Role of Transarterial Chemoembolization in the Era of Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor Combination Therapy for Unresectable Hepatocellular Carcinoma: A Retrospective Propensity Score Matched Analysis.

RATIONALE AND OBJECTIVES: As an effective locoregional therapy, transarterial chemoembolization (TACE) can induce vascular endothelial growth factor and PD-1/PDL-1 upregulation, accompanied by a reduction in tumor burden. The present study aimed to compare the efficacy of TACE combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) (TACE-TKI-ICIs) versus TKIs plus ICIs (TKI-ICIs) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The clinical data of 198 patients diagnosed with unresectable HCC who received a TKI (lenvatinib or sorafenib) plus an ICI (sintilimab or camrelizumab) with or without TACE were retrospectively reviewed between October 2019 and April 2022. Baseline characteristics of the TACE-TKI-ICI group and the TKI-ICI group were matched by propensity score matching in a 1:1 ratio. The tumor response, progression-free survival (PFS), and overall survival (OS) were evaluated and compared between the two groups. RESULTS: After matching, 54 patients were enrolled in each group. The objective response rate (ORR) and disease control rate (DCR) were higher in the TACE-TKI-ICI group (ORR: 63.0% vs. 29.6%, P < 0.001; DCR: 85.2% vs. 53.7%, P < 0.001). The median PFS was significantly longer in the TACE-TKI-ICI group (9.9 vs. 5.8 months; P = 0.026). The median OS between the two groups also reached a significant difference (not reached vs. 18.5 months; P = 0.003). CONCLUSION: In this retrospective study, the results indicated that the addition of TACE to TKI-ICI therapy could contribute to better tumor control, PFS, and OS benefits in patients with unresectable HCC.

Renal Lipoma-Like Angiomyolipoma of Tumour Thrombus Extending to the Confluence of Inferior Vena Cava with Right Atrium: A Rare Case Report and Literature Review.

Angiomyolipoma (AML) complicated with tumour thrombus extending to the confluence of inferior vena cava (IVC) with right atrium is rarely observed. We report a female AML patient admitted to our centre on January 21, 2020, with complication of tumour thrombus extending to the confluence of IVC with right atrium and had no sign of difficult breathing. She underwent whole-abdominal enhanced CT for abdominal pain and was diagnosed with a possible renal AML with tumour thrombus. Open radical nephrectomy and thrombectomy of vena cava were performed. Intraoperative transoesophageal echocardiography indicated that the tumour thrombus has reached the confluence of IVC with right atrium. The operation took 255 min with an intraoperative haemorrhage of 800mL. The patient was discharged 7 days after surgery. Pathology revealed lipoma-like AML. Immunohistochemistry showed vimentin (+), EMA (-), HMB45 (+), S-100 (-), SMA (+), TFE-3 (-), melan A (+). After 2 years of follow-up, we found that the patient showed full recovery and had no recurrence. Therefore, lipoma-like AML should also be followed closely for recurrence and metastasis. When AML involves IVC tumour thrombus, open thrombectomy and radical nephrectomy are safe and effective methods.

Deoxycholic acid induces gastric intestinal metaplasia by activating STAT3 signaling and disturbing gastric bile acids metabolism and microbiota.

Intestinal metaplasia (IM) is the inevitable precancerous stage to develop intestinal-type gastric cancer (GC). Deoxycholic acid (DCA) is the main bile acid (BA) component of duodenogastric reflux and has shown an increased concentration during the transition from chronic gastritis to IM associated with continued STAT3 activation. However, the mechanisms underlying how DCA facilitates IM in the gastric epithelium need exploration. We evaluated IM and bile reflux in corpus tissues from 161 subjects undergoing GC screening. Cell survival and proliferation, proinflammatory cytokine expression and TGR5/STAT3/KLF5 axis activity were measured in normal human gastric cells, cancer cells, and organoid lines derived from C57BL/6, FVB/N and insulin-gastrin (INS-GAS) mice treated with DCA. The effects of DCA on IM development were determined in INS-GAS mice with long-term DCA supplementation, after which the gastric bacterial and BA metabolic profiles were measured by 16S rRNA gene sequencing and LC-MS. We revealed a BA-triggered TGR5/STAT3/KLF5 pathway in human gastric IM tissues. In gastric epithelial cells, DCA promoted proliferation and apoptotic resistance, upregulated proinflammatory cytokines and IM markers, and facilitated STAT3 phosphorylation, nuclear accumulation and DNA binding to the KLF5 promoter. DCA triggered STAT3 signaling and the downstream IM marker KLF5 in mouse gastric organoids in vitro and in vivo. In INS-GAS mice, DCA promoted the accumulation of serum total BAs and accelerated the stepwise development of gastric IM and dysplasia. DCA induced gastric environmental alterations involving abnormal BA metabolism and microbial dysbiosis, in which the Gemmobacter and Lactobacillus genera were specifically enriched. Lactobacillus genus enrichment was positively correlated with increased levels of GCA, CA, T-α-MCA, TCA and ß-MCA in DCA-administrated INS-GAS mice. DCA promotes nuclear STAT3 phosphorylation, which mediates KLF5 upregulation associated with gastric inflammation and IM development. DCA disturbs the gastric microbiome and BA metabolism homeostasis during IM induction.

Genetic characterisation of sarcomatoid carcinomas reveals multiple novel actionable mutations and identifies KRAS mutation as a biomarker of poor prognosis.

BACKGROUND: Sarcomatoid component occurs in various epithelial malignancies and is associated with an aggressive disease course and poor clinical outcome. As it is largely rare, the molecular events underlying sarcomatoid carcinomas (SCs) remain poorly characterised. Here, we performed targeted next-generation sequencing (NGS) on patients with surgically resected SCs comprising distinct tissues of origin. METHODS: A total of 71 patients with pathological diagnosis of sarcomatoid carcinomas and underwent surgery were retrospectively enrolled in this study. Overall survival (OS) was defined as the time from surgery to death from any cause. Patients alive or lost to follow-up were censored. Genomic DNA from formalin-fixed paraffin-embedded samples was extracted for NGS and tumour mutation burden (TMB) analysis. RESULTS: In general, SCs occurred more commonly in males, except those of the gallbladder. SCs of the lung and the larynx were associated with a higher proportion of smokers (p=0.0015). Alterations in TP53, RB1, TERT and KRAS were highly frequent, with KRAS mutations being a biomarker of poor prognosis (median OS=8 vs 16 months, p=0.03). Multiple alterations in potentially actionable genes, including ROS1 and NTRK1 fusions and ERBB2 amplification, were detected in the extra-pulmonary cohort. A relatively high proportion (30%) of patients with extra-pulmonary SC had high TMB, with a median of 5.39 mutations per Mb. Lastly, copy number variations were common in SCs, and were non-overlapping between the primary and metastatic tumours. CONCLUSION: Taken together, our results suggest that comprehensive genetic testing may be necessary to inform treatment options and identify prognostic biomarkers.

Label-free multiphoton microscopic imaging as a novel real-time approach for discriminating colorectal lesions: A preliminary study.

BACKGROUND AND AIM: Although various endoscopic technologies have been developed to increase the visual diagnostic accuracy of colorectal precancerosis and early carcinoma, the biopsy-dependent pathology still remains the golden standard. During routine endoscopy, real-time optical histological diagnosis is desired. Without fluorescent label, multiphoton microscopy (MPM) imaging directly reveals live cellular morphology and tissue microenvironment based on intrinsic two-photon excited fluorescence and second harmonic generation signals. Its high-imaging resolution and performance are comparable with the histopathology. We thus aimed to initially investigate the original features of colorectal diseases under MPM and evaluate its potential for real-time diagnosis. METHODS: Experimental and diagnostic cohorts were designed. Multiphoton images of 40 ex vivo fresh tissues confirmed pathologically of colorectal normal tissues, hyperplastic polyps, adenomas, and adenocarcinomas were collected. Features were recorded to establish diagnostic standards with MPM. For the second cohort with 92 fresh tissues, we distinguished the various colorectal diseases with conclusive MPM features. RESULTS: Through the investigation, the colorectal diseases were presented differences in the crypt opening, gland structure, epithelial cells, and collagen fibers. With the typical features, we preliminarily tested the diagnostic efficiency and found that its sensitivity for distinguishing normal, hyperplastic polyps, adenoma and adenocarcinoma was 88.89%, 76.47%, 83.33%, and 97.92%, while the specificity was 99.32%, 94.00%, 94.92%, and 94.12%, respectively. CONCLUSION: The real-time multiphoton microscopic imaging can be effective to identify the colorectal lesions with high resolution. Via integrating with the endoscopes in the future, it could promote precise optical diagnosis in clinics.

Expression of vitamin D receptor in clear cell papillary renal cell carcinoma.

Clear cell papillary renal cell carcinoma (ccpRCC) is a recently recognized subtype of renal cell carcinoma. In this study, we investigated the clinicopathological and immunohistochemical features in a group of 26 cases of ccpRCC, with a special emphasis on the expression of vitamin D receptor (VDR). The mean age of patients was 53.3 years (range 36-74 years), and the mean tumor size was 2.5 cm (range 0.5 to 6.5 cm). During follow-up (range 12-121 months, median 50 months), no recurrence or metastasis was observed. Histopathologically, all cases of ccpRCC exhibited a tubular and papillary architecture, covered by tumor cells with clear cytoplasm. Immunohistochemistry showed intermediate (5/26, 19%) to diffuse (21/26, 81%) and moderate (2/26, 8%) to strong (24/26, 92%) membranous staining for VDR in each case. All cases (26/26, 100%) were diffuse and strong cytoplasmic and fibrillar staining for cytokeratin 7 (CK7), but negative forα-methylacyl-CoA-racemase (AMACR). Each case showed diffuse (26/26, 100%) and moderate (4/26, 15%) to strong (22/26, 85%) membranous staining for carbonic anhydrase IX (CA IX). In addition, the majority of cases showed negative for cluster of differentiation 10 (CD10) (20/26, 77%) and renal cell carcinoma maker (RCC-Ma) (24/26, 92%). This unique staining pattern is helpful for distinguishing ccpRCC from its mimics. Furthermore, VDR positive expression suggests that ccpRCC originates from the precursor epithelium of distal nephron.