Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation.

Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/ß inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

Preliminary analysis of immune-related markers in thymic carcinoid.

The immune-related microenvironment of thymic carcinoid has rarely been reported. We analyzed the expression of PD-L1 and VISTA, and the distribution of CD4+ T cells, CD8+ T cells and CD68+ macrophages in the thymic carcinoid by immunohistochemical staining, and showed the correlation between these markers and clinical survival, indicating the potential therapeutic prospects.

SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer.

Lymph node (LN) metastasis is one of the predominant metastatic routes of non-small cell lung cancer (NSCLC) and is considered as a leading cause for the unsatisfactory prognosis of patients. Although lymphangiogenesis is well-recognized as a crucial process in mediating LN metastasis, the regulatory mechanism involving lymphangiogenesis and LN metastasis in NSCLC remains unclear. In this study, we employed high-throughput sequencing to identify a novel circular RNA (circRNA), circTLCD4-RWDD3, which was significantly upregulated in extracellular vesicles (EVs) from LN metastatic NSCLC and was positively associated with deteriorated OS and DFS of patients with NSCLC from multicenter clinical cohort. Downregulating the expression of EV-packaged circTLCD4-RWDD3 inhibited lymphangiogenesis and LN metastasis of NSCLC both in vitro and in vivo. Mechanically, circTLCD4-RWDD3 physically interacted with hnRNPA2B1 and mediated the SUMO2 modification at K108 residue of hnRNPA2B1 by upregulating UBC9. Subsequently, circTLCD4-RWDD3-induced SUMOylated hnRNPA2B1 was recognized by the SUMO interaction motif (SIM) of ALIX and activated ALIX to recruit ESCRT-III, thereby facilitating the sorting of circTLCD4-RWDD3 into NSCLC cell-derived EVs. Moreover, EV-packaged circTLCD4-RWDD3 was internalized by lymphatic endothelial cells to activate the transcription of PROX1, resulting in the lymphangiogenesis and LN metastasis of NSCLC. Importantly, blocking EV-mediated transmission of circTLCD4-RWDD3 via mutating SIM in ALIX or K108 residue of hnRNPA2B1 inhibited the lymphangiogenesis and LN metastasis of NSCLC in vivo. Our findings reveal a precise mechanism underlying SUMOylated hnRNPA2B1-induced EV packaging of circTLCD4-RWDD3 in facilitating LN metastasis of NSCLC, suggesting that EV-packaged circTLCD4-RWDD3 could be a potential therapeutic target against LN metastatic NSCLC.

Identification of predictors of long-term survival and prognostic outcomes in thymic squamous cell carcinoma: A real-world study.

BACKGROUND: Although thymic squamous cell carcinoma (TSCC) is among the most prevalent forms of thymic carcinoma, there are relatively few studies on this tumor type, and its staging, optimal treatment strategies, and relevant prognostic factors remain controversial. METHODS: The present study analyzed 79 patients diagnosed with TSCC between January 2008 and January 2021. Kaplan-Meier curves and Cox univariate and multivariate regression analyses were used to explore factors associated with overall survival (OS) and progression-free survival (PFS) in the overall patient cohort and patient subgroups stratified according to the TNM stage. Time-dependent receiver operating characteristic (ROC) analyses were used to compare the TNM and Masaoka systems as predictors of patient prognosis. RESULTS: The 5- and 10-year OS rates in this study were 65.5% and 49.4%, respectively, with corresponding 5- and 10-year PFS rates of 52.3% and 37.9%. Survival outcomes were better for patients with early-stage disease (p < 0.001) and patients that underwent surgical treatment (p < 0.001). Neither extent of resection (p = 0.820) nor the surgical approach (p = 0.444) influenced patient survival. In individuals with advanced disease, all forms of adjuvant therapy including radiotherapy (p = 0.021), chemotherapy (p = 0.035), and chemoradiation (p = 0.01) significantly improved patient PFS, but only adjuvant chemoradiotherapy improved patient OS (p = 0.035). When predicting the patient survival outcomes, the TNM system was slightly superior to the Masaoka system (area under the ROC curve [AUC] at 5 years: OS, 0.742 vs. 0.723; PFS, 0.846 vs. 0.816). CONCLUSION: TSCC is an orphan malignancy with a poor prognosis. TNM staging may be superior to Masaoka staging as a predictor of TSCC patient prognosis. Surgery is the mainstay of TSCC treatment. Video-assisted thoracoscopy (VATS) should be considered for selected patients. Multimodal therapy was associated with excellent results for patients with advanced TNM stage, particularly when surgery was accompanied by adjuvant chemoradiation.

Real-world study of treatment and outcome of type B2 + B3 thymoma: The neglected part of thymoma.

BACKGROUND: This study aimed to examine the treatment and prognosis of patients with type B2 + B3 thymoma and compare it with those patients with type B2 and B3 thymoma. METHODS: We conducted a retrospective analysis of the results of 39 patients with type B2 + B3 thymoma, 133 patients with type B2 thymoma, and 64 patients with type B3 thymoma. The Kaplan-Meier technique was used to generate survival curves. For multivariate analysis, the Cox proportional hazard model was applied. RESULTS: With a median follow-up of 60 months (range: 1-128 months), the percentage of patients with tumor, node, metastasis (TNM) stage III and IV disease gradually increased from 19.5% to 25.6% to 35.9% among those with histological subtypes B2, B2 + B3, and B3, respectively, p = 0.045. Twenty-three patients experienced recurrence or metastasis. The total 10-year progression-free survival (PFS) rates were 86.0% overall (85.0% in type B2, 87.2% in type B2 + B3, and 87.5% in type B3). Age, R0 resection, and Masaoka-Koga stage were found to have a significant on PFS in all patients. There was no statistically significant difference in PFS between different histotypes of thymoma, p = 0.650. PFS was predicted by R0 resection in all histotypes and by the Masaoka-Koga stage in the type B2 subgroup. CONCLUSION: Combining the two staging methods to guide the diagnosis and treatment of patients with B2 + B3 thymoma is recommended. R0 resection is recommended to reduce recurrence. Patients with B2 + B3 thymoma have a prognosis similar to those with a B2 thymoma or a B3 thymoma alone.

Mucosa-associated lymphoid tissue lymphoma in thymus: a SEER analysis.

OBJECTIVES: The present study explores an extremely rare disease, thymic mucosa-associated lymphoid tissue (MALT) lymphoma, for its characteristics and prognostic factors by analyzing the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: From 2000 to 2018, cases with a diagnosed thymic MALT lymphoma were extracted. Clinical characteristics, treatments, and survival patterns of these cases were analyzed. RESULTS: Thymic MALT lymphoma (n = 26) accounted for 0.09% of all MALT lymphomas. With a sex ratio of 0.53 (male/female), 68% white population was affected. Most cases were diagnosed with Ann Arbor stage I (50%), yet advanced-stage did not show worse prognosis (p = 0.236). Different treatment protocols did not influence the overall prognosis (p > 0.99). The 5- and 10- year overall survival rates were 83.1% and 78.2%, respectively. Older than 70 years may be an independent risk factor for overall survival (HR = 7.166 [95% CI 1.173-43.756], p = 0.033). CONCLUSION: Thymic MALT lymphoma is a highly rare disease with a favorable prognosis. Ann Arbor staging might not be appropriate to classify severity of this disease or its treatment. Older people may have worse survival. A standardized treatment mode needs to be established, and surgery could remain as the mainstay.

A systematic review and meta-analysis of thymic mucosa-associated lymphoid tissue lymphoma.

Background: Mucosa-associated lymphoid tissue (MALT) lymphoma of the thymus is a rare disease. The present meta-analysis aims at accumulating current evidence to explore the clinical characteristics, treatments, and prognoses of thymic MALT lymphoma. Methods: We searched seven databases for studies published between the start date of database establishment and September 15, 2021. We included studies of patients with histological diagnoses and excluded those without data specifically on thymic MALT lymphoma. The quality was analyzed using an assessment tool. All data were tabulated. Pooled proportion was obtained using random-effects model. Statistical analysis was performed on R statistic software. Results: Overall, 52 case reports and 13 case series were eligible. The quality of case reports was inferior to that of case series in terms of selection (P<0.001). Based on the analysis of patients in the case reports, age, gender, concurrent diseases, and tumor size did not differ between limited-stage and advanced-stage cases. Surgery is the mainstay to treat thymic MALT lymphoma. The surgical approach and extent did not influence the occurrence of events. Patients at Ann Arbor stage I were prone to not receiving postoperative therapy (P=0.011), though it may not reduce the occurrence of events (P=0.637). The five-year overall survival (OS) rate and five-year progression-free survival (PFS) rate were 97.2% and 88.4%, respectively. Patients with advanced-stage disease were more likely to suffer events (P=0.009). Conclusions: Thymic MALT lymphoma is an extremely rare disease with a favorable prognosis. Currently available evidence is insufficient to draw solid judgments about treatment and prognosis. However, patients may benefit if thymectomy is chosen as the primary treatment. In some patients, lymph node sampling or dissection should be considered. In addition, if the patient is at an advanced-stage, postoperative therapy should be considered.

Real-world clinicopathological features and outcome of thymic neuroendocrine tumors: a retrospective single-institution analysis.

BACKGROUND: Thymic neuroendocrine tumors comprise a heterogeneous group of rare diseases. This study aimed to investigate the real-world clinicopathological features and treatment outcomes of thymic neuroendocrine tumors. RESULTS: A total of 104 patients diagnosed with thymic neuroendocrine tumors in a single institution from 1983 to 2021 were eligible. Fourteen (13.46%) and 28 (26.92%) patients diagnosed with thymic neuroendocrine tumors suffered from multiple endocrine neoplasia and ectopic adrenocorticotropic hormone syndrome, respectively. Ninety-seven (93.27%) patients underwent surgical resection, including 79 (81.44%) with radical resection. Except for 5 patients lost during follow-up, the 1-, 3- and 5-year overall survival rates were 91.8%, 70.2% and 54.6%, respectively. The median overall survival was 61.57 months. Multivariate analysis revealed that years at diagnosis (HR 0.559, 95% CI 0.364-0.857, p = 0.008), radical resection (HR 2.860, 95% CI 1.392-5.878, p = 0.004), pathological grade (HR 1.963, 95% CI 1.058-3.644, p = 0.033) and Masaoka-Koga stage (HR 2.250, 95% CI 1.548-3.272, p = 0.000) exerted significant differences in overall survival among 99 patients. In the surgery group, multivariate Cox regression analysis exhibited significant overall survival differences in years at diagnosis (HR 0.563, 95% CI 0.367-0.866, p = 0.009), neoadjuvant therapy (HR 0.248, 95% CI 0.071-0.872, p = 0.030), radical resection (HR 3.674, 95% CI 1.685-8.008, p = 0.001), pathological grade (HR 2.082, 95% CI 1.098-3.947, p = 0.025) and Masaoka-Koga stage (HR 2.445, 95% CI 1.607-3.719, p = 0.000). CONCLUSIONS: Radical resection and Masaoka-Koga stage were independent prognostic factors for the survival of patients with thymic neuroendocrine tumors. Systemic therapy and integrated management of patients with advanced-stage disease require high-level clinical evidence.

Comparative analysis of the long-term outcomes of segmentectomy and lobectomy for stage IA1 lung adenocarcinoma in patients with or without previous malignancy of other organs: a population-based study.

BACKGROUND: For early stage non-small cell lung cancer, whether limited resection can yield comparable outcomes to those of lobectomy hasn't been established. We compared Overall survival (OS) and lung cancer-specific survival (LCSS) after segmentectomy or lobectomy in stage IA1 (≤10 mm) lung adenocarcinoma (LUAD) patients. RESEARCH DESIGN AND METHODS: We retrospectively recruited patients who'd been diagnosed with lung cancer for the first time and treated with segmentectomy or lobectomy, with or without previous other malignancy. RESULTS: 1788 patients were included. After propensity score matching: 5-year OS were 85.6% for segmentectomy and 84.7% for lobectomy (p=0.951); 5-year LCSS were 93.5% for segmentectomy; and 93.0% for lobectomy (p=0.726). Cox regression analysis revealed segmentectomy was comparable to lobectomy in OS and LCSS. Having a second lung cancer later in life was associated with a worse LCSS for lobectomy (p<0.05) rather than segmentectomy. After patients were stratified according to malignancy history, subgroup analyses showed no significant prognosis differences between two surgeries. CONCLUSIONS: For stage IA1 LUAD patients who were diagnosed with lung cancer for the first time, with or without previous other malignancy, segmentectomy yields comparable outcomes to those of lobectomy. It may provide better outcomes for patients with multiple suspicious nodules.

Clinicopathological Features and Prognosis of Primary Mediastinal Malignant Germ Cell Tumors: A Retrospective Single-Institution Analysis.

BACKGROUND: Given the lack of evidence-supported guidance for therapeutic recommendations of primary mediastinal malignant germ cell tumors (PMMGCTs), our study aimed to investigate the clinicopathological features, treatment strategies, and prognostic factors of PMMGCTs. METHODS: We carried out a consecutive retrospective evaluation on a series of patients diagnosed with PMMGCTs in Peking Union Medical College Hospital from January 2000 to August 2020. RESULTS: A total of 58 patients were eligible, consisting of 51 males and seven females. There were 15 patients with seminomas, 39 with nonseminomatous germ cell tumors (NSGCTs), and four with mixed germ cell tumors (GCTs). The 5-year overall survival was 45%, with a median survival time of 32.37 months. Except for the lost follow-up of seven patients, a univariate analysis of overall survival on the remaining patients showed significant differences in pathological type (mixed GCTs were regarded as NSGCTs) (p=0.036), tumor size (>11cm) (p=0.006), and other sites metastases (OSM) (p=0.001), respectively. Multivariate Cox regression analysis revealed that OSM and surgical resection were independently associated with overall survival in all kinds of PMMGCTs. CONCLUSION: OSM was an independent risk factor for patients with PMMGCTs. Surgery was proved to contribute to long-term survival. More in-depth clinical evidence is urgently needed to guide the treatment of PMMGCTs.

Popliteal artery entrapment syndrome as a cause of failed treatment of a false popliteal aneurysm.

OBJECTIVE: Popliteal artery entrapment syndrome is a rare cause of popliteal artery aneurysms. We present a rare case of a false aneurysm associated with popliteal artery entrapment syndrome that was treated with endovascular repair that initially failed. CASE REPORT: A 60-year-old man with a false popliteal artery aneurysm and limb ischemia was treated with endovascular repair that initially failed. The popliteal artery was suspected to be compressed by an abnormal bundle of muscle according to the findings of a subsequent magnetic resonance imaging examination. The popliteal artery was entrapped by an abnormal slip of the medial gastrocnemius muscle head. Parts of the popliteus muscle were also involved in compression of the popliteal artery, which was not distinguished on preoperative magnetic resonance imaging. Thus, the patient was diagnosed with a mixed type of popliteal artery entrapment syndrome (types III and IV). Bypass with the small saphenous vein was then performed. The patient was finally discharged with satisfactory relief of his ischemic symptoms. CONCLUSION: Popliteal artery entrapment syndrome should be considered before treating popliteal artery aneurysms, especially atypical pseudoaneurysms without significant atherosclerosis. Definitive surgical management rather than endoluminal treatment is required unless combined with open decompressive surgery to correct the musculotendinous anatomy.

An Observational Study of Sex Differences in Takayasu Arteritis in China: Implications for Worldwide Regional Differences.

BACKGROUND: This study analyzes the demographics of patients affected by Takayasu arteritis (TA). The study further explores the correlation and other contributory factors to the regional differences between the ratios of females to males (sex ratio). METHODS: This was a retrospective study using 1,011 clinical cases diagnosed with TA (as per 1990 American College of Rheumatology criteria) between 1982 and 2015 collected from the Peking Union Medical College Hospital (PUMCH) database. Literature review of TA studies published from 1992 to 2016 via the PubMed search was also conducted with exclusion of the studies less than 50 cases. General characteristics, sex ratios and regional differences worldwide, sex ratio variation in different age group, relationship between sex ratio and gross domestic product (GDP) per capita, and main lesion involved in different sexual group were statistically analyzed. RESULTS: The average age of these 1,011 patients was 32.5 ± 15.1 years, with 763 women comprising 75.5% of the cohort, giving a female-to-male ratio (F:M ratio) of 3.1:1. The F:M ratio of TA patients at PUMCH was equal to that of a previous study from China, but significantly lower than that in Japan, Italy, Turkey, Mexico, Korea (all P < 0.05), but higher than that in India (P < 0.05), and Thailand (although not statistically significant at P = 0.08). The sex ratio of TA patients between PUMCH and Japanese databases significantly differed at all age groups (P < 0.05), with the exception of the youngest (≤9 years; P = 0.57) and oldest (≥70 years; P = 0.32) patients. A significant correlation between the TA F:M ratio and GDP per capita was observed, with a correlation coefficient of ρ = 0.730 (P = 0.04). A sex difference in lesion distribution was also observed: women had significantly more aortic arch involvement (P = 0.02), whereas lower limb artery involvement was more frequent in men (P < 0.001). CONCLUSIONS: The sex ratio of patients with TA in China significantly differed from that in many other countries. Genetics, dietary habits, and environmental conditions may affect the incidences of TA in female versus male patients. Aortic arch branch vessels are involved more frequently in women; renal artery and iliac artery involvements are more common in men.

A complicated case of innominate and right common arterial aneurysms due to Takayasu's arteritis.

BACKGROUND: Innominate artery aneurysms (IAAs) are relatively rare. Endovascular therapy has been an alternative to open surgery in some IAA cases, but open repair is still necessary in complicated cases. CASE SUMMARY: We report a 35-year-old female who suffered from Takayasu's arteritis. The patient did not get regular treatment, and IAA and right common carotid artery aneurysm developed, which complicated with occlusion of the left carotid artery, subclavian artery, and the initial part of the left vertebral artery. The patient also had moderate aortic valve insufficiency. With inflammation being controlled well, the patient received the surgery for arterial aneurysms of innominate and right common carotid arteries and aortic valve insufficiency. The shunts for cerebral blood supply were designed to protect the brain and the surgery was conducted successfully under extracorporeal circulation. CONCLUSION: The case illustrates that open surgery may be appropriate for some complicated IAAs, and brain protection is important.