ITMIG 2013 Annual Meeting report

Arun Rajan, M.D.

The 4th ITMIG Annual Meeting took place in Bethesda (Maryland, USA) on September 6-7, 2013 at the Bethesda Marriot hotel. More than 100 physicians (Oncologists, Pathologists, Radiotherapists and Thoracic Surgeons) attended this meeting, which was superbly organized by Arun Rajan.

The first day scientific program featured several very interesting Neurologic/Immunologic lectures concerning Myasthenia Gravis (MG) and other paraneoplastic syndromes associated with thymic malignancies. Dr. Lancaster (University of Pennsylvania,USA) summarized the commonest neurological paraneoplastic syndromes: MG, Morvan’s syndrome (fasciculations, hallucinations, cramps/muscles spasms, insomnia and encephalitis), Isaacs’ syndrome (acquired neuromyotonia), polymyositis, autoimmune muscle inflammation) and Stiff person syndrome (hyperexcitability at spinal cord level with painful muscle spasms and debilitating increase in muscle tone).

 

Dr. Khella (Department of Neurology, University of Pennsylvania, USA) reviewed the history of Quality of Life (QoL) measures in MG patients, remembering that the earliest and simplest category was the achievement of clinical remission. The Myasthenia Gravis Foundation of America (MGFA) Clinical Classification should not be used to measure a change in severity of the disease because of the availability of ordinal severity rating scales (e.g. the Manual Muscle Test for MG or Mantegazza’s MG Score). The development of a new MG specific questionnaire (MGQ), a self-administered, validated measure of functional status and the MG Composite scale, Individualized Neuromuscular QOL (INQoL), is an MG-specific measure of QOL developed for a treatment trial. To simplify and allow use in daily clinical practice a 15 item MG-specific QOL (MGQOL 15), tool drawn from the 60 question long MG QOL, has been developed and it has been validated in an 11-center prospective study of 175 patients with MG.

Dr. Kaminsky (Department of Neurology, George Washington University, USA) talked about the development of a MGFA sponsored registry, based on patient’s data submission (activated in July 2013). This is modeled on a highly successful patient-driven registry for multiple sclerosis.

 

Dr. Weksler

A superb review of interactions between thymoma and the immune system was given by Dr. Weksler (University of Pittsburg, USA). This presentation included several papers concerning the biological explanation of autoimmune disease development in patients with thymic neoplasms, as well as the increased risk of secondary cancers incidence in thymic malignancies. Dr. Weksler’s hypothesis was that that the disturbance in T cell lymphocytes (TCL)’s “education” originates in the non-neoplastic thymic epithelial cells, which may explain the immune deficiency prior to the diagnosis of thymoma, and also that the thymoma might be a marker of an already disturbed thymic epithelial cell.

 

 

Dr. Browne (Laboratory of Clinical Infectious Diseases, NIH, Bethesda, USA) outlined the inter-relationships between thymoma, anticytokine autoantibodies and immunodeficiency. It is well known that patients with thymic malignancies have high rates of autoimmunity leading to a variety of autoimmune diseases, the commonest of which is MG, caused by antiacetylcholine receptor autoantibodies. But high rates of autoantibodies to cytokines and aberrancies in B and T cell subsets have also been described, further complicating whether the basis of their immunological dysfunction is humoral, cellular or both. In this field scientific knowledge is not completely developed: further investigation into the relationship between anticytokine autoantibodies and thymoma might, in fact, explain the immunological complications which frequently are observed in thymoma patients, as well as inform us about underlying mechanisms of autoimmunity and anticytokine autoantibody production in general.

The cross-talk between mature single positive (SP) thymocytes and thymic medullary epithelial cells (mTEC) is critical for thymic development and maintenance of self tolerance, Dr. Hodes (NIH, Bethesda, USA) stated. In his experimental studies, he analyzed the role of CD28-CD80/86 and CD40-CD40L costimulatory interactions, which are mediators of negative selection and self tolerance, on mTEC development, finding that these costimulatory pathways are critical for medullary development and that their function involves regulation of LTa, LTb and RANK expression. Dr. Hodes’ results demonstrated a striking link between costimulatory requirements for negative selection of self-reactive T cells and the requirement of these same CD28 and CD40L costimulatory pathways for development of the medullary compartment in which negative selection occurs.

After lunch, the afternoon lectures were completely basic science oriented.

Dr. Gokmen-Polar (Pathology& Laboratory Medicina, Indiana University, Indianapolis, USA) talked about the usefulness of preclinical models for thymic tumors. The use of xenograft models will permit studies of target validation and pre-clinical assessment of targeted therapeutics in this cancer. These preclinical models can be used to validate the functional aspect of the novel molecular targets as well as to evaluate novel therapeutic agents in thymic malignancies.

The rarity of thymic neoplasms and the indolent behavior of thymomas have led to significant poor understanding of biologic behavior of these tumors; moreover difficulties in identifying thymoma and thymic carcinoma from the histological point of view, make essential progress in morphological classification or intraoperative assessment. The gene expression might be extremely useful, according to Dr Badve (Indiana University, USA). His group analyzed the gene expression in a series of 36 thymomas. Clustering based on gene expression analysis correlated to some extent with histologic classification (P=<0.05), but none of the molecular clusters were histologically pure as there was a crossover of different histologies within each cluster. The group further analyzed the correlation of gene expression with tumor stage and the development of metastasis. Predictive analysis of microarray (PAM) identified a 9 gene signature which was associated with tumor stage. Similarly, a combination of 10 genes could identify cases associated with metastasis with a high degree of certainty. This data initially showed that all the 19 genes together could reliably predict the outcomes of thymomas. The signature was further refined to include only the 9 of the 10 metastasis associated genes. The signature was independent of traditional prognostic factors such as tumor size, stage, histology type and extent of residual disease. Further plans include additional independent validation of the gene signature in other well annotated cohorts as well as prospective evaluation in clinical trial. 

Dr. Milan Radovich (Indiana University, Indianapolis, USA) showed the preliminary results of a next-generation sequencing of thymic malignancies. Taking advantage of this sophisticated technology, a comprehensive next-generation RNA sequencing on a set of thymomas was performed to examine the transcriptional landscape of this disease and to identify novel molecular hallmarks which can lead to more precise therapeutic interventions. Unsupervised hierarchical clustering of gene expression values revealed 100% concordance between gene expression clusters and WHO subtype. A subsequent unsupervised clustering of 705 precursor-microRNAs also showed substantial concordance between clusters and subtype. Thus, the next-generation RNA sequencing showed concordance with the WHO thymoma histologic classification and support the notion that AB thymomas are a variant of type A thymomas.

The need for a collaborative effort between different Institutions worldwide to develop clinical/biological knowledge on rare diseases has been outlined by Dr. Loehrer (Indiana University, Indianapolis, USA). The Cancer Care Engineering (CCE) project is a knowledge acquisition framework that integrates clinical observations, patient outcomes and translational research so as to improve treatment outcomes. The CCE Hub emerged as a unique tool to address these issues. The Hub database technology provided an opportunity to expand its capability through efforts with ITMIG. An “essential dataset” spreadsheet was developed and over 8000 cases have been collected through the CCE Hub ITMIG portal. Data came from hospitals in Turkey, Korea, China, Japan, UK, Thailand, Italy, Germany, Belgium, Netherlands, Argentina, Spain, France, Romania, Denmark, Greece, and the USA; ongoing collected data from the prospective database will be the object for research projects approved by ITMIG.

 

Dr. Xiaopan YaoIn the first day late afternoon an overview of ITMIG activities and projects was then presented. In particular, Dr, Huang (Memorial Sloan Kettering Cancer Center New York,USA) showed the results of the retrospective ITMIG database and outlined the scope and the opportunities of the prospective one. Dori Giroux (CRAB, USA) pointed out the tremendous effort of the cooperation between ITMIG, IASLC and CRAB to develop a new staging system for thymic malignancies, expected in 2016. Dr. Xiaopan Yao (New Haven, USA) spoke about the role and value of the statistical support on ongoing ITMIG projects, which have been also reported by Dr. Ahmad (MSKCC, New York, USA) on behalf of the the ITMIG Thymic Carcinoma/Neuroendocrine Tumors working group, and by Dr. Wakelee (Stanford University, USA). The results of the ITMIG Pathologists Workshop, as well as the new WHO thymic malignancies histological classification (expected in 2014, with the new WHO manual) were reported by Prof. Marx (University Medical Centre Mannheim, Germany). The Pathologist panel included physicians from Europe and USA; the new histological criteria to define Thymoma subtypes will be the subject of an ongoing ITMIG scientific publication. 

 

The ORDR grant state has been outlined by Dr. Korst (Ridgewood, New Yersey, USA), the new ITMIG President Elect; afterwards Dr. Bhora and Dr. Chen (St. Luke’s-Roosevelt Hospital Center, New York, USA) reported the preliminary results of the Lymph-Node map project, which will be the object of another ITMIG publication, expected in 2014.

 

The Masaoka award (for best oral presentation) was won by Prof. Nakajima (University of Tokyo, Japan) with his excellent presentation concerning the outcome of MG associated Thymic Epithelial Tumors. Based on more than 3000 cases collected through the Japanese Association for Research of Thymus (JART)’s database, Prof. Nakajima showed that 22% of patients with thymic epithelial tumor, more commonly with type B tumors, were complicated by MG. Almost all of the patients with both thymoma and MG had positive AchRAb, and 22.4% of thymoma patients without MG had positive AchRAb. In MG patients with thymoma, AchRAb correlated with MG severity, but MG had no impact on the overall survival of patients with thymic epithelial tumor.

The Rosai award (Best Poster Presentation) was won by Prof. Girard (University of Lyon, France): his presentation concerned the “Rythmic” (Réseau tumeurs THYMiques et Cancer), a nationwide network for thymic malignancies adopted in France. This first analysis of the RYTHMIC prospective cohort demonstrates the feasibility of a national multidisciplinary tumor board for thymic malignancies. Besides ensuring all patients an equal access to highly specialized treatment, this provides a comprehensive tool to assess interventions to improve the management of patients, increase the quality-of-care, and screen patients for future translational research and clinical trials.

The Best Thymic Cancer Paper award (Barbara Niebauer award) was won by Dr. Gomekin-Polar (Indiana University, Indianapolis, USA) with the study “A gene signature to distinguish Thymic Carcinoma from Thymoma”. Building on the first study of the group, which resulted in the development of a commercially available prognostic 9-gene signature that can accurately identify patients at high or low risk for metastases from thymomas, a 12-gene signature was found to have strong diagnostic accuracy for identifying thymomas and thymic carcinomas. A diagnostic gene expression profile was identified that can accurately distinguish thymomas and thymic carcinomas, making possible to assist in the accurate histological classification of difficult cases.

The 2013 ITMIG Meeting represented also an unique opportunity to visit Washington D.C. and its monumental sites, including also the White House.

The 2014 ITMIG Meeting was announced: it will take place in Antwerp (Belgium) on September 5-6, 2014: please, save this date, and see you in Belgium!