Safety of COVID-19 vaccine in patients with myasthenia gravis: a self-controlled case series study.

Background: The safety of COVID-19 vaccines has been clarified in clinical trials; however, some immunocompromised patients, such as myasthenia gravis (MG) patients, are still hesitant to receive vaccines. Whether COVID-19 vaccination increases the risk of disease worsening in these patients remains unknown. This study aims to evaluate the risk of disease exacerbation in COVID-19-vaccinated MG patients. Methods: The data in this study were collected from the MG database at Tangdu Hospital, the Fourth Military Medical University, and the Tertiary Referral Diagnostic Center at Huashan Hospital, Fudan University, from 1 April 2022 to 31 October 2022. A self-controlled case series method was applied, and the incidence rate ratios were calculated in the prespecified risk period using conditional Poisson regression. Results: Inactivated COVID-19 vaccines did not increase the risk of disease exacerbation in MG patients with stable disease status. A few patients experienced transient disease worsening, but the symptoms were mild. It is noted that more attention should be paid to thymoma-related MG, especially within 1 week after COVID-19 vaccination. Conclusion: COVID-19 vaccination has no long-term impact on MG relapse.

An observational study on the safety of COVID-19 vaccination in patients with myasthenia gravis.

OBJECTIVE: There is concern that the coronavirus disease (COVID-19) vaccine may trigger or worsen autoimmune diseases. The objective of this study was to determine the impacts of COVID-19 vaccination on symptom severity in patients with myasthenia gravis (MG). METHODS: A total of 106 enrolled patients with MG who were vaccinated against COVID-19 were followed up, and a questionnaire was used to document in detail the exacerbation of muscle weakness after vaccination and all other uncomfortable reactions after vaccination. Demographic, clinical characteristics, medication, and vaccination data were collected by follow-up interview. The main observation outcome was whether the MG symptoms of patients were exacerbated. The definition of exacerbation is according to the subjective feeling of the patient or a 2-point increase in daily life myasthenia gravis activity score relative to before vaccination, within 30 days after vaccination. RESULTS: Of 106 enrolled patients [median age (SD) 41.0 years, 38 (35.8%) men, 53 (50.0%) with generalized MG, 74 (69.8%) positive for acetylcholine receptor antibody, and 21 (19.8%) with accompanying thymoma], muscle weakness symptoms were stable in 102 (96.2%) patients before vaccine inoculation. Muscle weakness worsened in 10 (9.4%) people after vaccination, of which 8 patients reported slight symptom worsening that resolved quickly (within a few days). Two (1.9%) of patients showed serious symptom aggravation that required hospitalization. CONCLUSION: Our results suggest that inactivated virus vaccines against COVID-19 may be safe for patients with MG whose condition is stable. Patients with generalized MG may be more likely to develop increased muscle weakness after vaccination.

Covid-19 vaccines elicit effective IgG responses in an elderly thymus cancer patient with chemotherapy.

The rising need for repeated booster vaccinations against SARS-CoV-2 infections raises the question of whether chronic immunosuppressive chemotherapies influence the efficacy of vaccination. Here, we present the case of a 70-year-old post-thymoma surgery patient who received Vepesid (etoposide, Xediton Pharmaceuticals Inc) chemotherapy for six months before vaccination with Comirnaty (Pfizer-BioNTech COVID-19 mRNA Vaccine). The first two vaccinations elicited only minimal increases of IgG antibodies specific against the receptor-binding domain (RBD) on the spike protein (S1), while the third vaccination was effective in providing high, slowly subsiding antibody titers over a 7-month period. The patient also developed a cellular immune response after the third vaccination. Also, measuring of anti-polyethylene glycol (PEG) IgM titers before and after vaccinations showed no immunogenicity for PEG. Later, a single dose of Sinopharm (China National Pharmaceutical Group) inactivated virus-type vaccine was administered, which also modestly increased the level of IgG. A symptomless COVID-19 infection, however, greatly increased the serum level of anti-RBD IgG, which later subsided. This case confirms that an effective immune response can be achieved with a series of COVID-19 vaccinations despite cytostatic treatment in an old thymus cancer surviving patient in the absence of adverse reactions.

Relapsing COVID-19 infection as a manifestation of Good syndrome: a case report and literature review.

Good syndrome (GS) is a rare acquired immunodeficiency disease characterized by the presence of thymoma with combined B and T cell immunodeficiency in adults. Recurrent bacterial infections, particularly sinopulmonary infections caused by encapsulated bacteria, remain the most common infective presentation of GS; however, relapsing viral infections have also been reported, likely due to impaired T cell-mediated immunity. Relapsing COVID-19 infection, however, has not been previously reported as a manifestation of GS. We present two cases of relapsing COVID-19 infection in patients with GS; in one case, relapsing COVID-19 was the first manifestation of newly diagnosed GS.

Primary cardiac synovial sarcoma mimicking SARS-CoV-2 associated pericarditis.

Primary cardiac synovial sarcoma is an extremely rare tumor with a higher incidence in young men. The mean age of occurrence is 32 years. Synovial sarcomas are tumors with high aggressiveness, proliferate rapidly and metastasize to regional and distant lymph nodes or surrounding organs. The typical location of synovial sarcoma of the heart is the atrial and ventricular septum. Its size, the degree of infiltration of the surrounding tissues and the presence of metastases influence clinical symptoms, which are very non-specific. The low specificity of the symptoms complicates the clinical diagnosis and in most cases the tumor is detected during its progression or incidentally. The final diagnosis is based on histological examination. The primary and only method of treatment is a surgical solution with an effort to completely resect the tumor, followed by aggressive palliative chemotherapy. In the following paper, we present a case report of a 32-year-old man who was diagnosed with synovial cardiac sarcoma only on the basis of exacerbation of non-specific subjective complaints due to the complication in the form of of aneurysmal bleeding of the tumor mass.

SARS-CoV-2 vaccine in patients with thymic epithelial tumours with and without active or pre-existing autoimmune disorders: Brief report of a TYME network safety analysis.

BACKGROUND: International guidelines recommend severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine for patients with cancer. A substantial risk of developing vaccine-related autoimmune toxicities could be hypothesised for patients with thymic epithelial tumours (TETs) due to their high risk of autoimmune disorders (ADs). Moreover, a cross-reaction between SARS-CoV-2 spike protein antibodies and various tissue proteins has been shown, and antibodies against nucleoproteins showed overlaps in the autoimmune cross-reaction with antibodies to spike protein. Due to the rarity of TETs, no data addressing this hypothesis are available. METHODS: Patients with TETs who received SARS-CoV-2 vaccine, treated in 4 referral centres of the Italian Collaborative Group for ThYmic MalignanciEs (TYME) network between February 2021 and September 2021, were interviewed through a standardised 15-items questionnaire in order to describe the safety of SARS-CoV-2 vaccine in patients affected by TETs. RESULTS: Data from 245 doses of vaccine administered to 126 patients (41 = thymic carcinoma, 85 = thymoma; 38 with AD, of which 26 with active AD) were collected. Nine patients had a previous COVID-19-positive swab. No cases of AD reactivation or worsening of a pre-existing AD were seen in the study population. A new diagnosis of myasthenia gravis likely unrelated to the vaccine was made in two patients after the vaccination. Sixty-four patients (51%) experienced a total of 103 adverse events, all G1/G2, most commonly fatigue, new or worsening muscle pain and chills. None AE required patients' hospitalisation. CONCLUSIONS: SARS-CoV-2 mRNA vaccines appear to be safe in patients with TET, even in case of active or pre-existing AD.

Apoptotic colopathy as a manifestation of Good's syndrome.

The case was a 44-year-old patient with four years of evolution of respiratory infections, fever, weight loss of 30 kg and chronic diarrhea with inconclusive colonoscopy studies, managed as inflammatory bowel disease (IBD), with a history of thymomectomy four years previously. On physical examination, there was severe protein-calorie malnutrition, skin lesions compatible with herpes simplex infection and lower limb edema. Blood tests were requested when pancytopenia and hypoalbuminemia were negative for human immunodeficiency virus (HIV). Chest tomography showed a budding tree pattern and bronchiectasis, but SARS-CoV-2 was negative. A colonoscopy was performed, showing the presence of ulcers in the sigmoid colon with an infectious aspect vs IBD.

Robotic Resection of a Left Brachiocephalic Vein Aneurysm Mimicking Thymoma.

A 70-year-old man was scheduled for the robotic resection of a 21×16 × 30 mm thymic nodule incidentally detected by a computed tomography scan (CT) for thoracic trauma after a domestic accident. Positron emission tomography (PET) scan confirmed a low [18F]-FDG uptake (SUVmax = 1,9). During the surgery, the mass showed to be a saccular aneurysm of the left brachiocephalic vein (LBCV). A complete tangential resection of the aneurysm, with the use of EndoGIA stapler (Covidien® Endo GIA™) at its origin, was performed. The patient's recovery was uneventful, and postoperative CT with contrast administration confirmed the patency of the vein.

Improving outcomes of surgery in advanced infiltrative thymic tumours: the benefits of multidisciplinary approach.

BACKGROUND: For stage III or IVa thymic tumours, a multimodality approach is recommended. The role of surgery is to achieve complete resection. AIM: To present the outcomes of patients undergoing surgery for stage III or IVa thymoma. METHODS: Retrospective review of patients undergoing open surgery for stage III or IVa thymoma between 2016 and 2020 at a single centre was performed. Preoperative imaging, treatment plan, surgical approach, and postoperative outcomes were analyzed. RESULTS: Forty-seven patients underwent surgery for thymoma. Patients with clinical stage I/II thymoma or minimally invasive thymectomy were excluded. Thirteen patients with clinical stage III or IVa were included. Median sternotomy approach was used in four patients, of which one was redo sternotomy; a hemi-clamshell in four; and a combination of approaches in the remaining five patients. There was no postoperative mortality. Four patients had postoperative complications. Complete resection was achieved in all but two patients. At a median follow-up of 17.9 months, all patients were alive with no evidence of recurrence except one who died 4 months after surgery from coronavirus disease 2019 (COVID-19) pneumonia. CONCLUSIONS: Surgery for stage III and IVa thymoma is safe and can be achieved with complete macroscopic resection. To obtain adequate exposure of all structures involved in the tumour, combined surgical approaches can be used with no increased morbidity. The majority of patients, even after extrapleural pneumonectomy, did not receive adjuvant radiotherapy and had no evidence of local relapse.

History of the Discovery and Development of Biomodulina T (InmunyVital®), a Useful Immunomodulator with a Broad Range of Clinical Applications (preprint)

Biomodulina T, the active ingredient in InmunyVital®, is a polypeptide thymic factor that modulates immune responses and inflammation. Biomodulina T stimulates the differentiation, maturation and proliferation of CD3 T cell populations and CD4 and CD8 T cell subpopulations. Additionally, Biomodulina T improves the ability of T cells to produce cytokines, therefore enhancing T lymphocyte function. Additionally, Biomodulina T stimulates the thymus gland and, thus, promotes the recovery of normal thymus mass and size in children with thymic hypoplasia and restores the functions of immunosenescent T cells in aging people.The thymus gland slowly shrinks with age, and the levels of the thymic factors it produces decrease in the blood. Moreover, thymus-dependent immunity, including T cell immunity and thymus- dependent antibody production, decreases with thymus size in adult people. For that reason, older adults are generally at a higher risk of becoming severely ill from infectious diseases, such as influenza, COVID-19 and other diseases. As people age, “immunosenescence” occurs; immunosenescence means that with age, the ability to produce vigorous responses to infections gradually diminishes compared to that observed at younger ages during which the thymus gland, thymic factor levels, and immune responses are healthy and strong. In addition, in older adults, low-grade, chronic systemic inflammation, called “inflamm-aging”, occurs, and this phenomenon increases susceptibility to age-related inflammatory diseases.In 1984, with the aim of developing biological response modifiers, I established the laboratory of Biomodulators in Havana, where I created and developed the immunomodulatory thymic factor that I called “Biomodulina T”. The biological activity of Biomodulina T was demonstrated in several in vitro and in vivo studies in our laboratory and in independent laboratories. An extensive series of preclinical toxicological studies were conducted in different species, such as mice, rats, guinea pigs, rabbits and dogs. All these studies demonstrated that Biomodulina T is an active and safe thymic factor.We conducted clinical trials with Biomodulina T in patients with multiple sclerosis, chronic hepatitis B, rheumatoid arthritis, Crohn's disease, Behcet's syndrome, and selective deficiency of IgA as well as in geriatric populations. In 1994, I obtained the sanitary registration of Biomodulina T as an immunomodulatory drug.Since that time, we conducted other clinical trials in children with repeated infections and primary immunodeficiencies and in adults with systemic lupus erythematosus, uveitis, myasthenia gravis, chronic obstructive pulmonary disease (COPD), and respiratory infections.This article identifies the milestones involved in the creation and development of Biomodulina T. Since its discovery 35 years ago, the first and recent reports of new scientific advances show that Biomodulina T (InmunyVital®) is a modulator of immune responses and inflammation that is very useful for restoring the immune system in young and elderly people with allergies, asthma, immunodeficiency, autoimmune diseases, and infectious diseases. Biomodulina T is also useful as an immunotherapeutic agent for improving immune responses in the context of cancer and vaccines, for reversing immunosenescence and for improving the healthspan in general aging.

SARS-CoV-2-related pneumonia can be successfully managed in patients with metastatic neuroendocrine tumors: a critical point of view.

Primary neuroendocrine tumors of the thymus are extremely rare. In patients with advanced disease, tumor growth control, and sometimes also syndrome control are the main goals of systemic therapy. Unfortunately, no standard therapies are available in clinical practice; therefore, clinical studies are strongly recommended. Axitinib (AXI) is a tyrosine kinase inhibitor, currently under investigation in an international phase II/III trial including thymic neuroendocrine tumors. Over the past 5 months, the entire world has been facing a devastating medical emergency brought about by a pandemic due to a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, in late 2019. Since then, health professionals have been expending all their efforts on trying to provide the best available treatments for patients involved. Patients with cancer, especially those with thoracic involvement, are at higher risk of coronavirus disease 19 (COVID-19) and its complications because of their immunosuppressive status caused by the cancer and the anticancer therapies. As it remains unclear how to optimally manage such patients, we wished to report our experience with a patient with a metastatic neuroendocrine tumor of the thymus infected with SARS-CoV-2 in the hope that it may provide some insights and reflections on the management of cancer patients during this challenging time in our history.

Direct ACE2- Spike RBD Binding Disruption with Small Molecules: A Strategy for COVID-19 Treatment (preprint)

ACE2 is a key receptor for SARS-CoV-2 cell entry. Binding of SARS-Cov-2 to ACE2 involves the viral Spike protein. The molecular interaction between ACE2 and Spike has been resolved. Interfering with this interaction might be used in treating patients with COVID-19. Inhibition of this interaction can be attained via multiple routes: here we focus on identifying small molecules that would prevent the interaction. Specifically we focus on small molecules and peptides that have the capacity to effectively bind the ACE2: RBD contact domain to prevent and reduce SARS-CoV-2 entry into the cell. We aim to identify molecules that prevent the docking of viral spike protein (mediated by RBD) onto cells expressing ACE2, without inhibiting the activity of ACE2. We utilize the most recent ACE2-RBD crystallography resolved model (PDB-ID:6LZG). Based on animal susceptibility data we narrowed down our interest to the location of amino acid 34 (Histidine) located on ACE2. We performed an in silico screen of a chemical library of compounds with several thousand small molecules including FDA approved compounds. All compounds were tested for binding to the proximal binding site located close to histidine 34 on ACE2. We report a list of four potential small molecules that potentially have the capacity to bind target residue: AY-NH2, a selective PAR4 receptor agonist peptide (CAS number: 352017-71-1), NAD+ (CAS number: 53-84-9), Reproterol, a short-acting β2 adrenoreceptor agonist used in the treatment of asthma (CAS number: 54063-54-6), and Thymopentin, a synthetic immune-stimulant which enhances production of thymic T cells (CAS number: 69558-55-0). The focus is on a High Throughput Screen Assay (HTSA), or in silico screen, delineating small molecules that are selectively binding/masking the crucial interface residue on ACE2 at His34. Consequently, inhibiting SARS-CoV-2 binding to host ACE2 and viral entry is a potent strategy to reduce cellular entry of the virus. We suggest that this anti-viral nature of this interaction is a viable strategy for COVID19 whereas the small molecules including peptides warrant further in vitro screens.