Nanocages engineered from Bacillus Calmette-Guerin facilitate protective Vγ2Vδ2 T cell immunity against Mycobacterium tuberculosis infection

Tuberculosis (TB), induced by Mycobacterium tuberculosis (Mtb) infection, remains a top killer among infectious diseases. While Bacillus Calmette-Guerin (BCG) is the sole TB vaccine, the clumped-clustered features of BCG in intradermal immunization appear to limit both the BCG protection efficacy and the BCG vaccination safety. We hypothesize that engineering of clumped-clustered BCG into nanoscale particles would improve safety and also facilitate the antigen-presenting-cell (APC)’s uptake and the following processing/presentation for better anti-TB protective immunity. Here, we engineered BCG protoplasts into nanoscale membraned BCG particles, termed as “BCG-Nanocage” to enhance the anti-TB vaccination efficiency and safety. BCG-Nanocage could readily be ingested/taken by APC macrophages selectively; BCG-Nanocage-ingested macrophages exhibited better viability and developed similar antimicrobial responses with BCG-infected macrophages. BCG-Nanocage, like live BCG bacilli, exhibited the robust capability to activate and expand innate-like T effector cell populations of Vγ2+ T, CD4+ T and CD8+ T cells of rhesus macaques in the ex vivo PBMC culture. BCG-Nanocage immunization of rhesus macaques elicited similar or stronger memory-like immune responses of Vγ2Vδ2 T cells, as well as Vγ2Vδ2 T and CD4+/CD8+ T effectors compared to live BCG vaccination. BCG-Nanocage- immunized macaques developed rapidly-sustained pulmonary responses of Vγ2Vδ2 T cells upon Mtb challenge. Furthermore, BCG- and BCG-Nanocage- immunized macaques, but not saline controls, exhibited undetectable Mtb infection loads or TB lesions in the Mtb-challenged lung lobe and hilar lymph node at endpoint after challenge. Thus, the current study well justifies a large pre-clinical investigation to assess BCG-Nanocage for safe and efficacious anti-TB vaccination, which is expected to further develop novel vaccines or adjuvants. Graphical Abstract

Massive Calcified Epithelioid Hemangioendothelioma With Multifocal Involvement: An Imaging Diagnosis Dilemma and a Rare Case Report

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor that develops from vascular endothelial or pre-endothelial cells. More than 60% patients have single-organ involvement, and involvement of multiple organs including the liver, lungs, and bones is extremely rare. The typical radiographic features of EHE include multiple small nodules in both lungs, which are usually located near small- and medium-sized blood vessels and the bronchi, and solitary, multiple, or diffuse lesions located at the hepatic periphery, spreading within the branches of the portal and hepatic veins. Radiologic calcification has been rarely reported in the literature. Here, we firstly described a case of a 53-year-old woman with EHE who presented with lungs, liver, bone, and right hilar lymph node involvement, manifesting as massive calcification on computed tomography. This case reminds physicians that EHE may present with unusual imaging manifestations, like massive calcification, and should be considered during the diagnostic process.

Laparoscopic Splenic Hilar Lymph Node Dissection is Recommended for Pathologic Stage IIIA Middle and Upper Gastric Cancer: A Comparative Study with Standard D2 Laparoscopic Distal Gastrectomy

Purpose D2 lymphadenectomy is considered a standard procedure for distal gastrectomy (DG). However, whether splenic hilar (No. 10) lymph node (LN) should be included in the extent of D2 lymphadenectomy for total gastrectomy (TG) is still controversial. Therefore, we assessed the survival benefit of laparoscopic No.10 LN dissection based on the comparison of long-term survival of patients undergoing laparoscopic TG (LTG) with laparoscopic No.10 LN dissection and laparoscopic DG (LDG). Methods The clinicopathological data of 2069 patients who underwent laparoscopic radical gastrectomy were retrospectively analyzed. The survival of the LDG group, the LTG with dissection of No. 10 LN (LTG+No. 10) group and the LTG without dissection of No. 10 LN (LTG-No. 10) group was compared. Results After adjusting for age, pT stage, pN stage and pTNM stage by 1:1:1 propensity score matching (PSM), there were 373 patients in each group. Kaplan-Meier (K-M) survival analysis showed that only in the pIIIA stage, the 5-year survival overall survival (OS) and cancer specific survival (CSS) of the LTG+No. 10 group was significantly better than that of the LTG-No. 10 group and comparable with that of the LDG group. Multivariate Cox regression analyses showed that dissection of No. 10 LN was an independent favorable factor for OS and CSS in all patients and patients with pIIIA. Conclusion In patients with stage pIIIA, those undergoing LTG with No. 10 LN dissection could achieve a long-term outcome comparable to that of patients at the same pathological stage undergoing LDG.

Diagnostic value of endobronchial ultrasound elastography combined with rapid onsite cytological evaluation in endobronchial ultrasound-guided transbronchial needle aspiration

Background Endobronchial ultrasound (EBUS) elastography has been used in EBUS-guided transbronchial needle aspiration (EBUS-TBNA) to identify malignant lymph nodes based on tissue stiffness. Rapid onsite cytological evaluation (ROSE) has been widely utilized for onsite evaluation of sample adequacy and for guiding sampling during EBUS-TBNA. The aim of this study was to investigate the diagnostic value of combined EBUS elastography and ROSE in evaluating mediastinal and hilar lymph node status. Methods Retrospective chart review was performed from December 2018 to September 2020. Patient demographics, EBUS elastography scores, and ROSE, pathologic, and clinical outcome data were collected. The EBUS elastography scores were classified as follows: Type 1, predominantly nonblue; Type 2, partially blue and partially nonblue; and Type 3, predominantly blue. A receiver operating characteristic curve was used to compare the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio for evaluation of malignant lymph nodes among the EBUS elastography, ROSE, and EBUS combined with ROSE groups. Results A total of 245 patients (345 lymph nodes) were included. The sensitivity and specificity of the EBUS elastography group for the diagnosis of malignant lymph nodes were 90.51% and 57.26%, respectively. The sensitivity and specificity in the ROSE group were 96.32% and 79.05%, respectively. The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of EBUS elastography combined with ROSE were 86.61%, 92.65%, 11.78, and 0.14, respectively, and the area under the curve was 0.942. Conclusions Combining EBUS elastography and ROSE significantly increased the diagnostic value of EBUS-TBNA in evaluating mediastinal and hilar lymph node status compared to each method alone.

Clinicopathological characteristics of IgG4-related lung disease

Background Immunoglobulin G4-related lung disease (IgG4-RLD) is a rare entity. We retrospectively analyzed the clinical and histopathological characteristics of patients with pathologically confirmed IgG4-RLD to improve the diagnosis rate and reduce the risk of misdiagnosis. Methods We screened the pathological reports of 4838 patients with pulmonary surgery and/or biopsy specimens from April 2017 to April 2021 at Sun Yat-Sen Memorial Hospital affiliated with Sun Yat-Sen University, and specimens from 65 patients with suspected IgG4-RLD were subjected to immunohistochemical staining for IgG4 and IgG. Finally, 10 patients with definite IgG4-RLD that was pathologically confirmed were enrolled and analyzed. Results The incidence of pathologically confirmed IgG4-RLD was 0.2% (10/4838). The ten patients had an average age of 59.7 years at diagnosis, and the male-to-female ratio was 9:1. The initial clinical manifestations were nonspecific, and cough was the most common symptom (4/10). More than one organ was involved in most patients (8/10), and mediastinal/hilar lymph node involvement was often observed (7/10). Serum IgG4 was analyzed in 6 patients and found to be elevated. Serum tumor marker levels were within the normal range or were slightly elevated. Computed tomography (CT) of the chest and/or 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) imaging revealed that 5 patients had a mixed type, 3 patients had the solid nodular type, and 2 patients had the bronchovascular type. All pulmonary masses and large nodules with solid patterns had spiculated margins and inhomogeneous enhancement with or without pleural indentation and a lobulated appearance. Abundant lymphoplasmacytic cell infiltration and fibrosis were observed in all patients. The expression of IgG4 and IgG was upregulated in the pulmonary sections. Seven patients were treated with glucocorticoids with or without additional immunosuppressants and responded well. Conclusions The results of our study suggest that multiple imaging findings, an elevated serum IgG4 concentration, and no significant increase in serum tumor biomarkers could provide diagnostic support for IgG4-RLD, especially for isolated IgG4-RLD or IgG4-RLD that includes other organ involvement that does not aid in establishing the diagnosis.

A Case of Lung Adenocarcinoma with Pulmonary Hypertrophic Osteoarthropathy Showing Pathological Complete Response to a Pembrolizumab-Containing Chemoimmunotherapy

A 65-year-old woman with prolonged cough and presumed pulmonary hypertrophic osteoarthropathy was referred to our hospital. Computed tomography showed 2 tumors larger than 3 cm in size and massive hilar lymph node enlargement in the right lung. Pathological examination of the transbronchial lung biopsy specimen showed atypical malignant cells, presumed adenocarcinoma, with 1% positivity of programmed cell death 1 ligand (PD-L1). Three courses of chemoimmunotherapy with pembrolizumab (400 mg q3w), carboplatin (AUC 5 mg/mL · min q3w), and pemetrexed (500 mg/m² q3w) were well tolerated and brought about a quasi-complete response both of the lung tumors and lymph nodes and complete symptom relief of the pulmonary hypertrophic osteoarthropathy, finally leading to the surgical intervention, that is, lobectomy and lymph node dissection. Postoperative pathological examination showed no viable cancer foci both in the lung tumors and lymph nodes. The patient recovered uneventfully. Physicians should note the combination chemoimmunotherapy including pembrolizumab, with curative intent, to optimally treat patients with locally advanced non-small cell lung cancer (NSCLC) even if the NSCLC bears a small amount of PD-L1.

Optic Perineuritis as a Presenting Sign of Sarcoidosis

Purpose: To report a rare case of optic perineuritis as the presenting sign of sarcoidosis. Case summary: A 57-year-old man presented with decreased visual acuity and pain with extraocular movement in his left eye starting 2 weeks earlier. He had a history of asymptomatic optic perineuritis in that eye 18 months previously, which had improved after 1 month on oral prednisolone. His best corrected visual acuity had decreased to 20/50 and he also had relative afferent pupillary defect and color vision defects in the left eye. Slit lamp examination results were normal. There were no inflammatory reactions in the anterior chamber or vitreous. Fundoscopy showed optic disc edema. Orbital magnetic resonance imaging showed diffuse enhancement surrounding the left optic nerve. The serum levels of eosinophil cationic protein and angiotensin- converting enzyme were markedly increased. A chest radiograph showed bilateral hilar lymph node enlargement. A biopsy via endobronchial ultrasound-guided transbronchial needle aspiration revealed multifocal non-caseating granulomas. Acid fast bacilli stain showed no evidence of tuberculosis. Based on these findings, he was diagnosed with sarcoidosis. After treatment with high-dose intravenous methylprednisolone and subsequent tapering with oral prednisolone for 6 months, the visual acuity improved. Conclusions: Optic perineuritis can be the initial sign of sarcoidosis. Therefore, sarcoidosis should be considered in the differential diagnosis of optic perineuritis.