Long-term outcomes following surgical treatment for thymic epithelial tumor in Japan and an analysis of prognostic factors based on the Japanese Association for Research on the Thymus nationwide database.

PURPOSE: Patients with a thymic epithelial tumor (TET), comprising thymoma, thymic carcinoma (TC), and thymic neuroendocrine neoplasm (TNEN), are rarely encountered. The present study was conducted to determine the recent outcomes of surgical treatment for TET in Japan and clarify the significance of prognostic factors by analyzing a nationwide database created by the Japanese Association for Research on the Thymus (JART). METHODS: The JART database includes records of 2471 thymoma, 285 TC, and 56 TNEN cases surgically treated between 1991 and 2010. At the time of the final follow-up examination, 439 patients had died, with tumor the cause of death in 188. The disease-specific survival was examined using the Kaplan-Meier method, with Cox's proportional hazards model utilized to determine independent prognostic factors. RESULTS: The 10-year survival rate according to TNM-based Stage I, II, IIIA, IIIB, IVA, and IVB classification was 98.7%, 76.8%, 85.0%, 68.9%, 66.2%, and 59.8%, respectively. The T factor, M factor, and tumor size were independent prognostic factors in both thymoma and thymic carcinoma cases, while the N factor had tendency to be a prognostic factor in thymoma but not in thymic carcinoma cases. The WHO histological type was an independent factor in thymoma cases. CONCLUSION: The significance of pathology and TNM classification as prognostic factors was confirmed.

Prognostic factors for survival in advanced thymomas: The role of the number of involved structures.

BACKGROUND AND OBJECTIVES: The Masoka-Koga and tumor node metastases staging systems for thymoma are based on structures involved, but the prognostic role of the number of infiltrated/involved structures is still debated. We analyzed the prognostic role of involved structures and their combinations in locally advanced thymomas patients. METHODS: Data on 174 surgically treated locally advanced thymoma patients from 1/01/1990 to 31/12/2015 were reviewed. Clinical and pathological characteristic, involved structures, number of involved structures and different combinations were correlated to cancer specific survival (CSS) using Kaplan-Meier product-limit method. RESULTS: Five and 10-year CSS was 92% and 87%. Masaoka Stage 3 (p < 0.001), absence of pericardial involvement (p = 0.001), number of involved structures (p = 0.018), R0 (p < 0.001) and adjuvant radiotherapy (p = 0.008) were favorable prognostic CSS factors. A significant better prognosis was present in ≤2 involved structures vs >2 involved structures (5- and 10-year CSS: 95% and 93% vs. 80% and 51%). Multivariable analysis confirmed as independent prognostic factor R0 (p = 0.033, hazard ratio [HR]: 0.093, 95% confidence interval [CI] 0.010-0.827) and number of involved structures (p = 0.046, HR: 0.187, 95% CI: 0.036-0.968). In Masaoka Stage 3, patients with ≤2 involved structures had a significant better CSS than patients with >2 (10-year CSS: 98% vs. 73%, p = 0.008). CONCLUSIONS: The number of involved structures and the concomitant involvement of the pericardium seems to be associated with a poor prognosis in surgically treated advanced thymoma patients.

LOXL1­AS1 promotes thymoma and thymic carcinoma progression by regulating miR­525­5p­HSPA9.

Due to the lack of specific symptoms in early thymic epithelial tumours (TETs), patients are mostly in the advanced stage at the time of presentation. The aim of the present study was to explore the mechanism by which the long noncoding RNA (lncRNA) LOXL1­AS1 affects thymoma and thymic carcinoma progression by targeting the miR­525­5p­HSPA9 axis. Bioinformatics was used to analyse the process of LOXL1­AS1 targeting miR­525­5p­HSPA9 and its expression characteristics in TET. The relationships between LOXL1­AS1, miR­525­5p, HSPA9 and prognosis were analysed. The dual luciferase reporter assay was applied to verify targeting. The gene was knocked down or overexpressed by plasmid transfection. Cell counting kit 8 (CCK­8) assay, flow cytometry and Transwell assay were used to detect cell viability, apoptosis and invasion ability, respectively. Proteins and RNAs were examined by western blot analysis and qPCR, respectively. A tumour­burdened assay was used to perform in vivo verification. LOXL1­AS1 and HSPA9 were overexpressed in thymoma and thymic carcinoma; high levels of LOXL1­AS1 and HSPA9 were associated with poor prognosis, and there was a significant positive correlation between their levels. Downregulation of miR­525­5p expression was also associated with poor prognosis of patients. Clinical trials also demonstrated the same trends. miR­525­5p inhibited the expression of HSPA9 protein by targeting the 3'­untranslated region (UTR) of HSPA9 mRNA. LOXL1­AS1 promoted the expression of HSPA9 as a sponge targeting miR­525­5p. Animal experiment results also showed that knockdown of miR­525­5p promoted cancer by promoting the expression of HSPA9. In conclusion, LOXL1­AS1 and HSPA9 are highly expressed in thymoma and thymic carcinoma; miR­525­5p is expressed at low levels in thymoma and thymic carcinoma; and downregulation of miR­525­5p is associated with poor prognosis. In summary, this study demonstrates that LOXL1­AS1 acts as a sponge that targets miR­525­5p to promote HSPA9 expression, thereby promoting the growth and invasion and inhibiting apoptosis of thymoma and thymic carcinoma cells.

The safety and efficacy of Cyberknife® for thymic malignancy.

PURPOSE: To evaluate the safety and efficacy of Cyberknife® (CK) for the treatment of primary or recurring thymic tumours. MATERIALS AND METHODS: We retrospectively reviewed 12 patients (16 tumour lesions) with primary or recurring thymic tumours who were treated with CK between March 2008 and October 2017. Their data was stored in prospectively collected database. Kaplan-Meier method was used to calculate survival curves. RESULTS: Five patients (41.7%), who had inoperable disease or refused surgery, were treated with CK initially, and 7 patients (58.3%) were treated with CK when they had recurrence diseases. The disease sites treated with CK were primary tumour site (5), regional lymph nodes (4), tumour bed (3), chest wall (2), pleura (1), and bone (1). The median target volume was 43.8 cm3 (range, 13.1-302.5cm3) for the 16 tumour lesions. The median follow-up time was 69.3 months (range, 9.7-124.8 months). The median survival time was 48.2 months, and the 5-year and 10-year OS rates were 68.2% and 45.5%, respectively. A high response rate for the tumour lesions irradiated with CK was obtained. Only one patient (8%) experienced in-field recurrence, and the 5-year local recurrence free survival was 90.9%. A case indicated that CK may induce the abscopal effect, which provides the potential to combine CK and immunotherapy. No severe radiation related toxicities were observed, and no treatment related death occurred. CONCLUSION: CK treatment resulted in good outcomes, particularly local control, with minimal side effects, in highly selected patients with primary and recurring thymic tumours. More studies with larger sample are needed.

Identification of differentially expressed circular RNAs associated with thymoma.

BACKGROUND: Thymomas and thymic carcinomas are the most common tumor types among anterior mediastinal lesions. However, the relationship between molecular aberrations and thymoma patients are poorly understood, especially abnormal changes in the expression profiles of circRNAs. The purpose of the present study was to investigate the expression profiles of circRNAs in thymoma patients and their possible roles in the pathogenesis of thymoma. METHODS: Diseased tissues and surrounding normal thymic tissues in two thymoma patients were collected for circRNA sequencing. The top four upregulated circRNAs were selected as candidates and further validated with RT-PCR in 20 thymoma patients. Gene ontology and signal transduction network analyses of circRNA-related mRNAs were performed to analyze the functional properties. Survival analysis of their parental genes were also carried out to evaluate the clinical value of differentially expressed circRNA. RESULTS: A total of 73 circRNAs were differentially expressed in thymoma tissues using high-throughput sequencing. Among these circRNAs, hsa_circ_0001173, hsa_circ_0007291, hsa_circ_0003550, and hsa_circ_0001947 were significantly upregulated in thymoma tissues compared with normal thymic tissues. We identified that these four circRNA-related mRNAs were involved in cell-cell adhesion, MAPK pathways, and TNF pathway, which may contribute to the pathological immune disorder in thymoma. Finally, we also found that SCAP (hsa_circ_0007291 parental gene) and AFF2 (hsa_circ_0001947 parental gene) were all significantly related with progression-free survival (PFS) of thymoma patients in a Kaplan-Meier plot (p-value <0.05). CONCLUSIONS: The expression levels of hsa_circ_0001173, hsa_circ_0007291, hsa_circ_0003550, and hsa_circ_0001947 were significantly upregulated and positively correlated with immune imbalance in thymoma patients.

Primary thymus tumors: retrospective case analysis at a reference center in Latin America, 2011-2019.

BACKGROUND: Thymic tumors are unusual neoplasms, representing 0.2 to 1.5% of tumors in humans, but correspond to 20% of mediastinal tumors and 50% of those that occur in the anterior mediastinum. They tend to appear around the fourth and fifth decades of life without gender predilection. Up to 30% of patients are asymptomatic, therefore many are incidentally diagnosed. Radical thymectomy is the treatment of choice with high survival rates when detected in the early stages. METHODS: This was a retrospective descriptive study, including 18 adult patients' diagnosis of thymic neoplasm, who were managed with surgical resection from 2011 to 2019. Information about demographics, clinical characteristics, imaging findings, surgical and medical management, plus histological findings was obtained and reported. RESULTS: 18 patients with thymic tumors were included, of which specific histologic studies reveled thymomas, carcinomas, neuroendocrine tumors, thymolipoma and thymic cyst. Mean age was 52.7 years, with a predominance of male population. The main symptom was dyspnea, followed by cough and chest pain. Paraneoplastic syndromes such as myasthenia gravis, aplastic anemia and Cushing syndrome were reported. 89% of cases were treated by radical thymectomy alone, while only 2 cases required chemotherapy and radiotherapy. There were no surgical complications. Mean hospital stay length was 11. 9 days, with only 1 mortality during hospital admission. 5-year survival rate was 81%. CONCLUSIONS: The treatment of choice is radical thymectomy, which has been shown to positively impact patient mortality. Early detection is key to improve patient outcomes.

Mutation Profile of Thymic Carcinoma and Thymic Neuroendocrine Tumor by Targeted Next-generation Sequencing.

BACKGROUND: Thymic carcinoma is a rare mediastinal neoplasm, and little is known about its genetic variability, which has hampered the development of targeted therapies. PATIENTS AND METHODS: We tested a next-generation sequencing panel containing 50 common cancer-related genes in 48 cases of thymic carcinoma and 6 cases of thymic neuroendocrine tumor. RESULTS: We detected 42 variant calls in 21 of 54 cases. There was no significant difference in mutation frequency between thymic carcinoma and thymic neuroendocrine tumors. Among these, TP53 was the most frequently mutated gene (18.5%), followed by KIT (7.4%) and PDGFRA (5.6%). According to the gene pathways and groups, the p53 pathway, including TP53 and ATM, was most frequently affected (20.4%), followed by the receptor tyrosine kinase (RTK)/RAS pathway (18.5%) and PI3K pathway (5.6%). According to the OncoKB, an expert-guided precision oncology knowledge base, 7 genes among 10 cases (18.5%) were annotated with level 1 evidence, suggesting potentially therapeutic targets. Prognostic analyses, conducted in thymic squamous cell carcinomas, revealed that tumor cases harboring gene mutations in RTKs, including KIT (7.4%), PDGFRA (5.6%) and EGFR (3.7%), were significantly associated with a worse overall survival time (P = .0481). Among clinicopathologic factors, the advanced Masaoka stage was marginally associated with a worse overall survival (P = .0757). In the subsequent multivariate analysis, neither of the factors achieved statistical significance. CONCLUSIONS: In this preliminary next-generation sequencing study, we unexpectedly found evidence suggesting that several gene mutations might be therapeutic targets. The gene mutations in RTKs may be a valuable prognostic factor in thymic squamous cell carcinoma.

Prosthetic Reconstruction of Superior Vena Cava System for Thymic Tumor: A Retrospective Analysis of 22 Cases.

OBJECTIVE: This study aimed to report our experience in superior vena cava (SVC) resection and reconstruction for 22 thymic tumor patients and to make comparisons with previous related reports. METHODS: A retrospective study on 22 patients (15 thymomas, 7 thymic cancers) who underwent tumor resection with concomitant SVC reconstruction. All the patients underwent vascular conduit reconstruction by the cross-clamping technique. The corresponding data were reviewed, including clinical presentation, operation management (surgery procedure, selection of suitable graft, strategies against SVC syndrome, etc.), postoperative cares (antithrombotic agent application, treatments on brain edema, etc.), and follow-up information. RESULT: Two patients were myasthenic, well controlled by oral pyridostigmine. All resections were radical (R0). Ten patients received induction treatment. All the 15 thymoma patients were Masaoka stage III (type B1-B3). As for thymic cancer, six patients were Masaoka stage III and one was stage IVa. Wedge pulmonary resection was performed in three patients (two right upper lobe, one both upper lobe). Procedures included were single graft replacement in 12 patients, bilateral grafts in 9, and Y-shaped graft in 1 patient. Anticoagulation and dehydration agents were routinely applied after operation. No perioperative mortalities were observed. Major complication rate was 9.1%. The median survival time was 44.2 months (range, 4-92 months). Three- and 5-year overall survival rates were 80.8 and 44.0%, respectively. As for conduit patency, two grafts (9.1%) demonstrated evidence of occlusion during long-term follow-up, but no additional interventions were required due to no complications related. CONCLUSION: Our study, confirming data from existing literature, showed that the prosthetic reconstruction of the SVC system is a feasible additional procedure during resection of thymic tumor infiltrating the venous mediastinal axis, minimally increasing postoperative complications in experienced hands.

Different View on Tumor Size Dilemma in Tumor-Node-Metastasis Staging System for Thymoma.

BACKGROUND: Although tumor size is included in the definition of T descriptor in the tumor-node-metastasis (TNM) classification of many solid tumors, it is not considered for thymomas. This study aimed to assess the relationship of tumor diameters (the largest tumor diameter [LTD] and the mean tumor diameter [MTD]) with survival in thymoma patients undergoing surgical resection in a single center. METHODS: The study included 127 thymoma patients (age, 49.2 ± 15.2 years; 65 males), who were evaluated based on pathological tumor sizes according to the LTD and MTD ([largest diameter + shortest diameter] / 2) and divided into three subgroups for each parameter as: patients with an LTD of ≤5 cm, 5.1 to 10 cm, and >10 cm and patients with an MTD of ≤5, 5.1 to 10, and >10 cm. RESULTS: In thymoma patients, survival significantly differed according to the presence of myasthenia gravis (p = 0.018), resection status (R0 or R1; p = 0.001), T status (p = 0.015), and the Masaoka-Koga stage (p = 0.003). In the LTD subgroups, the overall survival of those with R0 resection was lower in those with an LTD of 5.1 to 10 cm than in those with an LTD of ≤5 cm (p = 0.051) and significantly lower in those with an MTD of 5.1 to 10 cm than in those with an MTD of ≤5 cm (p = 0.027). In the MTD subgroups, survival decreased as the tumor size increased. CONCLUSION: Both smaller tumor size and complete resection are associated with better survival in thymoma patients. Therefore, the largest or the mean tumor size might be considered as a criterion in the TNM staging for thymoma.

Comparison of Subxiphoid and Intercostal Uniportal Thoracoscopic Thymectomy for Nonmyasthenic Early-Stage Thymoma: A Retrospective Single-Center Propensity-Score Matching Analysis.

OBJECTIVE: The aim of this study was to compare early outcome between intercostal uniportal video-assisted thoracoscopic surgery (IU-VATS) versus subxiphoid uniportal video-assisted thoracoscopic surgery (SU-VATS) in thymectomy for non-myasthenic early-stage thymoma. METHOD: Retrospective analysis of 76 cases completed in our hospital from May 2018 to September 2019 with subxiphoid uniportal thoracoscopic thymectomy; a single incision of ∼3 cm was made ∼1 cm under the xiphoid process. The control group included 213 patients who received intercostal uniportal thoracoscopic thymectomy from August 2015, and propensity score matching was conducted. All patients who were clinically diagnosed with thymic tumor before surgery were treated with thymectomy. Perioperative outcomes between SU-VATS (n = 76) and IU-VATS, n = 76 were compared. RESULT: After propensity score matching, there were no statistically significant differences between the two groups in terms of age, gender, disease stage, maximal tumor size, or other baseline demographic and clinical variables. All operation was successfully completed; there were no significant differences in the operative time (88 vs. 81 minutes, p = 0.63), intraoperative blood loss (55 vs. 46 mL, p = 0.47), postoperative drainage time (2.2 vs. 2.5 days, p = 0.72), and postoperative hospital stay (3.2 vs. 3.4 days, p = 0.78) between the two groups. The visual analog scale (VAS) on postoperative days 1, 3, 7, and 30 was less in the SU-VATS group than that in the IU-VATS group. The VAS on days 60 and 180 did not differ significantly between the two groups. CONCLUSION: Thymectomy using SU-VATS is a feasible procedure; it might reduce early postoperative pain and lead to faster recovery.

Pathological and clinical features of enteric adenocarcinoma of the thymus. A pooled analysis of cases from a reference center and systematic review of the literature.

BACKGROUND: Primary enteric adenocarcinoma of the thymus (EAT) is a recently proposed rare subtype of thymic carcinoma. Unlike thymic carcinomas with squamous histology, for which clinical guidelines are available, little knowledge is available regarding the clinical and pathological features of EAT, and there is no consensus on the best treatment algorithm for such tumors. METHODS: We performed a systematic review of the literature, searching for all cases of EAT reported. We also retrospectively reviewed all cases of EAT treated at the European Institute of Oncology (IEO) between January 2000 and January 2020. Individual patient data were extracted and analyzed in order to delineate clinical and pathological features, as well as patients' prognosis and treatments outcome, evaluated in terms of Disease free Survival (DFS), Progression free survival (PFS) and overall survival (OS). RESULTS: Thirty-three cases (29 reported in literature and 4 new cases treated at IEO) of thymic adenocarcinoma deploying enteric differentiation as defined by WHO-criteria were analyzed. All tumors showed positive immunoreactivity for cytokeratin (CK) 20 and/or caudal type homeobox 2 (CDX2). Data on molecular profiling by next-generation sequencing were available in only 3 cases, and did not show actionable findings. At diagnosis, 11 pts had an early-stage (Masaoka I-II) and 22 a locally advanced (10 pts) or metastatic (12 pts) disease. Median-DFS of patients with localized disease was 12 months (95% CI, 7-19). Patients who received systemic chemotherapy were mostly treated with regimens commonly used for thymic epithelial tumors, with a discouraging PFS of 3-5 months for patients with stage IV disease. Median OS of the whole population was 34 months (95% CI, 24-NA:. mOS was not reached for patients with stage I-II disease versus 34 months in stage III-IV (p < 0.05). CONCLUSION: Available evidence suggests that EAT represents a distinct entity in the context of thymic epithelial tumors, characterized by aggressive clinical behavior, poor responsiveness to chemotherapy and dismal patients prognosis. More research is needed to better define optimal management strategies for patients with such rare disease.

The treatment and survival of patients with postoperative recurrent thymic carcinoma and neuroendocrine carcinoma: a multicenter retrospective study.

PURPOSE: There are few data available on the outcomes of postoperative recurrent thymic carcinoma (TC) and thymic neuroendocrine carcinoma (TNEC). The aim of this study is to evaluate the treatment and survival in patients with recurrent TC and TNEC after undergoing surgical resection. METHODS: A retrospective chart review was performed using our multicenter database to identify patients with a postoperative recurrence of TC and TNEC from 1995 to 2018. The clinicopathological factors were reviewed and the survival outcomes were analyzed. RESULTS: Sixty patients were identified among 152 patients who underwent resection of TC and TNEC. The median follow-up period from the first recurrence was 14.8 months (range 0-144). The 5-year post-recurrence survival was 23% for the whole cohort. According to a univariable analysis, advanced stage [hazard ratio (HR) 2.81, 95% confidence interval (CI) 1.09-9.54], interval between primary surgery and recurrence (HR 0.97, 95% CI 0.95-0.99), any treatment for recurrence (HR: 0.27, 95% CI 0.13-0.58) and chemotherapy for recurrence (HR: 0.46, 95% CI 0.22-0.95) were significant factors related to post-recurrence survival. CONCLUSIONS: Chemotherapy rather than surgery appears to be the mainstay treatment for managing patients with postoperative recurrent TC and TNEC and it may also be considered in multidisciplinary management. Further studies with a larger sample size are required to confirm our findings.

Expression Patterns and Prognostic Values of ORMDL1 in Different Cancers.

The mammalian orosomucoid-like gene family (ORMDL), containing ORMDL1, ORMDL2, and ORMDL3, is the important regulator of sphingolipid metabolism, which is relevant to cell growth, proliferation, migration, and invasion. Since the role of ORMDL1 in cancers remained unclear, the main purpose of our study was to explore the expression patterns and prognostic values of ORMDL1 in different tumors, especially in cholangiocarcinoma (CHOL), lymphoid neoplasm diffuse large B cell lymphoma (DLBCL), acute myeloid leukemia (LAML), and thymoma (THYM). Bioinformatics tools including GEPIA, CCLE, LinkedOmics, cBioPortal, and TIMER databases were used. As a result, the expression levels of ORMDL1 in tumor tissues and normal tissues varied in different cancers, especially significantly upregulated in CHOL, DLBCL, LAML, and THYM. Moreover, ORMDL1 mRNA was also highly expressed in cell lines of DLBCL and LAML. Further studies showed that ORMDL1 overexpression was associated with poor prognosis in DLBCL, but not significant in CHOL, LAML, and THYM. Consistently, there were genetic alterations of ORMDL1 in DLBCL, and patients with genetic alterations indicated worse survival. Coexpressed genes and related biological events with ORMDL1 in DLBCL were found via LinkedOmics, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The relationship between ORMDL1 and cancer immune cells was investigated, and ORMDL1 expression was positively correlated with infiltrating levels of B cells. In conclusion, ORMDL1 is suggested to be a tumorigenic factor and considered as the potential therapeutic target and prognostic biomarker in DLBCL.

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

OBJECTIVES: We examine the therapeutic efficacy of extended thymectomy with blood vessel resection and reconstruction in thymic carcinoma patients with great vessel invasion. METHODS: In 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). RESULTS: All 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). CONCLUSION: Extended 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.

Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial.

BACKGROUND: Thymic carcinoma is a rare malignant disease and standard treatment for advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The aim of this trial was to assess the activity and safety of lenvatinib as a second-line treatment in thymic carcinoma. METHODS: This single-arm, phase 2 trial done in eight institutions in Japan (five cancer centres, two medical university hospitals, and one public hospital) enrolled patients with pathologically confirmed unresectable advanced or metastatic thymic carcinoma that progressed following at least one platinum-based chemotherapy. Key inclusion criteria were age 20 years or older, at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 24 mg of lenvatinib orally once daily in 4-week cycles until disease progression or occurrence of unacceptable adverse events. The primary endpoint was objective response rate evaluated at the data cutoff date (Feb 22, 2019), by independent central review in the intention-to-treat population. This trial is registered on JMACCT, JMA-IIA00285, and on UMIN-CTR, UMIN000026777. FINDINGS: Between April 21, 2017, and Feb 22, 2018, 42 patients were enrolled and all patients were included in the activity and safety analysis. The median follow-up period was 15·5 months (IQR 13·1-17·5). The objective response rate was 38% (90% CI 25·6-52·0, p<0·0001). 16 (38%) of 42 patients had a partial response and 24 (57%) had stable disease. The most frequent grade 3 treatment-related adverse events were hypertension (27 [64%]) and palmar-plantar erythrodysaesthesia syndrome (three [7%]). No patient died from adverse events. INTERPRETATION: The activity and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These results suggest that lenvatinib could become a standard treatment option for patients with previously treated advanced or metastatic thymic carcinoma. FUNDING: Center for Clinical Trials, Japan Medical Association.

CD20+ tumor-infiltrating immune cells and CD204+ M2 macrophages are associated with prognosis in thymic carcinoma.

Thymic carcinoma is a rare malignant disease with no standard systemic chemotherapy. The purpose of the present study was to investigate tumor-infiltrating immune cells (TIIC) in the tumor microenvironment (TME), focusing on the impact of TIIC and program death-ligand 1 (PD-L1) expression on clinical outcomes in thymic cancer. Patients with thymic carcinoma resected between 1973 and 2017 were investigated. The tissue specimens were analyzed through immunohistochemical staining to elucidate the prognostic effects of TIIC, their ratios and PD-L1 in a preliminary cohort (n = 10). The density of TIIC as well as PD-L1 expression was evaluated in intraepithelial and tumor-stromal areas on the representative whole section of tumors. The immune factors showing significant association with disease-free survival (DFS) were evaluated in the total cohort (n = 42). TIIC in the preliminary population showed no significant difference between the two groups. However, CD8, CD20, CD204, FOXP3 and CD20/CD204 ratio demonstrated a tendency to act as predictive markers for recurrence. In the total cohort, significant differences were observed for CD8+ , CD20+ and CD204+ cells in tumor islets, and for CD8+ , CD20+ and FOXP3+ cells as well as the CD8/CD204 and CD20/CD204 ratios in the stroma, indicating their prognostic effect. The prognostic effect of the PD-L1 expression in tumor cells could not be established, possibly because of intratumoral heterogeneity. CD8, CD20 and CD204 positive TIIC in stroma were identified as possible better prognostic biomarkers, considering the heterogeneity of other biomarkers. The present study paves the way for exploring strategies of combination immunotherapy targeting B cell immunity in thymic carcinoma.

A national analysis of open versus minimally invasive thymectomy for stage I to III thymoma.

OBJECTIVE: The oncologic efficacy of minimally invasive thymectomy for thymoma is not well characterized. We compared short-term outcomes and overall survival between open and minimally invasive (video-assisted thoracoscopic and robotic) approaches using the National Cancer Data Base. METHODS: Perioperative outcomes and survival of patients who underwent open versus minimally invasive thymectomy for clinical stage I to III thymoma from 2010 to 2014 in the National Cancer Data Base were evaluated using multivariable Cox proportional hazards modeling and propensity score-matched analysis. Predictors of minimally invasive use were evaluated using multivariable logistic regression. Outcomes of surgical approach were evaluated using an intent-to-treat analysis. RESULTS: Of the 1223 thymectomies that were evaluated, 317 (26%) were performed minimally invasively (141 video-assisted thoracoscopic and 176 robotic). The minimally invasive group had a shorter median length of stay when compared with the open group (3 [2-4] days vs 4 [3-6] days, P < .001). In a propensity score-matched analysis of 185 open and 185 minimally invasive (video-assisted thoracoscopic + robotic) thymectomy, the minimally invasive group continued to have a shorter median length of stay (3 vs 4 days, P < .01) but did not have significant differences in margin positivity (P = .84), 30-day readmission (P = .28), 30-day mortality (P = .60), and 5-year survival (89.4% vs 81.6%, P = .20) when compared with the open group. CONCLUSIONS: In this national analysis, minimally invasive thymectomy was associated with shorter length of stay and was not associated with increased margin positivity, perioperative mortality, 30-day readmission rate, or reduced overall survival when compared with open thymectomy.

Surgical treatment of pleural recurrence of thymoma: is hyperthermic intrathoracic chemotherapy worthwhile?

OBJECTIVES: Recurrence of thymoma is described in 10-30% of cases after surgical resection. Iterative surgery for thymoma pleural relapses (TPRs) is often part of a multimodal treatment. Hyperthermic intrathoracic chemotherapy (HITHOC) following macroscopic radical surgery is an option that combines the effects of mild hyperthermia with those of chemotherapeutic agents. We evaluated the effectiveness of surgery + HITHOC, compared with surgery alone, in the treatment of TPR. METHODS: We retrospectively collected data of all patients who underwent surgery for TPR in our centre from 2005 to 2017. Relapses were treated by partial pleurectomy with radical intent, followed by HITHOC when not contraindicated. Patients were divided into 2 groups: surgery + HITHOC and surgery alone. We collected demographic and clinical data and analysed postoperative results together with oncological outcomes. RESULTS: Forty patients (27: surgery + HITHOC, 13: surgery alone), mean age 49.8 (±13.7) years, were included in this study. There were no perioperative deaths. We experienced 33.3% perioperative morbidity in the surgery + HITHOC group compared with 23.1% in the surgery alone group (P = 0.71). The overall survival rate was comparable between the 2 groups (P = 0.139), whereas the local disease-free interval was 88.0 ± 15 months in the surgery + HITHOC group and 57 ± 19.5 months in the surgery alone group (P = 0.046). The analysis of factors affecting the outcomes revealed that radical surgery is related with a better survival rate whereas the local disease-free interval was significantly influenced by HITHOC. CONCLUSIONS: The safety and feasibility of HITHOC in the treatment of TPR are already known, even if it should be reserved for selected patients. Surgery + HITHOC seems to be associated with a longer local disease-free time compared to surgery alone.

Impact of Definitive Radiotherapy and Surgical Debulking on Treatment Outcome and Prognosis for Locally Advanced Masaoka-Koga stage III Thymoma.

The role of definitive radiotherapy (dRT) and debulking surgery (DS) for patients with locally advanced, unresectable, Masaoka-Koga stage III thymomas was not well studied. Unresectable tumor refers to tumor that could not be completely resected because of invasion of surrounding organs. Consecutive patients with unresectable stage III thymomas between 2000 and 2017 were reviewed. According to the treatment intent and radiation dose, patients were categorized into a dRT group and a non-dRT group. The former group included patients who received radiotherapy at doses ≥ 54 Gy after DS or biopsy. The latter group included patients who did not receive radiotherapy and those who received a radiation dose < 54 Gy. A total of 82 patients were included. Compared with non-dRT, dRT significantly improved 5-year overall survival (OS, P = 0.003), progression-free survival (PFS, P = 0.008), and freedom from locoregional failure (FFLF, P < 0.001). Compared with biopsy alone, DS did not improve OS, PFS, FFLF. On multivariate analysis, dRT was an independent prognostic factor for OS (hazard ratio [HR]: 2.37, P = 0.024), PFS (HR: 2.40, P = 0.004), and FFLF (HR: 3.83, P = 0.001). In conclusion, dRT was an effective and beneficial treatment for patients with unresectable Masaoka-Koga stage III thymoma.