Tumor Microenvironment Analysis Identified Subtypes Associated With the Prognosis and the Tumor Response to Immunotherapy in Bladder Cancer.

Background: The efficiency of immune checkpoint inhibitors (ICIs) in bladder cancer (BLCA) treatment has been widely validated; however, the tumor response to ICIs was generally low. It is critical and urgent to find biomarkers that can predict tumor response to ICIs. The tumor microenvironment (TME), which may play important roles to either dampen or enhance immune responses, has been widely concerned. Methods: The cancer genome atlas BLCA (TCGA-BLCA) cohort (n = 400) was used in this study. Based on the proportions of 22 types of immune cells calculated by CIBERSORT, TME was classified by K-means Clustering and differentially expressed genes (DEGs) were determined. Based on DEGs, patients were classified into three groups, and cluster signature genes were identified after reducing redundant genes. Then TMEscore was calculated based on cluster signature genes, and the samples were classified to two subtypes. We performed somatic mutation and copy number variation analysis to identify the genetic characteristics of the two subtypes. Correlation analysis was performed to explore the correlation between TMEscore and the tumor response to ICIs as well as the prognosis of BLCA. Results: According to the proportions of immune cells, two TME clusters were determined, and 1,144 DEGs and 138 cluster signature genes were identified. Based on cluster signature genes, samples were classified into TMEscore-high (n = 199) and TMEscore-low (n = 201) subtypes. Survival analysis showed patients with TMEscore-high phenotype had better prognosis. Among the 45 differentially expressed micro-RNAs (miRNAs) and 1,033 differentially expressed messenger RNAs (mRNAs) between the two subtypes, 16 miRNAs and 287 mRNAs had statistically significant impact on the prognosis of BLCA. Furthermore, there were 94 genes with significant differences between the two subtypes, and they were enriched in RTK-RAS, NOTCH, WNT, Hippo, and PI3K pathways. The Tumor Immune Dysfunction and Exclusion (TIDE) score of TMEscore-high BLCA was statistically lower than that of TMEscore-low BLCA. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of TMEscore and tumor mutation burden (TMB) is 0.6918 and 0.5374, respectively. Conclusion: We developed a method to classify BLCA patients to two TME subtypes, TMEscore-high and TMEscore-low, and we found TMEscore-high subtype of BLCA had a good prognosis and a good response to ICIs.

First-Line Pazopanib Treatment in Metastatic Renal Cell Carcinoma: Real-World Data From a Single Chinese Center.

The response to pazopanib in patients with metastatic renal cell carcinoma (mRCC) has been found to differ in Western and Eastern populations. Here, we analyzed the efficacy and side effects of pazopanib as first-line therapy in 31 consecutive patients with mRCC who were treated at a single Chinese center. Thirty-one consecutive patients with mRCC (20 males and 11 females, median age 59 years) were treated with pazopanib between October 2017 and July 2019. All patients had received a pathological diagnosis of RCC by prior radical nephrectomy or biopsy. All cases were treated with pazopanib (800 mg/day orally) as first-line therapy. Administration was continued until disease progression or unacceptable toxicities occurred. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety were evaluated. Twenty-nine patients were eligible for final analysis. At the median follow-up of 12.7 months, 34.5% (10/29) patients achieved a partial response (PR), 41.4% (12/29) patients had stable disease (SD), seven (24.1%) patients had disease progression (PD), and one patient had died. The ORR and DCR were 34.5% and 75.9%, respectively, and the median PFS was 10.1 months (95% confidence interval, 4.1-17.7 months). OS could not be determined. The most common side effects were fatigue (11 cases, 37.9%), hand-foot syndrome (10 cases, 34.5%), change of hair color (10 cases, 34.5%), elevated alanine transaminase (ALT)/aspartate transaminase (AST) (10 cases, 34.5%), hypertension (seven cases, 24.1%), neutropenia (three cases, 10.3%), anemia (three cases, 10.3%), thrombocytopenia (two cases, 6.9%), and diarrhea (one cases, 3.4%). Major (grade 3 or higher) adverse events included hand-foot syndrome (two cases, 6.9%) and thrombocytopenia (one case, 3.4%). Most adverse events were ameliorated by dose reduction or treatment interruption. Remissions occurred in almost all patients with local recurrence or pulmonary metastases, whereas PD occurred in patients with bone, liver or brain metastases. Our real-world data suggest that pazopanib is definitely efficacious as first-line therapy for mRCC, with well-tolerated side effects. Different metastatic lesions may have different sensitivity to pazopanib. An additional, large sample, multicenter, prospective study is needed to confirm our results.

Development of a compact magnetic proton recoil spectrometer for measurement of deuterium-tritium neutrons.

A new compact magnetic proton recoil (MPR) neutron spectrometer has been designed for precise measurement of deuterium-tritium (DT) neutrons. This design is presented emphasizing the magnetic analyzing system, which is based on a compact quadrupole-dipole (QD) electromagnet. The focal plane detector (FPD) is also discussed with respect to application for the next step. The characteristics of the MPR spectrometer were calculated by using Monte Carlo simulation. A preliminary experiment was performed to test the magnetic analyzing system and the proton images of the FPD. Since the QD electromagnet design allows for a larger foil thickness and solid angle to be utilized, the MPR spectrometer defined in this paper can achieve neutron detection efficiency more than 5 × 10(-7) at an energy resolution of 1.5% for measuring DT neutrons.

[Expression and clinical significance of nuclear matrix protein 22 and cytokeratin 18 in transitional cell carcinoma of the bladder].

OBJECTIVE: To evaluate the expression and clinical significance of urinary nuclear matrix protein (NMP22) and cytokeratin 18 (CK18) for transitional cell carcinoma of the bladder. METHODS: Urinary NMP22 and CK18 levels of 293 patients with transitional cell carcinoma of the bladder, 400 patients with non-transitional cell carcinoma of the bladder, and 105 bladder benign disease were analysed by enzyme-linked-immunosorbent assay (ELISA). RESULTS: The levels of urinary NMP22 and CK18 in the patients with transitional cell carcinoma of the bladder (M = 17.3 U/ml, M(CK18) = 484.2 U/L) were significantly higher than those in the non-transitional cell carcinoma of the bladder (M = 6.8 U/ml, M(CK18) = 156.0 U/L) and the benign disease group (M(NMP22) = 2.3 U/ml, M(CK18) = 66.6 U/L) (P < 0.001). The sensitivity and specificity of urinary NMP22 and CK18 were 79.2%, 88.6% and 78.2%, 82.9%, respectively, for transitional cell carcinoma of the bladder before any treatment. The joint sensitivity of the two markers was 91.7%. The NMP22 and CK18 levels were significantly lower in the recovered patients after surgical operation (P < 0.01), while in patients with recurrence or metastasis the levels of the markers were significantly higher (P < 0.01). There was a significant relationship between NMP22 and CK18, (r = 0.689, P < 0.01). The levels of urinary nmp22 and CK18 were significantly different among pathological grade G1, G2, G3, and stage Ta, T1, T2, T3 (P < 0.01). CONCLUSION: NMP22 and CK18 are useful tumor marker for diagnosis of transitional cell carcinoma of the bladder and for monitoring the state of illness. The joint use of the two markers can improve the sensitivity of cancer detection. NMP22 and CK18 may become a new class of tumor markers, and to be the basis for development of a new assay with an increased efficacy for the detection and treatment of bladder cancer.