The role of TERT C228T and KDM6A alterations and TME in NMIBC treated with BCG.

We aimed to investigate the genomic and tumor microenvironmental (TME) profiles in non-muscle invasive bladder cancer (NMIBC) and explore potential predictive markers for Bacillus Calmette-Guérin (BCG) treatment response in high-risk NMIBC patients (according to European Association of Urology (EAU) risk stratification). 40 patients with high-risk NMIBC (cTis-T1N0M0) who underwent en bloc resection followed by BCG instillation were retrospectively enrolled. Surgical samples were subjected to Next Generation Sequencing (NGS) and multiplex immunofluorescence (mIF) assay. Genomic profiling revealed high prevalences of alterations in TERT (55%), KDM6A (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%) and ARID1A (20%). TME analysis showed different proportions of macrophages, NK cells, T cells subsets in tumoral and stromal compartment. Multivariate analysis identified TERT C228T and alteration in KDM6A as two independent factors associated with inferior RFS. The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment.

A combined pre- and intra-operative nomogram in evaluation of degrees of liver cirrhosis predicts post-hepatectomy liver failure: a multicenter prospective study.

Background: Adequate evaluation of degrees of liver cirrhosis is essential in surgical treatment of hepatocellular carcinoma (HCC) patients. The impact of the degrees of cirrhosis on prediction of post-hepatectomy liver failure (PHLF) remains poorly defined. This study aimed to construct and validate a combined pre- and intra-operative nomogram based on the degrees of cirrhosis in predicting PHLF in HCC patients using prospective multi-center's data. Methods: Consecutive HCC patients who underwent hepatectomy between May 18, 2019 and Dec 19, 2020 were enrolled at five tertiary hospitals. Preoperative cirrhotic severity scoring (CSS) and intra-operative direct liver stiffness measurement (DSM) were performed to correlate with the Laennec histopathological grading system. The performances of the pre-operative nomogram and combined pre- and intra-operative nomogram in predicting PHLF were compared with conventional predictive models of PHLF. Results: For 327 patients in this study, histopathological studies showed the rates of HCC patients with no, mild, moderate, and severe cirrhosis were 41.9%, 29.1%, 22.9%, and 6.1%, respectively. Either CSS or DSM was closely correlated with histopathological stages of cirrhosis. Thirty-three (10.1%) patients developed PHLF. The 30- and 90-day mortality rates were 0.9%. Multivariate regression analysis showed four pre-operative variables [HBV-DNA level, ICG-R15, prothrombin time (PT), and CSS], and one intra-operative variable (DSM) to be independent risk factors of PHLF. The pre-operative nomogram was constructed based on these four pre-operative variables together with total bilirubin. The combined pre- and intra-operative nomogram was constructed by adding the intra-operative DSM. The pre-operative nomogram was better than the conventional models in predicting PHLF. The prediction was further improved with the combined pre- and intra-operative nomogram. Conclusions: The combined pre- and intra-operative nomogram further improved prediction of PHLF when compared with the pre-operative nomogram. Trial Registration: Clinicaltrials.gov Identifier: NCT04076631.

KIF18B as a regulator in tumor microenvironment accelerates tumor progression and triggers poor outcome in hepatocellular carcinoma.

BACKGROUND: The tumor microenvironment plays an important role in the progression and recurrence of tumors and immunotherapy outcomes. The use of immune checkpoint blockers to improve the overall survival rate of patients with advanced hepatocellular carcinoma has yielded inconsistent outcomes. We examined the tumor microenvironment-related genes for their clinical significance and biological functions in hepatocellular carcinoma. METHODS: Bioinformatic analysis was performed to screen the differentially expressed genes and to identify the core gene of the tumor microenvironment in hepatocellular carcinoma. The expression of KIF18B in hepatocellular carcinoma cell lines and tumor samples was determined using western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. The malignancy-promoting ability of KIF18B was evaluated using Cell Counting Kit-8, colony formation, cell proliferation, migration and invasion, and xenograft tumor assays. RESULTS: KIF18B was identified as one of the core genes in the hepatocellular carcinoma microenvironment and was significantly associated with infiltrating immune cell subtypes and tumor cell stemness. Upregulation of KIF18B was associated with poor clinicopathological characteristics and poor patient outcomes; its downregulation inhibited the proliferation ability of hepatocellular carcinoma cells, which was consistent with the findings of in vivo experiments. Knockdown of KIF18B inhibited epithelial-mesenchymal transition which reduced the migration and invasion abilities of tumor cells. A pulmonary metastasis model confirmed that the downregulation of KIF18B inhibited hepatocellular carcinoma cell metastasis in vivo. CONCLUSION: KIF18B could be a useful marker for determining the treatment outcomes of immune checkpoint blockers in the context of hepatocellular carcinoma.

The Expression of Three Negative Co-Stimulatory B7 Family Molecules in Small Cell Lung Cancer and Their Effect on Prognosis.

BACKGROUND: In recent years, immune checkpoint inhibitors have shown significant effects in a variety of solid tumors. However, due to the low incidence of small cell lung cancer (SCLC) and its unclear mechanism, immune checkpoints in SCLC have not been fully studied. METHODS: We evaluated the expression of PD-L1, B7-H3, and B7-H4 in 115 SCLC tissue specimens using immunohistochemistry. The clinical data of patients with SCLC were retrospectively reviewed to investigate three negative co-stimulatory B7 family molecules' ability to affect the prognosis of SCLC. RESULTS: Among the SCLC patients with complete follow-up data (n = 107), sixty-nine (64.49%) expressed moderate to high B7-H3 levels, which correlated positively with tumor sizes (P < 0.001). Eighty (74.77%) patients expressed moderate to high B7-H4 levels, which correlated positively with metastases (P = 0.049). The positive expression of B7-H3 and B7-H4 correlated significantly with shortened overall survival (OS) (B7-H3, P = 0.006; B7-H4, P = 0.019). PD-L1 was positively expressed only in 13.08% of cancer tissues, and there was no significant correlation with prognosis. The Cox proportional hazards regression showed that B7-H3 was an independent prognostic indicator of OS (P = 0.028; HR = 2.125 [95% CI = 0.985-4.462]). CONCLUSIONS: Our results suggest that B7-H3 has a negative predictive effect on SCLC. This outcome provides a theoretical basis for the subsequent research on immune checkpoint inhibitors targeting B7-H3.

Research on circadian clock genes in non-small-cell lung carcinoma.

Circadian clock genes have become a hot topic in cancer research in recent years, and more and more studies are showing that clock genes are involved in regulating cell proliferation cycle and apoptosis of malignant tumors, neuroendocrine and immune function, and other processes. Lung cancer is a malignant tumor with increasing incidence worldwide. The pathogenesis of lung cancer is extremely complicated and includes genetic factors, living environment, and smoking, and the occurrence of lung cancer is related to the regulation of many oncogenes and tumor suppressor genes. But there are few studies on clock genes in lung cancer. Studies on clock genes may help to better understand the mechanism of lung cancer development for an improved treatment. The expressions of all 14 kinds of clock genes in adenocarcinoma (ADC) and squamous cell carcinoma (SCC), two main kinds of non-small-cell lung cancer (NSCLC), were studied based on integration and analysis of data from The Cancer Genome Atlas (TCGA) to show the association between clock gene expression and prognosis of cancer patients. Analysis of TCGA data indicated that overexpression of Cry2, BMAL1, and RORA with underexpression of Timeless and NPAS2 was associated with a favorable prognosis of ADC, and the expression of NPAS2 was associated with the time of patient survival. Additionally, the expression of Cry2 was related to TNM stage. In SCC, high expression of DEC1 was correlated with poor overall survival in patients and the expression of Timeless was associated with the time of patient survival. In NSCLC, circadian clock genes constitute cancer circadian rhythm by interacting with each other, showing that asynchrony with normal tissues, which collectively controlling the occurrence and development of NSCLC.

Comparative Clinical Analysis of Gastroenteropancreatic Neuroendocrine Carcinomas with Liver Metastasis and Primary Hepatic Neuroendocrine Carcinomas.

PURPOSE: The objective of this study was to analyze the clinical features and prognosis of gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) with liver metastasis and primary hepatic neuroendocrine carcinomas (PHNECs), as these rare hepatic neuroendocrine carcinomas have not been exhaustively studied. METHODS: The clinical data of 47 patients with hepatic NECs were retrospectively reviewed and categorized to analyze features and prognosis. RESULTS: The 47 studied cases comprised 13 cases of primary hepatic NECs (primary group) and 34 cases of metastatic hepatic NECs (metastatic group). Male patients were slightly dominant in both groups, while no age predilection was present. PHNECs were mostly single nodules located in the right lobe of the liver. Metastatic hepatic NECs originated mostly from the pancreas and stomach without distinction of the lobes of the liver. Univariate analysis showed that the treatment protocol (radical operation or others) was correlated with the overall survival (OS; p < 0.05) in the primary group, while treatment protocol and cytokeratin 7 (CK7) were associated with OS (p < 0.05) in the metastatic group. Cox proportional hazard regression showed that radical operation was an independent prognostic factor (p < 0.05) for OS in the metastatic group. CONCLUSIONS: No significant differences in the clinicopathological features between PHNECs and metastatic hepatic GEP NECs were found, but radical operation was significantly correlated with OS for both carcinomas. Radical operation is the first choice for patients who are eligible for operation.

Letter to the Editor.

BACKGROUND: Neuroendocrine tumors (NETs) are uncommon type of cancers, also known as APUD (amine precursor uptake decarboxylation) tumors, which are becoming increasingly prevalent. Alkaline phosphatase (ALP) is a poor prognosis factor in a number of hepatic diseases. However, its distribution and prognostic value in primary hepatic neuroendocrine tumors (PHNETs) are still not clear. In this study, our aim is to investigate the correlations between ALP and clinicopathological features and prognostic factors of PHNETs. METHODS: The clinical data of 22 patients with PHNETs were retrospectively reviewed to investigate whether ALP affects the prognosis of PHNETs. RESULTS: In this study, ALP is correlated to γ-glutamyl transpeptidase (GGT; p = 0.002) and the tumor location in the liver (p = 0.007), and increased levels of ALP had poor effects on overall survival (p = 0.006) and progression-free survival (p = 0.022). CONCLUSION: ALP was identified as an independent prognostic factor for overall survival of PHNETs.