Systemic treatment for thymic malignancies.

PURPOSE OF REVIEW: The management of thymic epithelial tumors is a paradigm of multidisciplinary collaboration. Chemotherapy may be administered as part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy, or as an exclusive treatment if local treatment is not achievable. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. RECENT FINDINGS: More options have become available for advanced, refractory, and recurrent thymic epithelial tumors, which include cytotoxic agents such as carboplatin-paclitaxel, pemetrexed, and oral etoposide. Angiogenesis targeting is a standard in advanced lines of treatment, after results of a phase II trial with sunitinib were reported. Ongoing studies are assessing the opportunity of targeting the immune-response checkpoint programmed death-1/programmed death ligand-1, with preliminary promising results whereas safety, with a higher risk of auto-immunity, may represent a concern. SUMMARY: Overall, a dramatic improvement in our knowledge of the management of thymic tumors has occurred in the past few years, resulting in the development of databases, translational research programmes, and clinical trials. Although access to innovative strategies represents a major challenge, as the rarity of the tumor precludes specific approval of drugs to be obtained, patient-centered initiatives, such as the establishment of dedicated networks, are warranted.

Novel Agents in the Treatment of Thymic Malignancies.

OPINION STATEMENT: The management of thymic tumours is a paradigm of multidisciplinary collaboration. Chemotherapy may be administered part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy, or as an exclusive treatment if local treatment is not achievable. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. Given the limited activity of cytotoxic agents in the advanced, refractory setting, novel and innovative agents are needed. The better understanding of thymic carcinogenesis may provide a rationale in this setting.Targeted agents approved for other solid tumors that have shown activity in thymic tumors include mTOR, KIT inhibitors, as well as somatostatin analogues. Anti-angiogenic agent sunitinib may be considered a standard in advanced lines of treatment. Ongoing studies are assessing the opportunity of targeting emerging targets, including PI3K, CDK, and immune checkpoint PD-1/PD-L1.

Idiopathic pulmonary fibrosis with benign SFTPC variant and pathogenic MARS1 mutations: can't see the forest for the trees!

Even in the absence of liver disease, MARS1 screening should be considered in severe lung fibrosis of young individuals. Interpretation of the genetic variants can evolve with improvement of knowledge (databases, bioinformatic tools) over time. https://bit.ly/45OxF5E.

Activation of the mTOR/ Akt pathway in thymic epithelial cells derived from thymomas.

The pathogenesis of thymic epithelial tumors remains poorly elucidated. The PIK3/Akt/mTOR pathway plays a key role in various cancers; interestingly, several phase I/II studies have reported a positive effect of mTOR inhibitors in disease control in thymoma patients. A major limit for deciphering cellular and molecular events leading to the transformation of thymic epithelial cells or for testing drug candidates is the lack of reliable in vitro cell system. We analyzed protein expression and activation of key players of the Akt/ mTOR pathway namely Akt, mTOR, and P70S6K in eleven A, B and AB thymomas as well as in normal thymuses. While only Akt and phospho-Akt were expressed in normal thymuses, both Akt and mTOR were activated in thymomas. Phospho-P70S6K was expressed in all thymic tumors whatever their subtypes, and absent in normal thymus. Interestingly, we report the activation of Akt, mTOR and P70S6 proteins in primary thymic epithelial cells maintained for short period of time after their derivation from seven AB and B thymomas. Finally, we showed that rapamycin (100 nM) significantly reduced proliferation of thymoma- derived epithelial cells without inducing cell death. Our results suggest that the activation of the Akt/ mTOR pathway might participate to the cell proliferation associated with tumor growth. Ultimately, our data enhance the potential role of thymic epithelial cells derived from tissue specimens for in vitro exploration of molecular abnormalities in rare thymic tumors.

Systemic Therapy in Advanced Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort.

INTRODUCTION: Thymic epithelial tumors (TETs) are rare malignancies that may be aggressive and difficult to treat. In the advanced setting, systemic treatments may be delivered as primary therapy before surgery or definitive radiotherapy, as exclusive treatment when no focal treatment is feasible, or in the setting of recurrences. Réseau tumeurs THYMIques et Cancer (RYTHMIC) is the nationwide network for TETs in France. The objective of the study was to describe the modalities and analyze the efficacy of systemic treatments for patients with advanced TETs included in the RYTHMIC prospective database hosted by the French Thoracic Cancer Intergroup. METHODS: All consecutive patients for whom systemic treatment was discussed at the RYTHMIC multidisciplinary tumor board from 2012 to 2015 and who received at least one cycle of treatment were included. The main end points were objective response and progression-free survival (PFS). RESULTS: A total of 236 patients were included in this analysis. Of those 236 patients, 91 received primary chemotherapy, leading to response rates of 83% for thymomas and 75% for thymic carcinomas and a median PFS of 23.2 months. A strong predictor of longer PFS was histologic type of thymoma (p < 0.001). Exclusive chemotherapy was delivered to 54 patients. The response rates were 31% for thymomas and 37% for thymic carcinomas. The median PFS was 6.2 months, and it was correlated to response rate (p = 0.001). Systemic therapy for a first, second, third, and fourth recurrence was delivered to 114, 81, 51, and 27 patients, respectively. The response rates ranged between 15% and 39% for thymomas and 4% to 21% for thymic carcinomas. The median PFS times were 7.7, 6.2, 5.9, and 6.5 months, respectively. CONCLUSION: Patients with advanced thymic malignancies may receive multiple lines of systemic therapy, with an opportunity for clinically relevant PFS rates for which objective response may be a surrogate. Our real-life study provides landmark efficacy data that are needed when designing clinical trials to assess innovative agents.

[Lung cancer: epidemiology and screening]. / Épidémiologie et dépistage des cancers bronchiques

Lung cancer: epidemiology and screening. The incidence of lung cancer in France is estimated 39 495 cases in 2012. Lung cancer is thus the second cancer in men after prostate cancer, and the third after breast cancer and colorectal cancer in women. Epidemiology of lung cancer is changing, with currently ongoing therapeutic innovation translating into mortality reduction. The main risk factor for lung cancer is tobacco-smoking, alongside genetic, occupational, and professional causes. Diagnosis is made at a metastatic stage for more than half of the patients, with limited survival despite treatment. Conversely, when diagnosed at an early stage, lung cancer is eligible to surgical resection, leading to a survival of more than 85% at 5 years. This leads to discuss the opportunity of screening in smokers.

Épidémiologie et dépistage des cancers bronchiques. L'incidence du cancer bronchopulmonaire en France est estimée à 39 495 cas en 2012. Le cancer bronchopulmonaire est ainsi le deuxième cancer chez l'homme, après celui de la prostate, et le troisième chez la femme après le cancer du sein et le cancer colorectal. L'épidémiologie des cancers bronchopulmonaires évolue, avec des progrès thérapeutiques aujourd'hui visibles sur la mortalité. Le principal facteur de risque du cancer bronchopulmonaire est le tabagisme, à côté de facteurs génétiques, environnementaux et professionnels. Le diagnostic est porté au stade métastatique pour plus de la moitié des patients, dont la survie est alors limitée malgré les traitements mis en oeuvre. À l'inverse, lorsque le cancer est diagnostiqué à un stade précoce, la résection chirurgicale, lorsqu'elle est possible, permet une survie spécifique supérieure à 85 % à 5 ans. Ainsi la question du dépistage organisé du cancer bronchopulmonaire est-elle aujourd'hui débattue, même si les preuves de son intérêt individuel sont établies.

[Thymic tumors]. / Tumeurs thymiques

Thymic tumors. Thymic epithelial tumors are rare malignancies, that may be aggressive and difficult to treat, with variable prognosis. The histopathological classification distinguishes two major tumor types: thymomas and thymic carcinomas. Autoimmune manifestations are observed in nearly one third of patients at diagnosis; myasthenia gravis is the most common, followed by pure red cell aplasia and hypogammaglobulinemia. Assessing the resectability of the tumor represents the first stage of the therapeutic strategy, as complete resection is the most significant prognostic factor on patient survival. For unresectable thymic tumors, treatment is then based on induction chemotherapy followed by surgical resection or radiotherapy. Following a call of the French National Cancer Institute, a network of expert centers for the management of thymic malignancies started in in 2012: RYTHMIC.

Tumeurs thymiques. Les tumeurs épithéliales thymiques sont des tumeurs rares, d'évolution et de pronostic variable. La classification histopathologique sépare deux principaux types tumoraux : les thymomes et les carcinomes thymiques. Des manifestations auto-immunes sont mises en évidence chez près d'un tiers des patients au moment du diagnostic ; la myasthénie est la plus fréquente, avec l'érythroblastopénie et l'hypogammaglobulinémie. L'évaluation de la résécabilité représente la première étape du traitement d'une tumeur thymique ; en effet, la résection complète représente le facteur pronostique le plus constant et le plus significatif sur la survie des patients. En cas de tumeur thymique non résécable, la stratégie thérapeutique repose sur une chimiothérapie d'induction suivie d'une résection chirurgicale ou d'une irradiation. Suite à un appel d'offres de l'Institut national du cancer en 2010, un réseau de soins national de centres experts sur les thymomes et carcinomes thymiques a été mis en place en 2012 : RYTHMIC (Réseau tumeurs thymiques et cancer).

Assessment of the ITMIG Statement on the WHO Histological Classification and of the Eighth TNM Staging of Thymic Epithelial Tumors of a Series of 188 Thymic Epithelial Tumors.

INTRODUCTION: Thymic epithelial tumors (TETs) are rare intrathoracic malignancies that are categorized histologically according to the WHO classification, which was recently updated in 2015 on the basis of a consensus statement of the International Thymic Malignancy Interest Group (ITMIG); at the same time, the standard Masaoka-Koga staging system is scheduled to be replaced by the eighth edition of the TNM staging classification by the American Joint Committee on Cancer/Union for International Cancer Control consortium. Our objectives were to analyze the feasibility of assessing ITMIG consensus major and minor morphological and immunohistochemical criteria and the eighth edition of the TNM staging classification in a routine practice setting. METHODS: This is a single-center study conducted at the Louis-Pradel Hospital of Lyon University, one of the largest centers for TETs in France. Overall, a large surgical series of 188 TETs diagnosed in 181 patients between 2000 and 2014 at our center were analyzed. RESULTS: There were 89 men (49%) and 92 women (51%); 57 patients (31%) presented with myasthenia gravis at time of diagnosis. According to the WHO classification, there were nine type A thymomas (5%), 67 type AB thymomas (36%), 19 type B1 thymomas (10%), 46 type B2 thymomas (24%), 27 type B3 thymomas (14%), and 20 thymic carcinomas (11%). ITMIG consensus major criteria were identified in 100% of type A, AB, B1, and B2 thymomas. After restaging according to the eighth edition of the TNM staging classification, there were 127 stage I (84%), three stage II (2%), 17 stage IIIa (11%), no stage IIIb, two stage IVa (1%), and three stage IVb (2%) thymomas. Significant correlation between histological type and stage at diagnosis was maintained after restaging according the TNM classification. CONCLUSION: Comprehensive analysis of our well-characterized surgical series of 188 TETs indicates the feasibility and the diagnostic value of the ITMIG consensus statement on WHO histological classification and highlights the major switch in staging when the eighth edition of the TNM staging classification is applied.