Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas

Background Multi-omics studies have shown a high and lack of common driver mutations in most thymomas (TH) and thymic carcinomas (TC) that hamper the development of novel treatment approaches. However, deregulation of apoptosis has been proposed as a common hallmark of TH and TC. BH3 profiling can be utilized to study the readiness of living cancer cells to undergo apoptosis and their dependency on pro-survival BCL-2 family proteins. Methods We screened a cohort of 62 TH and TC patient samples for expression of BCL-2 family proteins and used the TC cell line 1889c and native TH for dynamic BH3 profiling and treatment with BH3 mimetics. Results Immunohistochemical overexpression of MCL-1 and BCL-xL was a strong prognostic marker of TH and TC, and BH3 profiling indicated a strong dependency on MCL-1 and BCL-xL in TH. Single inhibition of MCL-1 resulted in increased binding of BIM to BCL-xL as an escape mechanism that the combined inhibition of both factors could overcome. Indeed, the inhibition of MCL-1 and BCL-xL in combination induced apoptosis in a caspase-dependent manner in untreated and MCL-1-resistant 1889c cells. Conclusion TH and TC are exquisitely dependent on the pro-survival factors MCL-1 and BCL-xL, making them ideal candidates for co-inhibition by BH3 mimetics. Since TH show a heterogeneous dependency on BCL-2 family proteins, upfront BH3 profiling could select patients and tailor the optimal therapy with the least possible toxicity.

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.

Comparative clinicopathological and immunohistochemical study of micronodular thymoma and micronodular thymic carcinoma with lymphoid stroma

AimTo elucidate the clinicopathological and immunohistochemical characteristics of micronodular thymomas (MNTs) and micronodular thymic carcinomas (MNCs) with lymphoid stroma.MethodsWe examined four cases of MNTs and three cases of MNCs pathologically and immunohistochemically.ResultsThere were prominent cystic changes infive of the seven cases. The neoplasms contained epithelial tumour cells arranged in a micronodular growth pattern lined by cystic walls and separated by abundant lymphoid stroma. Only the tumour cell component of MNCs showed signs of malignancy characterised by cytological atypia and increased mitotic activity. Neoplastic MNC epithelial cells showed strong positivity for CD5 and CD117. However, no immature lymphocytes (TdT-positive and CD99-positive) were present in and around the tumour nodules. None of the patients died or suffered from disease due to MNTs or MNCs.ConclusionMNTs and MNCs are rare and less aggressive forms of thymic tumours and can be differentially diagnosed by immunohistochemistry.

Cutaneous Metastasis of Thymic Carcinoma to the Frontal Scalp

Thymic carcinomas are a rare variant of thymic epithelial tumors. Compared to thymomas, they are much more aggressive, difficult to treat, and have a higher mortality rate. Metastasis outside of the mediastinum is rare and usually to sites such as the lung, lymph nodes, liver, pleura, or bones. We report a case of immunohistochemistry proven thymic carcinoma metastasis to the cutaneous surface of the frontal scalp in a 53-year-old Asian female.

IMPROVING THE SELECTIVE TREATMENT OF THYMUS TUMORS USING INTRA-ARTERIAL CHEMOEMBOLIZATION

Epithelial tumors of the thymus occur in the thymus and include thymomas and carcinomas of the thymus. Thymomas are the most common primary tumor in the anterior mediastinum, but are generally rare (1.5 cases / 1,000,000). Although thymomas can spread locally, they are much less invasive than thymic carcinomas. Patients with thymic carcinomas often have metastases. The 5-year survival of patients with thymoma reaches 90%. At the same time, the 5-year survival rate for thymic carcinoma is approximately 55% (NCCN Guidelines. Version 1.2020).Surgical treatment as an independent method can be used only when there are thymus tumors in encapsulated and minimally invasive tumors in the first degree, rarely in the second degree. In all other cases, patients are subject to combined, complex or conservative treatment. In combined and complex treatment, preference should be given to neoadjuvant methods, which allows to achieve regression of the tumor, reduces its volume, limits the invasion of surrounding tissues, as well as to transform the inoperable process into operability.Endovascular technologies, namely regional chemotherapy, in the preoperative period, as a preparatory stage, will increase the level of ablastics and antiblastics in surgical treatment of thymus and reduce the percentage of cytostatics on the whole body, as in intravenous administration. At patients with a paraneoplastic syndrome it is necessary to increase term of regression of displays of these syndromes.Intra-arterial administration of chemotherapeutics has certain advantages:• cytostatics in the arteries that supply blood to the tumor are injected directly into the affected area, which allows you to significantly increase the concentration of the drug in the tumor itself;• reduces the toxic effects of chemotherapy on the whole body;• longer action of drugs allows long-term contact of the cytostatic with tumor cells at all stages of the cell cycle.Another main detail of treatment is that after the introduction of the cytostatic, it is necessary to introduce special emboli (microspheres) to block the removal of the chemotherapeutic agent.The analysis of treatment is taking into account the stage, anamnestic data, the development of clinical manifestations, the results of laboratory and instrumental methods of examination.According to our evidence, taking into account clinical and anamnestic (complaints), laboratory, instrumental (CT OGK with IV contrast), certain conclusions were made in the treatment of thymic tumors.According to our observations, a method of complex treatment of thymic tumors was developed. In this technique, we used regional chemotherapy (namely intra-arterial administration of chemotherapy-cytostatics) as the main method.Object of study. Epithelial tumors of the thymus gland. Subject of study. Indicators of survival and quality of life of patients with malignant thymoma without surgical treatment. The results of radical surgical treatment after regional chemotherapy. Indicators of ablastic and antiblastic. Indicators of results of patients with paraneoplastic syndrome.The aim of the study. Increase the effectiveness of treatment of patients with epithelial tumors of the thymus by using intra-arterial chemoembolization as a neoadjuvant therapy to create ischemia and high concentrations of cytostatics in tumors for a long period of time to achieve devitalization of tumor tissue and reduce overall toxicity of chemotherapy.Objectives of the study.1. To determine the causes of unsatisfactory results of treatment of patients with epithelial tumors of the thymus using standard methods2. Improve the technique of intra-arterial chemoembolization in epithelial tumors of the thymus gland (technology, choice of cytostatics)3. To study the dynamics of biochemical markers (AFP, HGT) and antibodies to acetylcholine in paraneoplastic syndrome using intra-arterial chemoembolization4. To study pathomorphological changes in tumor tissue using intra-arterial chemoembolization5. To compare the clinical efficacy (increased tumor operability) of intra-arterial chemoembolization in the complex therapy of patients with epithelial tumors of the thymus gland.

Cell-free circulating tumor DNA (cfDNA) analysis of advanced thymic epithelial tumors (TETs).

8577 Background: Thymic epithelial tumors (TETs) are rare tumors originating from the epithelial cells of the thymus. Thymomas tend to be slowly growing, whereas thymic carcinomas are more aggressive and often metastasize wildly. TETs have a very low tumor mutational burden (TMB). cfDNA has been used in several tumor types to describe the molecular characteristics and select treatment options, especially in absence of tissue availability. There is no information on the cfDNA detected in TETs. The purpose of this study was to identify common genomic alterations occurring in circulating tumor DNA (ctDNA) in patients with advanced TETs, detected using a cfDNA assay. Methods: We retrospectively evaluated 157 TET samples from the Guardant Health database between November 2017 – November 2020. The cfDNA analysis interrogated single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes using a commercially available liquid biopsy assay (Guardant360; Guardant Health, Redwood City, CA) . We evaluated the frequency of genomic alterations based on diagnosis, age, and sex. Results: In this cohort, 66% of the patients had thymic carcinoma and 34% had thymoma. The median age was 60 years, and 59% of patients were male. 126 patients (80%) of this cohort had ≥1 somatic alteration detected. The most prevalent mutations detected are TP53 (55%), KIT (13%), EGFR (12%), BRCA2 (11%), PIK3CA (10%), ARID1A (10%), ATM (10%), KRAS (9%), APC (9%), and BRAF (9%). Mutations were more commonly observed in thymic carcinomas than thymomas, but statistical significance was not reached due to the small sample size. Frequencies of the observed genomic alterations are shown in the table below. Conclusions: This study confirms that advanced stage TETs shed tumor DNA into the circulation that can be picked up in the majority of patients, using a solid tumor platform, despite the low TMB typically observed in these tumors. This assay can potentially be used to monitor response to therapy. A more targeted gene panel, enriched for genes commonly mutated in TETs (e.g. GTF2I, BAP1, CYLD) might provide further insights in the future in the management of TETs.[Table: see text]

Thymic Carcinomas and Second Malignancies: A Single-Center Review

Thymic carcinomas account for less than 0.01% of new cancer diagnoses annually and are more aggressive than thymomas. Autoimmune disorders have been associated with thymomas and only recently with thymic carcinomas. Second malignancies are well described after thymomas. The aim of this study was to analyze the incidence of second malignancies in patients with thymic carcinomas. All cases of thymic carcinomas were identified from the pathology archives of Indiana University. Histological materials were reviewed and further correlated with clinical data to identify incidence of second cancers in patients with thymic carcinomas. Histological material was available for review in 92 cases of thymic carcinoma. Clinical data were available for 85 patients. Fourteen of these (16.5%) patients had a second malignancy; these included small cell lung carcinoma, “testicular cancer”, embryonal carcinoma, seminoma, breast carcinoma (two cases), prostatic adenocarcinoma, Hodgkin’s lymphoma, thyroid carcinoma, bladder carcinoma (two cases), renal cell carcinoma, and melanoma. The latter could precede, be concurrent with, or follow the diagnosis thymic carcinoma. The incidence of second cancers in patients with thymic carcinomas is similar to that reported for thymomas. Abnormalities in immunological surveillance may be responsible for this high incidence of second malignancies in thymic tumors.