HBV integrations reshaping genomic structures promote hepatocellular carcinoma.

OBJECTIVE: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further. DESIGN: Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice. RESULTS: These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (TERT), 6q, 8p, 16q, 9p (CDKN2A/B), 17p (TP53) and 13q (RB1), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials. CONCLUSION: HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.

Gastric tubular adenocarcinoma with diffuse neutrophils infiltrating: characteristics and probable treatment strategy.

BACKGROUND: Gastric adenocarcinoma is a highly heterogeneous malignancy with varying prognoses. In clinicopathological practice, we noticed a special tubular adenocarcinoma with diffuse neutrophils infiltrating (TADNI). However, the proportion and characteristics of TADNI remain unclear. This study aimed to evaluate the features of TADNI and explore probable treatments. METHODS: We divided 289 tubular adenocarcinoma cases into the TADNI and non-TADNI (nTADNI) groups by histological neutrophil quantity and performed immunohistochemistry of treatment-associated markers (CXCR1, CXCR2, PD-L1, CD8, HER2 and VEGFR2). Then we evaluated the clinical and morphological features in these cases. We also compared the value of histological features and peripheral blood neutrophil test. In addition, multiomics bioinformatic analyses were performed using the public datasets. RESULTS: In our cohort, TADNI accounted for 10.4% of all tubular adenocarcinoma cases. These cases had worse prognoses (especially the neutrophils mainly outside the tubes) than nTADNI cases. The histological identification of TADNI had more prognostic value than peripheral blood neutrophils. CXCR1/CXCR2 expression was significantly high in TADNI group which indicated that CXCR1/CXCR2 inhibitors might be beneficial for TADNI patients. There were no significant differences in the expression of PD-L1, CD8, HER2 and VEGFR2. The analyses of TCGA data confirmed that TADNI cases had poorer prognoses and higher CXCR1/CXCR2 expression. Bioinformatic results also revealed molecular features (more hsa-mir-223 expression, fewer CD8-positive T cells and regulatory T cells, tighter communication between tumor cells' CXCR1/CXCR2 and neutrophils' CXCL5/CXCL8) of this type. CONCLUSIONS: TADNI is a special morphological subtype with poorer prognoses and unique molecular characteristics, which might benefit from CXCR1/CXCR2 inhibitors.

The prognostic value of tumour-infiltrating lymphocytes, programmed cell death protein-1 and programmed cell death ligand-1 in Stage I-III triple-negative breast cancer.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) represent a robust biological prognostic biomarker in triple-negative breast cancer (TNBC); however, the contribution of different subsets of immune cells is unclear. We investigated the prognostic value of immune markers, including stromal TILs (sTILs), CD8+T and FOPX3+T cells, PD-1 and PD-L1 in non-metastatic TNBC. METHODS: In total, 259 patients with Stage I-III TNBC were reviewed. The density of sTILs along with the presence of total (t), stromal (s), and intratumoral (i) CD8+T cells and FOPX3+T cells were evaluated by haematoxylin and eosin and immunohistochemical staining. Immunohistochemical staining of PD-1, PD-L1 was also conducted. RESULTS: All immune markers were positively correlated with each other (P < 0.05). In the multivariate analysis, sTILs (P = 0.046), tCD8+T cells (P = 0.024), iCD8+T cells (P = 0.050) and PD-1 (P = 0.039) were identified as independent prognostic factors for disease-free survival (DFS). Further analysis showed that tCD8+T cells (P = 0.026), iCD8+T cells (P = 0.017) and PD-1 (P = 0.037) increased the prognostic value for DFS beyond that of the classic clinicopathological factors and sTILs. CONCLUSIONS: In addition to sTILs, inclusion of tCD8+T, iCD8+T cells, or PD-1 may further refine the prognostic model for non-metastatic TNBC beyond that including classical factors alone.

Prognostic significance of lymphovascular invasion in patients with pT1b esophageal squamous cell carcinoma.

BACKGROUND: Lymphovascular invasion (LVI) is a crucial predictor of lymph node metastasis (LNM). However, few studies have investigated the LVI positivity rate and its clinical significance in pT1b esophageal squamous cell carcinoma (ESCC) using immunohistochemistry and elastin staining. METHODS: We collected data from158 patients with pT1b ESCC who had undergone radical esophagectomy. All paraffin blocks of invasive carcinoma from each patient were subjected to HE staining, elastin staining + CK (AE1/AE3) immunohistochemistry (E&IHC), and CD31/D2-40 + CK (AE1/AE3) double immunohistochemistry (D-IHC). The LVI was classified into types, i.e., vascular invasion (VI) and lymphatic vessel invasion (LI), and its location, quantity, and clinical significance were explored. RESULTS: The positivity rates of VI by E&IHC (E-VI), VI by CD31D-IHC (CD31-VI), and LI by D2-40 D-IHC (D2-40-LI) were significantly higher than those obtained by HE staining (P < 0.001, respectively). CD31-VI and E-VI were independent adverse prognostic factors for recurrence-free survival (RFS), and they were significantly associated with poor distant metastasis-free survival and overall survival in pT1b ESCC. Intratumoral LVI was also crucial in pT1b ESCC, and L2 (the count of D2-40-LI was 5 or more) was the strongest predictor for LNM and RFS in pT1b ESCC. CONCLUSION: E&IHC and D-IHC can dramatically improve the detection rate of LVI in pT1b ESCC, and the classification and grading of LVI can help to improve the prediction of LNM and prognosis.

Comparison of the Clinicopathological Characteristics and Prognosis of Esophageal Squamous Cell Carcinoma with Intramural Metastases and Multiple Primary Carcinomas.

BACKGROUND: It is difficult to distinguish esophageal squamous cell carcinoma with intramural metastases (IM) from multiple primary oesophageal carcinoma (MPEC). Nevertheless, there are significant differences in their prognoses and treatments. Therefore, our study aims to clarify the clinicopathological and prognostic characteristics of these two entities and to provide clues for differential diagnosis. METHODS: We retrospectively analyzed 6304 patients who underwent esophagectomy without neoadjuvant therapy. The clinicopathological and prognostic features of patients with IM and MPEC were evaluated. P53 and Rb1 were detected by immunohistochemical (IHC) staining using a tissue microarray. RESULTS: Among the 6304 patients, 127 (2.0%) had IM, and 138 (2.2%) had MPEC. Patients with IM were more likely to have an advanced pT (p < 0.001), pN (p < 0.001), more lymphovascular invasion (p < 0.001) and neural invasion (p < 0.001). Additionally, patients with IM had an extremely poor prognosis compared to those with MPEC, with 5-year overall survival (OS) rates of 18.9% and 56.9%, respectively. Meanwhile, IM was found to be an independent poor prognostic indicator for OS and DFS. In the IM group, all patients showed consistent p53 expression in both primary and IM foci. Of note, Rb1 loss was found in 3 pairs of primary foci and metastases, along with p53 nonsense mutation. CONCLUSIONS: Patients with IM had more risk factors and extremely worse prognosis than those with MPEC. It is essential to discriminate IM from MPEC when managing multifocal carcinomas. IHC staining of p53 and Rb1 may aid in differential diagnosis.

A liquid biopsy signature predicts lymph node metastases in T1 oesophageal squamous cell carcinoma: implications for precision treatment strategy.

BACKGROUND: The treatment strategies for T1 oesophageal squamous cell carcinoma (ESCC) patients with or without lymph node metastasis (LNM) are different. Given the advantages of the minimally invasive, sensitive and real-time detection, liquid biopsy has become an important cancer diagnostic and prognostic tool. METHODS: MiRNA array and small-RNA sequencing were performed. Then, 222 formalin-fixed and paraffin-embedded tumour samples and 229 pretreatment serum samples from T1 ESCC patients were used to verify and evaluate the results. RESULTS: We demonstrated that serum miR-20b-5p could predict LNM in T1 ESCC patients. The AUC for serum miR-20b-5p was higher (0.827) than those for lymphovascular invasion (LVI) (0.751, P = 0.2128), invasion depth (0.662, P = 0.0027) and tumour differentiation grade (0.634, P = 0.0019). A nomogram for predicting LNM with three independent significant predictors (miR-20b-5p, LVI and invasion depth) was constructed with a concordance index of 0.931. Serum miR-20b-5p was also significantly correlated with disease-free survival (P < 0.001). An algorithm of improved T1 ESCC treatment strategy after biopsy and/or after endoscopic resection based on serum miR-20b-5p level was constructed. CONCLUSIONS: This study suggests that serum miR-20b-5p is a potential biomarker for predicting LNM and can be helpful for precise clinical decision-making strategies and improve treatment outcomes for T1 ESCC patients.

Hyperthermic intraperitoneal chemotherapy for patients with gastric cancer based on laboratory tests is safe: a single Chinese center analysis.

PURPOSE: About 15%-40% of gastric cancer patients have peritoneal metastasis, which leads to poor prognosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) is considered to be an effective treatment for these patients. This study evaluated the efficacy and safety of HIPEC in patients with gastric cancer diagnosed from laboratory tests. METHODS: The clinical and pathological data of 63 patients with gastric cancer who underwent HIPEC in 2017-2021 were prospectively recorded. Fifty-five patients underwent cytoreductive surgery + HIPEC, and eight patients received HIPEC alone. The factors associated with HIPEC safety and efficacy were analyzed. The primary endpoint was overall survival. RESULTS: The average patient age was 54.84 years and 68.3% of patients were male. Moreover, 79.4% of patients had a peritoneal carcinoma index (PCI) score of ≤ 7 and 61.9% had a completeness of cytoreduction score of 0. Because of peritoneal metastasis, 29 patients (46.03%) were classified as stage IV. Laboratory tests showed no differences in pre-HIPEC blood test results compared to post-HIPEC results after removing the effects of surgery. HIPEC treatment did not cause obvious liver or kidney damage. Serum calcium levels decreased significantly after HIPEC (P = 0.0018). The Karnofsky performance status (KPS) score correlated with the patient's physical function and improved after HIPEC (P = 0.0045). In coagulation tests, FDP (P < 0.0001) and D-dimer (P < 0.0001) levels increased significantly and CA242 (P = 0.0159), CA724 (P < 0.0001), and CEA (P < 0.0014) levels decreased significantly after HIPEC. Completeness of cytoreduction score was an independent prognostic factor. HIPEC did not show a survival benefit in patients with gastric cancer (P = 0.5505). CONCLUSION: HIPEC is a safe treatment for patients with gastric cancer with peritoneal metastasis based on the laboratory tests. However, the efficacy of this treatment on gastric-derived peritoneal metastases requires further confirmation.

Pesticide poisoning risk attributable to ambient temperature: a time series analysis in Qingdao China during 2007-2018.

Pesticide poisoning prevention has become a public health issue of great concern. We estimated the association between temperature and attributable risk of pesticide poisoning using 3,545 pesticide poisoning cases in Qingdao China from June 2007 to July 2018. A distributed lag non-linear model was applied to estimate the temperature-pesticide poisoning associated with the assessment of attributable number and fraction. The hot temperature is responsible for the pesticide poisoning incidence, with backward and forward attributable fractions, respectively, 7.79% and 7.61%. Most of the pesticide poisoning burden (backward attributable fraction 5.30% and forward attributable fraction 5.06%) was caused by mild hot (22°C-26°C), whereas the burden due to extreme hot (27°C-31°C) was small (backward attributable fraction 2.94% and forward attributable fraction 2.69%).

Both the serum AFP test and AFP/GPC3/SALL4 immunohistochemistry are beneficial for predicting the prognosis of gastric adenocarcinoma.

BACKGROUND: Both gastric adenocarcinoma with primitive enterocyte phenotype (GAPEP) (including hepatoid adenocarcinoma) and alpha-fetoprotein (AFP)-producing gastric adenocarcinoma have poor prognoses. However, the value of the serum AFP test and AFP/glypican-3 (GPC3)/spalt-like transcription factor 4 (SALL4) immunohistochemistry is still not clear, and these two methods have not yet been thoroughly compared. METHODS: We collected 421 consecutive non-neoadjuvant surgically or endoscopically resected gastric adenocarcinoma patients with serum AFP results before surgery (group A). We divided these cases into serum AFP-high (sAFP-H) and serum AFP-normal (sAFP-N) by serum AFP levels, and into GAPEP (expressing AFP, GPC3, or SALL4) and non-GAPEP (nGAPEP) by AFP/GPC3/SALL4 immunohistochemistry results. We also collected 12 non-resected gastric adenocarcinoma patients with serum AFP ≥ 7 ng/mL before treatment (group B). We analyzed these patients' clinicopathological characteristics and prognoses. RESULTS: Seventeen (4.04%) patients in group A were sAFP-H. These patients were younger and mainly had tubular adenocarcinoma with later pT (P = 0.014) and pN (P = 0.047) categories and more lymphovascular invasion (P < 0.001), perineural spread (P = 0.008), and metastases or recurrence (P < 0.001). For immunohistochemistry, 34 (8.08%) cases were GAPEP, and GAPEP cases also had later pT categories than nGAPEP cases (P = 0.001). Most group B patients with elevated serum AFP (especially > 1000 ng/mL) had simultaneous metastases, mainly liver metastases. Both the serological method and immunohistochemical method were useful for predicting prognosis (AUC sAFP = 0.625, AUC A/G/S-IHC = 0.723, z statistic = 1.726, P = 0.084). The serum AFP level (especially > 1000 ng/mL) is more specific (100%), and immunohistochemistry is more sensitive (50%). CONCLUSION: Both the serum AFP level and immunohistochemical expression of AFP/GPC3/SALL4 can be used to indicate a poor prognosis for gastric adenocarcinoma.

Age-associated genes in human mammary gland drive human breast cancer progression.

BACKGROUND: Aging is a comorbidity of breast cancer suggesting that aging-associated transcriptome changes may promote breast cancer progression. However, the mechanism underlying the age effect on breast cancer remains poorly understood. METHOD: We analyzed transcriptomics of the matched normal breast tissues from the 82 breast cancer patients in The Cancer Genome Atlas (TCGA) dataset with linear regression for genes with age-associated expression that are not associated with menopause. We also analyzed differentially expressed genes between the paired tumor and non-tumor breast tissues in TCGA for the identification of age and breast cancer (ABC)-associated genes. A few of these genes were selected for further investigation of their malignancy-regulating activities with in vitro and in vivo assays. RESULTS: We identified 148 upregulated and 189 downregulated genes during aging. Overlapping of tumor-associated genes between normal and tumor tissues with age-dependent genes resulted in 14 upregulated and 24 downregulated genes that were both age and breast cancer associated. These genes are predictive in relapse-free survival, indicative of their potential tumor promoting or suppressive functions, respectively. Knockdown of two upregulated genes (DYNLT3 and P4HA3) or overexpression of the downregulated ALX4 significantly reduced breast cancer cell proliferation, migration, and clonogenicity. Moreover, knockdown of P4HA3 reduced growth and metastasis whereas overexpression of ALX4 inhibited the growth of xenografted breast cancer cells in mice. CONCLUSION: Our study suggests that transcriptome alterations during aging may contribute to breast tumorigenesis. DYNLT3, P4HA3, and ALX4 play significant roles in breast cancer progression.

Is subtotal gastrectomy feasible for the treatment of gastric stump cancer located at the anastomotic site after distal gastrectomy for benign lesions?

BACKGROUND: Total gastrectomy (TG) is a widely accepted procedure for treating gastric stump cancer (GSC). However, subtotal gastrectomy (SG) would benefit elective patients with GSC. The aim of this study was to clarify the safety and long-term prognosis of SG in treating GSC after distal gastrectomy for benign lesions. METHODS: A total of 53 patients with GSC located at the anastomotic site or gastric body between May 1999 and December 2018 at our hospital were included. In total, 21 patients underwent SG, and the remaining 24 patients underwent TG. Clinicopathological data, operative data, and overall survival (OS) were compared. RESULTS: The operative duration, estimated blood loss volume, and length of hospital stay were similar between the SG and TG groups. The postoperative complications were similar between the two groups, but no cases of anastomotic leakage were noted in the SG group. TG was associated with significantly more retrieved lymph nodes than SG (18.5 ± 11.5 vs. 10.7 ± 9.2; p = 0.017), while the number of metastatic lymph nodes did not differ between the groups (2.9 ± 3.5 vs. 1.9 ± 3.6; p = 0.329). The median survival time in the SG group was 81.0 months (95% confidence interval (CI), 68.906 to 93.094 months), which was similar to the 45.0 months (95% CI, 15.920 to 74.080 months) observed in the TG group (p = 0.236). Both univariate and multivariate analyses showed that tumor location and histological type were prognostic factors, while surgery type was not a prognostic factor. Further stratified analyses according to tumor location revealed that OS was not significantly different between the two groups among patients with tumors located at the anastomotic site, while OS in the TG group was significantly better than that in the SG group among patients with tumors located in the gastric body (p = 0.046). CONCLUSIONS: The results of the current study indicate that SG is a suitable alternative surgical procedure for GSC located at the anastomotic site after distal gastrectomy for benign lesions. The short-term outcomes and long-term prognoses of SG are comparable with those of TG.

Differential effects of GLI2 and GLI3 in regulating cervical cancer malignancy in vitro and in vivo.

Advanced, recurrent, or persistent cervical cancer is often incurable. Therefore, in-depth insights into the molecular mechanisms are needed for the development of novel therapeutic targets and the improvement of current therapeutic strategies. In this study, we investigated the role of GLI2 and GLI3 in the regulation of the malignant properties of cervical cancer. We showed that down-regulation of GLI2, but not GLI3, with an inducible GLI2 shRNA inhibited the growth and migration of cervical cancer cell lines, which could be rescued by ectopic expression of GLI2. GLI2 appeared to support cell growth by regulating the mitosis, but not the apoptosis, of the cervical cancer cells. Mechanistically, these functions of GLI2 were in part mediated by the activation of AKT pathway. Knockdown of GLI2, but not GLI3, also inhibited xenograft growth of cervical cancer cells in vivo. Finally, analysis of TCGA data showed that high levels of GLI2, but not GLI3, conferred a poor prognosis in cervical cancer patients. These observations for the first time suggest that GLI2, but not GLI3, exerts a tumor-promoting role in cervical cancer and may be targeted as a novel therapeutic strategy.

Formation of macromolecules in wheat gluten/starch mixtures during twin-screw extrusion: effect of different additives.

BACKGROUND: Wheat gluten comprises a good quality and inexpensive vegetable protein with an ideal amino acid composition. To expand the potential application of wheat gluten in the food industry, the effect of different additives on the physicochemical and structural properties of wheat gluten/starch mixtures during twin-screw extrusion was investigated. RESULTS: Macromolecules were observed to form in wheat gluten/starch mixtures during twin-screw extrusion, which may be attributed to the formation of new disulfide bonds and non-covalent interactions, as well as Maillard reaction products. Additionally, the water retention capacity and in vitro protein digestibility of all extruded wheat gluten/starch products significantly increased, whereas the nitrogen solubility index and free sulfhydryl group (SH) content decreased, during twin-screw extrusion. Secondary structural analysis showed that α-helices disappeared with the concomitant increase of antiparallel ß-sheets, demonstrating the occurrence of protein aggregation. Microstructures suggested that the irregular wheat gluten granular structure was disrupted, with additive addition favoring transformation into a more layered or fibrous structure during twin-screw extrusion. CONCLUSION: The findings of the present study demonstrate that extrusion might affect the texture and quality of extruded wheat gluten-based foods and suggest that this process might serve as a basis for the high-value application of wheat gluten products. © 2017 Society of Chemical Industry.

Tumor stroma ratio, tumor stroma maturity, tumor-infiltrating immune cells in relation to prognosis, and neoadjuvant therapy response in esophagogastric junction adenocarcinoma.

Accurate predictions on prognosis and neoadjuvant therapy response are crucial for esophagogastric junction adenocarcinoma (EGJA) patients. Therefore, we aimed to investigate the predictive abilities of several indicators, including tumor stroma ratio (TSR), tumor stroma maturity (TSM), and the density and spatial distribution of tumor-infiltrating immune cells (TIICs), such as T cells, B cells, and tumor-associated macrophages (TAMs). Resection and biopsy specimens of a total of 695 patients were included, obtained from the National Cancer Center (NCC) and The Cancer Genome Atlas (TCGA) cohorts. TSR and TSM were evaluated based on histological assessment. TIICs were quantified by QuPath following immunohistochemical (IHC) staining in resection specimens, while the Klintrup-Mäkinen (KM) grade was employed for evaluating TIIC in biopsy specimens. Patients with high stromal levels or immature stroma had relatively worse prognoses. Furthermore, high CD8+T cell count in the tumor periphery, as well as low CD68+ TAM count either in the tumor center or in the tumor periphery, was an independent favorable prognostic factor. Significantly, the combination model incorporating TSM and CD163+TAMs emerged as an independent prognostic factor in both two independent cohorts (HR 3.644, 95% CI 1.341-9.900, p = 0.011 and HR 1.891, 95% CI 1.195-2.99, p = 0.006, respectively). Additionally, high stromal levels in preoperative biopsies correlated with poor neoadjuvant therapy response (p < 0.05). In conclusion, our findings suggest that TSR, TSM, CD8+T cell, CD68+TAMs, and CD163+TAMs predict the prognosis to some extent in patients with EGJA. Notably, the combined model incorporating TSM and CD163+TAM can contribute significantly to prognostic stratification. Additionally, high stromal levels evaluated in preoperative biopsy specimens correlated with poor neoadjuvant therapy response.

Bi-regional dynamic contrast-enhanced MRI for prediction of microvascular invasion in solitary BCLC stage A hepatocellular carcinoma.

OBJECTIVES: To construct a combined model based on bi-regional quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), as well as clinical-radiological (CR) features for predicting microvascular invasion (MVI) in solitary Barcelona Clinic Liver Cancer (BCLC) stage A hepatocellular carcinoma (HCC), and to assess its ability for stratifying the risk of recurrence after hepatectomy. METHODS: Patients with solitary BCLC stage A HCC were prospective collected and randomly divided into training and validation sets. DCE perfusion parameters were obtained both in intra-tumoral region (ITR) and peritumoral region (PTR). Combined DCE perfusion parameters (CDCE) were constructed to predict MVI. The combined model incorporating CDCE and CR features was developed and evaluated. Kaplan-Meier method was used to investigate the prognostic significance of the model and the survival benefits of different hepatectomy approaches. RESULTS: A total of 133 patients were included. Total blood flow in ITR and arterial fraction in PTR exhibited the best predictive performance for MVI with areas under the curve (AUCs) of 0.790 and 0.792, respectively. CDCE achieved AUCs of 0.868 (training set) and 0.857 (validation set). A combined model integrated with the α-fetoprotein, corona enhancement, two-trait predictor of venous invasion, and CDCE could improve the discrimination ability to AUCs of 0.966 (training set) and 0.937 (validation set). The combined model could stratify the prognosis of HCC patients. Anatomical resection was associated with a better prognosis in the high-risk group (p < 0.05). CONCLUSION: The combined model integrating DCE perfusion parameters and CR features could be used for MVI prediction in HCC patients and assist clinical decision-making. CRITICAL RELEVANCE STATEMENT: The combined model incorporating bi-regional DCE-MRI perfusion parameters and CR features predicted MVI preoperatively, which could stratify the risk of recurrence and aid in optimizing treatment strategies. KEY POINTS: Microvascular invasion (MVI) is a significant predictor of prognosis for hepatocellular carcinoma (HCC). Quantitative DCE-MRI could predict MVI in solitary BCLC stage A HCC; the combined model improved performance. The combined model could help stratify the risk of recurrence and aid treatment planning.

Distinct molecular profiles drive multifaceted characteristics of colorectal cancer metastatic seeds.

Metastasis of primary tumors remains a challenge for early diagnosis and prevention. The cellular properties and molecular drivers of metastatically competent clones within primary tumors remain unclear. Here, we generated 10-16 single cell-derived lines from each of three colorectal cancer (CRC) tumors to identify and characterize metastatic seeds. We found that intrinsic factors conferred clones with distinct metastatic potential and cellular communication capabilities, determining organ-specific metastasis. Poorly differentiated or highly metastatic clones, rather than drug-resistant clones, exhibited poor clinical prognostic impact. Personalized genetic alterations, instead of mutation burden, determined the occurrence of metastatic potential during clonal evolution. Additionally, we developed a gene signature for capturing metastatic potential of primary CRC tumors and demonstrated a strategy for identifying metastatic drivers using isogenic clones with distinct metastatic potential in primary tumors. This study provides insight into the origin and mechanisms of metastasis and will help develop potential anti-metastatic therapeutic targets for CRC patients.

Mucoepidermoid carcinoma of the esophagus with MAML2 gene rearrangement: Case report and literature review.

Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy but rarely occurs in the esophagus. It is easily confused with adenosquamous carcinoma and squamous cell carcinoma (SCC) with mucus-secreting components. MAML2 gene rearrangement detected by fluorescence in situ hybridization (FISH), RT-PCR or next-generation sequencing (NGS) can aid in the diagnosis. We present a case of esophageal MEC with MAML2 gene rearrangement detected by FISH. To the best of our knowledge, this is the first report of an esophageal MEC with MAML2 gene rearrangement. We also reveal that esophageal MEC patients were reported to have a higher risk of recurrence and death than SCC patients in previous literature. However, all the cases were diagnosed using previous diagnostic criteria and not confirmed by MAML2 gene rearrangement detection, and most of them might not be true MECs.

Tumor budding and tumor-infiltrating lymphocytes can predict prognosis in pT1b esophageal squamous cell carcinoma.

BACKGROUND: Tumor budding (TB) and tumor-infiltrating lymphocyte (TIL) are significant predictive indicators of lymph node metastasis (LNM) and unfavorable prognosis in various tumors. Currently, there is no gold standard for TB and TIL evaluation in esophageal squamous cell carcinoma (ESCC). This study aimed to identify the standard of TB and TIL evaluations and build a predictive model for prognosis among patients with pT1b ESCC. METHODS: We retrospectively analyzed the prognostic values of TB and TIL in 150 pT1b ESCC cases. Hematoxylin and eosin (H&E) and immunohistochemistry (IHC) of anti-pan cytokeratin (AE1/AE3) were used to analyze the threshold of TB, and intratumoral TIL and peritumoral TIL (pTIL) were evaluated using the receiver operating characteristic curves (ROC). RESULTS: We found that TB in a three-tiered grading system (low-TB: 0-4; middle-TB: 5-15; high-TB: ≥16) displayed an excellent prognosis prediction for LNM and survival based on IHC staining using a 20× objective lens. Low pTIL level (≤20%) was a significant indicator of LNM and unfavorable prognosis (p < 0.05). Moreover, lower tumor location and lymphovascular invasion (LVI) were correlated with an unfavorable prognosis (p < 0.05). A nomogram developed based on TB, pTIL, LVI, and tumor location showed good discrimination, as shown by the area under the ROC and calibration curves. CONCLUSION: We therefore recommend identifying TB using a 20× objective lens under IHC staining and TIL adjacent to the tumor. Additionally, a nomogram was built for facilitating individualized prediction of survival for patients with pT1b ESCC.

Modified stomach-partitioning gastrojejunostomy for initially unresectable advanced gastric cancer with outlet obstruction: A case report.

BACKGROUND: Chemotherapy followed by gastrojejunostomy remains the main treatment for unresectable gastric cancer (GC) in the middle- or lower-third regions with gastric outlet obstruction (GOO). Radical surgery is performed as part of a multimodal treatment strategy for selected patients who respond well to chemotherapy. This study describes a case of successful radical resection with completely laparoscopic subtotal gastrectomy after a modified stomach-partitioning gastrojejunostomy (SPGJ) for obstruction relief, in a patient with GOO. CASE SUMMARY: During the initial esophagogastroduodenoscopy, an advanced growth was detected in the lower part of the stomach, which caused an obstruction in the pyloric ring. Following this, a computed tomography (CT) scan revealed the presence of lymph node metastases and tumor invasion in the duodenum, but no evidence of distant metastasis was found. Consequently, we performed a modified SPGJ, a complete laparoscopic SPGJ combined with No. 4sb lymph node dissection, for obstruction relief. Seven courses of adjuvant capecitabine plus oxaliplatin combined with Toripalimab (programmed death ligand-1 inhibitor) were administered thereafter. A preoperative CT showed partial response; therefore, completely laparoscopic radical subtotal gastrectomy with D2 lymphadenectomy was performed after conversion therapy, and pathological complete remission was achieved. CONCLUSION: Laparoscopic SPGJ combined with No. 4sb lymph node dissection was an effective surgical technique for initially unresectable GC with GOO.

Significance of Siglec-15 expression in colorectal cancer: association with advanced disease stage and fewer tumor-infiltrating lymphocytes.

Siglec-15, a novel immune suppressor, is upregulated in many human cancers. The aim of this study was to explore the expression of Siglec-15 in colorectal cancer (CRC), and investigate whether Siglec-15 could be a potential target for cancer immunotherapy in patients with CRC. We performed immunohistochemical analyses of Siglec-15 on a cohort of 805 patients with CRC and made comparisons between clinicopathological characteristics, PD-L1 expression, CD3, CD8, CD45RO tumor-infiltrating lymphocytes (TILs), and prognosis. We found that Siglec-15 expression was commonly detected in tumor cells (48.3%) and tumor-associated stromal cells (33.4%), and was more frequently observed than PD-L1 expression in tumor cells. In contrast, Siglec-15 expression was weakly and scarcely found in normal mucosa (13%). Siglec-15 overexpression in tumor cells was associated with advanced TNM stage (p = 0.020). Co-expression of Siglec-15 and PD-L1 in tumor cells was found in 14.4% of patients, and Siglec-15 expression was detected in almost half of PD-L1 negative cases. Elevated Siglec-15 expression in tumor and stromal cells was associated with sparser CD45RO and CD8 TILs (p = 0.035 and p = 0.004, respectively). The expression of Siglec-15 did not have prognostic significance. In summary, compared to PD-L1, Siglec-15 protein expression is more prevalent in CRC and is associated with advanced disease stage and fewer TILs. These findings support Siglec-15 as a potential cancer immunotherapy target, in addition to PD-1/PD-L1 inhibitors, in patients with CRC.