1, indicating that these regions may have the same activity as in the rat. Expression of TTF-1 in several specific tissues implies that sheep TTF-1 in involved in sheep sexual development and reproductive capability. These results suggest a role of sheep TTF-1 in enhancing sheep reproduction performance and we propose it as a candidate gene for selection.

Thyroid transcription factor-1 expression in colorectal adenocarcinomas

Although thyroid transcription factor-1 (TTF-1) immunoreactivity is considered as a specific marker of lung and thyroid neoplasms, it may be positive in a proportion of extrapulmonary adenocarcinomas. This study examined the expression of TTF-1 in 555 colorectal adenocarcinomas using three commercial monoclonal antibodies: clone SPT24 (Novocastra) and 8G7G3/1 (Dako and Cell Marque), and compared the TTF-1 staining with other immunohistochemical markers, cytokeratin (CK) 7, CK 20, caudal-type homeobox transcription factor 2 (CDX2), and MUC2. The clinicopathological prognostic factors were compared with the TTF-1 expression status. Nuclear TTF-1 staining was detected in 24 cases (4.3%) with the SPT24 antibody and 18 cases (3.2%) with the 8G7G3/1 antibody. All cases positive for 8G7G3/1 were also positive for SPT24. CDX2 was expressed constantly in all 24 TTF-1-positive colorectal cancers, whereas CK7, CK20, and MUC2 were detected in 2 (8.3%), 23 (95.8%), and 8 (33.3%) cases, respectively. There was no correlation between TTF-1 expression and clinicopathological significance. To avoid potential pitfalls, TTF-1 should be interpreted in conjunction with the clinical setting, histological features, and the results of other markers, such as CK7, CK20, and CDX2. MUC2 can be used as supplementary information to confirm difficult cases.

Histologic patterns and molecular characteristics of lung adenocarcinoma associated with clinical outcome

Lung adenocarcinoma is histologically heterogeneous and has 5 distinct histologic growth patterns: lepidic, acinar, papillary, micropapillary, and solid. To date, there is no consensus regarding the clinical utility of these patterns. The authors performed a detailed semiquantitative assessment of histologic patterns of 240 lung adenocarcinomas and determined the association with patients' clinicopathologic features, including recurrence-free survival (RFS) and overall survival (OS) rates. In a subset of tumors, expression levels of 2 prognostic molecular markers were evaluated: thyroid transcription factor-1 (TTF-1) (n = 218) and a panel of 5 proteins (referred as the FILM signature index) (n = 185). Four mutually exclusive tumor histology pattern groups were identified: 1) any solid (38%), 2) any papillary but no solid (14%), 3) lepidic and acinar but no solid or papillary (30%), and 4) acinar only (18%). Patients in group 3 had a higher RFS rate than patients in group 1 (hazard ratio [HR], 0.4510; P = .0165) and group 2 (HR, 0.4253; P = .0425). Solid pattern tumors (group 1) were associated with a lower OS rate than nonsolid pattern tumors (all stages: HR; 1.665; P = .0144; stages I and II: HR, 2.157; P = .008). In the patients who had tumors with a nonsolid pattern, high TTF-1 expression was associated significantly with higher RFS (HR, 0.994; P = .0017) and OS (HR, 0.996; P = .0276) rates in all stages, and a high FILM signature index score was associated with lower RFS and OS rates in all stages (RFS: HR, 1.343; P = .0192; OS: HR, 1.371; P = .0156) and in stages I and II (RFS: HR, 1.419; P = .0095; OS: HR, 1.315; P = .0422). The presence of a solid histologic pattern was identified as a marker of unfavorable prognosis in patients with primary lung adenocarcinoma. High TTF-1 expression and low FILM signature index scores were associated with a better prognosis for patients who had tumors with a nonsolid pattern.

A clinicopathological and immunohistological re‐evaluation of adenosquamous carcinoma of the lung

Since the World Health Organization histological criteria were published in 1999, several studies have focused on adenosquamous carcinoma of the lung. Therefore, we aimed to clinicopathologically re-evaluate this tumor using immunohistochemical methods. In our hospital, there have been 21 surgically resected adenosquamous carcinomas. The frequency of adenosquamous carcinoma was 1.9% and the clinical data including the patient prognosis data obtained in this study were similar to those reported previously. A fluorodeoxyglucose positron emission tomography study first revealed that the median maximum standardized uptake value of adenosquamous carcinoma was 9.3 and ranged from 2.0 to 24.5. According to the results of immunohistochemical staining for thyroid transcription factor-1 (TTF-1) and p63, adenosquamous carcinomas were divided into four subgroups: group 1, TTF-1+ and p63+ (10 cases); group 2, TTF-1- and p63+ (six cases); group 3, TTF-1+ and p63- (three cases); and group 4, TTF-1- and p63- (two cases). Of the six group 2 tumors, three were composed of unique solid nests with mucin-filled cysts and showed characteristic p63 expression, which might suggest a special type of adenosquamous carcinoma. Immunohistochemical analysis of TTF-1 and p63 expression shows that adenosquamous carcinoma is composed of diverse tumor groups, for which the biological and histogenetic nature further needs to be clarified.

Thyroid Transcription Factor-1 in Primary CNS Tumors

In diagnostic pathology thyroid transcription factor-1 (TTF-1) is used as a relatively specific and sensitive diagnostic marker of thyroid and lung adenocarcinomas and lung carcinoids but has also been demonstrated in minor proportions of carcinomas from other organs as well as nonepithelial neoplasms. Two antibody clones are widely used for TTF-1 demonstration, 8G7G3/1 and SPT24, the latter being the most sensitive. Few studies have addressed the occurrence of TTF-1 in central nervous system (CNS) tumors with highly divergent results, a major reason for which seems to be use of different clones. Based on multitissue blocks we analyzed the TTF-1 expression in a series of 155 CNS tumors comparing antibody clones 8G7G3/1 and SPT24 in optimized protocols on the Benchmark Ultra stainer. With clone SPT24 TTF-1 staining was observed in 13 cases (8%). Among astrodendroglial and oligodendroglial tumors, TTF-1 expression was found in 10 of 56 grades III to IV tumors (18%), as opposed to 0 of 47 grades I to II tumors (0%). The TTF-1 expression in positive tumors was generally weak to moderate and focal (mean histoscore 28, range: 2 to 120). TTF-1 positivity was inversely correlated to the expression of nestin. Among 52 other CNS tumors, TTF-1 expression was found in 1 of 3 central neurocytoma (the only CNS tumor with a moderate, diffuse staining), 1 of 18 ependymal tumors, and 1 of 5 choroid plexus tumors, whereas 4 pineal tumors, 11 meningiomas, 8 embryonal tumors, and 4 mixed neuronal-glial tumors all were negative. None of the 155 tumors stained with the 8G7G3/1 antibody clone. TTF-1 expression in primary brain tumors should be taken into consideration when interpreting brain tumors of uncertain origin.

Significance of Thymidylate Synthase and Thyroid Transcription Factor 1 Expression in Patients with Nonsquamous Non-small Cell Lung Cancer Treated with Pemetrexed-Based Chemotherapy

This study is to evaluate whether thymidylate synthase (TS) or thyroid transcription factor 1 (TTF1) protein expression can predict clinical outcomes for pemetrexed-based chemotherapy in patients with nonsquamous non-small cell lung cancer (NSCLC). Two hundred eighty-five consecutive patients with nonsquamous NSCLC treated with pemetrexed-based chemotherapy were immunohistochemically analyzed for the expressions of TS and TTF1. TS and TTF1 expression were successfully analyzed in 193 and 284 cases, respectively. Tumors with TS-negativity or TTF1-positivity were more frequent in patients who were female, younger, had adenocarcinoma, or had never smoked. Higher response rates for pemetrexed-based chemotherapy were associated with TS-negativity (33.7% versus 14.1%, p = 0.002) and TTF1-positivity (28.1% versus 9.8%, p < 0.001). In univariate analysis, progression-free survival for pemetrexed-based chemotherapy was significantly longer in groups with adenocarcinoma (2.9 versus 1.4 months, p = 0.001), TS-negativity (4.1 versus 2.0 months, p = 0.001), and TTF1-positivity (3.8 versus 1.3 months, p < 0.001). In multivariate analysis, TS-negativity (hazard ratio [HR] = 0.70; 95% confidence interval [CI], 0.51-0.97) and TTF1-positivity (HR = 0.51; 95% CI, 0.35-0.73) were associated with longer progression-free survival. Patients with TTF1-positive tumors also had significantly longer overall survival times than patients with TTF1-negative tumors (25.4 versus 14.2 months, HR = 0.55; 95% CI, 0.39-0.77). Low TS or high TTF1 protein expression was significantly associated with better clinical outcomes in nonsquamous NSCLC patients who were treated with pemetrexed-based chemotherapy. The predictive role of TS or TTF1 expression should be further validated in a prospective randomized study.

Thyroid transcription factor-1 (TTF-1) gene: identification of ZBP-89, Sp1, and TTF-1 sites in the promoter and regulation by TNF-α in lung epithelial cells

Thyroid transcription factor-1 (TTF-1/Nkx2.1/TITF1) is a homeodomain-containing transcription factor essential for the morphogenesis and differentiation of the lung. In the lung, TTF-1 controls the expression of surfactant proteins that are essential for lung stability and lung host defense. In this study, we identified functionally important transcription factor binding sites in the TTF-1 proximal promoter and studied tumor necrosis factor-α (TNF-α) regulation of TTF-1 expression. TNF-α, a proinflammatory cytokine, has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) and inhibits surfactant protein levels. Deletion analysis of TTF-1 5'-flanking DNA indicated that the TTF-1 proximal promoter retained high-level activity. Electrophoretic mobility shift assay, chromatin immunoprecipitation, and mutational analysis experiments identified functional ZBP-89, Sp1, Sp3, and TTF-1 sites in the TTF-1 proximal promoter. TNF-α inhibited TTF-1 protein levels in H441 and primary alveolar type II cells. TNF-α inhibited TTF-1 gene transcription and promoter activity, indicating that transcriptional mechanisms play important roles in the inhibition of TTF-1 levels. TNF-α inhibited TTF-1 but not Sp1 or hepatocyte nuclear factor-3 DNA binding to TTF-1 promoter. Transactivation experiments in A549 cells indicated that TNF-α inhibited TTF-1 promoter activation by exogenous Sp1 and TTF-1 without altering their levels, suggesting inhibition of transcriptional activities of these proteins. TNF-α inhibition of TTF-1 expression was associated with increased threonine, but not serine, phosphorylation of Sp1. Because TTF-1 serves as a positive regulator for surfactant protein gene expression, TNF-α inhibition of TTF-1 expression could have important implications for the reduction of surfactant protein levels in diseases such as ARDS.

Wnt/β-Catenin Signaling Pathway Is a Direct Enhancer of Thyroid Transcription Factor-1 in Human Papillary Thyroid Carcinoma Cells

The Wnt/β-catenin signaling pathway is involved in the normal development of thyroid gland, but its disregulation provokes the appearance of several types of cancers, including papillary thyroid carcinomas (PTC) which are the most common thyroid tumours. The follow-up of PTC patients is based on the monitoring of serum thyroglobulin levels which is regulated by the thyroid transcription factor 1 (TTF-1): a tissue-specific transcription factor essential for the differentiation of the thyroid. We investigated whether the Wnt/β-catenin pathway might regulate TTF-1 expression in a human PTC model and examined the molecular mechanisms underlying this regulation. Immunofluorescence analysis, real time RT-PCR and Western blot studies revealed that TTF-1 as well as the major Wnt pathway components are co-expressed in TPC-1 cells and human PTC tumours. Knocking-down the Wnt/β-catenin components by siRNAs inhibited both TTF-1 transcript and protein expression, while mimicking the activation of Wnt signaling by lithium chloride induced TTF-1 gene and protein expression. Functional promoter studies and ChIP analysis showed that the Wnt/β-catenin pathway exerts its effect by means of the binding of β-catenin to TCF/LEF transcription factors on the level of an active TCF/LEF response element at [−798, −792 bp] in TTF-1 promoter. In conclusion, we demonstrated that the Wnt/β-catenin pathway is a direct and forward driver of the TTF-1 expression. The localization of TCF-4 and TTF-1 in the same area of PTC tissues might be of clinical relevance, and justifies further examination of these factors in the papillary thyroid cancers follow-up.

Cytoplasmic Staining of TTF-1 Antibody in the Diagnosis of Hepatocellular Carcinoma: Study on 299 Cases Using Tissue Microarray

The diagnosis of hepatocellular carcinoma (HCC) remains obscure in some complicated cases. Thyroid transcription factor-1 (TTF-1) was presumed to be helpful in the diagnosis of HCC. This paper aims to study the utility of TTF-1 in the diagnosis and differential diagnosis of HCC and to assign clinicopathological correlations. Immunohistochemical detection of TTF-1 is performed with tissue microarray which contains a total of 781 cases including 299 hepatocellular carcinomas (HCCs), 31 intrahepaticcholangiocarcinomas (ICCs), 86 metastatic adenocarcinomas (MACs), 5 metastatic hepatocellular carcinomas (mHCCs), 9 hepatoblastomas (HBs), 40 renal clear cell carcinomas (RCCs), 215 adjacent nonneoplastic hepatic tissue, and 96 normal hepatic tissue. The result shows that TTF-1 is positive in 55.2% (165/299) HCCs, 6.4% (2/31) ICCs, 3.5% (3/86) MACs, 60% (3/5) mHCCs, 33.3% (3/9) HBs, 0% (0/40) RCCs, 99.0% (213/215) adjacent nonneoplastic hepatic tissue, and 95.8% (93/96) normal hepatic tissue. Expression of TTF-1 is correlated with differentiation of HCC, but not with patients' age, gender, serum AFP, tumor size, number of tumor nodules, and tumor thrombus in vein or bile duct. These data suggest that TTF-1 antibody is sensitive and specific in HCC and might serve as a candidate for the diagnosis and differential diagnosis of HCC.

Thyroid transcription factor-1 expression in rare cases of mammary ductal carcinoma

Thyroid transcription factor-1 expression in rare cases of mammary ductal carcinoma

Utility of 10 Immunohistochemical Markers Including Novel Markers (Desmocollin-3, Glypican 3, S100A2, S100A7, and Sox-2) for Differential Diagnosis of Squamous Cell Carcinoma from Adenocarcinoma of the Lung

Recent clinical trials revealed that accurate histologic typing of non-small cell lung cancer, especially squamous cell carcinoma (SCC), is essential. We analyzed 10 antibodies expression in 150 SCC cases (53 well-, 51 moderately, and 46 poorly differentiated cases) and 159 adenocarcinoma (AC) cases (49 well-, 52 moderately, and 58 poorly differentiated cases). In all SCC and AC cases, p63 was the most sensitive marker for SCC (98.7%), followed by high-molecular-weight (HM) cytokeratin (CK) (97.3%), CK5/6 (93.3%), Sox2 (80%), thrombomodulin (79.3%), desmocollin-3 (72.7%), S100A7 (70.7%), S100A2 (63.3%), and glypican-3 (46.7%). Desmocollin-3 was the most specific marker for SCC (100%), followed by CK5/6 (98%), Sox2 (95.5%), glypican-3 (92.4%), S100A7 (86.8%), thrombomodulin (79.9%), S100A2 (64.6%), p63 (51.6%), and HMCK (33.3%). Thyroid transcription factor-1 (TTF-1) expression was observed in 87.4% of AC cases and 2.0% of SCC cases. When analyzing only poorly differentiated tumors, HMCK was the most sensitive marker for SCC (100%), followed by p63 (97.8%), CK5/6 (87.0%), Sox2 (71.7%), thrombomodulin (58.7%), desmocollin-3 (52.2%), S100A2 (50%), glypican-3 (45.7%), and S100A7 (45.7%). Desmocollin-3 was the most specific marker for poorly differentiated SCC (100%), followed by CK5/6 (98.3%), glypican-3 (94.8%), Sox2 (94.8%), S100A2 (81%), S100A7 (75.9%), thrombomodulin (72.4%), p63 (48.3%), and HMCK (36.8%). The 10-fold crossvalidated classification and regression tree analysis revealed that the combination of CK5/6 and TTF-1 was the best immunohistochemical marker panel for the differentiation between SCC and AC. CK5/6 is the best marker for differentiating SCC and AC, irrespective of the histological grade of the tumor. Thus, the combination of CK5/6 and TTF-1 is the most recommended combination of immunohistochemical markers.

Comparison of the expression levels of napsin A, thyroid transcription factor-1, and p63 in nonsmall cell lung cancer using cytocentrifuged bronchial brushings

Appropriate treatment of nonsmall cell lung cancer (NSCLC) depended on histologic type. The aim of this study was to evaluate the expression levels of Napsin A, thyroid transcription factor-1 (TTF-1), and p63 by immunostaining using CytoRich Red preserved cytocentrifuged bronchial brushings. The expression levels of Napsin A, TTF-1, and p63 were semiquantitatively evaluated using proportion and intensity scores in 12 patients from whom both bronchial brushing cytology and bronchial biopsy samples had been obtained, as well as in a selection of 64 resected NSCLC tissue samples, and 8 normal or benign bronchial brushing cytology samples. The nuclear expressions of TTF-1 and p63 allowed for good visualization of cancer cells, whereas the cytoplasmic expression of Napsin A in cancer cells was often more difficult to evaluate because medium-sized and large macrophages also expressed Napsin A. Napsin A and TTF-1 were reliable adenocarcinoma markers, and p63 was a reliable squamous cell carcinoma marker in cytology, and histology samples. The average scores of Napsin A, TTF-1, and p63 were highly correlated in bronchial brushing cytology and bronchial biopsy samples, whereas TTF-1 expression was significantly lower than Napsin A expression in resected NSCLC tissue samples (P < .001). Immunostaining of bronchial brushings fixed with CytoRich Red was useful in determining histologic types in NSCLC. It was suggested that the panels of Napsin A, TTF-1, and p63 were effective in identifying histologic type in NSCLC, and that a combination of either Napsin A and p63 or TTF-1 and p63 should be chosen, depending on morphology.

Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.

7579 Background: To evaluate whether thymidylate synthase (TS) or thyroid transcription factor 1 (TTF1) protein expression can predict clinical outcome for pemetrexed-based chemotherapy in patients with nonsquamous non-small cell lung cancer (NSCLC). Methods: Two hundred eighty-five consecutive patients with nonsquamous NSCLC treated with pemetrexed-based chemotherapy were immunohistochemically analyzed for the expression of TS and TTF1. Results: TS and TTF1 expression were successfully analyzed in 193 and 284 cases, respectively. Tumors with TS-negativity or TTF1-positivity was more frequent in groups of female, younger age, adenocarcinoma, or never-smoker. Higher response rates for pemetrexed-based chemotherapy were associated with TS-negativity (33.7% vs. 14.1%, P = 0.002) and TTF1-positivity (28.1% vs. 9.8%, P < 0.001), respectively. In univariate analysis, progression-free survival (PFS) for pemetrexed-based chemotherapy was significantly longer in groups of adenocarcinoma (2.9 vs. 1.4 months, P = 0.001), TS-negativity (4.1 vs 2.0 months, P = 0.001), and TTF1-positivity (3.9 vs. 1.3 months, P < 0.001). In multivariate analysis, TS-negativity (HR = 0.69; 95% CI, 0.50–0.96) and TTF1-positivity (HR = 0.51; 95% CI, 0.35–0.73) were associated with longer PFS, respectively. Patients with TTF1-positive tumors also had significantly longer overall survival time than patients with TTF1-negative tumors (25.4 vs. 14.2 months, HR = 0.55; 95% CI, 0.39–0.77). Conclusions: Low TS or high TTF1 protein expression was significantly associated with better clinical outcomes in nonsquamous NSCLC patients who were treated with pemetrexed-based chemotherapy. The predictive role of TS or TTF1 expression is required to be further validated in a prospective randomized study.

Clinicopathologic Characteristics and Outcomes of Patients with Anaplastic Lymphoma Kinase-Positive Advanced Pulmonary Adenocarcinoma: Suggestion for an Effective Screening Strategy for These Tumors

The purpose of this study was to analyze the clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase (ALK)-positive advanced pulmonary adenocarcinoma and to devise an effective screening strategy to identify such patients. We screened advanced pulmonary adenocarcinoma patients to identify ALK-positive cases. The presence of ALK rearrangements was confirmed by fluorescence in situ hybridization. Of the 221 screened patients, 45 demonstrated ALK rearrangements, and these individuals were younger than the ALK-negative patients (p < 0.001). The proportion of never smokers and light smokers was found not to differ according to the ALK status (p = 0.537). Epidermal growth factor receptor (EGFR) mutations and ALK rearrangements were found to be mutually exclusive. Thyroid-transcription factor-1 (TTF-1) expression was observed in all ALK-positive tumors for which immunohistochemistry data were available. The objective response rate and progression-free survival to first-line platinum-based chemotherapy showed no significant differences between ALK-positive and ALK-negative patients. On the other hand, no patient with ALK-positive tumors achieved objective tumor responses to EGFR tyrosine kinase inhibitors (TKIs). ALK rearrangements were not found among individuals who had EGFR mutations, an objective response to a previous EGFR TKI treatment or TTF-1-negative tumors. The clinical outcomes of platinum-based chemotherapy were found not to differ according to the ALK status. Both smokers and never/light smokers should be candidates for ALK screening. We suggest that the exclusion of patients with activating EGFR mutations, an objective response to previous EGFR TKIs, or TTF-1-negative tumors from ALK screening could be an effective enrichment strategy for ALK-positive cases.

Airway administration of dexamethasone, 3′-5′-cyclic adenosine monophosphate, and isobutylmethylxanthine facilitates compensatory lung growth in adult mice

The combination of dexamethasone, 8-bromo-3'-5'-cyclic adenosine monophosphate, and isobutylmethylxanthine, referred to as DCI, has been reported to optimally induce cell differentiation in fetal lung explants and type II epithelial cells. DCI administration is also known to modulate the expression levels of many genes known to be involved in the facilitation of lung growth. Recently, we found that RNA silencing of thyroid transcription factor 1 (TTF-1) delayed compensatory lung growth. DCI is also known to induce TTF-1 expression in pulmonary epithelial cells. From these findings, we hypothesized that DCI administration may facilitate compensatory lung growth. In the present study, using a postpneumonectomy lung growth model in 9-wk-old male mice, we found that compensatory lung growth was significantly facilitated by airway administration of DCI immediately following left pneumonectomy, as indicated by the increase in the residual right lung dry weight index. TTF-1 expression was significantly elevated by DCI administration, and transient knockdown of TTF-1 attenuated the facilitation of compensatory lung growth by DCI. These results suggested that DCI facilitated compensatory lung growth, at least in part, through the induction of TTF-1. Morphological analyses suggested that DCI administration increased the number of alveoli, made each of them smaller, and produced a net increase in the calculated surface area of the alveoli per volume of lung. The effect of a single administration was maintained during the observation period, which was 28 days. DCI with further modifications may provide the material to potentially augment residual lung function after resection.

Thyroid Transcription Factor-1 Regulates Feeding Behavior via Melanocortin Pathway in the Hypothalamus

OBJECTIVEα-Melanocyte–stimulating hormone (α-MSH) and agouti-related peptide (AgRP) control energy homeostasis by their opposing actions on melanocortin receptors (MC3/4R) in the hypothalamus. We previously reported that thyroid transcription factor-1 (TTF-1) controls feeding behavior in the hypothalamus. This study aims to identify the function of TTF-1 in the transcriptional regulation of AgRP and α-MSH synthesis for the control of feeding behavior.RESEARCH DESIGN AND METHODSTTF-1 activity in AgRP and pro-opiomelanocortin (POMC) transcription was examined using gel-shift and promoter assays and an in vivo model of TTF-1 synthesis inhibition by intracerebroventricular injection of an antisense (AS) oligodeoxynucleotide (ODN). Double immunohistochemistry was performed to colocalize TTF-1 and AgRP or α-MSH in the hypothalamic arcuate nucleus (ARC). To determine whether TTF-1 action on food intake is mediated through MC3/4R, we measured changes in food intake upon intracerebroventricular injection of MC3/4R antagonists (SHU9119 and AgRP) into rat brain preinjected with the AS ODN.RESULTSTTF-1 stimulated AgRP but inhibited POMC transcription by binding to the promoters of these genes. TTF-1 was widely distributed in the hypothalamus, but we identified some cells coexpressing TTF-1 and AgRP or α-MSH in the ARC. In addition, intracerebroventricular administration of leptin decreased TTF-1 expression in the hypothalamus, and AS ODN-induced inhibition of TTF-1 expression decreased food intake and AgRP expression but increased α-MSH expression. Anorexia induced by the AS ODN was attenuated by the administration of MC3/4R antagonists.CONCLUSIONSTTF-1 transcriptionally regulates synthesis of AgRP and α-MSH in the ARC and affects feeding behavior via the melanocortin pathway.

Spindle cell oncocytoma of the adenohypophysis in a woman: a case report and review of the literature

IntroductionSpindle cell oncocytoma of the adenohypophysis is a rare tumour recently reported by Roncaroli et al. in 2002. This tumour is considered a grade I tumour by the World Health Organization.Case presentationWe describe what is, to the best of our knowledge, the 14th case of its kind in the literature. A 45-year-old African woman presented clinical and radiological findings related to a nonfunctioning pituitary adenoma. The diagnosis was made on the basis of histological and immunohistochemical findings.ConclusionThe purpose of this work is to report a rare pituitary tumour and to describe its histological and immunohistochemical features, which were characterized by the expression of thyroid transcription factor 1 antigen by tumour cells. This fact could support the theory of a possible common origin of these tumours in pituicytomas. In fact, thyroid transcription factor 1 is considered to be a specific marker of pituicytes.

TTF‐1 and Napsin A double stain

Immunohistochemistry (IHC) for thyroid transcription factor-1 (TTF-1) is used to confirm the diagnosis of lung adenocarcinoma. Napsin A also has shown positivity in lung adenocarcinoma. A combined double stain for TTF-1 and napsin A has been proposed to achieve higher sensitivity and specificity. In this study, the authors evaluated the utility of this double stain in the diagnosis of lung adenocarcinoma in cell blocks of fine-needle aspirates (FNA). The authors used a cohort comprising 35 FNA cell blocks of lung adenocarcinoma and 24 FNA cell blocks of lung squamous cell carcinoma (SqCCA). IHC was performed; expressions of TTF-1 as brown nuclear stain and of napsin A as red cytoplasmic stain were identified. Twenty-six of 35 (74%) lung adenocarcinomas were positive for double staining with TTF-1/napsin A. Of 35 lung adenocarcinomas, only 2 (5%) were positive for TTF-1 alone and 3 (8%) were positive for napsin A alone. For the double stain TTF-1/napsin A, 3 of 24 (12%) lung SqCCAs were positive for both. Six of 24 (25%) cases were positive for TTF-1 alone, and none were positive for napsin A alone. For lung adenocarcinoma, TTF-1/napsin A has a sensitivity of 74%, specificity of 87%, accuracy of 79%, and a positive predictive value of 89%. The double IHC stain, TTF-1/napsin A, for the identification of pulmonary adenocarcinoma in FNA cell block materials was diagnostically useful. The use of napsin A alone demonstrated a greater degree of accuracy and appeared diagnostically useful as a single IHC stain.