Serum IgA as a Prognostic Beacon: Anticipating Systemic Therapy Efficacy in Metastatic Clear Cell Renal Cell Carcinoma.

OBJECTIVE: Immunotherapy-tyrosine kinase inhibitor (IO-TKI) therapy has revolutionized the treatment landscape for metastatic clear cell renal cell carcinoma (mccRCC); however, the absence of effective biomarkers poses a challenge in predicting the efficacy of these regimens. This study aims to explore the predictive and prognostic value of serum immunoglobulin A (IgA) in mccRCC patients undergoing IO-TKI therapy. METHODS: Ninety-six mccRCC patients treated with IO-TKI therapy from 2019 to 2023 were enrolled and serum IgA levels were assessed at the pretreatment baseline and after 3 months of treatment. RESULTS: Notably, baseline levels of IgA showed no correlation with the objective response rate. However, patients achieving complete or partial responses exhibited a remarkable decrease in IgA levels, while those with stable or progressive disease displayed an increase in IgA levels after 3 months of treatment. Furthermore, the dynamic alteration in IgA levels after 3 months of treatment demonstrated predictive value for both progression-free survival (PFS) and overall survival (OS). The time-dependent receiver operating characteristic curves exhibited outstanding performance in predicting PFS (AUC 0.793) and OS (AUC 0.738). CONCLUSION: Taken together, this study demonstrates that dynamic alteration of serum IgA after 3 months of treatment was significantly correlated with prognosis and therapeutic efficacy in mccRCC patients.

Prognosis and Clinicopathological Characters of Adult TFEB-Altered Renal Cell Carcinoma: A Single Center Experience of 18 Cases.

INTRODUCTION: TFEB-altered renal cell carcinoma (RCC) is a rare entity characterized by the rearrangement of the TFEB gene or TFEB amplified. The therapeutic implications and long-term survival of TFEB-altered RCC remain unclear, especially for metastatic cases. MATERIALS AND METHODS: The current study initially enrolled 7604 consecutive RCC patients at our center and a total of 248 patients were selected for FISH and immunohistochemistry (IHC) analysis. Eventually, eighteen TFEB-altered RCC patients were identified. We then reported the clinical, morphological, IHC, and radiological features of these cases. RESULTS: The median age at initial diagnosis was 45 years, ranging from 18 years to 66 years. The majority of the TFEB-altered RCC patients were male (61.1%), with localized disease (T1-2N0M0, 77.8%). The median split TFEB fluorescent signal was 24%, ranging from 15%-80%. The morphological characteristics of TFEB-altered RCC were variable, with acinar, papillary, solid, or nest patterns. IHC and magnetic resonance imaging features of TFEB-altered RCC were nonspecific. Nine patients with localized disease received partial nephrectomy and five patients with localized disease received radical nephrectomy. During the median follow-up of 67 months, no signs of recurrence or metastasis were found in these patients. Two patients had distant metastasis and received axitinib plus PD-1 immunotherapy. One of them died at 40-month follow-up and another still alive at 88-month follow-up. CONCLUSION: TFEB-altered RCC is an extremely rare variant, exhibited mixed morphological characteristics. The radiological feature lack specificity, resembling clear cell RCC or papillary RCC. Genetic analyses including FISH analysis is crucial in the diagnosis of TFEB-altered RCC. For localized TFEB-altered RCC, both radical nephrectomy and partial nephrectomy conferred satisfactory prognosis. For metastatic TFEB-altered RCC, immunotherapy-based drug combinations could be a promising treatment strategy.

Neutrophil extracellular traps in relationship to efficacy of systemic therapy for metastatic renal cell carcinoma.

BACKGROUND: The efficacy of systemic therapy regimens, such as immune checkpoint inhibitors and tyrosine kinase inhibitors (IO-TKI) and targeted therapy, for metastatic clear cell renal cell carcinoma (ccRCC) remains unpredictable due to the lack of effective biomarkers. Neutrophil extracellular trap (NET) plays an important role in promoting ccRCC. This study explores the NET predictive value of the efficacy in metastatic ccRCC. METHODS: In this retrospective study, patients with metastatic ccRCC who received targeted drugs and IO-TKI were included. Immunofluorescence staining was utilized to quantify the levels of tissue NETs through cell counts of H3Cit(+) and MPO(+) cells. RESULTS: A total of 183 patients with metastatic ccRCC were enrolled, including 150 patients who received TKIs and 33 patients who received IO-TKI. The levels of NETs in tumor tissue were significantly higher than in para-tumor tissue (p < 0.001). In terms of predicting drug efficacy, a correlation between NET levels and progression-free survival (PFS) was observed in the TKI with metachronous metastasis group (HR 1.73 [95% CI 1.02-2.91], log-rank p = 0.037), while no correlation was observed in the TKI with synchronous metastasis group and IO-TKI group. Regarding overall survival (OS), activated NET levels were associated with poor OS in both TKI (HR 1.60 [95% CI 1.05-2.43], log-rank p = 0.017) and IO-TKI group (HR 4.35 [95% CI 1.06-17.82], log-rank p =0.047). IMDC score (HR 1.462 [95% CI 1.030-2.075], p = 0.033) and tumor tissue NET levels (HR 1.733 [95% CI 1.165-2.579], p = 0.007) were independent prognostic risk factors for OS in patients with metastatic ccRCC.NET level was associated with poor OS in both TKI (HR 1.60 [95% CI 1.05-2.43], log-rank p = 0.017). CONCLUSIONS: The active NET levels in tumor tissue can predict drug efficacy in patients with metastatic ccRCC who received systemic therapy. Elevated levels of NETs in tumor tissue were also associated with poor efficacy in OS.

Neutrophil extracellular traps primed intercellular communication in cancer progression as a promising therapeutic target.

In addition to the anti-infection response, neutrophils are linked to tumor progression through the secretion of inflammation components and neutrophil extracellular traps (NETs) formation. NET is a web-like structure constituted by a chromatin scaffold coated with specific nuclear and cytoplasmic proteins, such as histone and granule peptides. Increasing evidence has demonstrated that NETs are favorable factors to promote tumor growth, invasion, migration, and immunosuppression. However, the cell-cell interaction between NETs and other cells (tumor cells and immune cells) is complicated and poorly studied. This work is the first review to focus on the intercellular communication mediated by NETs in cancer. We summarized the complex cell-cell interaction between NETs and other cells in the tumor microenvironment. We also address the significance of NETs as both prognostic/predictive biomarkers and molecular targets for cancer therapy. Moreover, we presented a comprehensive landscape of cancer immunity, improving the therapeutic efficacy for advanced cancer in the future.

ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14.

High aggressiveness is the main reason for the poor prognosis of hepatocellular carcinoma (HCC) patients. However, its molecular mechanisms still remain largely unexplored. ACADL, a mitochondrial enzyme that facilitates the primary regulated step in mitochondrial fatty acid oxidation, plays a role in HCC growth inhibition. However, the function of ACADL in tumor metastasis is not well elucidated. We found that the reduced expression of ACADL is closely associated with the loss of tumor encapsulation, extrahepatic metastasis, and poor prognosis in HCC patients. Upregulation of ACADL significantly inhibited HCC migration and invasion ability. Whereas knockdown of ACADL markedly enhanced cell invasive capability. Expression of matrix metalloproteinase-14 (MMP14) was negatively associated with the content of ACADL in HCC specimens. MMP14-positive patients with a low expression of ACADL showed worse outcome. Treatment with MMP14 agonist reversed the inhibitory effect of ACADL on HCC metastasis. In addition, ACADL negatively regulated MMP14 expression by inhibiting the STAT3 signaling pathway, as the sustained activation of STAT3 effectively restored the level of MMP14 in ACADL-overexpressed cells. Collectively, these findings disclose that ACADL represses HCC metastasis via STAT3-MMP14 pathway. This study may propose a promising strategy for the precise treatment of metastatic HCC patients.

ENO3 Inhibits Growth and Metastasis of Hepatocellular Carcinoma via Wnt/ß-Catenin Signaling Pathway.

ß-enolase (ENO3) is a metalloenzyme that functions during glycolysis and has been revealed ectopic expression in different cancers. However, the function and underlying modulatory mechanisms of ENO3 in hepatocellular carcinoma (HCC) are still elusive. Here, we discovered that ENO3 was remarkably down-regulated in human HCC tissue in contrast to those in noncancerous tissue. Moreover, low expression of ENO3 was related to the poor prognosis of HCC patients. Overexpression of ENO3 suppressed proliferative, migratory, and invasive abilities of HCC cells both in vitro and in vivo, whereas knocking down ENO3 led to the opposite effect. In addition, we revealed that ENO3 repressed the epithelial-mesenchymal transition (EMT) process with its biomarker variations. Mechanistic research unveiled that ENO3 suppressed the Wnt/ß-catenin signal, which subsequently modulated the transcription of its target genes associated with the proliferation and metastasis capacity of HCC cells. Taken together, our study uncovered that ENO3 acted as a tumor inhibitor in HCC development and implied ENO3 as a promising candidate for HCC treatment.

Highly sensitive gaseous formaldehyde sensor with CdTe quantum dots multilayer films.

A novel method for the direct detection of gaseous formaldehyde based on the fluorescence quenching of CdTe quantum dots (QDs)/polyelectrolyte multilayer films (QDMF) was proposed in this paper. The functional multilayer films were assembled by layer-by-layer (LBL) deposition of oppositely charged CdTe QDs and poly(dimethyldiallylemmonium chloride) (PDDA). Formaldehyde can quench the fluorescence of CdTe QDs multilayer films effectively. Under the optimization conditions, the fluorescence intensity of QDs decreased linearly with the increase of formaldehyde concentration in the range of 5-500ppb. The detection limit for formaldehyde was 1ppb. The quenching mechanism of CdTe QDs multilayer films by formaldehyde was also studied in detail. This proposed approach was simple, rapid and had excellent selectivity and sensitivity for the detection of gaseous formaldehyde.