Thymic Carcinoma Patients Research Articles

A single-center analysis of 71 patients with thymic carcinoma: the chronological changes in the surgical procedure and prognosis.

BackgroundEffective treatments for thymic carcinoma (TC) have not been established due to its rarity and the prognosis has not yet been improved. In the present study, data of patients who underwent treatment for TC at our single institution were retrospectively reviewed to investigate the chronological changes in the clinical characteristics, surgical procedure, and prognosis.MethodsA total of 71 patients were included in this study. To investigate the chronological changes, the patients were divided into two groups at January 2009, when minimally invasive surgery (MIS) for thymic epithelial tumors (TETs) was introduced.ResultsAmong the 71 TC patients, 24 patients underwent surgery through December 2008 (earlier period), and 21 underwent surgery from January 2009 (later period). The patients in the later group were more likely to be diagnosed by chest computed tomography (CT) scan without subjective symptom. The rates of MIS and complete resection were significantly higher and the number of the patients at the early stage were significantly greater in the later group. The 5-year overall survival (OS) rate of the patients who underwent surgery at earlier and later groups were 58.7% and 92.8% respectively (P<0.01).ConclusionsThe prognosis of TC has improved over time, thanks to early detection by CT screening and complete surgical resection.

Nomogram predicts the prognosis of patients with thymic carcinoma: A population-based study using SEER data.

Thymic carcinoma (TC) is a rare malignant tumor that can have a poor prognosis, and accurate prognostication prediction remains difficult. We aimed to develop a nomogram to predict overall survival (OS) and cancer-specific survival (CSS) based on a large cohort of patients. The Surveillance Epidemiology and End Results (SEER) database was searched to identify TC patients (1975-2016). Univariate and multivariable Cox regression analyses were used to identify predictors of OS and CSS, which were used to construct nomograms. The nomograms were evaluated using the concordance index (C-index), calibration curve, receiver operating characteristic curve, and decision curve analysis (DCA). Subgroup analysis was performed to identify high-risk patients. The analysis identified six predictors of OS (Masaoka stage, surgical method, lymph node metastasis, liver metastasis, bone metastasis, and radiotherapy) and five predictors of CSS (Masaoka stage, surgical method, lymph node metastasis, tumor size, and brain metastasis), which were used to create nomograms for predicting three-year and five-year OS and CSS. The nomograms had reasonable C-index values (OS: 0.687 [training] and 0.674 [validation], CSS: 0.712 [training] and 0.739 [validation]). The DCA curve revealed that the nomograms were better for predicting OS and CSS, relative to the Masaoka staging system. We developed nomograms using eight clinicopathological factors that predicted OS and CSS among TC patients. The nomograms performed better than the traditional Masaoka staging system and could identify high-risk patients. Based on the nomograms' performance, we believe they will be useful prognostication tools for TC patients.

Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas.

Simple SummaryThe biology of thymic epithelial tumours (TETs), including thymomas and thymic carcinomas, and particularly the extent of molecular dysregulation, is poorly understood. Through next-generation sequencing of 15 genes implicated in common solid tumours in 53 TETs, we found a larger number of single nucleotide variants (SNVs) in thymic carcinomas than thymomas. About 30% of thymic carcinomas had at least one somatic pathogenic gene variant in TP53, ERBB2, KIT, or KRAS, whereas variants of uncertain clinical significance in KIT, ERBB2, and FOXL2 were found exclusively in thymomas. The presence of somatic pathogenic variants was non-significantly associated with shorter disease-free survival in thymic carcinoma patients. No somatic pathogenic or likely pathogenic SNV was found in thymomas. Importantly, we also evaluated germline SNVs, adding to the number of known genetic alterations in TETs and thereby enhancing our molecular understanding of these neoplasms.A better understanding of the molecular pathogenesis of thymic epithelial tumours (TETs) could revolutionise their treatment. We evaluated thymomas and thymic carcinomas by next-generation sequencing (NGS) of somatic or germline single nucleotide variants (SNVs) in genes commonly mutated in solid tumours. In total, 19 thymomas and 34 thymic carcinomas were analysed for nonsynonymous SNVs in 15 genes by targeted NGS (reference genome: hg19/GRCh37). Ten SNVs in TP53 (G154V, R158P, L194H, R267fs, R273C, R306 *, Q317 *), ERBB2 (V773M), KIT (L576P), and KRAS (Q61L) considered somatic and pathogenic/likely pathogenic were detected in 10 of 34 (29.4%) thymic carcinomas. No somatic SNVs confirmed as pathogenic/likely pathogenic were found in thymomas. Rare SNVs of uncertain or unknown functional and clinical significance, to our knowledge not reported previously in TETs, were found in ERBB2 (S703R), KIT (I690V), and FOXL2 (P157S) in 3 of 19 (16%) thymomas. The most frequent germline SNVs were TP53 P72R (94% TETs), ERBB2 I655V (40% TETs), and KIT M541L (9% TETs). No significant difference in median disease-free survival (DFS) was found between thymic carcinoma patients with and without pathogenic SNVs (p = 0.190); however, a trend toward a longer DFS was observed in the latter (16.0 vs. 30.0 months, respectively). In summary, NGS analysis of TETs revealed several SNVs in genes related to the p53, AKT, MAPK, and K-Ras signalling pathways. Thymic carcinomas showed greater genetic dysregulation than thymomas. The germline and rare SNVs of uncertain clinical significance reported in this study add to the number of known genetic alterations in TETs, thus extending our molecular understanding of these neoplasms. Druggable KIT alterations in thymic carcinomas have potential as therapeutic targets.

Tumour immune microenvironment in resected thymic carcinomas as a predictor of clinical outcome.

The spatial distribution of tumour-infiltrating lymphocytes (TILs) is a novel descriptor characterising the tumour immune microenvironment (TIME). The aim of our study was to assess whether a specific TIME of surgically resected thymic carcinoma (TC) can predict tumour invasiveness, recurrence or survival. Digital microscopy was performed on 39 TCs immunohistochemically stained to investigate the activation of the immune checkpoint pathway (PD-L1/PD-1), along with density and spatial distribution of TILs phenotypes (CD3+, CD4+, CD8+, FOXP3+, CD56+). The impact of PD-L1 and TIL density considering the intratumoural (iTILs) and stromal (sTILs) distribution on pathological characteristics and clinical outcomes were analysed. In early TC stages, we observed a higher total density of CD3+ (p = 0.05) and CD8+ (p = 0.02) TILs. PD-L1 was expressed in 71.8% of TCs. In advanced TC stages, we observed a lower density of CD3+ (p = 0.04) and CD8+ (p = 0.01) iTILs compared to early stages. Serum concentrations of PD-L1 were significantly higher in TCs compared to healthy controls: 134.43 ± 18.51 vs. 82.01 ± 6.34 pg/ml (p = 0.001), respectively. High densities of stromal CD4+ TILs (54 vs. 32%, p = 0.043) and CD8+ TILs (65 vs. 17%, p = 0.048) were associated with improved freedom from recurrence (FFR) and cause-specific survival (CSS). High density of FoxP3+ TILs were associated with improved FFR (p = 0.03) and CSS (p = 0.003). Mapping TIL subpopulations complement the armamentarium for prognostication of TC outcomes. The improved outcome in patients with high density of TILs supports the use of immune checkpoint inhibitors in TC patients.

Multiparametric Magnetic Resonance Imaging for Assessing Thymic Epithelial Tumors: Correlation With Pathological Subtypes and Clinical Stages.

World Health Organization classification and Masaoka-Koga stage are widely used for thymic epithelial tumors (TETs). Reduced field-of-view (rFOV) diffusion-weighed imaging (DWI) proved to improve the image quality. Dynamic contrast-enhanced (DCE) MRI was commonly used in evaluating tumors. To investigate the value of multiparametric MRI in evaluating TETs. Retrospective. Eighty-seven participants including 38 low risk (52.08 ± 14.19 years), 30 high risk (52.40 ± 11.35 years), and 19 thymic carcinoma patients (59.76 ± 10.78 years). A 3 T, turbo spin echo imaging, echo planar imaging, volumetric interpolated breath-hold examination with radial acquisition trajectory. DCE-MRI and apparent diffusion coefficient (ADC) variables were compared. Diagnostic performances of single significant factor and combined model were compared. Parameters were compared using one-way ANOVA or independent-samples t test. Logistic regression was employed to investigate the combined model. Receiver operating curves (ROC) and DeLong's test were used to compare the diagnostic efficiency. ADC, Ktrans , and kep values were significantly different among low-risk, high-risk and carcinoma group (ADC, 1.279 ± 0.345 × 10-3 mm2 /sec, 0.978 ± 0.260 × 10-3 mm2 /sec, 0.661 ± 0.134 × 10-3 mm2 /sec; Ktrans 0.167 ± 0.071 min-1 , 0.254 ± 0.136 min-1 , 0.393 ± 0.110 min-1 ; kep 0.345 ± 0.113 min-1 , 0.560 ± 0.269 min-1 , 0.872 ± 0.149 min-1 ). They were significantly different for early stage and advanced stage (ADC, 1.270 ± 0.356 × 10-3 mm2 /sec vs. 0.845 ± 0.251 × 10-3 mm2 /sec; Ktrans 0.179 ± 0.092 min-1 vs. 0.304 ± 0.142 min-1 ; kep 0.370 ± 0.181 min-1 vs. 0.674 ± 0.362 min-1 ). The combination of them had highest diagnostic efficiency for WHO classification (AUC, 0.925; sensitivity, 83.7%; specificity, 89.5%), clinical stage (AUC, 0.879; sensitivity, 80.9%; specificity, 82.5%). Multiparametric MRI model may be useful for discriminating WHO classification and clinical stage of TETs. 4 TECHNICAL EFFICIENCY: Stage 2.

Association of lung immune prognostic index with survival outcome in advanced thymic carcinoma patients treated with palliative intent chemotherapy.

BackgroundThe prognostic implications of palliative chemotherapy for advanced or recurrent thymic carcinomas require full elucidation. The lung immune prognostic index (LIPI) is a novel prognostic index whose effectiveness has recently been reported in lung cancer patients. This study aimed to evaluate the clinical value of the LIPI in advanced or recurrent thymic carcinoma patients.MethodsWe retrospectively analyzed 41 advanced or recurrent thymic carcinoma patients undergoing palliative chemotherapy between January 2001 and December 2020. Survival‐time analysis was conducted using the Kaplan–Meier method and log‐rank test. Multivariate analysis using the Cox proportional hazards model was performed to investigate the predictive and/or prognostic value of the LIPI.ResultsMedian progression‐free survival (PFS) for first‐line chemotherapy and overall survival (OS) were significantly longer in the good‐LIPI group (LIPI: 0) than in the intermediate/poor‐LIPI group (LIPI: 1 or 2) (PFS: 13.4 vs. 6.8 months, p = 0.025; OS: 48.2 vs. 28.9 months, p = 0.00506). Multivariate analysis revealed that intermediate/poor LIPI was the adverse prognostic factor for PFS. With regard to OS, serum albumin <3.5 g/dl and an intermediate/poor LIPI were identified as independent adverse prognostic factors.ConclusionsOur study indicates that the LIPI is a potential prognostic marker in patients with advanced or recurrent thymic carcinoma undergoing palliative chemotherapy.

Surgical resection of Masaoka stage III thymic epithelial tumours with great vessels involvement: a retrospective multicentric analysis from the European Society of Thoracic Surgeons thymic database.

The aim of this study was to analyse the outcomes of an international cohort of patients affected by Masaoka stage III thymic epithelial tumours with vascular involvement and treated by surgery. Study design was the observational multicentre retrospective cohort study. Data were extracted from the European Society of Thoracic Surgeons thymic database; additional variables were collected. Inclusion criteria were as follows: stage III (Masaoka-Koga) thymic epithelial tumours; surgery with radical intention; clinical or pathological great vessels involvement; and radiologically suspected or diagnosed intraoperatively. Outcome items were analysed. Sixty-five patients submitted to surgery from 2001 to 2017 fulfilled inclusion criteria. Thymoma and thymic carcinoma patients did not differ for demographics and clinical characteristics. The majority of great vessel treated were superior vena cava or innominate veins (72.3%). Eleven patients (16.9%) had postoperative cardiopulmonary complications; vascular stenosis was observed in 3 patients (4.6%). The multivariable Cox analysis for disease-free survival showed an increased hazard of recurrence for thymic carcinoma (hazard ratio = 3.59; 95% confidence interval: 1.66-7.78, P = 0.001). The 1-, 3-, 5- and 10-year overall survival rates were 0.86, 0.84, 0.81, and 0.53, respectively. There was no significant difference in overall survival according to resection status or between thymoma and thimic carcinoma. The univariable Cox regression model did not show an increased hazard of death for myasthenic patients considering all resection status and for patients who received neoadjuvant therapy. We observed that clinical outcomes of patients treated for stage III thymic epithelial tumours with vascular involvement are satisfactory suggesting to increase the confidence in dealing with these complex surgeries. Complete resection should be achieved, even though extensive vascular reconstructions are required.

A phase 1 study of the safety, pharmacokinetics and pharmacodynamics of escalating doses followed by dose expansion of the selective inhibitor of nuclear export (SINE) selinexor in Asian patients with advanced or metastatic malignancies

Purpose:This phase 1 study aims to evaluate the tolerability and the recommended phase 2 dose of selinexor in Asian patients with advanced or metastatic malignancies.Experimental Design:A total of 105 patients with advanced malignancies were enrolled from two sites in Singapore (National University Hospital and the National Cancer Centre, Singapore) from 24 February 2014 to 14 January 2019. We investigated four dosing schedules of selinexor in a 3 + 3 dose escalation design with an additional Phase 1b expansion cohort. Adverse events were graded with the NCI Common Terminology Criteria for Adverse Events v 4.03. Pharmacodynamic assessments included nuclear cytoplasmic localization of p27, XPO1 cargo proteins pre and post selinexor dosing and pharmacokinetic assessments were conducted at doses between 40 and 60 mg/m2.Results:In our Asian patient cohort, dosing at 40 mg/m2 given 2 out of 3 weeks, was the most tolerable for our patients. At this dose level, grade 3 adverse events included fatigue (8%), hyponatremia (23%), vomiting (5%), thrombocytopenia (5%), and anaemia (2%). Selinexor had a rapid oral absorption with median Tmax of 2 h and no PK accumulation after multiple doses of tested regimens. Complete responses were seen in two lymphoma patients. Partial responses were noted in three diffuse large B cell lymphomas, one Hodgkin’s lymphoma and thymic carcinoma patient, respectively.Conclusion:Selinexor is tolerated by Asian patients at 40 mg/m2 twice a week given 2 out of 3 weeks. A 1-week drug holiday was needed as our patients could not tolerate the current approved continuous dosing regimens because of persistent grade 3 fatigue, anorexia and hyponatremia.

The role of radiation therapy in the management of primary thymic epithelial neoplasms

Therapeutic radiation plays an important role in the management of thymoma and thymic carcinoma. These two tumor types differ substantially in their aggressiveness and prognosis. The most pressing issue in radiotherapy is which thymoma and thymic carcinoma patients need radiation. Given that these are rare cancers, few randomized trials have been published. Controversy remains regarding which patients benefit from adjuvant radiation therapy. Existing literature spans patients treated over nearly 50 years, during which time radiation therapy has evolved from rudimentary 2-dimensional based planning to conformal 3-dimensional planning to yet more conformal dose painting techniques such as intensity-modulated radiation therapy and proton therapy. If the effect of radiation is small and the natural history of a disease long, as is the case for stage I favorable histology thymoma, then differences in techniques and toxicities may have as much of an impact as whether radiation was given or not.

Novel Tumor-Specific Antigens for Immunotherapy Identified From Multi-omics Profiling in Thymic Carcinomas.

Thymic carcinoma (TC) is the most aggressive thymic epithelial neoplasm. TC patients with microsatellite instability, whole-genome doubling, or alternative tumor-specific antigens from gene fusion are most likely to benefit from immunotherapies. However, due to the rarity of this disease, how to prioritize the putative biomarkers and what constitutes an optimal treatment regimen remains largely unknown. Therefore, we integrated genomic and transcriptomic analyses from TC patients and revealed that frameshift indels in KMT2C and CYLD frequently produce neoantigens. Moreover, a median of 3 fusion-derived neoantigens was predicted across affected patients, especially the CATSPERB-TC2N neoantigens that were recurrently predicted in TC patients. Lastly, potentially actionable alterations with early levels of evidence were uncovered and could be used for designing clinical trials. In summary, this study shed light on our understanding of tumorigenesis and presented new avenues for molecular characterization and immunotherapy in TC.

PECATI: A Multicentric, Open-Label, Single-Arm Phase II Study to Evaluate the Efficacy and Safety of Pembrolizumab and Lenvatinib in Pretreated B3-Thymoma and Thymic Carcinoma Patients

Thymic epithelial tumors are rare neoplastic proliferations of thymic epithelial cells. The aggressiveness of these malignancies increases as higher is the histologic subtype, being thymic carcinoma the most aggressive subtype, with a greater tendency to metastatic spread. In metastatic setting, there is no standard treatment after progression on platinum-based chemotherapy. In this scenario, monotherapy treatment either with lenvatinib, a multi-tyrosine kinase inhibitor with antiangiogenic properties, or pembrolizumab, an immune-checkpoint inhibitor, has reported clinical activity. Potential combination of both agents may have synergistic activity as reported in other cancer types. PECATI trial is a single-arm, investigator-initiated phase II study aiming to assess the activity and safety of the combination of lenvatinib and pembrolizumab in 43 patients with advanced B3-thymoma or thymic carcinoma who progressed on or after at least one previous line of platinum-based chemotherapy. The primary endpoint of the trial is 5-month progression-free survival rate and the secondary endpoints include overall response rate, duration of response, and overall survival.

Abstract 2252: Genome profiling of thymic carcinoma identifies putative driver mutations in the NF-κB signaling pathway

Abstract Background: Thymic epithelial tumors (TETs), including thymoma and thymic carcinoma (TC), are one of the rarest cancers. Unlike thymoma, TC is clinically agressive and responds poorly to first-line chemotherapy and second-line systemic therapy. Currently, sunitinib is the only receptor tyrosine kinase inhibitor approved for TC treatment. However, most TC patients do not have the corresponding c-Kit mutations. Because the molecular drivers of TC are almost unknown, characterization of the mutational landscape of TC will broaden our understanding of TC etiology and facilitate the development of effective targeted therapies. Methods: Comprehensive genomic profiling, including SNV, indels, copy number alterations and re-arrangement analysis, was performed with a 830-gene next-generation sequencing panel on tumor tissues from a cohort of 32 TET patients (16 TCs and 16 thymomas). Results: Recurrent mutated genes in this TET cohort were TP53, CYLD, KMT2C, BRCA1, CHD2, PBRM1, ARID2, ASXL1, BRD7, CDKN2A, EGFR, KIT, MYH9, NFKB1A, RB1 and TET2. TP53 is the most frequently mutated gene, seen in 31% (5/16) of TCs and 6% (1/16) of thymomas. We found two actionable mutations in TCs (KIT D579del and IDH1 R132C) and one in thymomas (KIT V560D). Consistent with previous reports, we observed recurrent mutations in multiple genes encoding epigenetic regulator proteins (ASXL1, TET2 KMT2C, CHD2, PBRM1, ARID2 and BRD7), all in TCs but not thymomas. Most importantly, we found four CYLD mutations (two stop gain, one frameshift and one missense) and two NFKBIA mutations (one frameshift and one in splicing-site) in 6 TC samples. Both CYLD and NFKBIA genes encode negative regulators of NF-κB signaling pathway. CYLD is a Ub-specific protease (USP)-type deubiquitinase that preferentially disassembles Lys63-Ub, a post-translational modification required for the activation of NF-κB, while NFKBIA causes trapping REL dimers induced inhibitory activity of dimeric NF-κB/REL protein complexes. Furthermore, genomic alterations in NFKBIA and CYLD were mutually exclusive. Our results indicated that loss-of-function mutations in CYLD and NFKBIA may function as the molecular drivers of TC through constitutive activation of NF-κB signaling pathway. Conclusion: Our findings provide an enhanced road map for the etiology of TC. Further investigation is warranted into the roles of NF-κB pathway and epigenetic regulators dysfunction in TC pathogenesis and their potential for clinical trials. Citation Format: Naixin Liang, Xiaomo Li, Tonghui Ma, Chao Gao, Zhili Cao, Lei Cao, Zhongxing Bing, Zhenhuan Tian, Chao Guo, Shanqing Li, Yadong Wang, Jianchao Xue, Ji Li, Xiaoguang Li, Peng Liu, Shuyang Zhang. Genome profiling of thymic carcinoma identifies putative driver mutations in the NF-κB signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2252.

Multi-institutional survey of thymic carcinoma patients in Hokushin region.

Thymic carcinoma is a rare neoplasm, and its prognosis is very poor. The purpose of this study was to validate the clinical and epidemiological factors, diagnosis and initial treatment of thymic carcinoma among all patients diagnosed in the registered hospital group. We surveyed retrospective data from 152,921 cancer patients in 22 principal hospitals. A total of 88 thymic carcinoma cases were newly diagnosed. These patients were 50 men and 38 women, with a median age of 66years old. Eight patients were discovered in cancer screening, 9 in a voluntary setting, 14 at health checkups, 25 at follow-up of other diseases, and 32 cases by introduction from another hospital. Only 14 cases had been diagnosed with localized disease, but 5 cases were accompanied by regional lymph node metastasis. Furthermore, 12 cases showed infiltration into adjacent organs, and 24 cases had distant metastasis. Eighty-three cases were diagnosed by a pathological diagnosis. A surgical approach, chemotherapy, and radiotherapy were performed for 29, 35 patients, and 31 patients, respectively, while 17 patients received best supportive care. The diagnosis of thymic carcinoma is still difficult, and this disease has a tragically rapid progression if when discovered during follow-up of other diseases. An innovative modality for the early detection of thymic carcinoma is needed in modern medical society.

Complete remission following icotinib administration in an advanced ectopic thymic carcinoma patient harbouring the EGFR exon 19 deletion.

BackgroundEctopic thymic carcinoma (TC) is an extremely rare disease with a poor prognosis. The main treatment for early TC is surgery, although an effective treatment for advanced TC is lacking.MethodsWe present the case of a 61‐year‐old man with advanced posterior mediastinum thymic squamous cell carcinoma. Amplification refractory mutation system (ARMS)–polymerase chain reaction (PCR) analysis was used to investigate the molecular and mutational characteristics of this tumour.ResultsAfter chemotherapy and radiotherapy, the tumour showed disease progression. Immunohistochemistry revealed that the tumour was positive for CD117 (specific for primary TC), CK19, CD56 and Ki67. ARMS‐PCR analysis revealed an EGFR exon 19 deletion in the patient. The patient subsequently received icotinib treatment and achieved complete remission for 3 years.ConclusionsThis case report suggests that tyrosine kinase inhibitors are a potential treatment strategy for patients with TC harbouring EGFR alterations.

A New Horizon of Liquid Biopsy in Thymic Epithelial Tumors: The Potential Utility of Circulating Cell-Free DNA.

BackgroundThymic epithelial tumors (TETs) are rare thoracic malignancies, commonly divided into two different histopathological entities, thymoma (T) and thymic carcinoma (TC). To date, there are no specific biomarkers for monitoring the biological course of these rare tumors. We carried out a single center study aiming at the detection of circulating cell-free DNA (ccfDNA) and the correlation of its levels with metastatic dissemination and histological subtype in patients with TETs.MethodsFrom July 2018 to January 2020, 5-ml blood samples from 26 patients with advanced TET (aTET) (11 patients with TC and 15 patients with T) and from six patients with completely resected TET (cr-TET), were prospectively obtained before the initiation of systemic therapy. Blood samples from 10 healthy donors were used as control. The QIAamp MinElute ccfDNA Kits was used for ccfDNA isolation from plasma; real-time PCR was used for cfDNA quantification.ResultsWe found significantly higher ccfDNA amount in patients with T and TC compared to controls, with median ccfDNA level of 3.3 ng/µl, 11.4 ng/µl and 25.6 ng/µl, for healthy donors, T and TC patients, respectively (p<0.001). No significant difference was found between cr-TET and controls (p = 0.175). ccfDNA concentrations were higher in metastatic (M1a and M1b) compared to non-metastatic (M0) TETs (25.6 ng/µl versus 7.2 ng/µl; p= 0.037). No significant correlation was found either between ccfDNA and disease stage, according to both the Masaoka-Koga (p= 0.854) and the TNM 8th edition staging systems (p = 0.66), or between ccfDNA levels and overall tumor burden, estimated according RECIST 1.1 criteria (r = 0.07, p = 0.725).ConclusionsTo the best of our knowledge, this is the first study that prospectively explores detection and quantification of ccfDNA in TETs. Higher baseline cfDNA levels have been observed in both advanced T and TC comparing to the control group.

Immunotherapy for thymoma.

Thymic epithelial tumors (TETs) are rare thymic neoplasms. There are approximately 1.5 cases per million TETs per year. They are the most common anterior mediastinal tumors in adults. Due to limited activity of available treatment options novel strategies and treatment options are needed and treatment with immune checkpoint inhibitors is an attractive option. Thymic epithelial tumors have one of the lowest tumor mutational burden among all cancer in adults, but high expression of PD-L1 on tumor cells and abundant CD8+ lymphocytes provide a strong rational for implementing immune checkpoint inhibitors (ICIs) which target PD-1/PD-L1 pathway in the treatment of TETs. Few small early stage clinical trials were published so far evaluating efficacy of pembrolizumab and avelumab in thymoma and thymic carcinoma patients. Al trials showed reasonable response rates and progression-free survival. Higher PD-L1 expression was predictor of response in all trials. However, increased incidence of immune-related adverse events was seen in TET patients treated with immune checkpoint inhibitors compared to patients with other cancers. At the moment, ICIs are not standard of care for patients with TET and larger trials are needed to establish the right role of ICIs regarding efficacy and safety of these agents.

Comparison of PD-L1 immunohistochemical assays and the significance of PD-L1 expression in thymoma.

Thymoma is a relatively rare malignancy, which is categorized as thymic epithelial tumor but known as the most common pathology that is developed in the anterior mediastinum. Complete resection is recommended for localized tumors and usually favorable prognosis can be obtained. However, poor survival period has been reported in unresectable cases exhibiting extensive invasion or distant metastasis, as effective chemotherapeutic regimens are restrained. We previously assessed expression of programmed death ligand 1 (PD-L1) and programmed death 1 (PD-1) and discussed their prospective application in the immunotherapy of thymic epithelial tumors. After our publication, additional studies using reliable PD-L1 antibodies, which are currently administered to predict efficacy of PD-1/PD-L1 blockade therapy were performed and further characterized PD-L1 in thymoma. Herein, recent knowledge in relation to the significance of PD-L1 expression in thymoma is reviewed based on recent findings using qualified PD-L1 clones. Most studies coherently found high expression of PD-L1 on the cell membrane and cytoplasm of tumor epithelial cells in accordance with previous reports, which is a predictive marker for effectiveness of anti-PD-1/PD-L1 drugs, even when approved PD-L1 antibodies were employed. On the other hand, PD-L1 expression on tumor infiltrating immune cells remains to be sufficiently determined. High PD-L1 expression can be expected in cases with high grade histological subtypes, such as type B2/B3 thymomas, or those with advanced stages III or IV of the disease. Interestingly, the level of PD-L1 expression was found to be upregulated after chemotherapy compared with that before, which could be explained by immunogenic cell death. The prognostic impact of PD-L1 expression in thymoma might be found only when thymic carcinoma patients were excluded. Furthermore, it also could be identified when we analyzed thymomas completely resected, distinct from biopsy and incompletely resected cases.

Relationship of possible biomarkers with malignancy of thymic tumors: a meta-analysis

BackgroundRole of biomarkers for promotion of tumor proliferation (BPTPs) and for promotion of apoptosis (BPAs) in thymic malignant tumors is still unclear. The purpose of this study was to evaluate the relationship between BPTPs and/or BPAs and malignancy of thymic malignant tumors.MethodsStudies on thymic malignant tumors and biomarkers were searched in PubMed, ISI Web of Knowledge, and Embase databases, and all statistical analyses were conducted using Review Manager.ResultsTwelve articles related to biomarkers and thymic malignant tumors were selected and analyzed. A relationship between BPAs and Masaoka stage was demonstrated for four markers, namely Bax, p73, Casp-9 and Bcl-2, included 138 stage I/II patients and 74 stage III/IV patients, and BPAs were significantly correlated with high Masaoka staging (P = 0.03). We further found a relationship between BPAs and degree of malignancy for four markers, namely Bax, p73, Casp-9 and Bcl-2, included 176 thymoma patients and 36 thymic carcinoma patients, and BPAs were significantly correlated with thymic carcinoma (P = 0.010). In addition, a relationship between BPTP and Masaoka staging was demonstrated for seven markers, namely Podoplanin, Glut-1, Muc-1, Egfr, Igf1r, c-Jun, and n-Ras, included 373 patients with stage I/II and 212 patients with stage III/IV, and BPTPs were significantly correlated with high Masaoka staging (P < 0.001). We also found a relationship between BPTPs and degree of malignancy for ten markers, namely Mesothelin, c-Kit (CD117), Egfr, Lat-1, Muc-1,Ema, Glut-1, Igf1r, c-Jun, and n-Ras, included 748 thymoma patients and 280 thymic carcinoma patients, and BPTPs were significantly correlated with thymic carcinoma (P < 0.001).ConclusionThese findings show that high levels of BPTPs or BPAs are more closely related to thymic carcinoma and Masaoka stage III/IV, suggesting that BPTPs and BPAs may play an important role in the occurrence and development of thymic malignant tumors.

Extended thymectomy with blood vessel resection and reconstruction improves therapeutic outcome for clinical stage III thymic carcinoma patients: a real-world research

ObjectivesWe examine the therapeutic efficacy of extended thymectomy with blood vessel resection and reconstruction in thymic carcinoma patients with great vessel invasion.MethodsIn total 26 patients diagnosed as clinical stage III thymic carcinoma with severe great vessel invasion were enrolled in this retrospective study. Among these patients, 14 cases received adjuvant chemo- and radiotherapy (non-operation subgroup, NOG), the other 12 patients received extended thymectomy with vessel resection and reconstruction followed by the adjuvant treatment (operation subgroup, OG).ResultsAll surgical procedures went smoothly with no perioperative death. R0 resection was obtained in all surgical cases, and we also observed a lymph node metastasis rate of 38.8%. The overall survival (OS) was 34 months for the whole cohort, 48 and 26 months for the OG and NOG respectively (p = 0.013). The median disease metastasis free survival (DMFS) was 47 months for the OG and 18 months for the NOG (p = 0.019).ConclusionExtended thymectomy with vessel resection is feasible for patients with clinical stage III thymic carcinoma. Surgery significantly improves the overall survival and the prognosis of clinical stage III thymic carcinoma.

Distinct genomic and immune microenvironment between thymomas and thymic carcinomas.

e13529 Background: Thymomas and thymic carcinomas which uniformly known as thymic epithelial tumors (TETs) are rare intrathoracic malignancies and a limited studies have been reported addressing the molecular biology and immune discrepancy. The main purpose of this study was to depict the genomic and transcriptomic landscape of thymomas and thymic carcinomas, as well as elucidate the differentiated immune microenvironment. Methods: Totally 15 thymomas and 7 thymic carcinomas patients were enrolled from January 2014 to July 2018. Treatment-naïve tissue samples were collected, and we also obtained matched peripheral blood mononucleocytes as negative control. DNA and RNA were co-extracted and performed with whole exon and transcriptome sequencing. The immune cell infiltration scores were estimated using ssGSEA algorithm. Results: Exome sequencing revealed that GTF2I mutation occurred in all of type A thymomas but was absent in the aggressive subtypes. The median tumor mutation burden of thymomas was 0.12/Mb, significantly lower than thymic carcinomas (median: 1.02/Mb, p = 0.001). Copy number variation was more common in thymic carcinomas than thymomas (83.3% vs 9.1%, p = 0.005). Top mutational signatures enriched in both thymomas and thymic carcinomas included age and Aristolochic acid exposure, while the APOBEC signature was more common in thymomas than thymic carcinomas (81.8% vs 16.7%, p = 0.03). As a confirmed immune escape event, loss of heterozygosity of human leukocyte antigen was identified in 9.1% of thymomas and 50% of thymic carcinomas. Via unsupervised clustering of immune infiltration, all tissue samples were classified into high- and low-infiltration subgroups. Remarkably, up to 71.4% of samples from thymic carcinomas and only 6.7% of samples from thymomas were defined as low immune cell infiltration. In consideration of specific immune cell types, macrophage ( p = 0.01) and neutrophil ( p = 0.02) were enriched in thymic carcinomas while CD56+ NK cell ( p = 0.005) was enriched in thymomas, indicating the evidential discrepancy about immune cell infiltration between two subtypes of TETs. Conclusions: This study elucidated the molecular and immune microenvironment discrepancy between two subtypes of TETs. From molecular perspective, thymomas and thymic carcinomas are entirely different diseases with different etiology and characterized by distinct immune infiltration, and thus should be managed with disparate therapeutic strategies. Findings in this study may also be useful in future targets development and exploration of immunotherapies in TETs.