Surgical outcomes of patients with locally advanced thymic epithelial tumor undergoing induction therapy followed by surgery: a narrative review.

Background and Objective: Thymic epithelial tumors (TETs), including thymomas and thymic cancers, are relatively rare malignancies originating from the thymus. Although complete surgical resection is the cornerstone of treatment for these tumors, the optimal management strategy for locally advanced cases remains uncertain. Neoadjuvant therapies, with their potential to improve the likelihood of complete resection, are promising, particularly in marginally operable cases. However, the current evidence supporting this approach is lacking. This review of the existing literature on the efficacy of induction therapy followed by surgical resection for stage III or IV locally advanced TETs aimed to provide an up-to-date perspective and highlighting directions for future clinical research. Methods: PubMed was searched using the keywords "surgery," "survival", "thymoma", "thymic cancer", and "induction therapy". Relevant articles including case series, retrospective studies, prospective studies, and review articles were reviewed and selected for this comprehensive narrative review. Key Content and Findings: This review included primarily revealed retrospective studies and a limited number of prospective phase II trials on induction therapy followed by surgery for stage III or IV locally advanced TETs. No randomized phase III studies were identified, indicating that a comprehensive evaluation of the benefits of induction therapy on overall survival (OS) has not yet been conducted. Induction therapies for both invasive thymoma and thymic cancer included chemotherapy, radiotherapy, and chemoradiotherapy, with anthracycline-based combination chemotherapies being the primary option. For exclusively invasive thymomas, the median rate of complete surgical resection and the 5-year OS rate were reported as 76% and 85%, respectively. Literature focusing on induction therapy for TETs, which includes both thymoma and thymic cancers, indicates that the rates of complete resection and 5-year OS are 76% and 70%, respectively. Conclusions: Our narrative review of retrospective and prospective studies highlighted promising long-term OS rates in patients with advanced TETs who underwent induction therapy followed by surgical resection. These findings support this multimodal treatment strategy in selected patients with stage III and IV TETs.

Postoperative radiotherapy for thymic epithelial tumors: a narrative review.

Background and Objective: Thymic epithelial tumors (TETs), including thymomas and thymic carcinomas, are rare mediastinal tumors. Surgical resection is the treatment strategy for resectable TETs, and postoperative radiotherapy (PORT) is administered to improve local control in patients with a high risk of recurrence. The rarity of TETs has led to a lack of randomized controlled trials, and the current indications for PORT rely largely on retrospective studies. This review analyzes the literature on TETs, highlighting PORT, to guide current research and future investigations. Methods: Studies that focused on TETs, addressed topics on PORT, and had English abstracts accessible online were eligible for inclusion in our review. We excluded case reports or review articles, articles written in languages other than English, articles published >30 years ago, and articles concerning thymic neuroendocrine tumors. Key Content and Findings: Masaoka or Masaoka-Koga staging, World Health Organization (WHO) histological subtype, and resection status indicate PORT in resected TETs. Current literature suggests that PORT does not improve overall survival in stage I-IIA TETs, with inconsistent results for stage IIB-III TETs. Patients with a higher risk, such as carcinomas or WHO type B, might benefit from PORT if they do not develop distant metastasis. Determining which patients will benefit most from PORT requires further investigation. For recurrent TETs, the significance of applying PORT is unclear because available data are limited. Given the long-term survival of TETs, late toxicities, including radiation pneumonitis, radiation-induced cardiotoxicities, and secondary malignancies, must be addressed. Proton beam radiotherapy might reduce toxicities by sparing organs at risk compared to conventional photon beam radiotherapy. The use of high-precision radiation therapy, along with emerging immunotherapy, targeted therapy, and minimally invasive surgery, could improve TET outcomes. Conclusions: This review consolidates the literature on PORT for TETs, factoring in the Masaoka-Koga staging, WHO histological subtypes, and resection status. Varying results regarding PORT efficacy have led to an undefined strategy for stage IIB-III TETs. Although advanced radiotherapy techniques promise to reduce radiation-induced toxicities, further research is needed to investigate the efficacy of PORT and combination therapy.

A case of a shrunken multilocular mediastinal cyst that developed into thymic carcinoma with lung metastases 13 years later.

Multilocular thymic cysts (MTC) are acquired multilocular cysts caused by inflammation. The rarity of such lesions and a lack of recognition make diagnosis and treatment difficult. Herein, we present our experience with a multilocular mediastinal cyst that resulted in the development of thymic cancer with metastasis over a period of 13 years. Computed tomography findings revealed an anterior mediastinal mass that was suspected to be an MTC in a 49-year-old man. The mass shrank gradually over a period of 7 years; however, growth was observed at 10 years after initial detection. At 13 years after detection, thymic carcinoma with multiple lung metastases was diagnosed. Resection was recommended during the follow-up period, but the patient refused treatment. A multilocular wall and location are factors that indicate MTC. However, even if a definitive diagnosis is not made, resection of multilocular anterior mediastinal cysts should be considered as determining the preoperative diagnosis is difficult. Nevertheless, our case suggests that the coexistence of tumors with cysts is possible, and the potential for malignant tumor development exists.

Characteristics and outcome of systemic treatment for metastatic or unresectable thymic carcinoma: A single institution experience.

BACKGROUND: Thymic carcinoma is a rare disease with an incidence of around 0.5 cases per million with a poor prognosis. The aim of this study was to assess patient outcomes with advanced thymic carcinoma receiving first-line chemotherapy. METHODS: In our retrospective cohort study, we included patients who underwent treatment for metastatic thymic carcinoma between January 2013 to December 2019 in our hospital. Overall survival, progression-free survival (PFS), objective response rates (ORR) and chemotherapy regimens were assessed and analyzed. RESULTS: A total of 27 patients were retrospectively analyzed. All patients received a platinum (cisplatin or carboplatin) based regimen as first-line chemotherapy (29.6% received ADOC, 11.1% received PE, 40.7% received CP, 14.8% received CAP). The median PFS on first-line chemotherapy was 199 days. The response rate was 40.7%. Median overall survival (OS) was 585 days. Positive CD5 staining was associated with better PFS. CONCLUSION: We highlight the critical role of platinum-based chemotherapy agents as a primary treatment modality in advanced thymic carcinoma, underscoring the efficacy of platinum as a first-line option for recurrent disease, even in cases previously treated with platinum. Additionally, our findings indicate that CD5 positivity could be associated with improved PFS, suggesting its potential as a prognostic marker.

Cine MR feature tracking analysis for diagnosing thymic epithelial tumors: a feasibility study.

BACKGROUND: To assess the feasibility of the cine MR feature tracking technique for the evaluation of cardiovascular-induced morphological deformation in the diagnosis of thymic epithelial tumors (TETs). METHODS: Our study population consisted of 43 patients with pathologically proven TETs including 10 low-grade thymomas, 23 high-grade thymomas, and 10 thymic carcinomas. Cine MR images were acquired using a balanced steady-state free precession sequence with short periods of breath-hold in the axial and oblique planes in the slice with the largest lesion cross-sectional area. The tumor margin was manually delineated in the diastolic phase and was automatically tracked for all other cardiac phases. The change rates of the long-to-short diameter ratio (∆LSR) and tumor area (∆area) associated with pulsation were compared between the three pathological groups using the Kruskal-Wallis H test and the Mann-Whitney U test. A receiver-operating characteristic (ROC) curve analysis was performed to assess the ability of each parameter to differentiate thymic carcinomas from thymomas. RESULTS: ∆LSR and ∆area were significantly different among the three groups in the axial plane (p = 0.028 and 0.006, respectively) and in the oblique plane (p = 0.034 and 0.043, respectively). ∆LSR and ∆area values were significantly lower in thymic carcinomas than in thymomas in the axial plane (for both, p = 0.012) and in the oblique plane (p = 0.015 and 0.011, respectively). The area under the ROC curves for ∆LSR and ∆area for the diagnosis of thymic carcinoma ranged from 0.755 to 0.764. CONCLUSIONS: Evaluation of morphological deformation using cine-MR feature tracking analysis can help diagnose histopathological subtypes of TETs and identify thymic carcinomas preoperatively.

Two Cases of Thymic Cancer in Patients with Lynch Syndrome.

We herein report two cases of thymic cancer with Lynch syndrome showing a high frequency of microsatellite instability and loss of mismatch repair protein expression without MLH1 promoter hyper-methylation. In Case 1, a 71-year-old man had a pathogenic germline variant in MLH1 and underwent tumor resection. No relapse has been reported thus far. In Case 2, a 43-year-old man underwent genetic testing that also showed a pathogenic germline variant in MLH1. Since these two cases had MLH variants, we suspect a possible association between thymic cancer with Lynch syndrome and germline pathogenic variants in MLH1.

Epidemiology of thymomas and thymic carcinomas in the United States and Germany, 1999-2019.

Introduction: Mediastinal tumors, particularly non-neuroendocrine thymic epithelial tumors (TET) are relatively uncommon, posing challenges for extensive epidemiological studies. This study presents a comprehensive analysis of these tumors in the United States (US) and Germany (GER) from 1999 to 2019. Methods: Patients aged 0-19 (n=478) and ≥20 years (n=17,459) diagnosed with malignant tumors of the anterior mediastinum were identified from the Surveillance, Epidemiology, and End Results registry (SEER) and the Zentrum für Krebsregisterdaten (ZfKD) databases. Results: Among patients aged ≥20 years, TETs accounted for the most prevalent anterior mediastinal tumors (US/GER: 63%/64%), followed by lymphomas (14%/8%). For patients <20 years, predominant tumors included germ cell tumors (42%/14%), lymphomas (38%/53%), and TETs (10%/27%). The overall annual incidence of thymoma was 2.2/2.64 (US/GER) per million inhabitants and for thymic carcinomas 0.48/0.42. The male-to-female ratio was 1:1.09/1.03, and the mean age 59.48 ± 14.89/61.33 ± 13.94. Individuals with thymomas, but not thymic carcinomas, exhibited a 21%/29% significantly heightened risk of developing secondary malignancies compared to controls with non-thymic primary tumors. Discussion: This study provides a comparative analysis of anterior mediastinal tumors, particularly TETs, in the US and GER over the past two decades. Furthermore, it highlights a significantly elevated incidence of secondary malignancies in thymoma patients.

Successful Diagnosis of Epithelial Thymic Cancer Case Using EBUS-TBNA.

Mediastinal masses are relatively uncommon. Surgical approach is often needed to diagnose mediastinal masses. Using endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) toward approaching a mediastinal mass has yet to be established. Here, we present a case of successful diagnosis of thymic cancer with the use of EBUS-TBNA.

Factors predicting recurrence in thymic epithelial neoplasms.

OBJECTIVES: Thymic epithelial neoplasms (TENs) represent a heterogeneous group of rare thoracic malignancies. We analysed the clinicopathological features, survival outcomes, risk factors, and patterns of recurrence in patients undergoing resection. METHODS: Records were reviewed for adult patients with TEN who underwent resection from 2006 to 2019. Survival rates were assessed using the Kaplan-Meier method. Univariable and multivariable analyses were performed using the log-rank test and Cox proportional hazards model. RESULTS: A total of 100 patients were analysed (51 females, median age 58 years). Thymoma was the most common histology (n = 92), followed by thymic carcinoma (n = 5) and thymic neuroendocrine tumour (n = 3). Stage II (Masaoka) tumours were most common (n = 51), followed by stage I (n = 27). World Health Organization B2/B3 was the most prominent histological subtype (n = 34). Complete resection (R0) was achieved in 91 patients: 86/92 thymoma, 4/5 thymic carcinoma and 1/3 neuroendocrine tumour. The most common treatment modality was surgery alone in 72 patients, followed by surgery and radiation therapy in 24, and adjuvant chemoradiotherapy in 3 patients. Only one patient with thymic carcinoma received neoadjuvant chemotherapy. The 10-year overall and disease-free survival rates were 86.6% and 83.9%, respectively. Recurrence was most common in neuroendocrine tumours (3/3). Risk factors for recurrence identified on multivariable analyses were: R1/2 resection (hazard ratio 9.30; 95% confidence interval 1.82-36.1), TEN subtype (hazard ratio 8.08; 95% confidence interval 1.24-34.6), and presence of lymphovascular invasion (hazard ratio 9.56; 95% confidence interval 2.56-25.8). CONCLUSIONS: Complete resection remains critical in patients with TEN. Incomplete resection, high-risk histology, and lymphovascular invasion highlight the need for effective adjuvant modalities. Given the rarity of these diseases, emphasis must be placed on collaborative research conducted on TEN.

Paraneoplastic Neuromyelitis Optica Spectrum Disorder Associated with Atypical Thymic Carcinoid: A Case Report.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease, occasionally accompanied by malignant tumors. Immunosuppressive therapy is the mainstay treatment for idiopathic NMOSD; no guidelines have been published for paraneoplastic NMOSD because it is rarely reported in the literature. We report a rare case of a 67-year-old man with paraneoplastic NMOSD associated with thymic carcinoid whose cells expressed aquaporin-4 antibody. After surgical resection, the patient's symptoms improved, and serum aquaporin-4 autoantibody turned negative. We believe that radiographic examination for mediastinal tumors in patients with NMOSD is necessary because thymic epithelial tumors could have a role in the pathogenesis of paraneoplastic NMOSD. After mediastinal tumor has been detected, they should be surgically resected to improve neurological symptoms.

Arginase Pathway Markers of Immune-Microenvironment in Thymic Epithelial Tumors and Small Cell Lung Cancer.

BACKGROUND: Key regulators of antitumor immunity such as arginase-1 and the adenosine pathway may have an important role in modulating the effect of immunotherapy. Here, we investigated the expression profile of these immune-related biomarkers in thymic epithelial tumors (TETs) and small cell lung cancer (SCLC), 2 solid tumors where immune checkpoint inhibitors have activity. MATERIALS AND METHODS: Immunohistochemical staining was performed using tissue microarrays of 123 TET (110 thymoma and 13 thymic carcinoma) and 125 SCLC cases. The expression profile of the following immune-related biomarkers was assessed: arginase-1, CD39, CD73, A2AR, PD-L2, and CD15. The expression profile was also correlated with clinical data. RESULTS: No sample was positive for arginase-1. In the adenosine pathway, the prevalence of positive staining for CD39, CD73, and A2AR was 4.9%, 2.5%, and 69.2%, in TETs and 0%, 1.7%, and 50.8%, in SCLC. The multivariate analysis showed that CD39 expression was significantly associated with worse disease related survival (hazard ratio [HR], 10.36; 95% confidence interval [CI]: 2.01-53.47; P= .005) and a shorter time-to progression (HR, 11.35; 95% CI, 2.11-61.23; P = .005) in TETs. Other biomarkers were not associated with disease related survival or time to progression in TETs. No biomarker was associated with survival in SCLC. CONCLUSION: Arginase-1 was not detectable in TETs and SCLC. Expression of markers in the adenosine pathway were present in both TETs and SCLC. CD39 expression in tumor cells may identify subsets of patients with TETs with an unfavorable prognosis.

Thymic Lymphoepithelial Carcinoma Associated with Epstein-Barr Virus: Experiences and Literature Review.

Thymic lymphoepithelial carcinoma (TLEC) is a primary thymic carcinoma that accounts for about 14% of all thymic epithelial tumors and is classified into 14 types. The histological morphology is similar to lymphoepithelioma, a type of undifferentiated nasopharyngeal carcinoma. It has been reported that squamous carcinoma accounts for approximately 80% of thymic carcinoma, followed by TLEC, which accounts for 6%. TLEC has been reported to be associated with Epstein-Barr virus (EBV), with EBV infection in TLEC tumor cells first noted by Lyvraz et al. in 1985. Tumors shown to be EBV-positive are classified as TLEC if lymphoplasmacytic infiltration is lacking. However, only about 50% of the cases are positive for EBV, which is lower compared to nasopharyngeal lymphoepithelioma. Instances of EBV infection in other types of thymic epithelial tumor have been reported at lower rates, which suggests that EBV infection may have an important influence on the carcinogenesis of TLEC, though the etiology is unknown. TLEC is a highly malignant tumor with poor prognosis, as affected patients have a median survival time of 22 months, according to 58 cases from the literature, while the 5-year survival rate is 34.4%. Presently, prognosis is not considered to be affected by the presence or absence of EBV positivity.

Thymic cancer: A not-so-indolent cause of pericardial effusion.

The incidence of pericardial effusion in the U.S. is roughly 3.4% [1]. While most causes of pericardial effusions are indolent and transient, malignancy is a much more insidious cause that cannot be overlooked. Most cases of documented pericardial effusion secondary to malignancy have been due to mass effect from benign thymic tumors, such as thymomas. Our case highlights a 41-year-old male who presented with a dry cough and epigastric pain, found to have a large pericardial effusion and incidental thymic mass. The mass was biopsied and found to be keratinizing squamous cell carcinoma. This case expands our knowledge base as clinicians that pericardial effusions can be caused by malignant extension of tumors, rather than simply by mass effect of benign tumors.

si-MALAT1 attenuates thymic cancer cell proliferation and promotes apoptosis via the miR-145-5p/HMGA2 pathway.

Metastasis-associated-lung-adenocarcinoma-transcript-1 (MALAT1) is a long non-coding RNA that is considered a potential tumor marker. The present study aimed to investigate the effect and mechanism of MALAT1 on cell proliferation and apoptosis in thymic cancer cells. IU-TAB-1, A549, HCT-116 and 293T cells were screened by reverse transcription-quantitative PCR to assess high-mobility group AT-hook 2 (HMGA2) expression in various types of cancer cells and were transfected with small interfering (si)RNA targeting MALAT1 (si-MALAT1). Cell proliferation was evaluated by Cell Counting Kit-8 assay. Cell apoptosis and cell cycle were examined using flow cytometry. The protein expression of cyclin D1, cyclin E, Bax, Bcl-2 and HMGA2 was determined by western blot analysis, while the associations between MALAT1 and microRNA (miR)-145-5p and between HMGA2 and miR-145-5p were determined by luciferase reporter assay. Among the four cell lines evaluated, IU-TAB-1 showed the highest expression of MALAT1; thus, IU-TAB-1 cells were selected for subsequent experiments. Compared with the findings in the control group, si-MALAT1 significantly decreased the cell proliferation of IU-TAB-1 cells, whereas the apoptosis levels and number of cells in G2 phase were increased. The protein expression levels of cyclin D1, cyclin E, Bcl-2 and HMGA2 were significantly decreased in the si-MALAT1 group compared with those in the control group, while Bax levels were significantly increased. After treatment with si-MALAT1 in combination with miR-145-5p mimics or inhibitors, cell proliferation and apoptosis were respectively enhanced and inhibited in IU-TAB-1 cells. miR-145-5p inhibited the luciferase activity of IU-TAB-1 cells transfected with the MALAT1 or HMGA2 3' untranslated region. In conclusion, si-MALAT1 significantly attenuated cell proliferation and apoptosis via the miR-145-5p/HMGA2 pathway in thymic cancer cells.

Small interfering-high mobility group A2 attenuates epithelial-mesenchymal transition in thymic cancer cells via the Wnt/ß-catenin pathway.

Thymus carcinoma is one of the thymic epithelial neoplasms with high metastasis, which does not have any good treatment at present. High mobility group A2 (HMGA2) is highly expressed in a variety of malignant tumors, such as lung cancer, colon cancer and ovarian cancer and is closely related to tumor invasion and metastasis. The present study aimed to investigate the effect and mechanism of HMGA2 on epithelial-mesenchymal transition (EMT) in thymic cancer cells. IU-TAB-1, A549, HCT-116 and 293T cells were screened by testing the protein expression level of HMGA2 though western blotting and subjected to HMGA2 interference [small interfering (si)-HMGA2]. Cell proliferation was evaluated using the Cell Counting Kit-8 assay. Cell migration and invasion were detected using the Transwell assay. Cell apoptosis was examined using flow cytometry and ß-catenin expression was observed by immunofluorescence. The levels of E-cadherin, vimentin, Wnt3a, Wnt5a and ß-catenin proteins were determined by western blotting. Among the four cell lines tested, IU-TAB-1 cells demonstrated the highest expression of HMGA2 (P<0.05) and were hence selected for subsequent experiments. Compared with the control group (untransfected cells), si-HMGA2 resulted in significantly decreased proliferation, migration and invasion of IU-TAB-1 cells, whereas apoptosis was increased (P<0.05). The protein expression of vimentin, Wnt3a, Wnt5a and ß-catenin was significantly decreased by si-HMGA2 compared with the control group (P<0.05), whereas E-cadherin expression was increased (P<0.05). After treatment with si-HMGA2 in combination with Wnt/ß-catenin agonists (SKL2001) or inhibitors (XAV-939), EMT was respectively enhanced or inhibited in IU-TAB-1 cells. Overall, si-HMGA2 may attenuate EMT in thymic cancer cells and the mechanism may be related to the Wnt/ß-catenin pathway.

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.

Thymic carcinoma with Lynch syndrome or microsatellite instability, a rare entity responsive to immunotherapy.

IMPORTANCE: Thymic carcinoma (TC) is a rare aggressive tumour occurring in adults characterised by one of the lowest tumor mutational burdens (TMB). Microsatellite instability (MSI) is a mutational signature, caused by defects in the DNA MisMatch Repair (MMR) system, that predicts benefit from immunotherapy and causes high TMB. Fragmentary and unstructured evidence of these conditions co-occurring are reported in literature. OBJECTIVE: Review available data on the co-occurrence of these two conditions and determine its frequency in our institute case series. DESIGN: We performed a systematic analysis of literature and a retrospective evaluation of all the cases of TET treated at our institution from 2000 to 2020, selecting patients with a medical history of multiple tumours to enhance a priori probability of identifying cases with underlying predisposition. RESULTS: Literature yielded 3 cases of patients with MSI TC, for which MMR gene alteration was reported. None of them received immunotherapy. Of 366 patients with TETs treated in our institute, 32 had a medical history of multiple tumours and 25 of 32 (19 thymomas and 6 TCs) had available tissue for MMR analysis. One patient with TC showed a high TMB, and MSI due to MLH1 mutation and was treated in a phase II study with avelumab and axitinib combination obtaining a long-lasting partial response. MLH1 alterations are shared across MSI TC cases. CONCLUSIONS AND RELEVANCE: This analysis highlights the usefulness of MSI testing in patients with TC. The observation of cases of TC occurring in patients with Lynch syndrome and the unexpected homogeneity of gene alterations support further investigation.

Radiotherapy for thymic epithelial tumours: a review.

Thymic epithelial tumours (TETs) represent a rare disease, yet they are the most common tumours of the anterior mediastinum. Due to the rare occurrence of TETs, evidence on optimal treatment is limited. Surgery is the treatment of choice in the management of TETs, while the role of postoperative radiotherapy (PORT) remains unresolved. PORT remains debated for thymomas, especially in completely resected stage II tumours, for which PORT may be more likely to benefit in the presence of aggressive histology (WHO subtype B2, B3) or extensive transcapsular invasion (Masaoka-Koga stage IIB). For stage III thymoma, evidence suggests an overall survival (OS) benefit for PORT after complete resection. For incompletely resected thymomas stage II or higher PORT is recommended. Thymic carcinomas at any stage with positive resection margins should be offered PORT. Radiotherapy plays an important role in the management of unresectable locally advanced TETs. Induction therapy (chemotherapy or chemoradiation) followed by surgery may be useful for locally advanced thymic malignancies initially considered as unresectable. Chemotherapy only is offered in patients with unresectable, metastatic tumours in palliative intent, checkpoint inhibitors may be promising for refractory diseases. Due to the lack of high-level evidence and the importance of a multidisciplinary approach, TETs should be discussed within a multidisciplinary team and the final recommendation should reflect individual patient preferences.