High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma.

Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon, aggressive type of non-Hodgkin lymphoma. Rituximab-containing chemoimmunotherapy with or without radiation therapy (RT) is standard first-line treatment. Relapsed or refractory (R/R) disease has long been treated with salvage chemotherapy followed by high-dose chemotherapy (HDC), with autologous stem cell transplantation (ASCT) in appropriate patients. We retrospectively analyzed all patients with R/R PMBCL treated with HDC/ASCT at our center between January 2000 and August 2022. The 60 study patients received either rituximab-BEAM (n = 37) or rituximab-gemcitabine/busulfan/melphalan (R-GemBuMel) with or without vorinostat (n = 23), followed by ASCT. Forty-six patients received mediastinal RT, either as prior consolidation of frontline therapy or following ASCT. At median follow-up of 6 years (range, .3 to 21 years), the 5-year progression-free survival (PFS) and overall survival (OS) rates of the whole group were 58% and 77%, respectively, for the entire cohort, 51% and 65% for the R-BEAM recipients, and 69% and 82% for R-vorinostat/GemBuMel recipients. Multivariable analyses showed that a negative positron emission tomography scan at ASCT (hazard ratio [HR], .28) and involvement of only 1 organ (HR, .33) were independently associated with improved PFS. In addition, receipt of R-vorinostat/GemBuMel (HR, .23) was an independent favorable predictor of OS. Our data indicate that HDC/ASCT is effective in R/R PMBCL, with improved outcomes in patients receiving R-vorinostat/GemBuMel.

Effects of comorbid diseases on clinical outcomes in patients with myasthenia gravis.

BACKGROUND: This cross-sectional study was undertaken to evaluate the existence and distribution of comorbid disorders among myasthenia gravis (MG) patients according to subgroups and to identify the effects of the comorbid diseases of MG patients on clinical outcomes. METHODS: The patients were divided into six subgroups according to serum antibodies, age at onset, and thymoma presence. All patients were treated in line with the International Consensus Guidance for Management of Myasthenia Gravis. To assess the clinical outcome after treatment for MG, we used the MGFA Post-intervention Status. In generalized MG patients, the good prognosis group included patients who were classified as having minimal-manifestation status or better. In ocular MG patients, the remission subgroup included patients who were classified as having complete stable remission or pharmacological remission status. RESULTS: Our study included 168 MG patients, 85 were female while 83 were male. Comorbid diseases were present in 124 (73.8%) MG cases. After at least 1 year of follow-up, 106 (86.8%) of the generalized MG patients were in the good prognosis group and 16 (13.2%) generalized MG patients were in the poor prognosis group. 27 (58.6%) ocular MG patients were in the remission group and 19 (41.3%) ocular MG patients were in the non-remission group. Hypertension increased the risk of poor prognosis by 3.55-fold among patients with generalized MG and type 2 DM increased the risk of not achieving remission by 9.32-fold among patients with ocular MG. CONCLUSION: Hypertension and type 2 DM had negative effects on the clinical outcomes of MG.

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.

Transplantation of Unirradiated Bone Marrow Cells after Total-Body Irradiation Prevents the Development of Thymic Lymphoma in Mice through Niche Competition.

Mouse models of radiation-induced thymic lymphoma are commonly used to study the biological effects of total-body irradiation (TBI) on the formation of hematologic malignancies. It is well documented that radiation-induced thymic lymphoma can be inhibited by protecting the bone marrow (BM) from irradiation; however, the mechanisms underlying this phenomenon are poorly understood. Here, we aimed to address this question by performing transplantation of BM cells from genetically engineered mice that have defects in tumor immunosurveillance or occupying different thymic niches. We found that BM cells from mice that have impaired tumor immunosurveillance, by deleting tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ) or perforin-1 (PRF1), remained sufficient to suppress the formation of radiation-induced thymic lymphoma. On the other hand, BM cells from Rag2-/-; γc-/- mice and Rag2-/- mice, which have defects in occupying thymic niches beyond double negative (DN2) and DN3, respectively, failed to inhibit radiation-induced lymphomagenesis in the thymus. Taken together, based on our findings, we propose a model where unirradiated BM cells suppress radiation-induced lymphomagenesis in the thymus by competing with tumor-initiating cells for thymic niches beyond the DN3 stage.

Case Report-Secondary Antibody Deficiency Due to Endogenous Hypercortisolism.

Therapeutic corticosteroids have an immunosuppressive function involving several pathways, including lymphocytopenia and hypogammaglobulinemia. While these effects have been well-described in patients that received corticosteroids for therapeutic reasons, the effects of endogenous corticosteroids on the immune system are less well-understood. Here, we describe a 21-year old patient with hypercortisolism due to an ACTH producing thymic tumor. In this patient, we observed a decrease in some of the immunoglobulin classes, and in specific B and T cell populations that resembled effects caused by corticosteroid treatment. IgG levels were restored following treatment and normalization of the hypercortisolism.

Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma.

BACKGROUND: Thymic epithelial tumors are PD-L1-expressing tumors of thymic epithelial origin characterized by varying degrees of lymphocytic infiltration and a predisposition towards development of paraneoplastic autoimmunity. PD-1-targeting antibodies have been evaluated, largely in patients with thymic carcinoma. We sought to evaluate the efficacy and safety of the anti-PD-L1 antibody, avelumab (MSB0010718C), in patients with relapsed, advanced thymic epithelial tumors and conduct correlative immunological studies. METHODS: Seven patients with thymoma and one patient with thymic carcinoma were enrolled in a phase I, dose-escalation trial of avelumab (MSB0010718C), and treated with avelumab at doses of 10 mg/kg to 20 mg/kg every 2 weeks until disease progression or development of intolerable side effects. Tissue and blood immunological analyses were conducted. RESULTS: Two of seven (29%) patients with thymoma had a confirmed Response Evaluation Criteria in Solid Tumors-defined partial response, two (29%) had an unconfirmed partial response and three patients (two thymoma; one thymic carcinoma) had stable disease (43%). Three of four responses were observed after a single dose of avelumab. All responders developed immune-related adverse events that resolved with immunosuppressive therapy. Only one of four patients without a clinical response developed immune-related adverse events. Responders had a higher absolute lymphocyte count, lower frequencies of B cells, regulatory T cells, conventional dendritic cells, and natural killer cells prior to therapy. CONCLUSION: These results demonstrate anti-tumor activity of PD-L1 inhibition in patients with relapsed thymoma accompanied by a high frequency of immune-related adverse events. Pre-treatment immune cell subset populations differ between responders and non-responders. TRIAL REGISTRATION: ClinicalTrials.gov - NCT01772004 . Date of registration - January 21, 2013.

Thymoma associated myasthenia gravis with atypical presentation of lipomatous tongue atrophy: a case report.

A 28-year-old female patient came to the outpatient dental clinic for multiple teeth extractions and full mouth rehabilitation suffer from myasthenia gravis (MG) primary presentation as tongue atrophy and facial muscles weakness and the symptoms became worries, the patient unable to speak as well and change her voice and complaining of dysphagia and dysarthria. Oral symptoms, treatment schedule and protocol, the selection, prescription and impacts of medications, and prevention of myasthenic crisis are all important; aspects should be considered by dentists and oral health care providers. Weakness of facial and oropharyngeal muscle is considered very popular at disease onset and therefore oral health providers are often the first medical professionals to observe these patients. Myasthenic patients seek particular approach and consultation in order to ensure ideal and proper dental management.

Immunodeficiency associated with tumour pathology: Good's syndrome.

The Good's syndrome (GS) is a low prevalence entity where thymoma often is associated with immunodeficiency. Patients may start presenting recurrent rhinosinusal infections, bronchopulmonary infections, haematological alterations and diarrhoea, secondary to immunodeficiency. They can also present respiratory symptoms and parathymic syndromes derived from the existence of thymoma, a slow-growing neoplasm located in the anterior mediastinum. We present the case of a 76-year-old man diagnosed with thymoma by image analysis, which had presented multiple episodes of pneumonia and two admissions to the hospital for diarrhoea of weeks of evolution. After finishing the study, the patient is diagnosed of GS. In this case, thymectomy prevented the appearance of parathymic syndrome, but without any effect on immunodeficiency symptoms. To decrease repeat infections, substitution therapy with immunoglobulins was started. The prognosis will depend mainly on the recurrent infectious and to a lesser extent on the thymic neoplasm.

Quiste tímico asociado a miastenia gravis / Thymic cyst associated with myasthenia gravis

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Modulating SIRT1 activity variously affects thymic lymphoma development in mice.

SIRT1 is a protein deacetylase with a broad range of biological functions, many of which are known to be important in carcinogenesis, however much of the literature regarding the role of SIRT1 in cancer remains conflicting. In this study we assessed the effect of SIRT1 on the initiation and progression of thymic T cell lymphomas. We employed mouse strains in which SIRT1 activity was absent or could be reversibly modulated in conjunction with thymic lymphoma induction using either the N-nitroso-N-methylurea (NMU) carcinogenesis or the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) transgene. Decreased SIRT1 activity reduced the development of thymic lymphomas in the NMU-treated mice but was permissive for the formation of lung adenomas. Conversely, in the NPM-ALK transgenic mice, decreased SIRT1 activity had a modest promoting effect in the development of thymic lymphomas. The results of the work presented here add to the growing body of evidence that sirt1 is neither an outright oncogene nor a tumor suppressor. These opposing results in two models of the same disease suggest that the influence of sirt1 on carcinogenesis may lie in a role in tumor surveillance.

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.

CXCR4 overexpression correlates with poor prognosis in myasthenia gravis-associated thymoma.

Thymoma is 1 rare type of tumor developed on the thymic epithelium; patients with thymoma also might have myasthenia gravis (MG). Because of the scarcity and complexity of MG-associated thymoma, its pathogenesis and etiology still remain unclear nowadays. The expression of C-X-C chemokine receptor type 4 (CXCR4) is absent or low in most healthy tissues but highly expressed in various types of tumors. Here, to determine the prognostic significance of CXCR4 in MG-associated thymoma, a total of 84 tissue samples were retrospectively examined. Our data demonstrated that CXCR4 was strongly associated with worse overall survival (hazard ratio, 2.11; 95% confidence interval, 1.08-4.11) and disease-free survival (hazard ratio, 1.84; 95% confidence interval, 1.03-3.29). Furthermore, both univariate and multivariate analyses confirmed that CXCR4 was an independent factor in predicting unfavorable overall survival. In conclusion, our findings suggest that CXCR4 might contribute to the clinical cancer progression, and CXCR4 could be a valuable prognostic biomarker in the therapy of MG-associated thymoma.

Thymoma associated with autoimmune diseases: 85 cases and literature review.

OBJECTIVES: To describe the clinical features, treatment, and outcome of autoimmune diseases (AD) in a cohort of patients with thymoma. DESIGN: Pathological records from three university hospitals, between 2005 and 2011, were reviewed to identify patients with thymoma. Patients with thymoma and AD were compared with patients with thymoma without AD. RESULTS: 47/85 (55%) cases of thymoma had AD, including myasthenia gravis (MG) (n=33), Hashimoto's thyroiditis (n=4), Isaac's syndrome (n=3), Morvan syndrome (n=2), pure red cell aplasia (n=2), systemic lupus (n=2), lichen planus (n=2), and one case of each following conditions: aplastic anemia, autoimmune hemolytic anemia, Good's syndrome, pemphigus, autoimmune hepatitis, Graves' disease, limbic encephalitis, and inflammatory myopathy. Six patients (7%) presented at least 2 ADs. The median duration of follow-up after surgery was 60 months (40-78 months). In 32 patients, the diagnosis of AD preceded the diagnosis of thymoma, in 9 patients, thymoma was diagnosed at the same time as the AD and 7 patients had been operated on when they developed an AD. We found a significative difference on the Masaoka stage between the MG patients and the patients who present another AD (p=0.028). No risk factor for developing an AD after thymectomy was identified. CONCLUSIONS: We describe here the long-term follow-up of a large series of AD related to thymoma. Our results confirm previous data concerning AD occurrence in patients with thymoma and suggest that preexisting autoimmunity is not a risk factor for developing autoimmune manifestations after thymectomy.

Intrathymic epidermoid cyst: a very rare condition.

A 65-year-old man presented with a nonspecific thymic neoplasm following blunt thoracic trauma. The lesion increased in size over 12 years, to reach 47 mm in diameter. After thymectomy, the lesion was described as an epidermoid lining cyst composed of thickened stratified squamous epithelium. We assume that this rare pathological condition was caused by skin tissue islands and fat migrating into the mediastinum.

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.

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.

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.