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.

Remarkable response to pazopanib plus vivolumab in a patient with pericardial synovial sarcoma carrying a novel genotype BRCA2 c.968dupT: A case report.

Pericardial synovial sarcomas (PSS) have a low incidence rate and are highly invasive with a dismal prognosis. Standard treatment includes surgery, radiotherapy and chemotherapy but with limited response. Here, we report the case of a 15-year-old nonsmoking youngster diagnosed with PSS who developed disease relapsed from surgery after 1 month. Next-generation sequencing (NGS) using baseline tissue was performed, and BRCA2 c.968dupT was detected. Then pazopanib (a multitargeted inhibitor) plus nivolumab (an immune checkpoint inhibitor) was administered, with a partial response and progression-free survival of 14 months. BRCA2 c.968dupT has not previously been reported in PSS and its response to targeted combination immunotherapy are not well characterized. Here, we report the efficacy of pazopanib combined with nivolumab in a PSS patient harboring BRCA2 c.968dupT and also provide the clinical evidence of the utility of NGS in exploring actionable mutations for solid tumor. Combination therapy based on immunotherapy may be a potential treatment choice for PSS harboring BRCA2 mutation.

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.

Myasthenia gravis treatment in the elderly presents with a significant iatrogenic risk: a multicentric retrospective study.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease treated with acetylcholinesterase inhibitors and immunosuppressant/immunomodulatory drugs. MG is frequently diagnosed in elderly patients, a fragile population in which treatment adverse effects (TAE) have not been evaluated until now. METHODS: We retrospectively analysed the files of all MG patients with disease onset after age 70 years in four French University Hospitals, including clinical, electrophysiological, biological, and treatment data, with an emphasis on TAE. MG outcomes were assessed using the Myasthenia Gravis Foundation of America (MGFA) status scale. RESULTS: We included 138 patients (59% of men) with a mean follow-up of 4.5 years (range 1-19). Mean age at diagnosis was 78 years (70-93). Anti-acetylcholine receptor antibodies were found in 87% of cases, electrophysiological abnormalities in 82%, and thymoma in 10%. MG outcome was good in a majority of cases, with 76% of treated patients presenting with alleviated symptoms at follow-up. TAE were observed in 41% of patients, including severe TAE in 14% of cases. Seven patients (5.1%) died, including four (2.9%) from MG-related respiratory failure, and three (2.2%) from MG treatment-related complications, i.e., sepsis in 2 cases and brain toxoplasmosis in 1 case. TAE were observed in 53% of patients treated with azathioprine, 23% of patients treated with corticosteroids, and 15% of patients treated with mycophenolate mofetil. CONCLUSIONS: This retrospective study demonstrates MG in the elderly presents with a significant iatrogenic risk, including fatal immunosuppressant-related infections.

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.

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

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

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.

Differentiation between rebound thymic hyperplasia and thymic relapse after chemotherapy in pediatric Hodgkin lymphoma.

BACKGROUND: Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. METHODS: After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. RESULTS: After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. CONCLUSION: Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.

Everolimus in combination with octreotide LAR in thymic atypical carcinoid.

Thymic atypical carcinoids are extremely rare tumors and have a poor prognosis owing to their aggressive clinical course. The efficacy of treatments other than complete surgical resection is unclear. We herein report a postoperative recurrent case of thymic atypical carcinoid treated with everolimus and octreotide long-acting repeatable (LAR). A 75-year-old woman was admitted to our department because a nodule was detected in the right lobe of thymus by annual computed tomography. The patient underwent thymothymectomy, and a diagnosis of thymic atypical carcinoid was made. One year and seven months after surgery, she developed multiple metastases in the lung, hilar and mediastinal lymph nodes, liver, and bone. Everolimus 10 mg/day was administered; however, the dose had to be reduced to 5 mg/day due to grade 3 hyperglycemia and grade 3 interstitial lung disease. Metastatic lesions other than liver metastasis markedly responded to everolimus, although the liver metastases gradually progressed. Three years and six months after surgery, she was administered octreotide LAR 30 mg per month in combination with everolimus. She has maintained stable disease for 8 months after the application of this combination therapy.

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.