Cutoff values of PD-L1 expression in urinary cytology samples for predicting response to immune checkpoint inhibitor therapy in upper urinary tract urothelial carcinoma.

BACKGROUND: The objective of this study was to determine the cutoff value of PD-L1 expression that can predict response to immune checkpoint inhibitor (ICI) immunotherapy for upper tract urothelial carcinoma (UTUC). METHODS: The concordance of PD-L1 expression between paired surgical resection specimens (SRSs) and urine cell blocks (UCBs) (cohort 1) was studied in a retrospective set of 58 UTUC patients to determine its suitability as a predictor of ICI immunotherapy efficacy. PD-L1 expression in UCBs obtained before neoadjuvant ICI immunotherapy was verified in a prospective set of 12 UTUC patients (cohort 2). PD-L1 (SP263 clone) expression was assessed for percentage (tumor proportional score) of tumor cell (TC) showing PD-L1 staining. RESULTS: The authors found an overall agreement of 94.4% (51 of 54) between UCBs and SRSs in cohort 1 (positive percent agreement = 100%, negative percent agreement = 93.8%, r value = 0.63). PD-L1 expression in <10% and ≥10% of tumor cells (TCs) of UCBs were the best predictors of negative (<25%) and positive (≥25%) expression in TCs of SRSs, respectively (concordance = 98.1%, r value = 0.93). These findings were verified in cohort 2: at the 10% cutoff for PD-L1 expression, the best response predictive value was 83.3% (5 of 6) in PD-L1-positive patients, and the nonresponse predictive value was 50% (3 of 6) in PD-L1-negative patients. The sensitivity, specificity, and area under the receiver operating characteristic curve values for predicting ICI immunotherapy efficacy based on PD-L1-expressing TCs in UCBs were 62.5%, 75%, and 0.688, respectively. CONCLUSIONS: Immunocytochemistry of UCBs is reliable for determining PD-L1 expression, which can predict the efficacy of ICI immunotherapy at a cutoff of 10%.

SSTR2 is a prognostic factor and a promising therapeutic target in glioma.

Gliomas are the most prevalent primary malignant central nervous system tumors among all tumors occurring in the brain and spinal cord. The poor outcome of glioma requires the discovery of novel biomarkers with potential therapeutic value. Somatostatin receptor subtype 2 (SSTR2) represents a diagnostic biomarker and potential therapeutic target in many cancers, such as meningioma and neuroendocrine tumors (NETs). However, the relationship of SSTR2 and glioma was unclear. Therefore, this study aimed to investigate the expression of SSTR2 and assess its prognostic and potential therapeutic value in a large cohort of patients with WHO grade I to IV glioma from a single Chinese center. Immunohistochemical analysis revealed that SSTR2 was highly expressed in 23.84% (72 of 302) of glioma (I-IV grade) samples. Among all glioma subtypes, high SSTR2 expression was detected mainly in oligodendroglioma, anaplastic oligodendroglioma, and astrocytoma, whereas SSTR2 was expressed at a low level, or not at all, in glioblastoma. Western blotting also confirmed the low expression of SSTR2 in glioblastoma cell lines. Statistical analysis showed that SSTR2 protein expression correlated significantly with WHO grade, the location of the tumor, epilepsy syndrome, mitosis (PHH3), proliferation index (Ki-67), IDH and 1p/19q-codeleted status. Kaplan-Meier analysis indicated that SSTR2 high expression was a good prognostic factor in glioma. In summary, this study demonstrated that SSTR2 might be a valuable prognostic factor and therapeutic target in certain glioma subtypes.

Exploration of prognostic biomarkers and therapeutic targets in the microenvironment of bladder cancer based on CXC chemokines.

BACKGROUND: Bladder cancer (BLCA) has a high rate of morbidity and mortality, and is considered as one of the most malignant tumors of the urinary system. Tumor cells interact with surrounding interstitial cells, playing a key role in carcinogenesis and progression, which is partly mediated by chemokines. CXC chemokines exert anti-tumor biological roles in the tumor microenvironment and affect patient prognosis. Nevertheless, their expression and prognostic values patients with BLCA remain unclear. METHODS: We used online tools, including Oncomine, UALCAN, GEPIA, GEO databases, cBioPortal, GeneMANIA, DAVID 6.8, Metascape, TRUST (version 2.0), LinkedOmics, TCGA, and TIMER2.0 to perform the relevant analysis. RESULTS: The mRNA levels of C-X-C motif chemokine ligand (CXCL)1, CXCL5, CXCL6, CXCL7, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16, and CXCL17 were increased significantly increased, and those of CXCL2, CXCL3, and CXCL12 were decreased significantly in BLCA tissues as assessed using the Oncomine, TCGA, and GEO databases. GEO showed that high levels of CXCL1, CXCL6, CXCL10, CXCL11, and CXCL13 mRNA expression are associated significantly with the poor overall survival (all p < 0.05), and similarly, those of CXCL2 and CXCL12 in the TCGA database (p < 0.05). The predominant signaling pathways involving the differentially expressed CXC chemokines are cell cycle, chemokine, and cytokine-cytokine receptor interaction. Moreover, transcription factors such as Sp1 transcription factor (SP1), nuclear factor kappa B subunit 1 (NFKB1), and RELA proto-oncogene, NF-KB subunit (RELA) were likely play critical roles in regulating CXC chemokine expression. LYN proto-oncogene, src family tyrosine kinase (LYN) and LCK proto-oncogene, src family tyrosine kinase (LCK) were identified as the key targets of these CXC chemokines. MicroRNAs miR200 and miR30 were identified as the main microRNAs that interact with several CXC chemokines through an miRNA-target network. The expression of these chemokines is closely associated with the infiltration of six categories of immune cells. CONCLUSION: We explored the CXC chemokines superfamily-based biomarkers associated with BLCA prognosis using public databases, and provided possible chemokine targets for patients with BLCA.

Detection of human papillomavirus distinguishes second primary tumors from lung metastases in patients with squamous cell carcinoma of the cervix.

BACKGROUND: In patients with squamous cell carcinoma of the cervix (SCCC), a squamous cell carcinoma (SqCC) in the lung represents either a second primary tumor or metastasis. This distinction between second primary tumors and lung metastases in patients with SCCC significantly influences patient prognosis and therapy. Here, we aimed to differentiate second primary tumors from lung metastases in patients with SCCC by exploring the HPV status in SqCCs involving the lung within a large cohort. METHODS: P16 expression was assessed using immunohistochemistry on tissue microarrays including a total of 415 primary lung SqCCs and 21 lung SqCCs with prior SCCC. Following this, we performed HPV DNA typing and the sensitive RNAscope in situ method to screen all the cases for HPV E6/E7 expression, which is a more reliable indicator of transcriptively active HPV in tumor cells. RESULTS: The p16 positive expression rate was 13.7% (57/415) in primary lung SqCCs, but HPV DNA was not detected in any of the 57 primary lung SqCC cases that positively expressed p16. In contrast, HPV DNA was detected in all cases (21/21) with prior SCCC. Consistently, all 21 lung SqCCs with prior SCCC (21/21) showed extensive HPV16 E6/E7 expression. In striking contrast, none of the primary lung SqCCs (0/415) had a detectable RNAscope signal. CONCLUSIONS: HPV does not seem to play a role in the development of primary lung SqCCs. HPV detection may be helpful in distinguishing second primary tumors from lung metastases in patients with SCCC.

Novel prognostic scores based on serum ferritin/globulin ratio in patients with hepatocellular carcinoma.

BACKGROUND: The level of ferritin has been shown to be associated with the prognosis of various tumors. In this study, we proposed prognostic indicator, named ferritin/globulin ratio (FGR), and to evaluate the important value in hepatocellular carcinoma (HCC). METHODS: A total of 472 HCC patients and 219 healthy controls were concluded in our retrospective study. The clinical characteristics were analyzed in these patients. The optimal cutoff value of the prognostic factors (α-fetoprotein, alanine aminotransferase, aspartate aminotransferase, ferritin, globulin and FGR) were determined by using receiver operating characteristic curve analysis, and then analyzed by univariate and multivariate Cox hazard models to evaluate the prognostic significance. RESULTS: Serum ferritin, globulin and FGR levels were significantly higher in HCC patients than in healthy controls. Multivariate analysis showed that FGR was a significant and independent risk factor OS (HR =1.575; 95% CI: 1.122-2.212; P=0.009) and DFS (HR =1.569; 95% CI: 1.117-2.204; P=0.009) in whole patients. Furthermore, we also classified the data according to α-fetoprotein (AFP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), highly significant differences of FGR were observed between the two groups in OS and DFS. High FGR levels were associated with poor OS and DFS in HCC patients. CONCLUSIONS: The serum FGR levels may serve as a significant predictor of prognosis in HCC patients.

The Survival Advantage of Females at Premenopausal Age Is Race Dependent in Colorectal Cancer.

BACKGROUND: A female prognostic advantage in younger individuals has been demonstrated in various cancers. Several large-scale analyses based on different racial backgrounds have reported inconsistent results in colorectal cancer. The aim of the present study was to evaluate the prognostic value of sex and age in patients with colorectal cancer of different ethnic groups. METHODS: We identified 71,812 eligible patients from the Surveillance, Epidemiology and End Results database. According to age at diagnosis, the patients were categorized into premenopausal age (≤45 yrs), menopausal age (46-54 yrs), and postmenopausal age (≥55 yrs) subgroups for further analysis. RESULTS: Multivariate analysis identified the female survival advantage to be significant in the premenopausal age subgroup (P = 0.002, HR (95% CI): 0.73 (0.60-0.89)), diminished in the menopausal age subgroup (P = 0.09), and absent in the postmenopausal age subgroup (P = 0.96). Furthermore, the female survival advantage at premenopausal age was significant only in white patients (P = 0.001, HR (95% CI): 0.68 (0.54-0.87)) and not in either American Indian/Alaska Native or Asian or Pacific Islander patients. There was a trend of better survival of females in black patients (P = 0.07). CONCLUSIONS: Sex was a major prognostic factor in colorectal cancer patients, especially premenopausal women, and the difference was also associated with race.