Clinical analysis of Chinese anti-low-density-lipoprotein-receptor-associated protein 4 antibodies in patients with myasthenia gravis.

BACKGROUND AND PURPOSE: Low-density-lipoprotein-receptor-associated protein 4 (LRP4) autoantibodies have recently been detected in myasthenia gravis (MG), but little is known about the clinical characteristics associated with this serological type. In this study, the clinical features of Chinese patients with anti-LRP4 antibody-positive MG were characterized. METHODS: A total of 2172 MG serum samples were collected from patients in various parts of China. An enzyme-linked immunosorbent assay was used to detect acetylcholine receptor (AChR) antibody and titin antibody, and cell-based assays were used to detect muscle-specific kinase antibody and LRP4 antibody. Clinical data for patients with MG were collected from different provinces in China. RESULTS: In total, 16 (0.8%) patients with LRP4-MG were found amongst 2172 total patients, including three patients with AChR/LRP4-MG. Additionally, 13 (2.9%) patients with LRP4-MG were found amongst 455 patients with double seronegative MG. The ratio of males to females for these 13 patients was 1:1.6, and 53.8% patients were children. A total of 91.7% of cases exhibited initial ocular involvement, and 58.3% of cases exhibited simple eye muscle involvement. Responses to acetylcholinesterase inhibitors and prednisone were observed. CONCLUSION: The expanded sample confirmed that the positive rate of LRP4 antibodies in China is lower than that in western countries. Our results highlighted the differences between LRP4-MG and other antibody groups. Children and female patients with LRP4-MG have a higher prevalence, often involving the ocular muscles and limb muscles. The clinical symptoms are mild, and satisfactory responses to treatment are often achieved.

Acquired T-Cell Immunodeficiency in Thymoma Patients.

Acquired T-cell immunodeficiency can occur in thymoma patients with or without hypogammaglobulinemia (Good's syndrome), but it has received little attention to date. It appears predominantly associated with lymphocyte-rich (i.e., cortical or mixed) thymomas and frequently coexists with autoimmune manifestations. The main abnormalities are an increase in circulating naive T cells, cutaneous T-cell anergy, TCR hyporesponsiveness in vitro as well as a numerical and functional impairment of regulatory T cells. All of these probably result from an abnormal T-cell maturation in the neoplastic thymic microenvironment. A better understanding of thymoma-related acquired T-cell immunodeficiency will be important for immunotherapy of this orphan disease as well as for the prevention and treatment of opportunistic infections, autoimmune complications and secondary malignancies that contribute to the morbidity and mortality of thymoma patients.

Seronegative Paraneoplastic Limbic Encephalitis Associated with Thymoma.

Paraneoplastic limbic encephalitis is an autoimmune syndrome characterized by the acute or subacute onset of encephalopathy, memory loss, confusion, temporal lobe seizures, and behavioral and mood changes. Although most patients with paraneoplastic limbic encephalitis have antineuronal antibodies, advances in the field now permit the diagnosis without autoantibody test results. In this case illustrating the new diagnostic criteria, we report a 70-year-old woman who was brought to the emergency room after the acute onset of cognitive impairment, altered mental status, and choreoathetoid movements. Brain magnetic resonance imaging showed hyperintense signals in both temporal lobes, and a chest computed tomogram revealed a thymoma. Because the patient met current diagnostic criteria for autoimmune limbic encephalitis, we were able to start treatment before her antibody tests were processed. The patient received immunotherapy and her tumor was resected. Her choreoathetoid movements disappeared and her other neurologic symptoms improved. Her cerebrospinal fluid proved to be negative for paraneoplastic limbic encephalitis antibodies. Most but not all patients with paraneoplastic limbic encephalitis associated with thymoma have evidence of paraneoplastic antibodies. Prompt management of the underlying malignancy determines whether patients survive and may minimize future cognitive and functional impairment. Practicing neurologists and psychiatrists should be aware of this diagnosis.

Myasthenia gravis: a comprehensive review of immune dysregulation and etiological mechanisms.

Autoimmune myasthenia gravis (MG) is characterized by muscle weakness caused by antibodies directed against proteins of the neuromuscular junction. The main antigenic target is the acetylcholine receptor (AChR), but the muscle Specific Kinase (MuSK) and the low-density lipoprotein receptor-related protein (LRP4) are also targets. This review summarizes the clinical and biological data available for different subgroups of patients, who are classified according to antigenic target, age of onset, and observed thymic abnormalities, such as follicular hyperplasia or thymoma. Here, we analyze in detail the role of the thymus in the physiopathology of MG and propose an explanation for the development of the thymic follicular hyperplasia that is commonly observed in young female patients with anti-AChR antibodies. The influence of the pro-inflammatory environment is discussed, particularly the role of TNF-α and Th17-related cytokines, which could explain the escape of thymic T cells from regulation and the chronic inflammation in the MG thymus. Together with this immune dysregulation, active angiogenic processes and the upregulation of chemokines could promote thymic follicular hyperplasia. MG is a multifactorial disease, and we review the etiological mechanisms that could lead to its onset. Recent global genetic analyses have highlighted potential susceptibility genes. In addition, miRNAs, which play a crucial role in immune function, have been implicated in MG by recent studies. We also discuss the role of sex hormones and the influence of environmental factors, such as the viral hypothesis. This hypothesis is supported by reports that type I interferon and molecules mimicking viral infection can induce thymic changes similar to those observed in MG patients with anti-AChR antibodies.

Thymoma-associated myasthenia gravis: On the search for a pathogen signature.

Myasthenia gravis (MG) is an autoimmune disease mainly mediated by anti-acetylcholine receptor (AChR) antibodies. In the late onset, a thymoma, tumor of the thymus, is quite frequent. However, the events leading to thymoma and MG are not understood. As thymoma-associated MG (MG-T) patients also display anti-interferon type I (IFN-I) neutralizing antibodies, we investigated if MG-T could be associated with an anti-viral signature. RT-PCR analyses demonstrated huge increases of IFN-I subtypes, IFN-α2, -α8, -ω and -ß, in thymoma-associated MG but not in thymomas without MG or in control thymuses. Next, we investigated if dsRNA signaling pathway involvement could be observed in MG-T, as recently observed in early-onset MG. We observed an abnormal regulation of dsRNA-sensing molecules with an increase of toll-like receptor 3 (TLR3), and a decrease of protein kinase R (PKR) and dsRNA helicases (RIG-I and MDA5) in thymoma from MG patients. We also detected a decreased expression of p53, the tumor suppressor that is known to be down-regulated by dsRNA. Altogether, these results strongly suggest that MG-T could be linked to a viral infection. As p16 (CDKN2A), a marker of HPV infections, was up-regulated in MG-T, we thus screened DNA from thymomas for human papillomavirus (HPV) by real-time PCR using HPV consensus SPF10 primers. RT-PCR results were negative for all samples tested. We confirmed the absence of HPV DNA detection by end point PCR using FAP primers to amplify a larger panel of HPV genotypes. Our data clearly demonstrate INF-I overexpression together with the activation of innate immunity pathways in thymoma-associated MG suggesting that MG might develop after a pathogen infection. We were not able to relate thymoma to HPV infections and the implication of other pathogens is discussed.

Thymoma complicated by acquired amegakaryocytic thrombocytopenia and pure red cell aplasia.

Although the association of pure red cell aplasia (PRCA) and aplastic anemia with thymoma is well-known, acquired amegakaryocytic thrombocytopenia (AAMT) is not a recognized paraneoplastic manifestation of thymoma. This report discusses a patient with recurrent thymoma complicated by myasthenia gravis, PRCA, and AAMT. Both PRCA and AAMT are diagnosed after a thymoma recurrence, 11 years after complete resection of the initial tumor and 9 months after chemotherapy for the relapsed disease. Both PRCA and AAMT responded to immunosuppression with cyclosporine, corticosteroid, and an abbreviated course of antithymocyte globulin, achieving a very good erythroid response and a complete remission for AAMT, suggesting that AAMT, although extremely rare, can be an immune-mediated paraneoplastic manifestation of thymoma.

Successful salvage chemotherapy with amrubicin for invasive thymoma associated with myasthenia gravis.

Anthracycline-based regimens with cisplatin have been commonly used for inoperable and relapsed thymoma. However, little information is available regarding the usefulness of salvage chemotherapy. Here, we describe a case of invasive thymoma associated with myasthenia gravis that showed a marked response to third-line chemotherapy, with single-agent amrubicin, a synthetic anthracycline analog and potent deoxyribonucleic acid topoisomerase II inhibitor. Amrubicin appears to have significant activity against invasive thymoma.

Predictors of outcome of myasthenic crisis.

There is paucity of study on predictors of myasthenic crisis (MC), prolonged ventilation and their outcome, a reason why this study was undertaken. Sixty-four patients with myasthenia gravis (MG) were included whose median age was 45 (6-84) years. Their clinical treatment, presence of thymoma, anti-acetylcholine receptor antibody (AchRAb), thymectomy, comorbidities, offending drugs and occurrence of MC were noted. Patients needing prolonged ventilation (>15 days) were noted. Hospital mortality, MG quality of life (QOL) at discharge and thereafter annual hospital visit, admission, expenditure and work day loss were enquired. Fourteen (21.9 %) patients had MC within 1-120 (median 8.5) months of disease onset within a median follow-up of 48 (3-264) months. The precipitating factors were infection in six, surgery in five, tapering of drugs in two and reaction to iodinated contrast in one patient. Male gender, bulbar weakness, AchRAb, thymoma, surgery and comorbid illnesses were related to MC. Eight of them (57.1 %) needed prolonged ventilation. Half the patients with MC had recurrent crisis (2-4 attacks). Death was not related to MC although MC patients had worse QOL, higher annual treatment expenditure with frequent hospital visit and hospitalization. In conclusion, association of comorbid illness with MC and prolonged ventilation highlights the need of close follow-up and appropriate management.

Thymoma versus thymic carcinoma: differences in biology impacting treatment.

A better understanding of the biology of both thymomas and thymic carcinomas has occurred in recent years thanks to advanced technologies such as comparative genomic hybridization, expression array analysis, and next-generation sequencing. Gene expression profiling and genomic clustering studies have shown that thymic tumors as classified by the 2004 WHO system do have different molecular features. Because of the rarity of these tumors, there is a paucity of high-quality clinical research data, and treatment decisions are often guided by the small amount of prospective trial data, retrospective series, and individual case reports. The literature does report on several advanced thymic tumors that have responded to new targeted agents, indicating that across the spectrum of thymic malignancies there may be clinically relevant molecular subsets. Genomic profiling distinguishes type B3 thymoma and thymic carcinoma from type A and B2 thymomas. Furthermore, type B2 thymomas can be separated from other subgroups in that it has a more distinctly lymphocytic component than the other groups in which epithelial cells predominate. The presence of KIT mutations in thymic carcinomas rather than in thymomas further adds to a growing body of evidence showing that underlying tumor biology may in the future lead to molecular classifications, which may enhance therapies for these rare tumors.

Long-term outcomes of robot-assisted radical thymectomy for large thymomas: A propensity matched analysis.

BACKGROUND: The aim of this study was to evaluate the long-term results of robot-assisted (RATS) thymectomy in the treatment of large thymomas, defined as larger than 5 cm. METHODS: We retrospectively reviewed 106 thymectomies from 2010 to 2020, creating two groups based on the surgical approach (open or RATS) and size. Kaplan-Meier and Cox-regression were used to estimate and identify risk factors of oncological outcomes. To perform a well-balanced analysis, a propensity score matched (PSM) analysis was conducted for large thymomas. RESULTS: From 2015, we performed 54 RATS thymectomies: 53.7% (n = 29) for small and 46.3% (n = 25) for large thymomas. Conversions were similar and all patients had a complete resection. The overall (82% vs. 92%, p = 0.57) and disease-free survival were comparable between RATS and open (92.5% vs. 93%, p = 0.67), outcomes confirmed after PSM for large thymomas. CONCLUSIONS: RATS thymectomy could be considered a valid option in selected patients with large thymomas.

Thymoma removal in a cat with acquired myasthenia gravis: a case report and literature review of anesthetic techniques.

UNLABELLED: HISTORY AND PRESENTATION: A 12 year old, 4.2 kg, domestic long hair, castrated male cat was presented with regurgitation, inability to retract the claws, general weakness, cervical ventroflexion and weight loss. A thymic mass was evident on radiographs. Acetylcholine receptor antibody titer was positive for acquired myasthenia gravis (MG). Thymectomy via midline sternotomy was scheduled. ANESTHETIC MANAGEMENT: Oxymorphone and atropine were administered subcutaneously as premedication, and anesthesia was induced with etomidate and diazepam given intravenously to effect. The cat's trachea was intubated and anesthesia was maintained with isoflurane in oxygen, and continuous infusions of remifentanil and ketamine. Epidural analgesia with preservative-free morphine was administered prior to surgery. Postoperative analgesia was provided by oxymorphone subcutaneously, interpleural bupivacaine, and fentanyl infusion. Postoperative complications included airway obstruction, hypoxemia and hypercapnia. FOLLOW-UP: The cat was discharged 3 days after surgery. Discharge medications included pyridostigmine and prednisone. Nine days after surgery, the cat had a significant increase in its activity level, and medications were discontinued. Histopathologically, the mass was consistent with a thymoma. Approximately 6 weeks later the cat became weak again and pyridostigmine and prednisone administration was resumed. CONCLUSION: The perioperative management of patients with MG for transsternal thymectomy is a complex task. The increased potential for respiratory compromise requires the anesthesiologist to be familiar with the underlying disease state, and the interaction of anesthetic and non-anesthetic drugs with MG. Careful monitoring of ventilation and oxygenation is indicated postoperatively.

Thymoma-associated myasthenia gravis: Clinical features and predictive value of antiacetylcholine receptor antibodies in the risk of recurrence of thymoma.

BACKGROUND: Thymoma-associated myasthenia gravis (TAMG) is one of the subtypes of myasthenia gravis with autoantibodies against the acetylcholine receptor (AChR-Ab). We analyzed the clinical features of our cohort of TAMG patients and the changes in AChR-Ab titer before and after thymectomy in order to identify factors predicting thymoma relapses. METHODS: We retrospectively assessed: age of MG onset, MG clinical status according to MGFA (Myasthenia Gravis Foundation of America), epoch of thymectomy, post-thymectomy status, oncological features and surgical approach. AChR-Ab dosages were measured both before and after thymectomy. Linear regression models were applied to identify clinical determinants of AChR-Ab titers and the Cox regression model was fitted to estimate the factors associated with the risk of thymoma recurrence. RESULTS: The study sample included 239 MG patients, 27 of whom experienced one or more recurrences (median follow-up time: 4.8 years). The AChR-Ab titers decreased after first thymectomy (P < 0.001); the decrease was more pronounced in female patients (P = 0.05), in patients diagnosed with MG at an older age (P = 0.003), and in those who had lower MG stage before surgery (P = 0.02) or higher Masaoka-Koga stage (P = 0.005). The risk of relapse was closely linked with the age of the patient, the Masaoka-Koga stage and the surgical approach. CONCLUSIONS: Presurgery levels of AChR-Ab or their change after surgery were not associated with thymoma recurrence. The reduction of AChR-Ab titers after thymectomy confirms an immunological role of thymoma in the pathogenesis of MG. KEY POINTS: Significant findings of the study: Young MG patients with an advanced Masaoka staging score of the primary tumor who underwent thymectomy with approaches different from sternotomy and VATS should be monitored for high risk of recurrence. WHAT THIS STUDY ADDS: No other study has ever investigated the changes in AChR-Ab titers before and after thymectomy in a large cohort of TAMG patients. The reduction of AChR-Ab titers after thymectomy suggests an immunological role of thymoma in the pathogenesis of MG.

Immunodeficiency and thymoma in Good syndrome: Two sides of the same coin.

Good Syndrome is a rare clinical entity first described as the conjunction of thymoma and hypogammaglobulinemia, and more recently depicted as a complex disease integrating a medical history of thymoma with humoral immunodeficiency (more accurately stated: hypogammaglobulinemia) with or without cellular immunodeficiency, recurrent infections, autoimmunity, paraneoplastic syndromes and diverse aberrations in the immunological profile. This condition has an ominous prognosis with a high mortality rate secondary to recalcitrant infectious diseases. Understanding the possible discordances in clinical presentation and the temporal relationship between manifestations and immunological alterations is key to prevent misdiagnosis and complications. To this end, here we provide two illustrative patients with Good Syndrome that share common clinical manifestations and yet show unique and opposed immunological profiles, thereby highlighting the pivotal interest of a comprehensive immunological profiling in these patients. We conducted a thorough review of existing literature on the elusive molecular mechanisms underlying the syndrome and provide a clinical assessment algorithm to facilitate the management of these challenging patients.

Evidence that endogenous ecotropic virus is not expressed in AKR thymic lymphoid cells of chimeric hosts.

AKR/J thymocytes derived from fetal liver cells do not produce virus when they differentiate in lethally irradiated B10.K mice, whereas spleen and bone marrow cells are virus producers. In contrast, B10.K thymocytes that differentiate in lethally irradiated AKR mice become virus producers. These results suggest that infection of the thymus in AKR mice is initiated in thymic stromal cells.

Radiation leukemia in C57BL/6 mice. I. Lack of serological evidence for the role of endogenous ecotropic viruses in pathogenesis.

The humoral immune response against endogenous ecotropic murine leukemia viruses (MuLV) was examined in irradiated and control C57BL/6 mice. Control mice developed antibodies against MuLV slowly throughout life. In contrast, within 2-3 mo after irradiation 90% of irradiated C57BL/6 mice had developed detectable antibodies against MuLV. The characteristics of this immune response, however, were identical in control and irradiated mice in terms of peak titers, specificity for endogenous ecotropic MuLV, and reactivity against the ecotropic viruses' glycoprotein (gp71). Moreover, the rate of appearance of antibodies against MuLV in irradiated mice and the peak titers were generally not affected by age at irradiation, dose of irradiation (two, three, or four treatments of 175 R), or bone marrow reconstitution. Although the ability of irradiation to accelerate the appearance of antibody in a population of C57BL/6 mice suggested activation of endogenous ecotropic MuLV, there was no apparent correlation between the appearance of this immune response or its persistence and the development of lymphoma. Thus, the incidence of lymphoma was comparable in mice that: (a) developed no immune response; (b) developed an immune response only transiently after irradiation; or (c) developed an immune response which persisted until death from lymphoma. Moreover, experimental conditions that alter the ability of irradiation to induce leukemia, such as age, dose, or bone marrow reconstitution did so without significantly altering either the rate of appearance of a humoral immune response to MuLV or its peak titers. The results, therefore, fail to demonstrate any seroepidemological relationship between endogenous ecotropic MuLV and radiation-induced leukemia.

Radiation leukemia in C57BL/6 mice. II. Lack of ecotropic virus expression in the majority of lymphomas.

The expression of endogenous ecotropic viruses in radiation-induced thymomas of C57BL/6 mice was examined. Competition radioimmunoassays for AKR MuLV gp71, p30, and p12 were used for viral antigen expression. 3 of 40 lymphomas had readily detectable ecotropic gp71 at levels of 95-689 ng/mg protein; the remainder of the tumors had no detectable gp71 (less than 1.0 ng/mg protein). 30 thymomas were characterized by the presence of MuLV p30 at levels of 1-10 ng/mg protein, levels that were comparable to those found in thymus extracts from age-matched, nonirradiated control. 10 tumors were characterized by having p30 levels of 10-30 ng/mg protein. In one tumor significant levels of AKR MuLV p12 were detectable. Since B-tropic and N-tropic viruses from C57BL/6 mice have glycoproteins (gp71) indistinguishable from AKR MuLV gp71 and the N-tropic virus had a p12 serologically identical to AKR MuLV p12, these results demonstrate that overt endogenous B-tropic virus was detectable in 2 of 40 thymomas and endogenous N-tropic virus was detectable in 1 of 40 thymomas. The lack of overt expression of gp71 or p12 was also confirmed by cytotoxicity assays using monospecific antisera to these viral proteins. Radiation-induced lymphomas were also examined for the presence of reverse transcriptase after chromatography of tissue extracts on poly G-Sepharose. One tumor, which was characterized by the lack of gp71, also had no detectable reverse transcriptase; whereas one tumor with gp71 was characterized by readily detectable levels of reverse transcriptase in cellular extracts. The presence of viral RNA was examined using AKR cDNA. Low levels of RNA capable of hybridizing with AKR cDNA were found in age-matched, nonirradiated mice; these hybrids had Tm's of 72 degrees C, while hybrids with AKR MuLV 70S RNA had Tm's of 80 degrees C. In 1 of 12 thymomas the concentration of hybridizable RNA and the Tm of the hybrids were identical to control values. In 9 of 12 thymomas the concentration of hybridizable sequences increased approximately three-to fivefold and the Tm of these hybrids varied from 73 to 75 degrees C. In 1 of 12 thymomas the concentration of hybridizable sequences increased over 100-fold, hybridized completely with AKR MuLV cDNA, and the hybrids had Tm's of 79 degrees C. This thymoma was also characterized by the presence of the AKR MuLV type of gp71 and p12. One tumor was characterized by a 10-to 100-fold increase in hybridizable sequences, which only partially hybridized with AKR MuLV cDNA, and hybrids had a Tm of 73 degrees C. This tumor was characterized by the presence of AKR MuLV gp71 but not AKR MuLV p12. The results taken together demonstrate that overt endogenous ecotropic virus expression is only rarely detectable in radiation-induced thymomas of C57BL/6 mice.

Preferentially expressed antigen in melanoma as a novel diagnostic marker differentiating thymic squamous cell carcinoma from thymoma.

Thymic squamous cell carcinoma (TSQCC), accounting for 70-80% of thymic carcinoma cases, is distinct from thymoma. However, differential diagnosis for type B3 thymoma is sometimes challenging, even with established markers for TSQCC, including KIT and CD5, which are expressed in ~ 80% of TSQCCs and ~ 3% of thymomas. Novel TSQCC-specific markers would facilitate precise diagnosis and optimal treatment. Herein, we found that preferentially expressed antigen in melanoma (PRAME) may be a novel TSQCC-specific diagnostic marker. We comprehensively profiled 770 immune-related mRNAs in 10 patients with TSQCC and two healthy controls, showing that PRAME and KIT were significantly upregulated in TSQCC (adjusted p values = 0.045 and 0.0011, respectively). We then examined PRAME expression in 17 TSQCCs and 116 thymomas via immunohistochemistry. All 17 (100%) TSQCCs displayed diffuse and strong PRAME expression, whereas eight of 116 (6.8%) thymomas displayed focal and weak expression (p < 0.0001). KIT and CD5 were positive in 17 (100%) and 16 (94.1%) TSQCCs, respectively, whereas one (0.9%) type B3 thymoma showed double positivity for KIT and CD5. The KIT-/CD5-positive type B3 thymoma was negative for PRAME. Thus, combinatorial evaluation of PRAME with KIT and CD5 may facilitate a more precise diagnosis of TSQCC.

[Therapeutic strategy in myasthenia gravis]. / Strategie therapeutique au cours de la myasthenie.

The purpose of the treatment of autoimmune myasthenia gravis is to directly improve neuromuscular transmission, and also to reduce the production or presence of the nicotinic acetylcholine receptor (achR). Acetylcholinesterase inhibitors are the first line treatment with the rapid onset of effect, for all types of myasthenia gravis (ocular, generalized myasthenia gravis, seronegative or seropositive patients). Plasmapheresis or intravenous immunoglobulin (IVIg) is the treatment for exacerbations. Their main advantage is the rapid onset of the effect. Three to five plasma exchanges or IVIg infusions (1.2 to 2 g/b.w administered over 2-5 days) are usually recommended. In case of suspected thymoma, thymectomy should be always performed. The option of thymectomy is discussed in young patients less than 50 years old with unstable myasthenia gravis, even if thymoma lesions are not suspected. Corticosteroids and/or immunosuppressive agents are used in severe forms of the disease. A few randomized studies have shown the efficacy of the therapeutic agents. Corticosteroids are considered a major treatment of myasthenia gravis but the doses and periods of time are still being debated. The combination of corticosteroids and immunosuppressive agents are recommended early to spare corticosteroids. The treatment of myasthenia gravis should be modulated regularly (minimal doses for example).

Thymoma developing 30 years after mantle radiation for Hodgkin's lymphoma.

Treatment-related malignancies are widely reported in the medical literature. They are usually chemotherapy-related leukemias or radiation-induced solid tumors. Here we present a case of a 47-year-old woman treated with mantle radiation for Hodgkin's lymphoma who later developed a thymoma in the setting of a venous thrombosis. A review of the literature including surveillance recommendations for secondary malignancies will be discussed.

Tobacco smoking and alcohol consumption as risk factors for thymoma - A European case-control study.

PURPOSE: Hardly anything is known about the aetiology of thymoma. This paper presents data regarding tobacco smoking and alcohol consumption in relation to thymoma from the first case-control study performed on this rare tumour. METHODS: A European multi-centre case-control study including incident cases aged 35-69 years with thymoma between 1995 and 1997, was conducted in seven countries. A set of controls, used in seven parallel case-control studies by the same research group was used, including population-based controls from five countries and hospital controls with colon cancer from two countries. Altogether 103 cases, accepted by a reference pathologist, 712 colon cancer controls, and 2071 population controls were interviewed. RESULTS: Tobacco smoking was moderately related with thymoma (OR 1.4, 95% CI 0.9-2.2), and a tendency to dose-response was shown (p = 0.04), with an increased risk for heavy smokers defined as ≥41 pack-years (OR 2.1, 95% CI 1.1-3.9). A high consumption of spirits defined as ≥25 g of alcohol per day was associated with an increased risk of thymoma (OR 2.4, 95% CI 1.1-5.4), whereas no association was found with beer or wine. CONCLUSIONS: Tobacco smoking and a high intake of spirits were indicated as risk factors for thymoma.