Tumor-associated macrophage-derived transforming growth factor-ß promotes colorectal cancer progression through HIF1-TRIB3 signaling.

Tumor-associated macrophages (TAMs), one of the most common cell components in the tumor microenvironment, have been reported as key contributors to cancer-related inflammation and enhanced metastatic progression of tumors. To explore the underlying mechanism of TAM-induced tumor progression, TAMs were isolated from colorectal cancer patients, and the functional interaction with colorectal cancer cells was analyzed. Our study found that coculture of TAMs contributed to a glycolytic state in colorectal cancer, which promoted the stem-like phenotypes and invasion of tumor cells. TAMs produced the cytokine transforming growth factor-ß to support hypoxia-inducible factor 1α (HIF1α) expression, thereby upregulating Tribbles pseudokinase 3 (TRIB3) in tumor cells. Elevated expression of TRIB3 resulted in activation of the ß-catenin/Wnt signaling pathway, which eventually enhanced the stem-like phenotypes and cell invasion in colorectal cancer. Our findings provided evidence that TAMs promoted colorectal cancer progression in a HIF1α/TRIB3-dependent manner, and blockade of HIF1α signals efficiently improved the outcome of chemotherapy, describing an innovative approach for colorectal cancer treatment.

ABCB1 and ABCG2 restricts the efficacy of gedatolisib (PF-05212384), a PI3K inhibitor in colorectal cancer cells.

BACKGROUND: Overexpression of ABC transporters is a big challenge on cancer therapy which will lead cancer cells resistance to a series of anticancer drugs. Gedatolisib is a dual PI3K and mTOR inhibitor which is under clinical evaluation for multiple types of malignancies, including colorectal cancer. The growth inhibitory effects of gedatolisib on colorectal cancer cells have been specifically studied. However, the role of ABC transporters on gedatolisib resistance remained unclear. In present study, we illustrated the role of ABC transporters on gedatolisib resistance in colorectal cancer cells. METHODS: Cell viability investigations of gedatolisib on colorectal cancer cells were determined by MTT assays. The verapamil and Ko143 reversal studies were determined by MTT assays as well. ABCB1 and/or ABCG2 siRNA interference assays were conducted to verify the role of ABCB1- and ABCG2-overexpression on gedatolisib resistance. The accumulation assays of gedatolisib were conducted using tritium-labeled paclitaxel and mitoxantrone. The effects of gedatolisib on ATPase activity of ABCB1 or ABCG2 were conducted using PREDEASY ATPase Kits. The expression level of ABCB1 and ABCG2 after gedatolisib treatment were conducted by Western blotting and immunofluorescence assays. The well-docked position of gedatolisib with crystal structure of ABCB1 and ABCG2 were simulated by Autodock vina software. One-way ANOVA was used for the statistics analysis. RESULTS: Gedatolisib competitively increased the accumulation of tritium-labeled substrate-drugs in both ABCB1- and ABCG2-overexpression colorectal cancer cells. Moreover, gedatolisib significantly increased the protein expression level of ABCB1 and ABCG2 in colorectal cancer cells. In addition, gedatolisib remarkably simulated the ATPase activity of both ABCB1 and ABCG2, suggesting that gedatolisib is a substrate drug of both ABCB1 and ABCG2 transporters. Furthermore, a gedatolisib-resistance colorectal cancer cell line, SW620/GEDA, was selected by increasingly treatment with gedatolisib to SW620 cells. The SW620/GEDA cell line was proved to resistant to gedatolisib and a series of chemotherapeutic drugs, except cisplatin. The ABCB1 and ABCG2 were observed overexpression in SW620/GEDA cell line. CONCLUSIONS: These findings suggest that overexpression of ABCB1 and ABCG2 may restrict the efficacy of gedatolisib in colorectal cancer cells, while co-administration with ABC transporter inhibitors may improve the potency of gedatolisib.

Evaluation of Epidemiologic Factors, Radiographic Features, and Pathologic Findings for Predicting Peritumoral Brain Edema in Meningiomas.

BACKGROUND: Despite several treatment options that are available for meningiomas, surgery is the only method currently practiced. Peritumoral brain edema (PTBE) in meningiomas causes difficulty marginalizing the dissection in an intraoperative setting. PURPOSE: To evaluate whether the epidemiological variables, imaging characteristics, and pathologic parameters are correlated with the presence of PTBE in meningiomas. STUDY TYPE: Retrospective study from 2015 to 2018. SUBJECTS: In all, 550 patients with histopathologically confirmed meningioma were included. After exclusion of patients with extradural, spinal, and intraventricular meningiomas and those with image artifacts, a total of 441 patients were included in the final analysis. FIELD STRENGTH/SEQUENCE: Images were performed with 3T MR scanners and axial/sagittal T1 WI, axial/coronal T2 WI and axial/sagittal/coronal contrast-enhanced T1 WI after administration of 0.1 mmol/kg of body weight of Gd-DTPA. ASSESSMENT: Fourteen variables were patients' age, sex, skull changes, calcification, density, location, margin, volume, cerebrospinal fluid (CSF) cleft, signal intensity (SI) on T2 WI, degree and pattern of contrast enhancement, WHO histological classification, and Ki-67 labeling index. STATISTICAL TESTS: The relationship between each factor and the formation of PTBE was examined by multivariate logistic regression analysis. RESULTS: After multivariate logistic regression, the absence of CSF cleft (odds ratio [OR]: 63.43, 95% confidence interval [CI]: 27.24-121.42, P = 1.2 × 10-8 ), non-skull base location (OR: 15.32, 95% CI: 5.81-28.23, P = 0.0008), high SI on T2 WI (OR: 5.05, 95% CI: 2.27-14.88, P = 0.01), and G I uncommon subtypes (OR: 4.75, 95% CI: 1.42-15.94, P = 0.01) were found to be significant independent factors associated with the occurrence of PTBE in meningiomas. In patients with PTBE-positive meningiomas, there was no significant correlation between the volume of PTBE and the volume of the tumor (r = 0.17, P = 0.60). DATA CONCLUSION: These factors may be suggestive of anticipating the formation of PTBE. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;52:174-182.

Efficacy of cryoablation combined with sorafenib for the treatment of advanced renal cell carcinoma.

OBJECTIVE: To determine the safety and efficacy of cryoablation combined with sorafenib for the treatment of advanced renal cell carcinoma. MATERIAL AND METHODS: We conducted an observational study in 156 patients with advanced renal cell carcinoma unsuitable for surgical treatment. Participants received cryoablation + sorafenib (n = 67) or sorafenib only (n = 89). Objective response rate (ORR), disease control rate (DCR), progression-free survival time (PFS), overall survival (OS), change in immune function after treatment, rate of adverse events, and quality of life were compared between the two groups. RESULTS: In the cryoablation + sorafenib group, ORR and DCR were significantly higher and PFS and OS were significantly longer than in the sorafenib only group (both p < .05). Immune function-related indicators were significantly improved after treatment in the cryoablation + sorafenib group (p < .05), but no significant difference was found between before and after treatment in the sorafenib only group (p > .05). The incidence of targeted drug-related side effects was not significantly different between the groups (p > .05), and cryoablation did not increase the risk of side effects of targeted drugs. CONCLUSION: Cryoablation combined with sorafenib had superior clinical efficacy compared with sorafenib-only for the treatment of advanced renal cell carcinoma unsuitable for surgical treatment. Moreover, this combined therapy may enhance the body's anti-tumor immunity and effectively prolong PFS and OS without compromising patient quality of life, thus representing a new treatment strategy for advanced renal cell carcinoma.

The oncologic results of cryoablation in prostate cancer patients with bone metastases.

OBJECTIVE: To explore the role of whole gland cryoablation plus ADT in prostate cancer (PCa) with bone metastases compared with ADT treatment alone in metastatic PCa. METHODS: A total of 30 patients with biopsy-proven PCa with bone metastases underwent cryoablation and ADT treatment. The control group consisted of 30 men who were initially treated with ADT only and who were followed until progression, development of castration resistant PCa or death. Patients were pair matched for age, PSA level, clinical stage, preoperative biopsy Gleason score and bone metastases. Time to clinical progression, time to CRPC, cancer-specific survival and overall survival were analysed using descriptive statistical analysis. RESULTS: Age at diagnosis, baseline PSA, biopsy Gleason score and ECOG status were comparable between the two groups. Prostate cryoablation was well tolerated and no serious complications occurred. At the last follow-up, patients in the cryoablation and ADT treatment group had a lower median PSA nadir (0.4 ng/ml vs. 0.8 ng/ml, p < 0.01) and longer time to CRPC (33 ± 0.9 mo vs. 22 ± 0.8 mo, p < 0.01). Further analyses detected the statistically significant benefits of cryoablation treatment not only in PFS (41 ± 1.4 mo vs. 22 ± 0.8 mo, p < 0.01), but also in CSS (52 ± 1.9 mo vs. 32 ± 2.4 mo, p ± 0.01) and OS (41 ± 1.5 mo vs. 28 ± 1.7 mo, p < 0.01). Moreover, there were fewer palliative procedures for local progression in the cryoablation group than the controls. CONCLUSIONS: Cryoablation plus ADT might be a treatment option in the multimodality management of metastatic prostate cancer. Further investigations are warranted.

Immunological response induced by cryoablation against murine H22 hepatoma cell line in vivo.

OBJECTIVES: To describe immunological consequences induced by cryoablation against H22 cells in vivo. METHODS: Adult BALB/c mice underwent subcutaneous implantation of H22 cells. All of them were assigned into three groups randomly: group A (false surgery), group B (cryoablation) and group C (cryoablation plus Freund's adjuvant). Animals were sacrificed 1, 2 and 3 weeks after treatment. Serum IFN-γ and IL-4, Th1/Th2 in spleens and cytotoxicity were detected. RESULTS: Compared with that of group A, (1) INF-γ of group B was higher, but IL-4 was lower; cryoablation plus Freund's adjuvant enhanced these effects. (2) Th1/Th2 rose significantly in both group B and group C. (3) Strong cytolytic activity against H22 cells of group B and group C was found on day 7, 14 and 21. CONCLUSIONS: Our study showed a marked shift toward Th1 and IFN-γ expression after cryoablation, with an immuno-stimulatory effect against murine H22 hepatoma Cell.

Clinicopathological and Prognostic Factors in 106 Prostate Cancer Patients Aged ≤55 Years: A Single-Center Study in China.

BACKGROUND Early-onset prostate cancer patients (aged ≤55 years) from Western countries have been well characterized in previous studies. However, the clinicopathological and prognostic characteristics of early-onset Chinese prostate cancer patients have not yet been assessed. This study aimed to examine the clinicopathological and prognostic factors of prostate cancer patients aged ≤55 years in a single Chinese center. MATERIAL AND METHODS One hundred six prostate cancer patients aged ≤55 years with complete clinicopathological data who were treated at our hospital between January 2000 and June 2014 were selected for this study. Survival rate was investigated by Kaplan-Meier analysis, and prognostic factors were examined by univariate and multivariate analysis. RESULTS The median time from the onset of symptoms to diagnosis was 3.5 months (range, 2-55 months). The median time after endocrine therapy to development of androgen-independent prostate cancer was 10.5 months. A total of 54 patients died (50.9%), of whom 96.2% died from prostate cancer. The 1-, 3-, and 5-year overall survival rates were 88.7%, 66.2%, and 36.0%, respectively. Univariate and multivariate analysis showed that T staging, visceral metastasis, pathological pattern, and Gleason sum were independent prognostic factors in these patients. CONCLUSIONS Prostate cancer patients aged ≤55 years are often omitted or misdiagnosed in China. Furthermore, the pathology patterns in this age group were mostly complicated with a high degree of malignancy. Late staging, visceral metastasis, pathological pattern, and high Gleason score were independent prognostic factors in these patients. Comprehensive therapy combined with local therapy is an effective treatment strategy.

Oncological outcomes of cryosurgery as primary treatment in T3 prostate cancer: experience of a single centre.

OBJECTIVE: To assess the oncological outcomes and determine prognostic factors for overall survival (OS), cancer-specific survival (CSS), and biochemical progression-free survival (BPFS) after cryosurgery for clinical stage T3 prostate cancer. PATIENTS AND METHODS: Between 2002 and 2007, 75 patients with clinical stage T3 prostate cancer received cryosurgery as primary treatment in our institution. No adjuvant treatment was provided until biochemical failure. After biochemical failure, hormone therapy was administered. Kaplan-Meier analysis was used to calculate the OS, CSS, and BPFS. Cox regression was used to identify factors predictive of survival. RESULTS: Clinical stage T3a (cT3a) was detected in 60% (45/75) of patients and cT3b detected in 40% (30/75). The 5-year OS, CSS, and BPFS rates were 85.3%, 92.0%, and 48%, respectively. There was a significant difference when comparing the pT3a with the pT3b group for 5-year OS (88.9% vs 80%, P = 0.02) and BPFS (55.6% vs 36.7%, P = 0.01), but there was no difference in CSS (93.3% vs 90%, P = 0.63). Stage, Gleason score, and nadir prostate-specific antigen (PSA) were associated with BPFS, while Gleason score and nadir PSA were the most significant predictors for CSS. CONCLUSIONS: Cryosurgery can offer good 5-year OS, CSS, and BPFS rates for cT3 prostate cancer, and there was no difference between T3a and T3b for CSS. Gleason score and nadir PSA were the most significant predictors of survival. Further clinical trials are warranted for evaluating the role of cryosurgery for cT3 prostate cancer.

Clinical prognostic value of CD4+CD25+FOXP3+regulatory T cells in peripheral blood of Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma patients.

BACKGROUND: CD4+CD25+ forkhead box P3 (FOXP3)+ regulatory T cells (Tregs) accumulate in malignant tumors and negatively regulate antitumor immunity. However, the clinical significance of Tregs in HCC remains unclear. To determine the prognostic value of Tregs, we conducted a retrospective study on 264 patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) who underwent transcatheter arterial chemoembolization (TACE). METHODS: We measured the proportion of peripheral blood Tregs in 105 healthy donors and 264 HCC patients (stage B) prior to and following TACE between 2005 and 2007. All HCC patients were followed up until December 2012. The correlations between the proportion of Tregs and clinicopathologic factors were analyzed, and long-term survival rate after TACE according to the percentage of Tregs was assessed by univariate and multivariate analyses. RESULTS: The 1-, 2-, 3-, 4- and 5-year cumulative survival rates were 62.1%, 32.6%, 16.5%, 10.4% and 6.9%, respectively, and the median survival time was 19.0 months. The cumulative survival rate was significantly lower in patients with higher levels of peripheral blood Treg cells compared to those with lower Treg levels (p<0.001). Furthermore, we found that both pre- and post-TACE peripheral blood Treg levels showed significant negative association with overall survival time (p<0.001). CONCLUSIONS: Elevated peripheral blood CD4+CD25+FOXP3+Treg levels are an independent predictive factor of poor survival after TACE for HCC (stage B) patients. These results suggest that targeting Tregs may improve patient outcomes, and provide a strong rationale for testing these approaches in future immunotherapy-based clinical trials.

[Efficacy and safety of low-dose high intensity focused ultrasound combined with S-1 and oxaliplatin in metastatic colorectal patients with pelvic masses].

OBJECTIVE: To evaluate the efficacy and safety of the regimen of low-dose high intensity focused ultra-sound (HIFU) plus S-1 and oxaliplatin (SOX) in the treatment of metastatic colorectal cancer patients with pelvic masses. METHODS: A total of 46 patients with metastatic colorectal cancer were recruited and divided into 2 groups: Twenty patients received concurrent HIFU plus S-1 and oxaliplatin (SOX) while another 26 patients SOX alone. The baseline characteristics, progressive-free survival, overall survival time and adverse events were retrospectively analyzed. RESULTS: The median PFS was 11.2 months (95% CI 9.8-12.7) in the HIFU+SOX group and 7.1 months (95% CI 5.8-8.4) in the SOX group (P = 0.003). And the overall survival time in two groups were 21.9 months (95% CI 18.0-25.9) and 16.9 months (95%CI 14.1-19.6) (P = 0.072) respectively. Major toxic effects included grade 3/4 neutropenia (15%), anemia (10%), thrombocytopenia (10%), diarrhea (15%) and hand-foot syndrome (10%) in the HIFU+SOX group. And it showed no statistically significant differences with the SOX group. CONCLUSION: The combined regimen of HIFU and SOX is effective and well-tolerated in patients of late-stage colorectal cancer with pelvic masses.

Analysis of clinical efficacy and long-term prognosis of patients with hepatocellular carcinoma treated with PD-L1 inhibitor targeting.

BACKGROUND: The most effective clinical treatment for hepatocellular carcinoma (HCC) is surgery, but most patients are diagnosed when the disease has progressed. OBJECTIVE: To examine the long-term prognosis and clinical effectiveness of PD-L1 inhibitor-targeted therapy for patients suffering from HCC. METHODS: Ninety-six patients with advanced HCC who were admitted to our hospital between December 2019 and April 2022 were split into two groups based on the treatment plan after a retrospective analysis: 43 patients in the control group underwent sorafenib-based targeted therapy, while dulvalizumab was used to treat 53 patients in the observation group. Observation indexes were used to assess the clinical effectiveness and long-term prognosis of HCC patients receiving targeted therapy with dulvalizumab, which included the disease control rate, tumor markers, immune function, survival, quality of survival, and the occurrence of unfavorable side effects such as thrombocytopenia, leukopenia, vomiting, and rash. RESULTS: The initial KPS scores, CEA, CA199, AFP, CD3+, CD4+, CD4+/CD8+, IgG, IgM, and IgA levels did not differ significantly between the two groups (P> 0.05). After treatment, the observation group showed a significantly higher disease control rate (92.45% vs. 74.42%) and improved KPS score, OS, PFS, CD3+, CD4+, CD4+/CD8+, IgG, IgM, and IgA levels compared to the control group. Additionally, the observation group exhibited significantly reduced CEA, CA199, and AFP levels, and a lower overall incidence of adverse reactions (16.98% vs. 51.16%) compared to the control group (P< 0.05). CONCLUSION: The clinical efficacy of dulvalizumab-targeted treatment of HCC among PD-L1 inhibitors is better, enhancing the disease's ability to be controlled considerably lowering patients' levels of tumor markers. This greatly boosts patients' immune systems, extends their lives and improves the quality of their survival. The frequency of negative reactions is minimal and safe.

Efficacy and Safety of CT-guided Percutaneous Cryoablation for Hepatocellular Carcinoma at High-risk Sites.

OBJECTIVE: This study aims to assess the efficacy and safety of CT-guided percutaneous cryoablation in treating hepatocellular carcinoma (HCC) located explicitly in high-risk sites. MATERIALS AND METHODS: Data were collected retrospectively from 685 HCC patients undergoing percutaneous cryoablation at Tianjin Medical University Cancer Hospital between January 2018 and December 2021. Of these, 106 patients had lesions in high-risk sites, defined as a minimum distance of less than 10 mm from the heart/great vessels, diaphragm, gastrointestinal tract, and gallbladder, as determined by preoperative CT or MRI imaging. Technical success rate, complete ablation rate, and complications at 1, 12, and 24 months post-surgery were evaluated. A statistical analysis of the ablation effect difference between the high-risk site and non-high-risk site groups was conducted, utilizing propensity score matching (PSM) to mitigate patient selection bias. Univariate and multivariate logistic regression analyzes were performed to identify risk factors for the incidence of coronary heart disease. RESULTS: The study comprised 106 cases in the high-risk group and 218 cases in the non-high-risk group. After PSM analysis until December 2021, 95 matched pairs were included. Both groups demonstrated a 100% intraoperative technical success rate, and no major complications related to cryoablation were observed. Follow-up ranged from 24 to 38 months. The complete ablation rate was 82.1% and 71.7% in the high-risk group and 83.9% and 73.9% in the non-high-risk group at 12 and 24 months, respectively. There was no significant difference in complete ablation rates between the two groups before and after PSM (P > 0.05). Multivariate analysis identified the distance between the tumor edge and high-risk site ≤ 5 mm and preoperative transarterial chemoembolization (TACE) treatment as independent risk factors for cryoablation effect. CONCLUSION: CT-guided percutaneous cryoablation proves to be a safe and effective approach for HCC patients with high-risk sites, serving as an alternative to surgical treatment.

Arterial chemotherapy for hepatocellular carcinoma in China: consensus recommendations.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer-related deaths globally. Hepatic arterial infusion chemotherapy (HAIC) treatment is widely accepted as one of the alternative therapeutic modalities for HCC owing to its local control effect and low systemic toxicity. Nevertheless, although accumulating high-quality evidence has displayed the superior survival advantages of HAIC of oxaliplatin, fluorouracil, and leucovorin (HAIC-FOLFOX) compared with standard first-line treatment in different scenarios, the lack of standardization for HAIC procedure and remained controversy limited the proper and safe performance of HAIC treatment in HCC. Therefore, an expert consensus conference was held on March 2023 in Guangzhou, China to review current practices regarding HAIC treatment in patients with HCC and develop widely accepted statements and recommendations. In this article, the latest evidence of HAIC was systematically summarized and the final 22 expert recommendations were proposed, which incorporate the assessment of candidates for HAIC treatment, procedural technique details, therapeutic outcomes, the HAIC-related complications and corresponding treatments, and therapeutic scheme management.

Association between the 8473T>C polymorphism of PTGS2 and prostate cancer risk: a metaanalysis including 24,716 subjects.

BACKGROUND: Prostaglandin endoperoxide synthase 2 (PTGS2) is involved in prostate cancer (PCa) by stimulating cell proliferation, promoting angiogenesis, inhibiting apoptosis, and mediating immune suppression. 8473T>C, located in the 3' UTR of the PTGS2 gene, has been considered to influence PCa risk. METHODS: We searched Medline, PubMed, Elsevier, and Web of Science (updated to February 5, 2012) using the following search terms: '8473T>C' or 'rs5275', 'genetic variant' or 'polymorphism', 'prostate cancer', 'cancer', 'PTGS2' or 'COX-2'. Odds ratios with 95% confidence intervals were assessed by using fixed or random effect models. Both funnel plot and Egger's test were used to assess the publication bias. RESULTS: Finally, 5 case control studies were included. Overall, no evidence was observed of a relationship between the 8473T>C and PCa risk in any genetic model. No significant association was found in the studies whose controls conform to the Hardy-Weinberg equilibrium. In the stratified analysis, significant association was detected in other populations (except for Caucasians), which were based on hospitals. CONCLUSION: The 8473T>C polymorphism may have little association with PCa risk among Caucasians, but might be involved in PCa risk in other ethnicities. Nevertheless, more well-designed studies with a larger sample size including different ethnicities should be conducted.

ABHD17C, a metabolic and immune-related gene signature, predicts prognosis and anti-PD1 therapy response in pancreatic cancer.

BACKGROUND: PDAC is a highly malignant and immune-suppressive tumor, posing great challenges to therapy. METHODS: In this study, we utilized multi-center RNA sequencing and non-negative matrix factorization clustering (NMF) to identify a group of metabolism-related genes that could effectively predict the immune status and survival (both disease-free survival and overall survival) of pancreatic ductal adenocarcinoma (PDAC) patients. Subsequently, through the integration of single cell sequencing and our center's prospective and retrospective cohort studies, we identified ABHD17C, which possesses metabolic and immune-related characteristics, as a potential biomarker for predicting the prognosis and response to anti-PD1 therapy in PDAC. We then demonstrated how ABHD17C participates in the regulation of the immune microenvironment through in vitro glycolytic function experiments and in vivo animal experiments. RESULTS: Through screening for pancreatic cancer metabolic markers and immune status, we identified a critical molecule that inhibits pancreatic cancer survival and prognosis. Further flow cytometry analysis confirmed that ABHD17C is involved in the inhibition of the formation of the immune environment in PDAC. Our research found that ABHD17C participates in the metabolic process of tumor cells in in vitro and in vivo experiments, reshaping the immunosuppressive microenvironment by downregulating the pH value. Furthermore, through LDHA inhibition experiments, we demonstrated that ABHD17C significantly enhances glycolysis and inhibits the formation of the immune suppressive environment. In in vivo experiments, we also validated that ABHD17C overexpression significantly mediates resistance to anti-PD1 therapy and promotes the progression of pancreatic cancer. CONCLUSION: Therefore, ABHD17C may be a novel and effective biomarker for predicting the metabolic status and immune condition of PDAC patients, and provide a potential predictive strategy for anti-PD1 therapy in PDAC.

Molecular characterization of MET fusions from a large real-world Chinese population: A multicenter study.

PURPOSE: MET is a notable driver gene in the diversity of aberrations with clinical relevance, including exon 14 skipping, copy number gain, point mutations, and gene fusions. Compared with the former two, MET fusions are severely under-reported, leaving a series of unanswered questions. In this study, we addressed this gap by characterizing MET fusions in a large, real-world Chinese cancer population. METHODS: We retrospectively included patients with solid tumors who had DNA-based genome profiles acquired through targeted sequencing from August 2015 to May 2021. MET fusion-positive (MET+) patients were subsequently selected for clinical and molecular characterization. RESULTS: We screened 79,803 patients across 27 tumor types and detected 155 putative MET fusions from 122 patients, resulting in an overall prevalence of 0.15%. Lung cancer comprised the majority of MET+ patients (92, 75.4%). Prevalence was markedly higher in liver cancer, biliary tract cancer, and renal cancer (range 0.52%-0.60%). It was lower in ovarian cancer (0.06%). A substantial proportion (48/58, 82.8%) of unique partners were reported for the first time. High heterogeneity was observed for partners, with ST7, HLA-DRB1, and KIF5B as the three most common partners. Mutational landscape analysis of lung adenocarcinoma (n = 32) revealed a high prevalence of TP53 in MET+ alterations, EGFR L858R, EGFR L861Q, and MET amplification. CONCLUSION: To our knowledge, this is currently the largest study in characterizing MET fusions. Our findings warrant that further clinical validation and mechanistic study may translate into therapeutic avenues for MET+ cancer patients.

The analysis of immunogenic cell death induced by ablation at different temperatures in hepatocellular carcinoma cells.

Introduction: Ablation therapy is a commonly used tool in the management of hepatocellular carcinoma (HCC). After ablation, dying cancer cells release a variety of substances that trigger subsequent immune responses. Immunogenic cell death (ICD) has been a trending topic in recent years and has been discussed many times along with oncologic chemotherapy. However, the subject of ablative therapy and ICDs has been little discussed. The purpose of this study was to investigate whether ablation treatment induces ICD in HCC cells and whether different types of ICDs arise because of different ablation temperatures. Methods: Four different HCC cell lines (H22, Hepa-16, HepG2 and SMMC7221) were cultured and treated under different temperatures (-80°C, -40°C, 0°C, 37°C, and 60°C). Cell Counting Kit-8 assay was performed to analyze the viability of different cell lines. Apoptosis was detected by flow cytometry assay, and a few ICD-related cytokines (calreticulin, ATP, high mobility group box 1, and CXCL10) were detected by immunofluorescence or enzyme-linked immunosorbent assay. Results: The apoptosis rate of all kinds of cells increased significantly in -80°C group (p < 0.01) and 60°C group (p < 0.01). The expression levels of ICD-related cytokines were mostly significantly different between the different groups. For calreticulin, Hepa1-6 cells and SMMC7221 cells showed significantly higher protein expression levels in 60°C group (p < 0.01) and significantly lower protein expression levels -80°C group (p < 0.01). The ATP, high mobility group box 1 and CXCL10 expression levels were significantly higher in 60°C, -80°C and -40°C group of all four cell lines (p < 0.01). Conclusion: Different ablative treatments could induce different types of ICDs in HCC cells, providing a promising track for the development of individualized cancer therapies.

Systemic Chemotherapy With or Without Hepatic Arterial Infusion Chemotherapy for Liver Metastases From Pancreatic Cancer: A Propensity Score Matching Analysis.

BACKGROUND: The significance of systemic chemotherapy (SCT) combined with hepatic arterial infusion (HAI) chemotherapy in the treatment of pancreatic ductal adenocarcinoma with liver metastases (PACLM) remains unclear. Based on previous studies, this single-center propensity score matching (PSM) study aimed to explore the efficacy of SCT with or without HAI for PACLM. PATIENT AND METHODS: The PSM method was used to screen 661 cases of PACLM who received SCT at Tianjin Medical University Cancer Institute and Hospital from 2001 to 2020. According to the 1:6 ratio with PSM, 385 patients were divided into the SCT+HAI group (n = 55) and the SCT group (n = 330). After a median follow-up of 49 (range 7-153) months, overall survival (OS) and survival-related prognostic factors were analyzed. RESULTS: The main baseline characteristics of the SCT+HAI group and the SCT alone group were matched appropriately (P > .05). After PSM, the median OS for patients in the 2 groups was 10.6 and 7.6 months, respectively (P = .02). Multivariate analysis revealed that peritoneal metastases (P = .03), CA199 ≥ 500U/mL (P = .03), and lactate dehydrogenase (LDH) ≥ 250U/L (P = .03) were prognostic factors of poor survival, modern SCT plus HAI (P = .04) was a protective factor. CONCLUSION: Our findings indicated that adequate cycles of SCT+HAI result in better survival than SCT alone in patients with PACLM. Patients with peritoneal metastases, markedly elevated CA19-9 and LDH have a poorer prognosis. The conclusion has yet to be validated in randomized controlled clinical trials.

Hepatic arterial infusion chemotherapy combined with anti-PD-1/PD-L1 immunotherapy and molecularly targeted agents for advanced hepatocellular carcinoma: a real world study.

Background: Molecular targeted therapy combined with immunotherapy significantly improves the prognosis of patients with advanced liver cancer. Additionally, hepatic arterial infusion chemotherapy (HAIC) can improve the prognosis of patients with advanced liver cancer. This real-world study aimed to evaluate the clinical efficacy and safety of HAIC combined with molecular targeted therapy and immunotherapy in the treatment of primary unresectable hepatocellular carcinoma (uHCC). Methods: A total of 135 patients with uHCC were enrolled in this study. Progression-free survival (PFS) was the primary endpoint. The efficacy of the combination therapy was assessed based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines. Overall survival (OS), adverse events (AEs) and surgical conversion rate were the secondary endpoints. Univariate and multivariate Cox regression analyses were performed to examine independent prognostic factors. For sensitivity analysis, inverse probability weighting (IPW) was used to balance the influence of the tested confounding factors between groups to verify the robustness of conversion surgery for survival benefits. The E-values were estimated to assess robustness to unmeasured confounders. Results: The median number of therapies was three. Approximately 60% of the patients had portal vein tumour thrombosis (PVTT). The most common targeted drugs were lenvatinib and bevacizumab, whereas the most common immunotherapy drug was sintilimab. The overall objective response rate (ORR) was 54.1%, and the disease control rate (DCR) was 94.6%. A total of 97 (72%) patients experienced AEs of grades 3-4. Fatigue, pain and fever were the most common symptoms of grade 3-4 AEs. The median PFS was 28 months and 7 months in the successful and unsuccessful conversion groups, respectively. The median OS was 30 months and 15 months in the successful and unsuccessful conversion groups, respectively. Successful conversion surgery, sex, hapatic vein invasion, BCLC stage, baseline tumour size, AFP levels and maximum therapeutic response were independent prognostic factors for PFS. Successful conversion surgery, number of interventions, hapatic vein invasion and total bilirubin levels were independent prognostic factors for OS. After IPTW, no standardised differences exceeding 0.1 were found. IPW-adjusted Kaplan-Meier curves showed that successful conversion surgery was an independent prognostic factor for both PFS and OS. The E-values of successful conversion surgery were 7.57 and 6.53 for OS and PFS, respectively, which indicated a relatively robust impact of successful conversion surgery on the prognosis of patients. Conclusion: Patients with primary uHCC undergoing HAIC combined with immunotherapy and molecular targeted therapy have a higher tumour regression rate and the side effects are manageable. Patients undergoing surgery after combination therapy have survival benefits.

[Clinical features and prognostic analysis in prostate cancer patients under 59 years of age: a report of 72 cases].

OBJECTIVE: To explore the clinicopathological characteristics and prognostic factors in prostate cancer patients under 59 years of age. METHODS: From January 2000 to October 2011, 566 prostate cancer patients underwent treatments. Among them, 72 (12.7%) patients under 59 years of age with the integrated clinical data were reviewed. The median follow-up period was 25 months (range: 1 - 108) and the median age 55 years (range: 16 - 59). Four (5.5%) cases had the clinical stage of II, 12 (16.7%) cases of stage III and 56 (77.8%) cases of stage IV. Progression-free survival (PFS), overall survival (OS) and prognostic factors were analyzed. RESULTS: The rate of adenocarcinoma was 86.1% (62/72) and the Gleason score of 8-10 69.1% (29/42). Special type carcinoma accounted for 13.9% (10/72). The median time to androgen-independent prostate cancer (AIPC) was 12 months after endocrine therapy. The 1-, 3- and 5-year PFS were 53.8%, 12.1% and 6.1% and those for OS 85.2%, 58.8% and 15.6% respectively. The prognostic factors were age, baseline prostate special antigen (PSA), types of pathology, tumor stage and local treatment by univariate analysis. The type of pathology was an independent prognostic factor of affecting significantly the prognosis by multivariate analysis. CONCLUSION: Prostate cancer patients under 59 years of age are characterized by misdiagnosis, complexity of pathology and high malignancy. Comprehensive regiment with predominant local therapy is an effective approach.