Steroid-resistant minimal change nephrotic syndrome associated with thymoma treated effectively with rituximab following thymectomy and cyclosporine: a case report.

BACKGROUND: Minimal change nephrotic syndrome (MCNS) can be complicated by thymoma; however, no standard therapy for thymoma-associated MCNS has yet been established. We herein describe a case of steroid-resistant MCNS associated with thymoma, treated effectively with rituximab. CASE PRESENTATION: A 71-year-old Japanese man was referred to our department with severe proteinuria (20 g/gCr). Renal biopsy showed minimal change disease and computed tomography revealed an anterior mediastinal mass. Based on these findings, he was diagnosed with thymoma-associated MCNS. He was treated with oral prednisolone (50 mg/day) and cyclosporine, and underwent thymectomy and plasma exchange. However, no improvement in proteinuria was observed. He therefore received intravenous rituximab 500 mg, resulting in a marked decrease in proteinuria from 5328 to 336 mg/day after 1 week. CONCLUSIONS: This case suggests that rituximab might be an effective therapy in patients with steroid-resistant MCNS associated with thymoma.

Advanced thymic carcinoma with a hepatic metastasis treated with chemotherapy and staged resection.

Thymic carcinoma is rare, with resulting treatment of patients with extrathoracic metastasis being on a case-by-case basis. We describe the management of a woman in her 70s with an incidentally discovered cystic hepatic lesion with confirmation of a solitary extrathoracic metastasis from a synchronous primary thymic carcinoma. Following chemotherapy and staged resection of the metastasis and the primary tumour, the patient remained free of disease on radiological surveillance 6 months postoperatively.

Dexamethasone improves thymoma-associated myasthenia gravis via the AKT-mTOR pathway.

Clinically, thymoma patients are often complicated with myasthenia gravis (MG). Dexamethasone, a glucocorticoid with anti-inflammatory effects, could be used as an immunosuppressant for thymoma-associated MG, but the mechanism of action remains to be explored. In this study, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, weighted gene co-expression network analysis (WGCNA) of potential targets was performed by screening the intersection targets of dexamethasone and thymoma-associated MG from the database. Furthermore, the key targets and core active components were identified by topological analysis of the protein-protein interaction (PPI) network. Molecular docking technology was applied to screen the complexes with stable binding of dexamethasone and core targets. Patients with thymoma were divided into two groups according to whether they received dexamethasone before operation, and immunohistochemistry and western blot were used to verify the selected target of dexamethasone in treating thymoma-associated MG. The results showed that the action pathway of dexamethasone on the disease was closely enriched to phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/AKT), mammalian target of rapamycin (mTOR) signaling pathways. The expressions of AKT1 and its downstream molecule mTOR in the thymoma microenvironment of thymoma-associated MG patients who did not receive dexamethasone before operation were higher than those in the group receiving dexamethasone before operation. This study demonstrates that dexamethasone can promote apoptosis through the AKT-mTOR pathway for the treatment of thymoma-associated MG, as validated by network pharmacology predictions and clinical specimen experiments, and can be verified by large-scale clinical trials in the future. This study also provides theoretical support and new research perspectives for this disease.

GOOD SYNDROME: CYTOMEGALOVIRUS RETINITIS CASE CHALLENGE.

PURPOSE: To describe cytomegalovirus retinitis in a patient with Good syndrome (hypogammaglobulinemia and thymoma), ocular progression despite treatment and fatal outcome. METHODS: A 71-year-old woman with unilateral panuveitis of unknown cause and a history of thymoma resection was referred to the clinic. Visual acuity was 20/100 in her right eye and light perception in her left eye. In slit-lamp examination, the right eye had inferior, fine, pigmented keratic precipitates, 2+ anterior chamber cells, cataract, and 2+ vitreous cells, with no fundus detail and normal ocular ultrasound results. Left eye presented a white cataract, chronic hypotony, and increased choroidal thickness with calcifications. Laboratory evaluations showed normal or negative results for common causes of infection and inflammation. Prednisolone acetate eye drops were started, with improvement of AC inflammation. Cataract surgery was performed, reaching visual acuity of 20/30. Two years later, visual acuity had decreased and 2+ vitritis and retinitis were found. On clinical suspicion of masquerade syndrome, a vitrectomy biopsy was performed; pathologic assessments reported no data on ocular lymphoma. Leukopenia and lymphopenia were found: immunoglobulin levels, CD4 count, and viral load revealed systemic immunosuppression. The aqueous tap was positive for cytomegalovirus. Oral valganciclovir and intravitreal ganciclovir were initiated. RESULTS: In a patient with previous resection of thymoma and hypogammaglobulinemia, final diagnosis was Good syndrome, with cytomegalovirus retinitis being secondary to immunosuppression. Despite treatment, cytomegalovirus retinitis progressed and systemic deterioration resulted in mortal outcome. CONCLUSION: Good syndrome is an extremely rare disease, and association with cytomegalovirus retinitis is uncommon. To the authors' knowledge, only 14 cases exist in the literature.

Characteristics and outcome of systemic treatment for metastatic or unresectable thymic carcinoma: A single institution experience.

BACKGROUND: Thymic carcinoma is a rare disease with an incidence of around 0.5 cases per million with a poor prognosis. The aim of this study was to assess patient outcomes with advanced thymic carcinoma receiving first-line chemotherapy. METHODS: In our retrospective cohort study, we included patients who underwent treatment for metastatic thymic carcinoma between January 2013 to December 2019 in our hospital. Overall survival, progression-free survival (PFS), objective response rates (ORR) and chemotherapy regimens were assessed and analyzed. RESULTS: A total of 27 patients were retrospectively analyzed. All patients received a platinum (cisplatin or carboplatin) based regimen as first-line chemotherapy (29.6% received ADOC, 11.1% received PE, 40.7% received CP, 14.8% received CAP). The median PFS on first-line chemotherapy was 199 days. The response rate was 40.7%. Median overall survival (OS) was 585 days. Positive CD5 staining was associated with better PFS. CONCLUSION: We highlight the critical role of platinum-based chemotherapy agents as a primary treatment modality in advanced thymic carcinoma, underscoring the efficacy of platinum as a first-line option for recurrent disease, even in cases previously treated with platinum. Additionally, our findings indicate that CD5 positivity could be associated with improved PFS, suggesting its potential as a prognostic marker.

An Overview of the Use of Anti-Angiogenic Agents in the Treatment of Thymic Epithelial Tumors.

Angiogenesis significantly influences the carcinogenesis of thymic epithelial tumors (TET). Both thymomas and thymic carcinoma (TC) overexpress VEGF-A and VEGFR-1 and -2. This review aims to provide an appraisal of the use of anti-angiogenics in the treatment of TET. The literature research identified 16 studies that were deemed eligible for further analysis. Seven studies assessed the clinical efficacy of sunitinib and five studies the use of apatinib and/or anlotinib. The multicenter Japanese phase II REMORA trial investigated the efficacy of lenvatinib, which is a multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The objective response rate was 38% (25.6-52%), which is the highest documented in TET that progressed after first-line chemotherapy. Anti-angiogenic agents may be useful in the treatment of TET, which are not amenable to curative treatment. Their toxicity profile seems to be acceptable. However, angiogenesis inhibitors do not appear to have a major influence on either thymomas or TC, although multikinase inhibitors may have some effect on TC. The current evidence suggests that the most active agent is lenvatinib, whereas sunitinib could be proposed as an acceptable second-line therapy for TC. Further research concerning the combination of immune checkpoint inhibitors with anti-angiogenic drugs is warranted.

A late relapse thymoma and pure red cell aplasia case with an over 5 years of clinical response under everolimus.

Although several agents showed some clinical activity in patients with recurrent thymoma, there is no standard treatment option. Here, we report a late relapse thymoma and pure red cell aplasia case, responsive to everolimus with over 5 years of clinical benefit following multiple lines of treatment. Everolimus controlled the rapidly progressive disease in our patient without significant toxicity.

Locally advanced thymoma; does neoadjuvant chemotherapy make a difference?

BACKGROUND: Regardless of its rare occurrence, Thymoma remains the most frequently encountered primary tumor of the anterior mediastinum comprising about 50% of all masses in the region. Surgical resection, via thymectomy, remains the mainstay treatment modality. In locally advanced and borderline resectable tumors, neoadjuvant chemotherapy (NACT) may be utilized to increase the chance of R0 resection, raising the question of its efficacy and safety. METHODS: Demographic and clinical data from patients who presented to a tertiary cancer center between January 2015-October 2021 with a diagnosis of thymoma and underwent curative surgical resection was collected. Computed tomography scan was used to delineate clinical staging, tumor size and to detect post-therapeutic variations in tumor burden. The response evaluation criteria in solid tumors (RECIST) was used to classify the effect of NACT on tumor burden. The pathological response was determined by measuring the percentage of necrotic tissue. RESULTS: A total of 23 patients were diagnosed with thymoma. Most patients were male with a mean age 46 (± 15) years at diagnosis. The most common clinical stage was stage II with 5 patients (22%). A total of 12 patients had NACT as compared to 11 patients who had upfront surgery. The mean change in tumor volume was 165 cm3 (p = 0.079) and the change in and maximum diameter was 1.53 ± 1.49 cm (p < 0.01). The effect of NACT on tumor burden based on RECIST criteria was minimal as 8 patients had stable disease. Based on pathological findings, the average necrotic portion of the tumor was 39.5% (p = 0.152). The overall survival rate is 95.65%, mean survival was 115 months (4-125). Recurrence occurred in 5 patients. The NACT group had a higher risk for recurrence (4; 33.3%) with a mean survival of 43.8 months compared to 59.6 months in those who did not receive induction therapy. CONCLUSIONS: The exact role of induction chemotherapy in locally advanced thymoma patients remains controversial. NACT effect after utilizing radiological and pathological assessment tools was not found to significantly improve oncological outcomes compared to upfront surgery in locally advanced disease, with minimal radiologic and pathologic effect. To further demonstrate the impact of induction chemotherapy, we recommend multicentric collaborative studies.

Efficacy and safety of nivolumab for patients with pre-treated type B3 thymoma and thymic carcinoma: results from the EORTC-ETOP NIVOTHYM phase II trial.

BACKGROUND: Thymic malignancies are rare intrathoracic tumors, which may be aggressive and difficult to treat. They represent a therapeutic challenge in the advanced/metastatic setting, with limited treatment options after the failure of first-line platinum-based chemotherapy. They are frequently associated with autoimmune disorders that also impact oncological management. MATERIALS AND METHODS: NIVOTHYM is an international, multicenter, phase II, two-cohort, single-arm trial evaluating the activity and safety of nivolumab [240 mg intravenously (i.v.) q2 weeks] alone or with ipilimumab (1 mg /kg i.v. q6 weeks) in patients with advanced/relapsed type B3 thymoma or thymic carcinoma, after exposure to platinum-based chemotherapy. The primary endpoint is progression-free survival rate at 6 months (PFSR-6) based on RECIST 1.1 as per independent radiological review. RESULTS: From April 2018 to February 2020, 55 patients were enrolled in 15 centers from 5 countries. Ten patients (18%) had type B3 thymoma and 43 (78%) had thymic carcinoma. The majority were male (64%), and the median age was 58 years. Among the 49 eligible patients who started treatment, PFSR-6 by central review was 35% [95% confidence interval (CI) 22% to 50%]. The overall response rate and disease control rate were 12% (95% CI 5% to 25%) and 63% (95% CI 48% to 77%), respectively. Using the Kaplan-Meier method, median progression-free survival and overall survival by local assessment were 6.0 (95% CI 3.1-10.4) months and 21.3 (95% CI 11.6-not estimable) months, respectively. In the safety population of 54 patients, adverse events (AEs) of grade 1/2 were observed in 22 (41%) patients and grade 3/4 in 31 (57%) patients. Treatment-related AEs of grade 4 included one case of neutropenia, one case of immune-mediated transaminitis, and two cases of myocarditis. CONCLUSIONS: Nivolumab monotherapy demonstrated an acceptable safety profile and objective activity, although it has been insufficient to meet its primary objective. The second cohort of NIVOTHYM is currently ongoing to assess the combination of nivolumab plus ipilimumab.

Study Design and Rationale for Marble Study: A Phase II Trial of Atezolizumab (MPDL3280A) Plus Carboplatin and Paclitaxel in Patients With Advanced or Recurrent Thymic Carcinoma (JTD2101).

BACKGROUND: Thymic carcinoma (TC) is a rare thymic epithelial tumor, and advanced or recurrent TC has limited prognosis. Treatment for chemotherapy-naïve, advanced, or recurrent TC remains unchanged with the combination of carboplatin and paclitaxel; therefore, a new treatment strategy is warranted. Immune checkpoint blockades inhibiting the programmed cell death-1 (PD-1) pathway (PD-1 and its ligand, PD-L1) have shown potential as a monotherapy for TC, although the efficacy of monotherapy was moderate for previously treated TC. We hypothesized that the combination of an anti-PD-L1 antibody, atezolizumab, with carboplatin and paclitaxel, would be effective in inducing immunogenic cell death in patients with advanced or recurrent TC. METHODS: We initiated a multicenter, single-arm, open-label phase II study of atezolizumab combined with carboplatin and paclitaxel for metastatic or recurrent TC. Eligible patients will receive atezolizumab plus carboplatin and paclitaxel every 3 weeks for up to 6 cycles, followed by atezolizumab every 3 weeks for up to 2 years until progression or unacceptable toxicity. A total of 47 patients will be enrolled in this study, with a 24-month enrollment period and 12-month follow-up. The primary endpoint is the objective response rate (ORR), based on an independent central review. The secondary endpoints are the investigator-assessed ORR, disease control rate, progression-free survival, duration of response, overall survival, and safety. RESULTS: This study aims to establish the safety and efficacy of atezolizumab combined with carboplatin and paclitaxel in patients with advanced or recurrent TC. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT), jRCT2031220144. Registered on June 18, 2022, https://jrct.niph.go.jp/en-latest-detail/jRCT2031220144.

Thymoma with pleural metastases. / Tymom med pleurametastaser.

Metastatic thymoma is a rare and serious condition that is treated with cytostatics according to the guidelines. Cytostatics have limited efficacy and are toxic. This case report illustrates how glucocorticoid treatment can have a significant effect.

Immune checkpoint inhibitor sintilimab-induced lethal myocarditis overlapping with myasthenia gravis in thymoma patient: A case report.

RATIONALE: Immune checkpoint inhibitors have been extensively used and significantly improved the clinical outcomes in multiple types of cancer. But the immune-related adverse events occur frequently, particularly in thymoma. The cardiac immune-related adverse, which is relatively rare but fatal, have been increasing reported. PATIENT CONCERNS: A 45-year-old thymoma patient was admitted to our hospital after receiving anti-programmed cell death-1 treatment with sintilimab 14 days later, accompanied by abdominal pain, intermittent chest tightness and dizziness. DIAGNOSES: The laboratory tests revealed elevated serum troponin I. Electrocardiogram reported the prolongation of QTc interval. Echocardiography showed small amount of pericardial effusion, a left ventricular ejection fraction of 71%. Coronary artery computed tomography angiography revealed localized noncalcified plaque in the middle of the left anterior descending artery and mild stenosis of the lumen. Enhanced computed tomography scanning of the whole abdomen showed no abnormal signs in the parenchyma organs. Combining the results of the examinations, the Immune checkpoint inhibitor induced myocarditis was diagnosed. INTERVENTIONS: The patient was treated with glucocorticoids (120 mg/day, IV, methylprednisolone) within 24 hours of admission. Seven days later, the patient experienced tachy ventricular arrhythmia and cardiogenic shock and was transferred to intensive care unit after electrical cardioversion, tracheal intubation and cardiopulmonary resuscitation. Intravenous immunoglobulin therapy at 25 g/day was given and methylprednisolone was reduced to 40 mg/day for the next 3 days. Intravenous esmolol and lidocaine were used for correcting arrhythmias. Ventilator positive pressure ventilation was used for respiratory support. She was administrated with plasmapheresis when the electrocardiogram monitoring showed ventricular arrhythmia storms. OUTCOME: The patient progressed to ventricular arrhythmia storms and cardiac failure, which eventually resulted in death. LESSONS: The case aims to raise awareness of immune-mediated cardiotoxicity and bring thoughts to the prospects of immunotherapy in thymoma.

Sustained antitumor response to lenvatinib with weekend-off and alternate-day administration in chemotherapy-refractory thymic carcinoma: a case report.

Lenvatinib is a multitargeted kinase inhibitor and maintaining its dose intensity has been shown to be beneficial in patients with thyroid and hepatocellular carcinomas. However, most patients require lenvatinib interruption and dose reduction due to the high incidence of adverse events (AEs). Lenvatinib was recently approved in Japan for patients with unresectable thymic carcinoma; however, real-world evidence of its clinical benefit is limited. Here, we report the case of chemotherapy-refractory thymic carcinoma in a patient who was administered a starting dose of lenvatinib using a 5-day on/2-day off (weekend-off) protocol, followed by alternate-day administration after fatigue onset derived from overt or subclinical hypothyroidism. Consequently, the patient exhibited a durable response to lenvatinib, with a 17-month progression-free survival without any severe or intolerable AEs. The present case suggests that maintaining lenvatinib dose intensity using such alternative administration regimens contributes to favorable clinical outcomes in thymic carcinoma.

Anlotinib in patients with relapsed or refractory thymic epithelial tumors: a study of 50 cases.

The optimal pharmaceutical regimen for advanced thymic epithelial tumors (TETs) remains controversial when first-line chemotherapy fails. This retrospective study aims to evaluate the efficacy and safety of anlotinib treatment for patients with relapsed and refractory TETs. Patients with progressive disease after failure of platinum-based chemotherapy were enrolled in this study. Anlotinib was orally taken once a day at an initial dose of 12 mg (10 mg when body weight <60 kg). The cycle was repeated every 3 weeks (2 weeks of treatment followed by 1-week rest). Objective response rate (ORR) and progression-free survival (PFS) were recorded as primary endpoints. There were 50 patients enrolled in this study from October 2018 to June 2021 at a median age of 50 (range 23-79) years old. Patients with thymoma and thymic carcinoma were 33 (66%) and 17 (34%), respectively. The ORR in thymoma and thymic carcinoma patients were 33% (11/33) and 41% (7/17), respectively. The median PFS (mPFS) was 7 (95% CI, 5.9-10.2) months in thymoma patients and 6 (95% CI, 4.6-9.3) months in the thymic carcinoma group. Eleven patients experienced dose reduction due to toxicities, among whom, eight patients discontinued treatment even after dose reduction. Six patients with thymoma showed myasthenia gravis deterioration during treatment, and two of them died of myasthenia gravis crisis. Anlotinib is active in patients with advanced TETs refractory to routine chemotherapy. Prescription of anlotinib to patients with myasthenia gravis should be made cautiously.

Understanding the landscape of immunotherapy in thymic epithelial tumors.

Thymic epithelial tumors (TETs) are a rare group of malignancies arising from the thymus. Surgery remains the foundation of treatment for patients with early-stage disease. Limited treatment options are available for the treatment of unresectable, metastatic, or recurrent TETs and are associated with modest clinical efficacy. The emergence of immunotherapies in the treatment of solid tumors has generated significant interest in understanding their role in TET treatment. However, the high rates of comorbid paraneoplastic autoimmune disorders, particularly in thymoma, have tempered expectations regarding the role of immune-based therapies. Clinical studies of immune checkpoint blockade (ICB) in thymoma and thymic carcinoma have revealed higher frequencies of immune-related adverse events (IRAEs) and limited efficacy. Despite these setbacks, the growing understanding of the thymic tumor microenvironment and systemic immune system has advanced the understanding of these diseases and provided opportunities for novel immunotherapy modalities. Ongoing studies are evaluating numerous immune-based treatments in TETs with the goal of improving clinical efficacy and mitigating IRAE risk. This review will provide insight into the current understanding of the thymic immune microenvironment, outcomes of previous ICB studies, and review treatments currently being explored for the management of TET.

The efficacy of small molecule anti-angiogenic drugs in previously treated Thymic carcinoma.

BACKGROUND: Antiangiogenic drugs have shown initial efficacy in the treatment of advanced thymic carcinomas (TCs); however, data are limited. In this study, we provide real-world data relating to the efficacy of antiangiogenic drugs for the treatment of patients with TCs. METHODS: We retrospectively collected data on clinical progress after first-line chemotherapy in TCs patients who were treated with small molecule antiangiogenic drugs at our institution between January 2010 and December 2021. Tumor response was evaluated according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Progression free survival and overall survival were calculated using the Kaplan-Meier method. RESULTS: Of the 17 patients enrolled, 13 (76.5%) received apatinib and four (23.5%) anlotinib monotherapy with an objective response rate of 23.5%. Eleven (64.7%) patients had stable disease. The median follow-up period was 46.0 months (95% confidence interval [CI], 33.0-59.0 months). The median progression survival and overall survival were 7.9 months (95% CI, 6.5-9.3) and 47.0 months (95% CI, 35.4-58.6), respectively. In the 13 patients receiving apatinib, the median PFS was 7.0 months (95% CI, 5.0-9.0), compared with 8.0 months (95% CI, 2.7-13.3 months) for patients in the anlotinib group (P = 0.945). The most common grade 3 adverse events (AEs) were hypertension (n = 3, 23.1%), followed by proteinuria and hand-foot syndrome (HFS, n = 2, 15.4%). There were no grade 4 AEs although eight patients (47.1%) required mid-course discontinuation. CONCLUSION: For refractory TCs, small molecule antiangiogenic drugs are efficacious as second- or post-line treatments. The toxicity of antiangiogenic therapy is manageable.

Combination carboplatin and nab-paclitaxel as a first-line treatment for advanced thymic carcinoma.

Thymic carcinoma is a very rare neoplasm for which no optimal chemotherapeutic regimen has been established to date. Hence, we performed this study to investigate the efficacy and safety of carboplatin plus nanoparticle albumin-bound (nab)-paclitaxel as a first-line regimen for patients with advanced thymic carcinoma. We conducted this multi-institutional retrospective cohort study of patients with advanced thymic carcinoma who had received carboplatin plus nab-paclitaxel as a first-line chemotherapy between August 2013 and December 2021. Twelve patients were included in this study and were subjected to efficacy and safety analysis. Their median age was 62 years (range, 47-74 years), and all had an Eastern Cooperative Oncology Group performance status score of 0 or 1. After a median follow-up time of 19.7 months, the overall response rate was 50%; the median progression-free and overall survival times were 8.8 months and 23.3 months, respectively. Chemotherapy-related peripheral neuropathy was observed in 2 patients (16%; each with grade 1). Other toxicities were manageable, and there were no treatment-related deaths. Carboplatin plus nab-paclitaxel as a first-line chemotherapy regimen showed good efficacy and safety in patients with advanced thymic carcinoma.

Immune checkpoint blockers in patients with unresectable or metastatic thymic epithelial tumours: A meta-analysis.

BACKGROUND: For patients with advanced thymic epithelial tumours (TET), there is no standard second-line treatment after platinum-based chemotherapy. Although immune checkpoint blockers (ICB) are a potential treatment strategy, their efficacy seems limited with an increased risk of immune-related adverse events (ir-AEs), thus hampering their application in daily clinical practice. METHODS: We performed a meta-analysis to better evaluate the existing evidence about the activity and safety of ICB in the setting of unresectable or metastatic advanced TET previously treated with platinum-based chemotherapy. RESULTS: Six phase I/II trials met the eligibility criteria including a total of 166 evaluable patients (77% thymic carcinoma, 23% thymoma) evaluable for activity after being treated with pembrolizumab, nivolumab, avelumab or atezolizumab. The overall response rate to ICB was 18.4% (95% CI: 12.3-26.5), and the one-year progression-free survival rate and one-year overall survival rate were 26.0% (95% CI: 19.6-34.6) and 66.9% (95% CI: 59.6-75.2%), respectively. The incidence of grade 3-5 ir-AEs was 26.4%, with 17.1% in thymic carcinoma and 58.3% in thymoma. CONCLUSIONS: Despite the absence of a robust demonstration of efficacy in the context of randomised trials, our results suggest ICB as a potential strategy in patients with pretreated TET, mainly among patients with thymic carcinoma. Close monitoring is strongly advised to detect severe immune-toxicity.