Thyroid Transcription Factor-1 Expression Research Articles

Differentiation of pathological subtypes and Ki-67 and TTF-1 expression by dual-energy CT (DECT) volumetric quantitative analysis in non-small cell lung cancer

BackgroundTo explore the value of dual-energy computed tomography (DECT) in differentiating pathological subtypes and the expression of immunohistochemical markers Ki-67 and thyroid transcription factor 1 (TTF-1) in patients with non-small cell lung cancer (NSCLC).MethodsBetween July 2022 and May 2024, patients suspected of lung cancer who underwent two-phase contrast-enhanced DECT were prospectively recruited. Whole-tumor volumetric and conventional spectral analysis were utilized to measure DECT parameters in the arterial and venous phase. The DECT parameters model, clinical-CT radiological features model, and combined prediction model were developed to discriminate pathological subtypes and predict Ki-67 or TTF-1 expression. Multivariate logistic regression analysis was used to identify independent predictors. The diagnostic efficacy was assessed by the area under the receiver operating characteristic curve (AUC) and compared using DeLong’s test.ResultsThis study included 119 patients (92 males and 27 females; mean age, 63.0 ± 9.4 years) who was diagnosed with NSCLC. When applying the DECT parameters model to differentiate between adenocarcinoma and squamous cell carcinoma, ROC curve analysis indicated superior diagnostic performance for conventional spectral analysis over volumetric spectral analysis (AUC, 0.801 vs. 0.709). Volumetric spectral analysis exhibited higher diagnostic efficacy in predicting immunohistochemical markers compared to conventional spectral analysis (both P < 0.05). For Ki-67 and TTF-1 expression, the combined prediction model demonstrated optimal diagnostic performance with AUC of 0.943 and 0.967, respectively.ConclusionsThe combined predictive model based on volumetric quantitative analysis in DECT offers valuable information to discriminate immunohistochemical expression status, facilitating clinical decision-making for patients with NSCLC.

Aberrant Expression of Pneumocytic Markers (TTF-1 and Napsin-A) in Biliary Duct and Gallbladder Adenocarcinomas; A Potential Diagnostic Pitfall.

Cholangiocarcinomas and gallbladder carcinomas are epithelial tumours with biliary differentiation. On histology and immunohistochemistry, they resemble adenocarcinomas and possess overlapping immunohistochemical profiles. Diagnosing these tumours is best done using appropriate imaging and clinical features with compatible immunohistochemistry. Immuno-staining for thyroid transcription factor-1 (TTF-1) and novel aspartic proteinase of pepsin A (Napsin-A) is believed to be specific for primary pulmonary adenocarcinomas. We herein report uncommon instances of strong and diffuse expression of these markers in two examples of adenocarcinomas arising from the bile duct and gallbladder. A review of the literature and a summary of similar studies relating to aberrant TTF-1 and Napsin-A expression in biliary tract adenocarcinomas are presented.

Pulmonary Adenocarcinoma with Enteric Differentiation without TTF-1 Expression Is a Very Rare Subtype with Limited Treatment Options and Poor Prognosis

Plain Language SummaryPulmonary adenocarcinoma with enteric differentiation (PAED) without expression of thyroid transcription factor-1 (TTF-1) is an extremely rare and hard-to-treat variant of lung cancer. We collected clinicopathological data of 121 Caucasian patients with pulmonary adenocarcinoma without TTF-1 expression, their systemic therapy options, and the efficacy of their systemic treatment including 79 cases without a PAED and 42 cases with a PAED, compared these subgroups, and investigated patients’ response to chemotherapy and immunotherapy as first-line treatment. A comparison of clinicopathological data of TTF-1-negative PAED and non-PAED patients revealed a significantly lower frequency of high programmed death receptor ligand 1 (PD-L1) expression in PAED resulting in the lack of single-agent immunotherapy (p = 0.032) in this subgroup. Frequencies of an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutation were high in both groups (46.7% and 50.0%), but a G12C gene mutation was seldomly noted (in 6.7% and 18.5% of patients with evaluable data). Median overall survival (OS) was poor in both groups (10 and 12 months). The majority of PAED patients received platinum-based and taxane-containing chemotherapy or chemo-/immunotherapy with an objective response rate of 31.6% and a disease control rate of 57.9%. Median progression-free survival (PFS) and OS of PAED patients with systemic therapy were very poor (3.9 months and 5.9 months). Caucasian patients with a TTF-1-negative PAED have a poor prognosis with reduced response rates to standard first-line systemic therapy and short survival times (PFS and OS).

Unraveling the influence of TTF-1 expression on immunotherapy outcomes in PD-L1-high non-squamous NSCLC: a retrospective multicenter study.

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. 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. 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). 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.

TTF-1 negativity as a biomarker of outcomes to immunotherapy, chemoimmunotherapy, and KRAS G12C inhibitors in lung adenocarcinoma.

8608 Background: Thyroid transcription factor 1 (TTF-1) expression is routinely assessed in lung adenocarcinomas (LUAD) and is negative (TTF-1Neg) in 15-20% of cases. Whether these tumors differ from LUAD expressing TTF-1 (TTF-1Pos) in terms of biologic features and outcomes is unclear. Methods: Patients (pts) with LUAD and available TTF-1 expression by IHC at five institutions were included. Clinicopathologic, genomic, and outcomes data were compared according to TTF-1 expression. Results: Among 3,315 pts with LUAD, TTF-1 was negative in 15% (N=499). Compared to TTF-1Pos (N=2,816), pts with TTF-1Neg LUAD were more likely male (44% vs 38%, P=0.01), smokers (82% vs 74%, P&lt;0.001), with stage IV disease at diagnosis (76% vs 71%, P&lt;0.001), and lower median PD-L1 tumor proportion score (TPS, 1% vs 10%, P&lt;0.001). At stage IV diagnosis, TTF-1Neg cases less commonly had brain metastasis than TTF-1Pos cases (35% vs 44%, P=0.04), but more frequently had bone metastasis (53% vs 45%, P=0.03). TTF-1Neg LUAD was enriched for KRAS, STK11, KEAP1, SMARCA4, and CDKN2A mutations (q&lt;0.05), while TTF-1Pos LUAD was enriched for EGFR and MET mutations (q&lt;0.05). Compared to TTF-1Pos LUAD, TTF-1Neg LUAD had higher prevalence of KRAS G12D (12% vs 4%, P&lt;0.001) and G12V mutations (11% vs 7%, P=0.001), but similar frequency of G12C mutations (14% vs 15%, P=0.82). The association between TTF-1 and treatment outcomes was next investigated. Pts with stage III unresectable TTF-1Neg LUAD who received durvalumab after chemo-radiation (N=20), compared to TTF-1Pos cases (N=174), had shorter median progression-free survival (mPFS, 7.6 vs 24.7 months, P=0.01) and overall survival (mOS, 22.7 months vs not reached, P=0.01). Among pts with stage IV LUAD, TTF-1Neg cases treated with immune checkpoint inhibitors (N=237), compared to TTF-1Pos (N=1,161), had worse objective response rate (ORR, 17% vs 28%, P&lt;0.001), mPFS (2.5 vs 4.7 months, P&lt;0.001) and mOS (9.8 vs 20.9 months, P&lt;0.001). Similarly, pts with TTF-1Neg LUAD (N=297) treated with chemoimmunotherapy, compared to TTF-1Pos cases (N=920), had worse ORR (27% vs 42%, P&lt;0.001), mPFS (4.6 vs 8.1 months, P&lt;0.001) and mOS (11.2 vs 23.4 months, P&lt;0.001). TTF-1 negativity retained its association with worse outcomes after adjusting for treatment line, ECOG performance status, smoking status, PD-L1 TPS, STK11/ KEAP1 mutation status in multivariable cox regression models. Lastly, pts with KRAS G12C mutated TTF-1Neg LUAD treated with KRAS inhibitors (N=25), compared to TTF-1Pos (N=138), had worse ORR (12% vs 35%, P=0.03), mPFS (2.7 vs 5.9 months, P&lt;0.001), and mOS (4.4 vs 12.1 months, P&lt;0.001). After excluding mucinous LUAD cases, which are more commonly TTF-1Neg, similar results were observed. Conclusions: TTF-1 negativity identifies a unique clinicopathologic and genomic subset of LUAD with worse outcomes to diverse systemic therapies.

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.

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.

Effect of the thyroid transcription factor 1 expression and treatment discontinuation due to adverse events on progression-free survival in patients with advanced non-squamous non-small cell lung cancer treated with pembrolizumab plus pemetrexed and platinum chemotherapy: a Japanese four-hospital, retrospective study.

Although a significant improvement in progression-free survival (PFS) has been reported in the thyroid transcription factor 1 (TTF-1) positive patients under treatment for non-squamous non-small cell lung cancer (NS-NSCLC), including immune checkpoint inhibitor therapy, the association between TTF-1 expression and adverse event occurrence remains unclear. Therefore, this study investigated the impact of TTF-1 and its adverse events on PFS during pembrolizumab plus pemetrexed and platinum chemotherapy for NS-NSCLC. Patients who received the pembrolizumab plus pemetrexed and platinum chemotherapy from 1/1/2018 to 12/31/2022 and whose TTF-1 expression was measured were included in the study. This was a retrospective study conducted using electronic medical records. The mean age of the 79 patients was 67.5 ± 8.4 years, with 75.95% patients being male. Among them, 59.49% were TTF-1 positive. PFS comparison between TTF-1-positive and -negative patients showed a trend toward longer PFS for TTF-1 positive patients, though the results were statistically insignificant (P = 0.190). Proportional hazards analysis indicated significant PFS extension from treatment interruption, as adverse events related to cancer therapy stopped (hazard ratio [HR] = 0.32, P = 0.005) and the number of anticancer agents used (HR = 0.01, P < 0.001). Additionally, pembrolizumab plus pemetrexed and platinum chemotherapy for TTF-1-positive NS-NSCLC significantly extended PFS after treatment discontinuation as related adverse events stopped (827 vs. 210 days, P = 0.021). Measurement of TTF-1 may accordingly serve as a predictor of treatment response to the pembrolizumab plus pemetrexed and platinum chemotherapy. It may also be a predictor of patient prognosis when treatment is discontinued due to related adverse events.

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.