OBJECTIVES:To investigate the role of antigranulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies in Aspergillus infections. METHODS:A retrospective study (2017-2025) was conducted to determine the prevalence and clinical significance of neutralizing anti-GM-CSF autoantibodies in adult patients with chronic invasive Aspergillus rhinosinusitis (CIARS) and chronic pulmonary aspergillosis (CPA). Neutralizing capacity of anti-GM-CSF autoantibodies was confirmed via STAT5 phosphorylation inhibition assays. Firth's penalized likelihood logistic regression was used to identify independent risk factors for blindness in CIARS. RESULTS:High-titer neutralizing autoantibodies were detected in 6.0% (8/133) of patients with CIARS, significantly higher than in patients with CPA (1.3% [3/224]; P = 0.022) and healthy controls (0%; P = 0.023). Most patients with autoantibodies were phenotypically immunocompetent. In the CIARS cohort, autoantibody positivity was strongly associated with orbital involvement (87.5% vs 36.8%; P = 0.007) and blindness (50.0% vs 15.2%; P = 0.030). Multivariable Firth regression identified anti-GM-CSF autoantibody positivity as an independent driver of blindness (adjusted OR 6.55, 95% CI: 1.37-31.32; P = 0.019), distinct from the risk posed by sphenoid sinus involvement. CONCLUSIONS:Neutralizing anti-GM-CSF autoantibodies define a specific, high-risk immunologic endotype in CIARS, characterized by aggressive orbital extension in otherwise immunocompetent hosts. Routine screening for anti-GM-CSF autoantibodies in invasive Aspergillus rhinosinusitis could facilitate early risk stratification and prompt aggressive intervention to preserve vision.

Background To investigate the seroprevalence of Aspergillus IgG antibodies among patients with chronic invasive Aspergillus rhinosinusitis (CIARS) and to assess their prognostic value for extrasinonasal involvement and therapeutic outcomes. Methods A total of 132 patients with histopathologically confirmed CIARS were included. Serum Aspergillus IgG antibody levels were measured by enzyme-linked immunosorbent assay. Univariate and multivariable analyses were conducted to identify independent predictors of extrasinonasal involvement. To evaluate the prognostic value of antibody monitoring, serial Aspergillus IgG levels were assessed, and their association with radiological remission was analyzed. Results Among the 132 patients, 50 (37.9%) tested positive for Aspergillus IgG antibodies. Seropositivity was significantly higher among patients with extrasinonasal involvement than among those without such involvement (59.2% vs 8.9%; P < .001). Multivariable analysis identified positive serum Aspergillus IgG antibodies (odds ratio [OR] = 11.28, 95% confidence interval [CI]: 3.67-34.64, P < .001), sphenoid sinus involvement (OR = 4.72, 95% CI: 1.89-11.79, P < .001), and ethmoid sinus involvement (OR = 5.22, 95% CI: 1.53-17.86, P = .008) as independent predictors of extrasinonasal involvement. Serial antibody monitoring was conducted to evaluate treatment outcomes, revealed a significant decrease in Aspergillus IgG levels in the radiological and clinical remission groups after antifungal therapy (median = 16.12 NovaTec units [NTU]; interquartile range [IQR] = 12.87-21.96 vs median = 9.21 NTU; IQR = 6.52-13.23; P < .001). In contrast, no significant change was observed in the stable disease group. Conclusions Aspergillus IgG antibody is a promising noninvasive biomarker associated with extrasinonasal invasion and disease progression in CIARS.

Mucormycosis is a medical emergency associated with high morbidity and mortality, primarily affecting immunocompromised individuals. The treatment of mucormycosis remains challenging due to the limited effective antifungal options. This study aimed to assess the real-world efficacy and safety of long-term, low-dose amphotericin B colloidal dispersion (ABCD) in the treatment of mucormycosis. This retrospective study at Huashan Hospital included mucormycosis patients treated with ABCD between August 1, 2021, and April 30, 2024. Efficacy and safety were assessed, and prognostic factors for 90-day mortality were identified using a Cox proportional hazards model. Thirty-eight patients were included. Pulmonary mucormycosis was the most common (60.5

PURPOSE:The nature of true neoplastic cells of giant cell tumor of bone (GCTB) remains unverified. As the effect of denosumab on true neoplastic cells needs to be clarified, direct targeting of these cells remains unclear. METHODS:In this study, we obtained 32 formalin-fixed paraffin-embedded (FFPE) GCTB tissue blocks, performing H&E staining and immunohistochemistry staining of CD68. Multinucleated giant cells, monocytes, and CD68-negative mononuclear spindle cells were accurately captured by laser capture microdissection. The DNA of these cells was extracted, digested with HpaII and subjected to nested PCR amplification. We isolated and cultured GCTB primary tumor cells. The primary tumor cells were treated with denosumab and PDGFRA inhibitors. CCK8 assays and RT-qPCR were performed to reveal the effect of the inhibitors. RESULTS:In HUMARA-heterozygous samples, CD68 negative mononuclear spindle cells appeared as only one main peak after digestion, which suggests that the CD68 negative mononuclear spindle cells are monoclonal. Denosumab had no direct effect on the growth of GCTB primary tumor cells. PDGFRA inhibitor Avapritinib had a direct inhibitory effect on the growth of the tumor cells and altered the tumor cell phenotype. AKT inhibitors had a similar inhibitory effect as Avapritinib. Avapritinib altered the expression of AKT-related genes, and down-regulated pGSK3β. The downregulation of pAKT and pGSK3β was partially reversed by co-treatment with the AKT agonist SC79, suggesting PI3K/AKT as a downstream pathway of PDGFRA. CONCLUSION:CD68 negative mononuclear spindle cells are the true neoplastic cells of GCTB. PDGFRA inhibition may be a novel targeted therapy for GCTB.

Benign fibrous histiocytoma (BFH) within the intracerebral region is remarkably rare. Our report details 2 cases of unusual BFH instances that exhibit no adhesion to the dura mater or cerebral falx, accompanied by a comprehensive literature review. While magnetic resonance imaging demonstrates specific characteristics for BFH, it does not readily differentiate BFH from more common brain neoplasms like gliomas and metastatic tumors. The definitive diagnosis of BFH depends primarily on histopathological and immunohistochemical examinations. Total surgical resection is considered an efficacious therapeutic approach, emphasizing the necessity for prolonged postoperative surveillance to detect any potential tumor recurrence or metastasis.

Abstract Introduction: Breast cancer is still challenging despite advanced therapies. Disintegrin and metalloproteinase 10 (ADAM10) is best known for shedding the extracellular domain of transmembrane proteins, such as Notch, EGFR, HER2, E-cadherin, CD44, thus participating in carcinogenesis. Here, we performed a comprehensive analysis about the clinicopathological features, predictive value of ADAM10 and immune profiles in breast cancer. Methods: ADAM10 genomic, transcriptome, prognostic data, and immune profiles in breast cancer were retrieved from the Oncomine, The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA) and Genotype-Tissue Expression (GTEx) databases. They were analysed with ggpolt2, survminer, GSVA R packages or online tools. Clinical data of breast cancer patients were collected from Huashan Hospital. ADAM10 protein expression was detected by immunohistochemistry. The correlation between clinicopathological characteristics and ADAM10 protein expression were analysed by logistic regression, and prognostic value of ADAM10 were evaluated by Kaplan-Meier method and Cox regression. Results: ADAM10 mRNA was overexpressed in breast cancer compared with normal tissues. Luminal A, luminal B and HER2-enriched subtypes showed higher ADAM10 mRNA levels of than basal-like group. Gene alterations in ADAM10, high mRNA and protein levels of ADAM10 correlate with worse prognosis. HER2-enriched subtype tended to have a favourable OS with low ADAM10 expression. In addition, ADAM10 is associated with specific immune cells (T helper, Tcm, Tem cells, etc) and is positively related to PD-L1. Conclusion: High mRNA and protein expression of ADAM10 is associated with adverse outcome. ADAM10 contributes as an independent prognostic factor and a promising therapeutic target in breast cancer.

BackgroundCentral nervous system (CNS) aspergillosis is an uncommon but fatal disease, the diagnosis of which is still difficult. ObjectivesWe aim to explore the diagnositic performance of noncultural methods for CNS aspergillosis. MethodsIn this retrospective study, all pathologically confirmed rhinosinusitis patients in whom cerebrospinal fluid (CSF) galactomannan (GM) test and metagenomic next-generation sequencing (mNGS) had been performed were included. We evaluated the diagnostic performances of CSF GM optical density indexes (ODI) at different cut-off values and compared performance with mNGS in patients with and without CNS aspergillosis, as well as in patients with different manifestations of CNS aspergillosis. ResultsOf the 21 proven and probable cases, one had positive culture result, five had positive mNGS results and 10 had a CSF GM ODI of >0.7. Sample concordance between mNGS and GM test was poor, but best diagnostic performance was achieved by combination of GM test (ODI of >0.7) and mNGS, which generated a sensitivity of 61.9% and specificity of 82.6%. Further investigation of combination diagnostic performances in different kind of CNS aspergillosis was also conducted. Lowest sensitivity (42.9%) was identified in abscess group, while increased sensitivity (60.0%) was achieved in abscess with encephalitis groups. Combination test exhibited the best performance for encephalitis patients who had only CSF abnormalities, in whom the sensitivity and specificity were 77.8% and 82.6%, respectively. ConclusionsIn conclusion, combination of these two tests might be useful for diagnosis of CNS aspergillosis associated with fungal rhinosinusitis, especially in encephalitis patients.

Background To define the role of C1qa in host defense against Cryptococcus neoformans lung infection, we investigated its susceptibility to cryptococcal lung infection in mice deficient in complement factor C1qa (C1qa(-/-)). Methods We established a wild-type (WT) and C1qa-deficient murine inhalation model with C. neoformans. We compared the host survival rate, inflammatory responses, and pathogenicity of C. neoformans during the infection course between WT and C1qa(-/-) mice. Results The mortality rate of C1qa-deficient mice was significantly higher than that of wild-type mice. The increased formation of Titan cells in the lungs was associated with augmented inflammation in C1qa-deficient mice. The capacity of lung homogenate supernatant from C1qa-deficient mice to induce Titan formation in vitro was greater compared with that of wild-type mice. The C. neoformans isolated from the lungs of infected C1qa-deficient mice was more resistant to macrophage killing in vitro and caused significantly higher mortality after administration to mice compared with that isolated from WT mice. Conclusions These findings reveal a novel role of C1qa in host defense against C. neoformans infection by regulating host inflammation and pathogen virulence and provide new insight into the C1q-mediated lung environment underlying the transition from yeast to Titan cell.

There are concerns on avoiding diagnostic delay and misdiagnosis for chronic pulmonary aspergillosis due to its high morbidity and mortality. A proportion of CPA patients test negative for Aspergillus IgG.

目的:通过对肺隐球菌病CT影像与组织病理的比对分析,提高对肺隐球菌的认识和诊断的准确性.方法:本研究纳入复旦大学附属华山医院2010年1月至2019年12月经胸部CT发现、视频辅助胸腔镜手术(video-assisted thoracoscopic surgery,VATS)切除、术后病理确诊的53例肺隐球菌病患者.通过比对胸部CT和组织病理图像特点,分析引起肺隐球菌影像学改变的组织学基础.结果:胸部CT显示在53例肺隐球菌病灶中,49例结节状、3例斑片状、1例斑片结节混合影;49例病灶不超过3 cm,其中24例小于1 cm;45例病灶距胸膜不超过1 cm;50例为高密度或高低密度混杂影,3例为磨玻璃影;18例病灶内见空泡,4例见透亮区,4例见支气管充气征,3例见空洞;24例病灶边缘见毛刺,13例边缘呈分叶状;31例病灶与周围肺组织分界清,22例与周围组织分界不清,出现晕征/磨玻璃影、血管集束和胸膜凹陷.组织学特点:53例肺隐球菌病灶中49例为肉芽肿性炎症,4例为非肉芽肿性组织细胞反应;肉芽肿病变中12例有炎性坏死、3例空洞形成、3例脓肿和1例隐球菌湖形成,8例见残留肺泡、3例见扩张支气管;病灶边缘机化13例,纤维包裹及炎性增宽肺泡隔各4例;病灶周围见出血及水肿18例,血管扩张、纠集和穿透共15例,胸膜牵拉10例.结论:肺隐球菌病的各种组织学特点导致了相应的影像学改变.了解引起肺隐球菌感染CT影像改变的组织学,结合穿刺标本的组织学检查可避免过诊断为恶性肿瘤,减少不必要的手术治疗.

肺淋巴瘤样肉芽肿病(pulmonary lymphomatoid granulomatosis，PLG)临床特征呈非特异性，与其他常见的肺部疾病类似，包括各种感染性疾病、结节病、血管炎、肺癌等，易被临床医师忽视。现报道1例36岁男性患者，反复发热，双肺可见多发团片状高密度影，经分子病理学检测与免疫组织化学检查诊断为EB病毒相关性PLG(3级)，继发噬血细胞综合征，PLG(3级)进展迅速，预后差。提示活组织检查对PLG的早期病理诊断和有效治疗至关重要。

BackgroundDifferential diagnosis of patients with suspected infections is particularly difficult, but necessary for prompt diagnosis and rational use of antibiotics. A substantial proportion of these patients have non-infectious diseases that include malignant tumors. This study aimed to explore the clinical value of metagenomic next-generation sequencing (mNGS) for tumor detection in patients with suspected infections. MethodsA multicenter, prospective case study involving patients diagnosed with suspected infections was conducted in four hospitals in Shanghai, China between July 2019 and January 2020. Based upon mNGS technologies and chromosomal copy number variation (CNV) analysis on abundant human genome, a new procedure named Onco-mNGS was established to simultaneously detect pathogens and malignant tumors in all of the collected samples from patients. ResultsOf 140 patients screened by Onco-mNGS testing, 115 patients were diagnosed with infections; 17 had obvious abnormal CNV signals indicating malignant tumors that were confirmed clinically. The positive percent agreement and negative percent agreement of mNGS testing compared to clinical diagnosis was 53.0% (61/115) and 60% (15/25), vs. 20.9% (24/115) and 96.0% (24/25), respectively, for conventional microbiological testing (both P <0.01). Klebsiella pneumoniae (14.8%, 9/61) was the most common pathogen detected by mNGS, followed by Escherichia coli (11.5%, 7/61) and viruses (11.5%, 7/61). The chromosomal abnormalities of the 17 cases included genome-wide variations and local variations of a certain chromosome. Five of 17 patients had a final confirmed with malignant tumors, including three lung adenocarcinomas and two hematological tumors; one patient was highly suspected to have lymphoma; and 11 patients had a prior history of malignant tumor. ConclusionThis preliminary study demonstrates the feasibility and clinical value of using Onco-mNGS to simultaneously search for potential pathogens and malignant tumors in patients with suspected infections.

环孢子虫病是一种肠道寄生虫病，人体通过食入被环孢子虫卵囊污染的水和食物而感染，摄入的卵囊通过侵犯小肠上皮细胞进入人体，尤以空肠为主，进而出现慢性肠炎的临床表现。本例患者以腹水为主要表现，血、腹水和骨髓检查结果均提示嗜酸性粒细胞水平增高明显，曾拟诊为"嗜酸细胞性胃肠炎"，并予以糖皮质激素治疗，患者腹胀症状一度出现好转，但在停药3个月后再次出现腹水，最终通过小肠黏膜病理和粪便直接涂片法在光学显微镜下找到环孢子虫卵囊确诊，服用复方磺胺甲噁唑得以痊愈。

Background: Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat, because it is so aggressive with shorter survival. Chemotherapy remains the standard treatment due to the lack of specific and effective molecular targets. The aim of the present study is to investigate the potential roles of A Disintegrin and Metalloproteinase 10 (ADAM10) on TNBC cells and the effects of combining ADAM10 expression and neoadjuvant chemotherapy treatment (NACT) to improve the overall survival in breast cancer patients. Methods: Using a series of breast cancer cell lines, we measured the expression of ADAM10 and its substrates by quantitative real-time PCR assay (qRT-PCR) and western blot analysis. Cell migration and invasion, cell proliferation, drug sensitivity assay, cell cycle and apoptosis were conducted in MDA-MB-231 cells cultured with ADAM10 siRNA. The effect of ADAM10 down-regulation by siRNA on its substrates was assessed by western blot analysis. We performed immunohistochemical staining for ADAM10 in clinical breast cancer tissues in 94 patients receiving NACT. Results: The active form of ADAM10 was highly expressed in TNBC cell lines. Knockdown of ADAM10 in MDA-MB-231 cells led to a significant decrease in cell proliferation, migration, invasion and the IC 50 value of paclitaxel and adriamycin, while induced cell cycle arrest and apoptosis. And these changes were correlated with down-regulation of Notch signaling, CD44 and cellular prion protein (PrPc). In clinical breast cancer cases, a high ADAM10 expression in pre-NACT samples was strongly associated with poorer response to NACT and shorter overall survival. Conclusions: These data suggest the previously unrecognized roles of ADAM10 in contributing to the progression and chemo-resistance of TNBC.

Glutathione S-transferase (GST) family members play an important role in detoxification, metabolism and carcinogenesis. The aim of this study is to investigate the effect of Glutathione S-transferase A1 (GSTA1) on the prognosis of HCC and to understand its role in tumor progression and the possible mechanism. GSTA1 in HCC was assessed using immunohistochemical staining, and it was found that HCC patients with better pathological differentiation had higher GSTA1 abundance. Further, high GSTA1 expression was correlated with low AFP, absent PVTT, and early stage TNM for HCC patients. Higher GSTA1 indicated longer overall survival and disease-free survival, while lower GSTA1 indicated poorer prognosis. Subsequently, lentiviral vector carrying GSTA1 gene was successfully constructed and maintained high expression in 97H and SNU449 liver cancer cells. We found that high GSTA1 restrained liver cancer cell proliferation, migration and invasion in vitro. Western blot showed that LKB1 and p-AMPK were upregulated while p-mTOR, p-p70 S6 Kinase and MMP-9 were downregulated in high GSTA1 groups. Taken together, high GSTA1 correlated with satisfactory prognosis of HCC. Additionally, GSTA1 may act as a protective factor through suppression of tumorigenesis by targeting AMPK/mTOR in HCC.

BACKGROUND:Chronic and granulomatous invasive fungal rhinosinusitis are important causes of blindness and craniocerebral complications. However, the classification of these 2 diseases remains controversial.METHODS:We retrospectively analyzed patients with chronic and granulomatous invasive fungal rhinosinusitus in a Chinese tertiary hospital from 2009 to 2017, with a focus on classification and comparisons.RESULTS:Among 55 patients enrolled in our study, 11 (11/55, 20%) had granulomatous invasive fungal rhinosinusitis (GIFRS) and 44 (44/55, 80%) had chronic invasive fungal rhinosinusitis (CIFRS). Aspergillus fumigatus and Dematiaceous hyphomycetes were identified in 2 patients with GIFRS. Compared with granulomatous type, CIFRS was more frequently encountered in immunocompromised patients (P = .022), and the time from onset to diagnosis was much shorter (P = .001). Proptosis and orbital apex syndrome showed no significant difference between granulomatous and CIFRS in our study. The treatment options and prognosis of both diseases also showed no significant difference.CONCLUSIONS:Despite the consensus on histopathology, the classification of the chronic and granulomatous types may need further evaluation in clinical considerations.

Background: Patients with non-muscle-invasive bladder cancer (NMIBC) need accurate estimations of the risk of recurrence and progression. Physicians can offer individualized therapy after identifying high-risk tumors. In our study, we compared the applicability of European Organization for Research and Treatment of Cancer (EORTC) risk tables and American Urological Association (AUA) risk stratification in Chinese patients with NMIBC. Methods: We retrospectively studied 301 patients with NMIBC who underwent transurethral resection of bladder tumor (TURBT) between October 2000 and July 2009 at Huashan Hospital of Fudan University and analyzed their parameters. The recurrence and progression rates at 1 and 5 years postoperatively were calculated along with 95% confidence intervals. We compared them with results obtained from the EORTC risk tables and AUA risk stratification. P values <.05 were considered statistically significant. Results: The median patient age was 67 years (21-92 years) and the median follow-up duration was 46 months (2-151 months). We used EORTC risk tables to classify patients into 3 groups, depending on whether they suffered recurrence or progression after TURBT. Kaplan-Meier curves showedsignificant differencesamong the 3 recurrence-free survival (RFS) levels (P<.0001, log-rank test) and among the 3 progression-free survival (PFS) levels (P<.0001, log-rank test). AUA risk stratification showed the same results. Both classifications were suitable to predict recurrence and progression in Chinese patients. However, for high-risk patients in both series, Kaplan-Meier curves showed significant differences between RFS levels (P<. 0001, log-rank test) and between PFS levels (P<. 0001, log-rank test). EORTC risk tables were stricter and AUA was more sensitive in assigning patients to a high-risk group. Conclusion: EORTC risk tables are better than AUA risk stratification for predicting recurrence and progression in Chinese patients with NMIBC, especially among high-risk patients.