Early Thymectomy Is Associated With Long-Term Impairment of the Immune System: A Systematic Review.

Background and Aims: Congenital heart diseases (CHDs) are diagnosed in approximately 9 in 1,000 newborns, and early cardiac corrective surgery often requires partial or complete thymectomy. As the long-term effect of early thymectomy on the subsequent development of the immune system in humans has not been completely elucidated, the present study aimed to evaluate the effects of thymus removal on the functional capacity of the immune system after different periods. Methods: A systematic review of the literature was performed using MEDLINE, EMBASE, LILACS and Scopus. The inclusion criteria were original studies that analyzed any component of the immune system in patients with CHD who had undergone thymectomy during cardiac surgery in the first years of life. The results were evaluated for the quality of evidence. Results: Twenty-three studies were selected and showed that patients who underwent a thymectomy in the first years of life tended to exhibit important alterations in the T cell compartment, such as fewer total T cells, CD4+, CD8+, naïve and CD31+ T cells, lower TRECs, decreased diversity of the TCR repertoire and higher peripheral proliferation (increased Ki-67 expression) than controls. However, the numbers of memory T cells and Treg cells differed across the selected studies. Conclusions: Early thymectomy, either partial or complete, may be associated with a reduction in many T cell subpopulations and TCR diversity, and these alterations may persist during long-term follow-up. Alternative solutions should be studied, either in the operative technique with partial preservation of the thymus or through the autograft of fragments of the gland. Systematic Review Registration: Prospero [157188].

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.

Age-related transcriptional modules and TF-miRNA-mRNA interactions in neonatal and infant human thymus.

The human thymus suffers a transient neonatal involution, recovers and then starts a process of decline between the 1st and 2nd years of life. Age-related morphological changes in thymus were extensively investigated, but the genomic mechanisms underlying this process remain largely unknown. Through Weighted Gene Co-expression Network Analysis (WGCNA) and TF-miRNA-mRNA integrative analysis we studied the transcriptome of neonate and infant thymic tissues grouped by age: 0-30 days (A); 31days-6 months (B); 7-12 months (C); 13-18 months (D); 19-31months (E). Age-related transcriptional modules, hubs and high gene significance (HGS) genes were identified, as well as TF-miRNA-hub/HGS co-expression correlations. Three transcriptional modules were correlated with A and/or E groups. Hubs were mostly related to cellular/metabolic processes; few were differentially expressed (DE) or related to T-cell development. Inversely, HGS genes in groups A and E were mostly DE. In A (neonate) one third of the hyper-expressed HGS genes were related to T-cell development, against one-twentieth in E, what may correlate with the early neonatal depletion and recovery of thymic T-cell populations. This genomic mechanism is tightly regulated by TF-miRNA-hub/HGS interactions that differentially govern cellular and molecular processes involved in the functioning of the neonate thymus and in the beginning of thymic decline.

Microdeletion 22q11.2 syndrome: Does thymus incidental surgical resection affect its immunological profile?

BACKGROUND: The del22q11 syndrome patients present immunological abnormalities associated to thymus alterations. Up to 75% of them present cardiopathies and thymus is frequently removed during surgery. The thymectomy per se has a deleterious effect concerning lymphocyte subpopulations, and T cell function. When compared to healthy controls, these patients have higher infections propensity of variable severity. The factors behind these variations are unknown. We compared immunological profiles of del22q11.2 Syndrome patients with and without thymectomy to establish its effect in the immune profile. METHODS: Forty-six del22q11.2 syndrome patients from 1 to 16 years old, 19 of them with partial or total thymectomy were included. Heart disease type, heart surgery, infections events and thymus resection were identified. Immunoglobulin levels, flow cytometry for lymphocytes subpopulations and TREC levels were determined, and statistical analyses were performed. RESULTS: The thymectomy group had a lower lymphocyte index, both regarding total cell count and when comparing age-adjusted Z scores. Also, CD3+, CD4+ and CD8+ lower levels were observed in this group, the lowest count in those patients who had undergone thymus resection during the first year of life. Their TREC level median was 23.6/µL vs 16.1µL in the non-thymus group (p=0.22). No differences were identified regarding immunoglobulin levels or infection events frequencies over the previous year. CONCLUSION: Patients with del22q11.2 syndrome subjected to thymus resection present lower lymphocyte and TREC indexes when compared to patients without thymectomy. This situation may be influenced by the age at the surgery and the time elapsed since the procedure.

Glucocorticoids, master modulators of the thymic catecholaminergic system?

There is evidence that the major mediators of stress, i.e., catecholamines and glucocorticoids, play an important role in modulating thymopoiesis and consequently immune responses. Furthermore, there are data suggesting that glucocorticoids influence catecholamine action. Therefore, to assess the putative relevance of glucocorticoid-catecholamine interplay in the modulation of thymopoiesis we analyzed thymocyte differentiation/maturation in non-adrenalectomized and andrenalectomized rats subjected to treatment with propranolol (0.4 mg.100 g body weight-1.day-1) for 4 days. The effects of beta-adrenoceptor blockade on thymopoiesis in non-adrenalectomized rats differed not only quantitatively but also qualitatively from those in adrenalectomized rats. In adrenalectomized rats, besides a more efficient thymopoiesis [judged by a more pronounced increase in the relative proportion of the most mature single-positive TCRalphabetahigh thymocytes as revealed by two-way ANOVA; for CD4+CD8- F (1,20) = 10.92, P < 0.01; for CD4-CD8+ F (1,20) = 7.47, P < 0.05], a skewed thymocyte maturation towards the CD4-CD8+ phenotype, and consequently a diminished CD4+CD8-/CD4-CD8+ mature TCRalphabetahigh thymocyte ratio (3.41 +/- 0.21 in non-adrenalectomized rats vs 2.90 +/- 0.31 in adrenalectomized rats, P < 0.05) were found. Therefore, we assumed that catecholaminergic modulation of thymopoiesis exhibits a substantial degree of glucocorticoid-dependent plasticity. Given that glucocorticoids, apart from catecholamine synthesis, influence adrenoceptor expression, we also hypothesized that the lack of adrenal glucocorticoids affected not only beta-adrenoceptor- but also alpha-adrenoceptor-mediated modulation of thymopoiesis.

Glucocorticoids, master modulators of the thymic catecholaminergic system?

There is evidence that the major mediators of stress, i.e., catecholamines and glucocorticoids, play an important role in modulating thymopoiesis and consequently immune responses. Furthermore, there are data suggesting that glucocorticoids influence catecholamine action. Therefore, to assess the putative relevance of glucocorticoid-catecholamine interplay in the modulation of thymopoiesis we analyzed thymocyte differentiation/maturation in non-adrenalectomized and andrenalectomized rats subjected to treatment with propranolol (0.4 mg·100 g body weight-1·day-1) for 4 days. The effects of β-adrenoceptor blockade on thymopoiesis in non-adrenalectomized rats differed not only quantitatively but also qualitatively from those in adrenalectomized rats. In adrenalectomized rats, besides a more efficient thymopoiesis [judged by a more pronounced increase in the relative proportion of the most mature single-positive TCRαβhigh thymocytes as revealed by two-way ANOVA; for CD4+CD8- F (1,20) = 10.92, P < 0.01; for CD4-CD8+ F (1,20) = 7.47, P < 0.05], a skewed thymocyte maturation towards the CD4-CD8+ phenotype, and consequently a diminished CD4+CD8-/CD4-CD8+ mature TCRαβhigh thymocyte ratio (3.41 ± 0.21 in non-adrenalectomized rats vs 2.90 ± 0.31 in adrenalectomized rats, P < 0.05) were found. Therefore, we assumed that catecholaminergic modulation of thymopoiesis exhibits a substantial degree of glucocorticoid-dependent plasticity. Given that glucocorticoids, apart from catecholamine synthesis, influence adrenoceptor expression, we also hypothesized that the lack of adrenal glucocorticoids affected not only β-adrenoceptor- but also α-adrenoceptor-mediated modulation of thymopoiesis.

[Congenital anomalies of thymic origin in the neck]. / Anomalías congénitas de origen tímico en el cuello.

RATIONALE: A symptomatic mass in the thymus is due to anomalies in the development of the pharyngeal pouches and is also an unusual cause of consultation. These anomalies may be found anywhere along the natural path of the embryonic thymus, from the angle of the jaw to the upper mediastinum. AIM: To review the epidemiology, pathogenesis, diagnosis, and management of congenital anomalies of thymic origin in the neck. MATERIAL AND METHOD: A MEDLINE search was carried out, using the Cochrane methodology, for articles published from January 1980 to January 2007 using the terms "thymus gland," "cervical mass." Following this bibliographical search, the texts considered most relevant by the authors were selected. CONCLUSIONS: While this anomaly is relatively common, its level of presentation is very low and it should always be considered in the differential diagnosis of congenital masses in the neck. New diagnostic imaging techniques provide an early and more accurate diagnosis, thus allowing a better outcome in these patients.

Ectopia tímica. Reporte de un caso / Thymus ectopy. Report of a case

La localización ectópica del Timo es rara, aunque debido a su patrón de migración, durante el desarrollo, el tejido tímico puede ser encontrado en cualquier lugar del recorrido y a veces fuera de él. Este tejido usualmente no presenta anomalía funcional, pero puede requerir cirugía, al ser considerado como masa mediastinal o pulmonar, para descartar patología. Se presenta un infrecuente caso de ectopia tímica en un recién nacido de 12 hs. con dificultad respiratoria atendido en el Hospital Pediátrico de Matanzas. Se realiza un breve recuento morfológico que auxilia en la comprensión de la singularidad e importancia del caso...(AU)

True thymic hyperplasia associated with a unilocular thymic cyst: an unusual combination not previously reported.

A mediastinal tumor mass in a 53-year-old woman with the sole complaint of persistent cough was studied and found to be a true thymic hyperplasia associated with a unilocular thymic cyst, felt to be of the congenital type. The bilobed thymus obtained was macroscopically and microscopically normal except for the size (12 x 12 x 3.5 cm) and weight (97 g). It showed normal thymic tissue segregated in lobules separated by adipose septa and with good corticomedullary separation. There were numerous Hassall corpuscles in the medullary portion. The thymus-to-adipose ratio was approximately 80:20. In the anterior aspect of the thymus, there was a 5-cm unilocular cyst, filled with a clear watery fluid, and with smooth and gray white inner surfaces. Microscopically, the cyst was lined by a cubic and low cylindrical nonciliated epithelium with normal-appearing thymic tissue in the cyst wall. This very unusual combination of true thymic hyperplasia and unilocular thymic cyst has not been previously reported in the literature.

Thymectomy in myasthenia gravis: response, complications, and associated conditions.

BACKGROUND: Thymectomy is considered the most effective treatment for achieving sustained improvement as well as remission in patients with myasthenia gravis (MG), and most neurologists favor the use of this procedure. The main focus of many current studies is to determine response-predicting factors. METHODS: Clinical records of 152 patients with an established diagnosis of MG who underwent thymectomy at our institution were reviewed. The purpose was to evaluate outcome of surgical management for MG and prognostic factors that influence that outcome. RESULTS: The majority of patients were women (119 of 152); mean age was 32.10 +/- 14.42 years, while time elapsed from diagnosis to surgery was 20.67 +/- 19.7 months. Transsternal thymectomy was performed on 113 patients and transcervical on 39. Forty percent of patients achieved remission and 28% showed improvement; with this, a good response to thymectomy was seen in 68% of patients (n = 103). The most important variables associated with remission were <60 years of age, <2 years of preoperative symptoms, and use of pyridostigmine at low doses. Factors related with poor response were >60 years of age, preoperative Osserman stage other than II, use of high doses of pyridostigmine, use of corticosteroids, and presence of thymic atrophy or thymoma in histopathologic analyses. There was no mortality, although 20 patients (13%) presented complications. CONCLUSIONS: Mexican patients with MG undergoing thymectomies show improvement and remission rates similar to those reported by other studies. Age, length of symptoms, thymic pathology, and medications appear to be predictors of response to thymectomy for MG.

[Thymectomy in myasthenia gravis: long-term evolution and predictive factors]. / Timectomía en la miastenia gravis: evolución a largo plazo y factores pronósticos.

INTRODUCTION: Thymectomy is a surgical procedure which is generally accepted for treatment of myasthenia gravis. OBJECTIVE: To describe the long-term evolution of 217 myasthenic patients who had had thymectomies in the Hospital Clinico Quirurgico Hermanos Ameijeiras in La Habana, Cuba. PATIENTS AND METHODS: We determined the stage of evolution of 217 patients, followed-up periodically, with an average observation time of 83.4 months and an interval of between 5 and 155 months. We also studied the frequency of remission and the influence of a group of variables on this, as well as the mortality and its causes. RESULTS: The clinical state of the patients was: remission 77 (35.4%); pharmacological remission 45 (20.7%); significant improvement 70 (32.2%); the same or worse 5 (2.3%); deaths 11 (5%), and unknown 9 (4.1%). The cases with thymomas had a more unsatisfactory course than the other patients, with fewer remissions and greater mortality. Over the first five years of the evolution of the disease, there was a 30% rate of remission; after five years this rose to 35-40% and after ten years reached 47%. The age of the patient, duration of symptoms, histology of the thymus, age of onset of the disease and duration of follow-up did not have any significant effect (p < 0.05) on the long-term evolution of the thymectomy, in contrast to the gravity of the condition according to Osserman's scale. CONCLUSION: The results of thymectomy, in our study were good and similar to the results reported in the international literature.

Características clínicas de 217 pacientes Miasténicos clasificados de acuerdo con la histología del Timo / Clinical characteristics in 217 myasthenic patients classified according to the histology of the thymus

Estudio retrospectivo de 217 pacientes con miastenia gravis, timectomizados. De los pacientes de la serie, 189 (87,1 por ciento) presentaron alguna alteración histológica y en 28 (12,9 por ciento) se encontró un timo sin anormalidades patológicas. La hiperplasia tímica fue la alteración más frecuente (73,7 por ciento), en tanto que la presencia de timoma fue menos común (13,4 por ciento). Las principales características clínicas halladas en el grupo con hiperplasia fueron la presentación de la enfermedad por debajo de los 30 años, mercado predominio del sexo femenino y baja frecuencia de complicaciones de la timectomía. En la mayoría de los casos con timoma, el inicio de la miastenia ocurrió después de la cuarta década. En estos casos hallamos formas más severas de la miastenia, mayor número de complicaciones de la timectomía y más alta mortalidad posoperatoria. También se destacan los beneficios de la timectomía sobre otros tratamientos(AU)

Características clínicas de 217 pacientes Miasténicos clasificados de acuerdo con la histología del Timo / Clinical characteristics in 217 myasthenic patients classified according to the histology of the thymus

Estudio retrospectivo de 217 pacientes con miastenia gravis, timectomizados. De los pacientes de la serie, 189 (87,1 por ciento) presentaron alguna alteración histológica y en 28 (12,9 por ciento) se encontró un timo sin anormalidades patológicas. La hiperplasia tímica fue la alteración más frecuente (73,7 por ciento), en tanto que la presencia de timoma fue menos común (13,4 por ciento). Las principales características clínicas halladas en el grupo con hiperplasia fueron la presentación de la enfermedad por debajo de los 30 años, mercado predominio del sexo femenino y baja frecuencia de complicaciones de la timectomía. En la mayoría de los casos con timoma, el inicio de la miastenia ocurrió después de la cuarta década. En estos casos hallamos formas más severas de la miastenia, mayor número de complicaciones de la timectomía y más alta mortalidad posoperatoria. También se destacan los beneficios de la timectomía sobre otros tratamientos

Atrophy of the tongue with persistent articulation disorder in myasthenia gravis: report of 10 patients.

Ten patients with atrophy of the tongue, from a group of 752 with generalized acquired myasthenia gravis (MG), were studied. Tongue atrophy developed late in the majority of patients and was accompanied by tongue paresis (70% of the cases) and eventually associated to atrophy of other muscles of the palate, especially the uvula. All the patients exhibited severe forms of MG with bulbar involvement, mainly persistent dysphonia and dysphagia, almost always refractory to treatment. There is no correlation among atrophy of the tongue, sex, and thymus pathology. There is correlation between severeness of symptoms and early, persistent and treatment refractory dysphonia and dysphagia.

Myasthenia gravis in Jamaica: clinical, immunological and genetic studies

Clinical, immunological and genetic parameters were studied in 73 Jamaican patients with myasthenia gravis (Mg). The reported biomodal clinical distribution of females with early onset of disease and males with late onset was not observed. The female to male ratio was 2:1. The most frequent manifestations of disease were ptosis (84.9 percent), general muscle weakness (68.5 percent), bulbar symptoms (41.1 percent) and diplopia (32.9 percent). Unusual presenting features such as unilateral ptosis, recurrent chest infection and stumbling while walking resulted in diagnosis being missed in 5.8 percent of cases. The sensitivity of radiommunoassay in detecting acetylcholine receptor antibody (AchR-Ab) in sera from a subgroup of 35 MG patients was 71.4 percent whilst that of the ELISA was only 14.2 percent. There was no correlation between HLA-type, thymic pathology and course of disease. HTLV-I could not be implicated in the pathogenesis of this disease. There was a paucity of other associated autoimmune conditions among MG patients. Thymectomy was an important therapeutic modality in that improvement was observered in 22 cases and remission in 11. (AU)

Myasthenia gravis in Jamaica: clinical, immunological and genetic studies

Clinical, immunological and genetic parameters were studied in 73 Jamaican patients with myasthenia gravis (Mg). The reported biomodal clinical distribution of females with early onset of disease and males with late onset was not observed. The female to male ratio was 2:1. The most frequent manifestations of disease were ptosis (84.9%), general muscle weakness (68.5%), bulbar symptoms (41.1%) and diplopia (32.9%). Unusual presenting features such as unilateral ptosis, recurrent chest infection and stumbling while walking resulted in diagnosis being missed in 5.8%of cases. The sensitivity of radiommunoassay in detecting acetylcholine receptor antibody (AchR-Ab) in sera from a subgroup of 35 MG patients was 71.4%whilst that of the ELISA was only 14.2%. There was no correlation between HLA-type, thymic pathology and course of disease. HTLV-I could not be implicated in the pathogenesis of this disease. There was a paucity of other associated autoimmune conditions among MG patients. Thymectomy was an important therapeutic modality in that improvement was observered in 22 cases and remission in 11.

Timectomía en miastenia gravis / Timectomy in myasthenia gravis

Se presentan los resultados obtenidos en 38 pacientes portadores de miastenia gravis, quienes fueron sometidos a timectomía en el Instituto Nacional de Enfermedades Neoplásicas, habiéndose logrado mejoría clínica en el 82% de los casos y remisión completa de la enfermedad en el 55% de éstos. La miastenia gravis responde mejor a la timectomía cuando es de corta evolución, los pacientes son adultos jóvenes y el estudio anatomopatológico del timo muestra sólo hiperplasia con normocelularidad. se usó esternotomía longitudinal media en el 90 de los casos y el peso promedio del timo extirpado fué de 234.6 gramos. Las complicaciones post operatorias mas frecuentes estuvieron dadas por crisis miastémica y neumopatía, habiendo fallecido tres pacientes en el inmediato post operatorio debido a crisis miasténicas

Acetylcholine receptor antibody in myasthenia gravis.

Radioimmunoassay techniques were used to detect antibodies to the acetylcholine receptor (AAChR) in 164 patients with adult-onset myasthenia gravis. AAChR levels above 0.6 nM/l were considered pathological and were found in 67% of the patients with an average value of 58.99 +/- 125.02 nM/l (0.6-900.0). Correlation, with clinical functional status, the histopathological thymus alterations and the different therapeutics used did not disclose any statistically significant differences.