HDS screening with patient-derived primary cells guided individualized therapy for esophageal squamous cell carcinoma-in vivo and vitro.

Objective: To analyze and evaluate the role of the High-throughput Drug Sensitivity (HDS) screening strategy in identifying highly sensitive drugs against esophageal squamous cell carcinoma (ESCC). Methods: A total of 80 patients with progressive ESCC were randomly divided into the observation (40 cases) and the control groups (40 cases). In the observation group, primary ESCC cells were isolated from the tumor tissues with a gastroscope, and drug sensitivity screening was performed on cells derived from the 40 ESCC cases using the HDS method, followed by verification in a patient-derived tumor xenograft (PDX) mouse model. Finally, the differences in the therapeutic efficacy (levels of CEA, CYFRA21-1, SCCA after chemotherapy and the rates of overall survival, local progression, and distant metastasis at 12 months and 18 months time points after chemotherapy) were compared between the observation group (Screened drug-treated) and the control group (Paclitaxel combined with cisplatin regimen-treated). Results: Forty ESCC patients were screened for nine different high-sensitive chemotherapeutics, with the majority showing sensitivity to Bortezomib. Experiments on animal models revealed that the tumor tissue mass of PDX mice treated with the HDS-screened drug was significantly lower than that of the Paclitaxel-treated mice (p < 0.05), and the therapeutic efficacy of the observation group was better than the control group (p < 0.05). Conclusion: HDS screening technology can be beneficial in screening high-efficacy anticancer drugs for advanced-stage ESCC patients, thereby minimizing adverse drug toxicity in critically ill patients. Moreover, this study provides a new avenue for treating advanced ESCC patients with improved outcomes.

Magnifying image-enhanced endoscopy-only mode boosted early cancer diagnostic efficiency: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: Magnifying image-enhanced endoscopy (MIEE) is an advanced endoscopy with image enhancement and magnification used in preoperative examination. However, its impact on the detection rate is unknown. METHODS: We conducted an open-label, randomized, parallel (1:1:1), controlled trial in 6 hospitals in China. Patients were recruited between February 14, 2022 and July 30, 2022. Eligible patients were aged ≥18 years and undergoing gastroscopy in outpatient departments. Participants were randomly assigned to the MIEE-only mode (o-MIEE) group, white-light endoscopy-only mode (o-WLE) group, and MIEE when necessary mode (n-MIEE) group (initial WLE followed by switching to another endoscope with MIEE if necessary). Biopsy sampling of suspicious lesions of the lesser curvature of the gastric antrum was performed. Primary and secondary aims were to compare detection rates and positive predictive value (PPV) of early cancer and precancerous lesions in these 3 modes, respectively. RESULTS: A total of 5100 recruited patients were randomly assigned to the o-MIEE (n = 1700), o-WLE (n = 1700), and n-MIEE (n = 1700) groups. In the o-MIEE, o-WLE, and n-MIEE groups, 29 (1.51%; 95% confidence interval [CI], 1.05-2.16), 4 (.21%; 95% CI, .08-.54), and 8 (.43%; 95% CI, .22-.85) early cancers were found, respectively (P < .001). The PPV for early cancer was higher in the o-MIEE group compared with the o-WLE and n-MIEE groups (63.04%, 33.33%, and 38.1%, respectively; P = .062). The same trend was seen for precancerous lesions (36.67%, 10.00%, and 21.74%, respectively). CONCLUSIONS: The o-MIEE mode resulted in a significant improvement in diagnosing early upper GI cancer and precancerous lesions; thus, it could be used for opportunistic screening. (Clinical trial registration number: ChiCTR2200064174.).

Early development of esophageal squamous cell cancer: Stem cells, cellular origins and early clone evolution.

Esophageal squamous cell carcinoma (ESCC), a highly malignant cancer with poor prognosis, is an example of the classical view of cancer development based on stem cell origin and multistep progression. In the past five years, the applications of large-scale sequencing and single-cell sequencing have expanded to human esophageal normal tissues and precancerous lesions, which, coupled with the application of transgenic lineage tracing technology in mouse models, has provided a more comprehensive and detailed understanding of esophageal stem cell heterogeneity and early clonal evolution of ESCC. In this review, we discuss the heterogeneity of esophageal basal-layer stem cells and their potential relationship with cells of ESCC origin. We present evidence that expansion of NOTCH1 mutants may call into play an evolutionarily conserved anti-cancer mechanism and mold the model of early clonal evolution in ESCCs. Finally, we discuss the potential avenues in this context. This review provides a focused understanding of the early development of ESCC, as a background for early tumor detection, intervention, and prevention strategies.

Endoscopic features of esophageal high-grade intraepithelial neoplasia dominated by cytological atypia.

Little is known about esophageal high-grade intraepithelial neoplasia dominated by cytological atypia (HGINc). We aimed to elucidate the endoscopic features of HGINc compared with esophageal high-grade intraepithelial neoplasia dominated by architectural atypia (HGINa). All patients pathologically diagnosed as esophageal high-grade intraepithelial neoplasia after endoscopic submucosal dissection at our center between January 2018 and December 2019 were included in this study. According to the pathological diagnosis, the patients were divided into two groups: HGINa group and HGINc group. Basic characteristics and endoscopic information were collected in detail. Data were analyzed statistically. Binary logistic regression was performed and a predictive model for HGINc was established. Then we evaluated its predictive value and built a nomogram for clinical application. A total of 175 patients were included in this study (126 with HGINa and 49 with HGINc). Among 228 lesions found in all patients, there were 148 HGINa and 80 HGINc. The independent relevant factors for HGINc were tobacco and alcohol usage, color, and gross type. To predict risk of HGINc, a three-factor model (TFM) was established with a highest area under curve (AUC) as 0.869 (95% CI, 0.852, 0.939). When the cut-off value was set as 0.3569184, the diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for HGINc was 81.14%, 88.75%, 77.03%, 67.62%, and 92.68%, respectively. HGINc differs greatly in endoscopic features from HGINa in our study. It's important to reduce misdiagnosis that our model was established with good predictive value for clinical application.

Single-cell transcriptomics provides insights into the origin and microenvironment of human oesophageal high-grade intraepithelial neoplasia.

BACKGROUND: High-grade intraepithelial neoplasia (HIN) is the precursor of oesophageal squamous cell carcinoma. The molecular and functional properties of HIN are determined by intrinsic origin cells and the extrinsic microenvironment. Yet, these factors are poorly understood. METHODS: We performed single-cell RNA sequencing of cells from HINs and adjacent tissues from the human oesophagus. We analysed the heterogeneity of basal layer cells and confirmed it using immunostaining. Aneuploid cells in HIN were studied using primary cell culture combined with karyotype analysis. We reconstructed the lineage relationship between tumour and normal populations based on transcriptome similarity. Integration analysis was applied to our epithelial data and published invasive cancer data, and results were confirmed by immunostaining and 3D organoid functional experiments. We also analysed the tumour microenvironment of HIN. RESULTS: The basal layer contained two cell populations: KRT15high STMN1low and KRT15high STMN1high cells, which were located mainly in the interpapillary and papillary zones, respectively. The KRT15high STMN1low population more closely resembled stem cells and transcriptome similarity revealed that HIN probably originated from these slow-cycling KRT15high STMN1low cells. 3D Organoid experiments and RNA-sequencing showed that basal-cell features and the differentiation ability of the normal epithelium were largely retained in HIN, but may change dramatically in tumour invasion stage. Moreover, the tumour microenvironment of HIN was characterised by both inflammation and immunosuppression. CONCLUSIONS: Our study provides a comprehensive single-cell transcriptome landscape of human oesophageal HIN. Our findings on the origin cells and unique microenvironment of HIN will allow for the development of strategies to block tumour progression and even prevent cancer initiation.

Anemoside B4 sensitizes human colorectal cancer to fluorouracil-based chemotherapy through src-mediated cell apoptosis.

Currently, 5-Fluorouracil (5-FU) based chemotherapy is the primary option for colorectal cancer after surgery, whereas chemotherapy resistance related mortality is observed in a large proportion of patients. Anemoside B4 (AB4) is a triterpene saponin, which exhibits a considerable activity in oncotherapy. In this study, we explored the efficacy of AB4 in FU-based chemotherapy in colorectal cancer cells and the underlying molecular mechanisms. Our results indicated a significant synergistic activity of AB4 in 5-FU treated colorectal cancer cells. Furthermore, AB4 treatment eliminated colorectal cancer stem cells by promoting apoptotic cell death in 5-FU resistant colorectal cancer cells. Mechanically, AB4 activated caspase-9 pathway in 5-FU resistant colorectal cancer cells. Elevated Src activity induced cell apoptosis and cancer stem cells elimination effects in AB4 treated colorectal cancer cells. In conclusion, AB4 showed promising sensitization effect in the FU-based chemotherapy of colorectal cancer. Our study may pave a way to ameliorate FU-based chemotherapeutic efficiency in colorectal cancer.

Diverse regulatory manners of human telomerase reverse transcriptase.

Human telomerase reverse transcriptase (hTERT) is the core subunit of human telomerase and plays important roles in human cancers. Aberrant expression of hTERT is closely associated with tumorigenesis, cancer cell stemness maintaining, cell proliferation, apoptosis inhibition, senescence evasion and metastasis. The molecular basis of hTERT regulation is highly complicated and consists of various layers. A deep and full-scale comprehension of the regulatory mechanisms of hTERT is pivotal in understanding the pathogenesis and searching for therapeutic approaches. In this review, we summarize the recent advances regarding the diverse regulatory mechanisms of hTERT, including the transcriptional (promoter mutation, promoter region methylation and histone acetylation), post-transcriptional (mRNA alternative splicing and non-coding RNAs) and post-translational levels (phosphorylation and ubiquitination), which may provide novel perspectives for further translational diagnosis or therapeutic strategies targeting hTERT.

Regulation of the master regulator FOXM1 in cancer.

FOXM1 (forkhead box protein M1) is a critical proliferation-associated transcription factor that is widely spatiotemporally expressed during the cell cycle. It is closely involved with the processes of cell proliferation, self-renewal, and tumorigenesis. In most human cancers, FOXM1 is overexpressed, and this indicates a poor prognosis for cancer patients. FOXM1 maintains cancer hallmarks by regulating the expression of target genes at the transcriptional level. Due to its potential role as molecular target in cancer therapy, FOXM1 was named the Molecule of the Year in 2010. However, the mechanism of FOXM1 dysregulation remains indistinct. A comprehensive understanding of FOXM1 regulation will provide novel insight for cancer and other diseases in which FOXM1 plays a major role. Here, we summarize the transcriptional regulation, post-transcriptional regulation and post-translational modifications of FOXM1, which will provide extremely important implications for novel strategies targeting FOXM1.

Transplantation of autologous esophageal mucosa to prevent stricture after circumferential endoscopic submucosal dissection of early esophageal cancer (with video).

BACKGROUND AND AIMS: Esophageal stricture is a common adverse event after endoscopic submucosal dissection (ESD) when it involves the entire circumference of the esophagus. We aimed to assess the effectiveness and safety of endoscopic transplantation of autologous esophageal mucosa in preventing stricture formation after circumferential ESD. METHODS: Nine patients who underwent circumferential ESD for early esophageal cancer were enrolled. After the patients underwent ESD, autologous esophageal mucosal patches were attached to the ulcer surface by using hemoclips and were then fixed with a covered metal mesh stent. The stent was removed 7 days after the procedure. The patients were followed up with endoscopy at scheduled times. RESULTS: Epithelialization occurred within a median of 7.1 days, with a graft survival rate of 96.5%. Strictures occurred at a mean of 24.7 days (range 18-34 days) after the procedure. The median number of endoscopic balloon dilatation sessions was 2.7 (range 0-6). CONCLUSIONS: Transplantation of autologous esophageal mucosa could be a safe way of relieving the severity of esophageal stricture after circumferential ESD.

Organic Boundary Location Based on Color-Texture of Visual Perception in Wireless Capsule Endoscopy Video.

This paper addresses the problem of automatically locating the boundary between the stomach and the small intestine (the pylorus) in wireless capsule endoscopy (WCE) video. For efficient image segmentation, the color-saliency region detection (CSD) method is developed for obtaining the potentially valid region of the frame (VROF). To improve the accuracy of locating the pylorus, we design the Monitor-Judge model. On the one hand, the color-texture fusion feature of visual perception (CTVP) is constructed by grey level cooccurrence matrix (GLCM) feature from the maximum moments of the phase congruency covariance and hue-saturation histogram feature in HSI color space. On the other hand, support vector machine (SVM) classifier with the CTVP feature is utilized to locate the pylorus. The experimental results on 30 real WCE videos demonstrate that the proposed location method outperforms the related valuable techniques.

Hue-texture-embedded region-based model for magnifying endoscopy with narrow-band imaging image segmentation based on visual features.

BACKGROUND AND OBJECTIVE: Magnification endoscopy with narrow-band imaging (ME-NBI) has become a feasible tool for detecting diseases within the human gastrointestinal tract, and is more applied by physicians to search for pathological abnormalities with gastric cancer such as precancerous lesions, early gastric cancer and advanced cancer. In order to improve the reliability of diseases detection, there is a need for applying or proposing computer-assisted methodologies to efficiently analyze and process ME-NBI images. However, traditional computer vision methodologies, mainly segmentation, do not express well to the specific visual characteristics of NBI scenario. METHODS: In this paper, two energy functional items based on specific visual characteristics of ME-NBI images have been integrated in the framework of Chan-Vese model to construct the Hue-texture-embedded model. On the one hand, a global hue energy functional was proposed representing a global color information extracted in H channel (HSI color space). On the other hand, a texture energy was put forward presenting local microvascular textures extracted by the PIF of adaptive threshold in S channel. RESULTS: The results of our model have been compared with Chan-Vese model and manual annotations marked by physicians using F-measure and false positive rate. The value of average F-measure and FPR was 0.61 and 0.16 achieved through the Hue-texture-embedded region-based model. And the C-V model achieved the average F-measure and FPR value of 0.52 and 0.32, respectively. Experiments showed that the Hue-texture-embedded region-based outperforms Chan-Vese model in terms of efficiency, universality and lesion detection. CONCLUSIONS: Better segmentation results are acquired by the Hue-texture-embedded region-based model compared with the traditional region-based active contour in these five cases: chronic gastritis, intestinal metaplasia and atrophy, low grade neoplasia, high grade neoplasia and early gastric cancer. In the future, we are planning to expand the universality of our proposed methodology to segment other lesions such as intramucosal cancer etc. As long as these issues are solved, we can proceed with the classification of clinically relevant diseases in ME-NBI images to implement a fully automatic computer-assisted diagnosis system.

Long-term outcomes of endoscopic resection of gastric GISTs.

OBJECTIVE: Although the endoscopic treatment of gastric stromal tumors is a recently accepted therapy, the long-term outcomes of this approach remain unknown. The aims of this study were to assess the long-term effectiveness and safety of endoscopic resection for gastric GISTs. METHODS: A total of 60 consecutive patients undergoing endoscopic resection of gastric GISTs were enrolled in a retrospective single-center study. Clinical data, perioperative complications, histopathologic characteristics of the tumors, and long-term outcomes were recorded. RESULTS: Sixty patients successfully underwent complete resection of lesions, including 25 cases of endoscopic submucosal dissection (ESD) and 35 cases of endoscopic full-thickness resection (EFTR), with an average tumor size of 1.76 ± 1.55 cm (range 0.5-7.6 cm). The average operation time was 43.97 ± 26.95 min (range 11.7-138.9 min). Two cases were observed with an intraoperative hemorrhage of 200 mL, which were successfully managed by hemostatic forceps. Perforations of 2-11 mm of ESD occurred in four cases (4/25) and were well closed with endoclips, with no conversions to surgical operation. Mucosal laceration of esophagus occurred in 1 case, when a large tumor was removed. The average length of hospitalization was 6.50 ± 3.06 days (range 3-21 days). Out of a total of 60 patients, 44 (73.3%) were at very low risk, 10 (16.7%) were at low risk, 5 (8.3%) were at intermediate risk, and 1 (1.7%) was at high risk. All patients were followed-up for 36.15 ± 12.92 months (range 14-73 months). Primary tumor recurrence occurred in 1 patient who underwent a second operation after 32 months, and no other cases were observed to have either tumor recurrence or metastasis. CONCLUSIONS: For long-term outcomes, endoscopic resection of ESD or EFTR is a safe and effective approach for removing gastric stromal tumors (<5 cm), and it can be a resection technique for them with no metastasis.