Our experience with robotic-assisted thymic surgery.

Thoracic surgery is increasingly influenced by the development of minimally invasive approaches which have also influenced surgery in the area of the anterior mediastinum. The previously standard approach to the thymus via partial sternotomy was gradually replaced by the videothoracoscopic approach in most cases. In recent years, robotically assisted surgery has been gaining ground worldwide in this area, as well. The aim of our paper is to provide a comprehensive overview of procedures in the field of the thymus, including their indications, and to share our first experience with robot-assisted thymus surgery. At the 3rd Department of Surgery, since the start of the robot-assisted thymus surgery program, 23 thymectomies have been performed using this approach, of which 17 were performed for thymoma, 3 for myasthenia gravis, and 3 for parathyroid adenoma localized in thymus tissue. From our experience and the available data, it follows that the length of hospitalization, the rate of complications and the resulting effect of robot-assisted procedures is comparable to VTS procedures; however, the robot-assisted surgery also allows for mini-invasive treatment even in significantly obese patients and in patients with advanced thymic tumors who would otherwise be indicated for open thymectomy.

Does Surgical Removal of the Thymus Have Deleterious Consequences?

The role of immunosenescence, particularly the natural process of thymic involution during aging, is increasingly acknowledged as a factor contributing to the development of autoimmune diseases and cancer. Recently, a concern has been raised about deleterious consequences of the surgical removal of thymic tissue, including for patients who undergo thymectomy for myasthenia gravis (MG) or resection of a thymoma. This review adopts a multidisciplinary approach to scrutinize the evidence concerning the long-term risks of cancer and autoimmunity postthymectomy. We conclude that for patients with acetylcholine receptor antibody-positive MG and those diagnosed with thymoma, the removal of the thymus offers prominent benefits that well outweigh the potential risks. However, incidental removal of thymic tissue during other thoracic surgeries should be minimized whenever feasible.

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].

Quantitative Histogram Analysis of T2-Weighted and Diffusion-Weighted Magnetic Resonance Images for Prediction of Malignant Thymic Epithelial Tumors.

PURPOSE: To assess the value of histogram analysis for differentiating a high-risk thymic epithelial tumor (TET) from a low-risk TET using T2-weighted images and the apparent diffusion coefficient (ADC). METHODS: Forty-nine patients with histopathologically proven TET after thymectomy were enrolled in this study and retrospectively classified as having low-risk TET (low-risk thymoma) or high-risk TET (high-risk thymoma or thymic carcinoma). Twelve parameters were obtained from the quantitative histogram analysis. The histogram parameters were compared using the Mann-Whitney U test. Diagnostic efficacy was estimated by receiver-operating characteristic curve analysis. RESULTS: Twenty-five patients were classified as having low-risk TET and 24 as having high-risk TET. The mean ADC value showed diagnostic efficacy for differentiating high-risk TET from low-risk TET, with an area under the curve of 0.7, and was better than when using conventional methods alone. CONCLUSION: The ADC-based histogram analysis could help to differentiate between high-risk and low-risk TETs.

Tumor immunity is related to 18 F-FDG uptake in thymic epithelial tumor.

BACKGROUND: 2-deoxy-2-[fluorine-18] fluoro-d-glucose (18 F-FDG) positron emission tomography (18 F-FDG-PET) is a convenient modality to assess the metabolic activity within tumor cells. However, there is no consensus regarding the relationship between 18 F-FDG uptake and the immune environment in thymic epithelial tumors (TETs). We conducted a clinicopathological study to elucidate the relationship between 18 F-FDG uptake and programmed death ligands 1 and 2 (PD-L1/PD-L2) expression in patients with TETs. METHODS: A total of 108 patients with histologically confirmed TETs classified as thymomas or thymic carcinomas who underwent surgical resection or biopsy or needle biopsy and 18 F-FDG PET before any treatment between August 2007 and March 2020 were enrolled in this study. Tumor specimens underwent immunohistochemical staining for PD-L1, PD-L2, GLUT1, HIF-1α, VEGFR2, VEGF-C, and ß2 adrenergic receptor. RESULTS: High uptakes of SUVmax , SUVmean , MTV, and TLG were identified in 28 (25.9%), 61 (56.5%), 55 (50.9%), and 55 (50.9%) of 108 patients, respectively. High uptake of SUVmax significantly correlated with PS (performance status) of 1-2, thymic carcinoma, and advanced stage, and SUVmax on 18 F-FDG uptake displayed a close association with PD-L1 and PD-L2 expressions, but not with MTV and TLG. Our analysis revealed that SUVmax was identified as being significant relationship for positive PD-L1/PD-L2 expression. GLUT1, HIF-1α, and VEGFR2 were significantly associated with the expression of PD-L1/PD-L2 from the biological viewpoint. CONCLUSION: 18 F-FDG accumulation was closely associated with the expression of PD-L1/PD-L2, which, in turn, was correlated with glucose metabolism and hypoxia. PD-L1/PD-L2 could affect the glucose metabolism and hypoxia in thymic tumor cells.

Clinical Genomic, phenotype and epigenetic insights into the pathology, autoimmunity and weight management of patients with Myasthenia Gravis (Review).

Myasthenia Gravis (MG) is an autoimmune disease that affects neuromuscular junctions and is characterized by muscle weakness as a result of autoantibodies against certain proteins. As a heterogeneous disorder, MG presents with different types, including neonatal, ocular and generalized in both juveniles and adults. Different types of antibodies serve a role in how MG presents. The main biological characteristic of MG is the production of antibodies against the muscular acetylcholine receptor; however, other types of antibody have been associated with the disorder. The role of the thymus gland has been established and thymectomy is a possible treatment of the disease, along with traditional medication such as pyridostigmine bromide (Mestinon) and immunosuppresants. In recent years, steps have been made towards developing more sensitive diagnostic methods. Additionally, novel treatments have demonstrated promising results. Developing new assays may lead to an increased understanding of the disease and to unravelling the genetic pathway that leads to the development of neuromuscular diseases.

Concurrent thyrolipomatosis and thymolipoma in a patient with myasthenia gravis: a case report and review of the literature.

We present a case of a man with a background of myasthenia gravis who presented with a neck lump, which was diagnosed as thyrolipomatosis in continuity with a very large thymolipoma. Following removal of these lesions, the patient's myaesthenic symptoms improved. While thymolipomas are often seen in the context of myasthenia gravis, thyrolipomatosis is a rare entity and to our knowledge the concurrent finding of both lesions with myasthenia gravis has never been reported. We highlight the important imaging features of both entities and the clinical importance of recognising them.

Thymomectomy plus total thymectomy versus simple thymomectomy for early-stage thymoma without myasthenia gravis: a European Society of Thoracic Surgeons Thymic Working Group Study.

OBJECTIVES: Resection of thymic tumours including the removal of both the tumour and the thymus gland (thymothymectomy; TT) is the procedure of choice and is recommended in most relevant articles in the literature. Nevertheless, in recent years, some authors have suggested that resection of the tumour (simple thymomectomy; ST) may suffice from an oncological standpoint in patients with early-stage thymoma who do not have myasthenia gravis (MG) (non-MG). The goal of our study was to compare the short- and long-term outcomes of ST versus TT in non-MG early-stage thymomas using the European Society of Thoracic Surgeons thymic database. METHODS: A total of 498 non-MG patients with pathological stage I thymoma were included in the study. TT was performed in 466 (93.6%) of 498 patients who had surgery with curative intent; ST was done in 32 (6.4%). The completeness of resection, the rate of complications, the 30-day mortality, the overall recurrence and the freedom from recurrence were compared. We performed crude and propensity score-adjusted comparisons by surgical approach (ST vs TT). RESULTS: TT showed the same rate of postoperative complications, 30-day mortality and postoperative length of stay as ST. The 5-year overall survival rate was 89% in the TT group and 55% in the ST group. The 5-year freedom from recurrence was 96% in the TT group and 79% in the ST group. CONCLUSION: Patients with early-stage thymoma without MG who have a TT show significantly better freedom from recurrence than those who have an ST, without an increase in postoperative morbidity rate.

LOXL1­AS1 promotes thymoma and thymic carcinoma progression by regulating miR­525­5p­HSPA9.

Due to the lack of specific symptoms in early thymic epithelial tumours (TETs), patients are mostly in the advanced stage at the time of presentation. The aim of the present study was to explore the mechanism by which the long noncoding RNA (lncRNA) LOXL1­AS1 affects thymoma and thymic carcinoma progression by targeting the miR­525­5p­HSPA9 axis. Bioinformatics was used to analyse the process of LOXL1­AS1 targeting miR­525­5p­HSPA9 and its expression characteristics in TET. The relationships between LOXL1­AS1, miR­525­5p, HSPA9 and prognosis were analysed. The dual luciferase reporter assay was applied to verify targeting. The gene was knocked down or overexpressed by plasmid transfection. Cell counting kit 8 (CCK­8) assay, flow cytometry and Transwell assay were used to detect cell viability, apoptosis and invasion ability, respectively. Proteins and RNAs were examined by western blot analysis and qPCR, respectively. A tumour­burdened assay was used to perform in vivo verification. LOXL1­AS1 and HSPA9 were overexpressed in thymoma and thymic carcinoma; high levels of LOXL1­AS1 and HSPA9 were associated with poor prognosis, and there was a significant positive correlation between their levels. Downregulation of miR­525­5p expression was also associated with poor prognosis of patients. Clinical trials also demonstrated the same trends. miR­525­5p inhibited the expression of HSPA9 protein by targeting the 3'­untranslated region (UTR) of HSPA9 mRNA. LOXL1­AS1 promoted the expression of HSPA9 as a sponge targeting miR­525­5p. Animal experiment results also showed that knockdown of miR­525­5p promoted cancer by promoting the expression of HSPA9. In conclusion, LOXL1­AS1 and HSPA9 are highly expressed in thymoma and thymic carcinoma; miR­525­5p is expressed at low levels in thymoma and thymic carcinoma; and downregulation of miR­525­5p is associated with poor prognosis. In summary, this study demonstrates that LOXL1­AS1 acts as a sponge that targets miR­525­5p to promote HSPA9 expression, thereby promoting the growth and invasion and inhibiting apoptosis of thymoma and thymic carcinoma cells.

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.

Micronodular Thymoma With Lymphoid Stroma: A Trio of Cases, With Diverse-associated Histological Features.

Introduction. Micronodular thymoma with lymphoid stroma (MNTLS) is a rare thymoma subtype characterized by distinctive histological appearance, unique clinical profile, and indolent course with good prognosis. In addition to its distinctive morphology, MNTLS may be associated with diverse histological features, such as thymic cysts and conventional thymoma, complicating the diagnostic picture further. Materials and methods. We report herein an account of 3 elderly patients (male-02; female-01), who presented with anterior mediastinal mass, and underwent robotic thymectomy. Microscopic examination revealed MNTLS in all 3 cases. In addition, 2 cases showed associated histological features in the form of a multilocular thymic cyst and conventional (type B2) thymoma, respectively. All 3 patients are doing well without recurrence or metastasis at 34, 28, and 19 months postsurgery. Conclusions. Awareness of this rare thymoma subtype is vital among pathologists to avoid misdiagnosis and ensure appropriate patient management. To date, only a few cases of this rare thymoma subtype have been reported in the literature, mostly as single case reports.

T cell phenotype in paediatric heart transplant recipients.

Paediatric heart transplantation recipients suffer an increased incidence of infectious, autoimmune and allergic problems. The relative roles of thymus excision and immunosuppressive treatments in contributing to these sequelae are not clear. We compared the immunological phenotypes of 25 heart transplant recipients (Tx), 10 children who underwent thymus excision during non-transplantation cardiac surgery (TE) and 25 age range-matched controls, in two age bands: 1-9 and 10-16 years. Significant differences from controls were seen mainly in the younger age band with Tx showing lower CD3 and CD4 cell counts whilst TE showed lower CD8 cell counts. Naïve T cell and recent thymic emigrant proportions and counts were significantly lower than controls in both groups in the lower age band. T cell recombination excision circle (TREC) levels were lower than controls in both groups in both age bands. There were no differences in regulatory T cells, but in those undergoing thymus excision in infancy, their proportions were higher in TE than Tx, a possible direct effect of immunosuppression. T cell receptor V beta spectratyping showed fewer peaks in both groups than in controls (predominantly in the older age band). Thymus excision in infancy was associated with lower CD8 cell counts and higher proportions of Tregs in TE compared to Tx. These data are consistent with thymus excision, particularly in infancy, being the most important influence on immunological phenotype after heart transplantation.

Case Report: Unmanipulated Matched Sibling Donor Hematopoietic Cell Transplantation In TBX1 Congenital Athymia: A Lifesaving Therapeutic Approach When Facing a Systemic Viral Infection.

Congenital athymia can present with severe T cell lymphopenia (TCL) in the newborn period, which can be detected by decreased T cell receptor excision circles (TRECs) on newborn screening (NBS). The most common thymic stromal defect causing selective TCL is 22q11.2 deletion syndrome (22q11.2DS). T-box transcription factor 1 (TBX1), present on chromosome 22, is responsible for thymic epithelial development. Single variants in TBX1 causing haploinsufficiency cause a clinical syndrome that mimics 22q11.2DS. Definitive therapy for congenital athymia is allogeneic thymic transplantation. However, universal availability of such therapy is limited. We present a patient with early diagnosis of congenital athymia due to TBX1 haploinsufficiency. While evaluating for thymic transplantation, she developed Omenn Syndrome (OS) and life-threatening adenoviremia. Despite treatment with anti-virals and cytotoxic T lymphocytes (CTLs), life threatening adenoviremia persisted. Given the imminent need for rapid establishment of T cell immunity and viral clearance, the patient underwent an unmanipulated matched sibling donor (MSD) hematopoietic cell transplant (HCT), ultimately achieving post-thymic donor-derived engraftment, viral clearance, and immune reconstitution. This case illustrates that because of the slower immune recovery that occurs following thymus transplantation and the restricted availability of thymus transplantation globally, clinicians may consider CTL therapy and HCT to treat congenital athymia patients with severe infections.

Micronodular Thymomas With Prominent Cystic Changes: A Clinicopathological and Immunohistochemical Study of 25 Cases.

Twenty-five cases of micronodular thymomas with prominent cystic changes are presented. The patients are 13 men and 12 women between the ages of 38 and 69 years. Clinically, the majority of patients presented with nonspecific symptoms of cough, chest pain, and dyspnea. Four patients were asymptomatic. Diagnostic imaging showed the presence of an anterior mediastinal mass and surgical resection of the tumor mass was performed in all the patients. Histologically, all the tumors were characterized by the presence of cystic structures of varying sizes lined by different types of epithelium. In addition, the tumors were characterized by nodules of epithelial cells embedded in a lymphocyte-rich stroma with germinal centers. Twenty-one tumors were encapsulated while 4 tumors were minimally invasive. Immunohistochemical stains were positive for keratin in the nodular epithelial component while CD45 and CD20 were positive in the lymphoid component. Clinical follow-up ranging from 12 to 24 months was obtained in 19 patients. All the patients were alive and well without disease. No clinical follow-up was available in 6 patients. The cases presented in this article highlight the existence of cystic micronodular thymomas, which can be easily misdiagnosed as a multilocular thymic cyst.

Robotic surgery vs. open surgery for thymectomy, a retrospective case-match study.

The robotic approach in the treatment of thymus diseases has been described in many papers, but few studies have compared the early outcome of patients after robotic and open transsternal procedure. Our study aims to confirm the non-inferiority of the robotic technique in terms of feasibility, safety and postoperative patient recovery compared to the open standard. This is a retrospective cohort study in which we compare 114 patients who underwent thymectomy for a thymus disease at our thoracic surgery unit. Our robotic surgery programme started in February 2012 with the treatment of mediastinal diseases. Since then, we have performed 57 robotic thymectomies (Group A). This series was compared with 57 patients who underwent open thymectomies (Group B) performed before 2012, and all were properly matched through a propensity score. Hospital and ICU stay, postoperative pain, use of painkillers, operative time and complications rate were analysed. Postoperative pain, evaluated through the Visual Analogue Scale (VAS), was significantly lower in the robotic surgery group (p < 0.001), which was associated with a trend to lower use of painkillers in Group A, although it was not significant (p = 0.06). No statistical differences were observed between the two groups in terms of ICU stay (p = 0.080), although the total hospital stay was significantly longer in Group B (p = 0.003). No statistical differences were observed in operative time (p = 0.492) and complications rate (p = 0.950). The robotic-assisted technique showed the same operative time and complications rate compared with open surgery, thereby confirming its safety and feasibility in myasthenic patients as well as in Masaoka I-II thymomas. The lower postoperative pain and the shorter hospital stay associated with prompt mobilisation and faster chest drainage removal showed the great advantage of the minimally invasive robotic approach in these patients.

Operative bleeding during thoracoscopic thymectomy: Causes and management strategies.

Bleeding during thoracoscopic thymectomy is a potentially critical complication that necessitates either immediate effective thoracoscopic control or conversion to an open approach. It can be difficult to manage and the surgeon must respond quickly in order to keep the patient safe . In this video tutorial we present various forms of intraoperative bleeding that can occur during thoracoscopic thymectomy and discuss how to manage them in patients with myasthenia gravis. Our management techniques include compression, clipping, stitching, and safe conversion to an open approach.

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.

Case report: cardiac herniation following robotic-assisted thymectomy.

BACKGROUND: The first reported case of cardiac herniation was in 1948 and occurred following pericardiectomy during a lung cancer resection. Although rare, this potentially fatal surgical complication may occur following any operation in which a pericardial incision or resection is performed. The majority of literature on cardiac herniation involves case reports after intrapericardial pneumonectomy. Currently, there are no reports of cardiac herniation after thymectomy with pericardial resection. CASE PRESENTATION: A 44-year-old Asian female with symptomatic myasthenia gravis was referred for thymectomy. Originally thought to have Bell's Palsy, her symptoms began with right eyelid drooping and facial weakness. Over time, she developed difficulty holding her head up, upper extremity weakness, difficulty chewing and dysarthria. These symptoms worsened with activity. She was found to have positive acetylcholine receptor binding antibody on her myasthenia gravis panel. A preoperative CT scan demonstrated a 3.5 cm × 2 cm anterior mediastinal mass along the right heart border and phrenic nerve. A complete thymectomy, via right-sided robotic-assisted approach was performed en bloc with a portion of the right phrenic nerve and a 4 cm × 4 cm portion of pericardium overlying the right atrium and superior right ventricle. Upon undocking of the robot and closure of the port sites, the patient became acutely hypotensive (lowest recorded blood pressure 43/31 mmHg). The camera was reinserted and demonstrated partial cardiac herniation through the anterior pericardial defect toward the right chest. An emergent midline sternotomy was performed and the heart was manually reduced. The patient's hemodynamics stabilized. A vented Gore-Tex 6 cm × 6 cm patch was sewn along the pericardial edges with interrupted 4-0 prolene to close the pericardial defect. CONCLUSION: This potentially fatal complication, although rare, should always be considered whenever there is hemodynamic instability entry or resection of the pericardium during surgery. We now routinely sew in a pericardial patch using our robotic surgical system for any defect over 3 cm × 3 cm that extends from the mid- to inferior portions of the heart.