Effect of RAS and BRAF mutations on peritoneal metastasis risk and cytoreductive surgery/hyperthermic intraperitoneal chemotherapy efficacy in colorectal cancer: A systematic review and meta-analysis.

BACKGROUND: Colorectal cancer (CRC) patients with peritoneal metastasis (CRC-PM) have a worse prognosis than those with liver and lung metastases. Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective locoregional treatment for CRC-PM. To date, the prognostic analysis of CRS/HIPEC mostly focuses on clinical and pathological characteristics; however, genetic characteristics, such as RAS/BRAF mutation status, are not sufficient. This study aimed to systematically assess the correlation between RAS/BRAF status and PM risk, as well as the prognostic efficacy of CRS/HIPEC for CRC. METHOD: This study was written in accordance with the 2020 guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. We searched PubMed, EMBASE, and the Cochrane library with the following keywords: "Peritoneal Neoplasms," "raf Kinases" and "ras Proteins". The fixed-effects model and inverse variance method were used for analysis. Odds ratios (OR) and 95 % confidence intervals (CI) were used to reflect the risk of PM associated with RAS/BRAF mutations. Hazard ratios (HR) and 95 % CI were used to evaluate the effects of RAS/BRAF mutations on the prognosis of CRS/HIPEC. RESULT: Eighteen articles included 5567 patients. In the risk analysis of PM, patients with BRAF mutation were more likely to have PM than those with wild-type BRAF (OR = 2.28, 95 % CI = 1.73-3.01, P < 0.001, I2 = 0 %). In contrast, there was no significant difference in the effect of RAS mutation and wild-type on PM of CRC (OR = 1.28, 95 % CI = 0.99-1.66, P = .06, I2 = 0 %). In a prognostic analysis of CRS/HIPEC, RAS mutation predicted poor overall survival (HR = 1.68, 95 % CI = 1.39-2.02, P < 0.001, I2 = 1 %) and disease-free survival (HR = 1.61, 95 % CI = 1.34-1.94, P < 0.001, I2 = 42 %). The results for BRAF mutation was consistent with the prognostic impact of RAS mutation's overall survival (HR = 2.57, 95 % CI = 1.93-3.44, P < 0.001, I2 = 0 %) and disease-free survival (HR = 1.90, 95 % CI = 1.40-2.56, P < 0.001, I2 = 82 %). CONCLUSION: BRAF mutation, rather than RAS mutation, was a high-risk factor for CRC-PM. And both BRAF and RAS mutations negatively affected the prognosis of CRS/HIPEC in CRC-PM patients. Our results could provide suggestions for the selection of comprehensive treatment for CRC-PM with RAS/BRAF mutations.

Structural modification strategies of triazoles in anticancer drug development.

The triazole functional group plays a pivotal role in the composition of biomolecules with potent anticancer activities, including numerous clinically approved drugs. The strategic utilization of the triazole fragment in the rational modification of lead compounds has demonstrated its ability to improve anticancer activities, enhance selectivity, optimize pharmacokinetic properties, and overcome resistance. There has been significant interest in triazole-containing hybrids in recent years due to their remarkable anticancer potential. However, previous reviews on triazoles in cancer treatment have failed to provide tailored design strategies specific to these compounds. Herein, we present an overview of design strategies encompassing a structure-modification approach for incorporating triazoles into hybrid molecules. This review offers valuable references and briefly introduces the synthesis of triazole derivatives, thereby paving the way for further research and advancements in the field of effective and targeted anticancer therapies.

Direct Synthesis of α- and ß-2'-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation.

2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.

Prognostic value of circulating tumor cells associated with white blood cells in solid cancer: a systematic review and meta-analysis of 1471 patients with solid tumors.

BACKGROUND: The clinical relevance of circulating tumor cell-white blood cell (CTC-WBC) clusters in cancer prognosis is a subject of ongoing debate. This study aims to unravel their contentious predictive value for patient outcomes. METHODS: We conducted a comprehensive literature search of PubMed, Embase, and Cochrane Library up to December 2022. Eligible studies that reported survival outcomes and examined the presence of CTC-WBC clusters in solid tumor patients were included. Hazard ratios (HR) were pooled to assess the association between CTC-WBC clusters and overall survival (OS), as well as progression-free survival (PFS)/disease-free survival (DFS)/metastasis-free survival (MFS)/recurrence-free survival (RFS). Subgroup analyses were performed based on sampling time, treatment method, detection method, detection system, and cancer type. RESULTS: A total of 1471 patients from 10 studies were included in this meta-analysis. The presence of CTC-WBCs was assessed as a prognostic factor for overall survival and PFS/DFS/MFS/RFS. The pooled analysis demonstrated that the presence of CTC-WBC clusters was significantly associated with worse OS (HR = 2.44, 95% CI: 1.74-3.40, P < 0.001) and PFS/DFS/MFS/RFS (HR = 1.83, 95% CI: 1.49-2.24, P < 0.001). Subgroup analyses based on sampling time, treatment method, detection method, detection system, cancer type, and study type consistently supported these findings. Further analyses indicated that CTC-WBC clusters were associated with larger tumor size (OR = 2.65, 95% CI: 1.58-4.44, P < 0.001) and higher alpha-fetoprotein levels (OR = 2.52, 95% CI: 1.50-4.22, P < 0.001) in hepatocellular carcinoma. However, no significant association was found between CTC-WBC clusters and TNM stage, depth of tumor invasion, or lymph node metastasis in the overall analysis. CONCLUSIONS: CTC-WBC clusters are negative predictors for OS and PFS/DFS/MFS/RFS in patients with solid tumors. Monitoring CTC-WBC levels may provide valuable information for predicting disease progression and guiding treatment decisions.

Regulatory mechanisms and therapeutic implications of insulin-like growth factor 2 mRNA-binding proteins, the emerging crucial m6A regulators of tumors.

Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) serve essential biological functions as post-transcriptional performers, participating in the acquisition or maintenance of tumor hallmarks due to their distinct protein structures. Emerging evidence indicates that IGF2BPs belong to the class III type of RNA N6-methyladenosine (m6A) modification readers, controlling RNA stability, storage, localization, metabolism, and translation in multiple vital bioprocesses, particularly tumorigenesis and tumor progression. Here, we discuss the underlying regulatory mechanisms and pathological functions of IGF2BPs which act as m6A readers in the context of tumor pathogenesis and multidrug resistance. Furthermore, we highlight the potential of IGF2BPs as drug targets in clinical tumor treatment. Hence, precise and novel tumor therapeutic approaches could be uncovered by targeting epigenetic heterogeneity.

Clinical Prompt Learning With Frozen Language Models.

When the first transformer-based language models were published in the late 2010s, pretraining with general text and then fine-tuning the model on a task-specific dataset often achieved the state-of-the-art performance. However, more recent work suggests that for some tasks, directly prompting the pretrained model matches or surpasses fine-tuning in performance with few or no model parameter updates required. The use of prompts with language models for natural language processing (NLP) tasks is known as prompt learning. We investigated the viability of prompt learning on clinically meaningful decision tasks and directly compared this with more traditional fine-tuning methods. Results show that prompt learning methods were able to match or surpass the performance of traditional fine-tuning with up to 1000 times fewer trainable parameters, less training time, less training data, and lower computation resource requirements. We argue that these characteristics make prompt learning a very desirable alternative to traditional fine-tuning for clinical tasks, where the computational resources of public health providers are limited, and where data can often not be made available or not be used for fine-tuning due to patient privacy concerns. The complementary code to reproduce the experiments presented in this work can be found at https://github.com/NtaylorOX/Public_Clinical_Prompt.

Individualized Choice of Simultaneous Cholecystectomy in Patients with Gastric Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Patients undergoing gastrectomy for gastric cancer are more likely to develop gallstones than the general population. Prophylactic cholecystectomy remains controversial. METHODS: Studies from 2000-2022 were systematically searched in the PubMed, EMBASE, and Cochrane Library databases. The search included simultaneous cholecystectomy or risk factors for gallstone formation with gastrectomy alone. Major prognostic factors included complications and mortality, and risk factor analyses included age, sex, TNM stage, gastrectomy type, lymph node dissection, diabetes, and duodenal exclusion. Random effects regression models were used to analyze risk estimates and data were presented as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). RESULTS: There were no significant differences in postoperative morbidity (OR 1.12, 95% CI 0.90-1.39; p = 0.33, I2 = 11%) and mortality (OR 1.23, 95% CI 0.62-2.43; p = 0.56, I2 = 0%) between gastrectomy alone and simultaneous cholecystectomy. Older age (OR 1.48, 95% CI 1.36-1.59; p < 0.001, I2 = 59%), male sex (OR 1.38, 95% CI 1.10-1.71; p = 0.004, I2 = 77%), total gastrectomy (OR 1.50, 95% CI 1.25-1.81; p < 0.001, I2 = 72%), diabetes mellitus (OR 1.38, 95% CI 1.17-1.63; p < 0.001, I2 = 8%), and duodenal exclusion (OR 1.77, 95% CI 1.47-2.15; p < 0.001, I2 = 30%) were risk factors for cholecystolithiasis. CONCLUSIONS: Simultaneous cholecystectomy did not increase the incidence of postoperative complications or mortality. Older age, male sex, total gastrectomy, duodenal exclusion, and diabetes were risk factors for gallstone development after gastrectomy.

The negative impact of opioids on cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

PURPOSE: As one of the most effective analgesics, opioids are essential for patients with cancer-related pain, even in the context of the opioid abuse crisis. The current meta-analysis aimed to identify whether concomitant exposure to opioids can affect the efficacy of ICIs and lead to a worse prognosis. METHODS: PubMed, Embase, and the Cochrane Library were searched based on the PRISMA checklist, through April 2022, for the following terms: ("opioids" OR "concomitant medication") AND ("Neoplasm" OR "Carcinoma" OR "Cancer" OR "Tumor") AND ("Immunotherapy" OR "Immune Checkpoint Inhibitor" OR "PD-L1 Inhibitor" OR "PD-1 Inhibitor" OR "CTLA-4 Inhibitor"). The outcomes considered were overall survival (OS) and progression-free survival (PFS) calculated using the random-effects or fixed-effects model. RESULTS: After screening 531 studies, a total of 7 articles involving 2690 patients were eligible for quantitative analysis. The use of opioids was negatively correlated with OS (HR 1.75, 95%CI 1.32-2.31, P < 0.001; I2 = 81%, P < 0.001) and significantly reduced the PFS (HR 1.61, 95%CI 1.41-1.83, P < 0.001; I2 = 0%, P = 0.63) of patients treated with ICIs. Similar results were obtained in each subgroup analysis. While NSAIDs could lead to poor OS (HR 1.25, 95% CI 1.03-1.51, P = 0.02; I2 = 0%, P = 0.60) but not PFS (HR 1.11, 95% CI = 0.89-1.39, P = 0.36) for ICIs patients. And sensitivity analyses confirmed the reliability of the results. CONCLUSION: Opioids significantly reduced OS and PFS in patients receiving ICI therapy. Thus, the use of different types of opioids should be considered with caution, and it is necessary to actively develop alternative treatments.

Efficacy of neoadjuvant immunotherapy in advanced colorectal cancer: a meta-analysis of cross-sectional studies.

BACKGROUND: Although neoadjuvant immunotherapy is being widely studied, there is no consensus on its efficacy in microsatellite-stable (MSS) or mismatch repair proficient (pMMR) colorectal cancer (CRC). This meta-analysis aimed to evaluate studies on neoadjuvant immunotherapy for advanced CRC to assess its efficacy and provide new clinical guidelines. METHODS: We searched literature databases to identify studies that assessed the efficacy of neoadjuvant immunotherapy in advanced CRC. The outcomes evaluated were pathological complete response (pCR), major pathological response (MPR), R0 resection, and anal preservation rates. Heterogeneity among the included studies was assessed by sensitivity analysis, and publication bias was evaluated using Begg and Egger tests. RESULTS: Eleven articles were included in the analysis. The pCR, MPR, R0 resection, and anal preservation rates reported in these studies were 39 and 49, 97, and 76%, respectively. The MSI-H and MSS groups had pooled pCR rates of 70 and 24%, respectively. The pCR rates for the induction, consolidation, and concurrent immuno-chemoradiotherapy (CRT) subgroups were 43, 33, and 27%, respectively, and those for the single and double immunotherapy subgroups were 34 and 40%, respectively. CONCLUSION: Neoadjuvant immunotherapy combined with CRT is effective in treating MSI-H/dMMR advanced CRC. It could also be a new first-line therapeutic option for MSS/pMMR advanced CRC.

Circular RNA MTCL1 promotes advanced laryngeal squamous cell carcinoma progression by inhibiting C1QBP ubiquitin degradation and mediating beta-catenin activation.

BACKGROUND: Circular RNAs (circRNAs) are involved in regulatory processes of ubiquitination and deubiquitination in various tumors at post-transcriptional epigenetic modification level. However, the underlying mechanism and its biological functions of circRNAs in the advanced laryngeal squamous cell carcinoma (LSCC) remain obscure. METHODS: RNA sequencing and quantitative real-time PCR (qRT-PCR) assays were applied to screen for circRNAs differentially expressed in LSCC tissues and cell lines. The candidate RNA-binding proteins and target signalling pathway were detected by RNA pull-down and mass spectrometry, in situ hybridization (ISH), immunohistochemistry (IHC), qRT-PCR assays, and bioinformatics analysis. The functional roles of these molecules were investigated using in vitro and in vivo experiments including EdU, transwell, wound healing, western blot assays, and the xenograft mice models. The molecular mechanisms were identified using RNA pull-down assays, RNA immunoprecipitation (RIP), Co-IP, ISH, Ubiquitination assay, bioinformatics analysis, and the rescue experiments. RESULTS: Here, we unveil that microtubule cross-linking factor 1 circRNA (circMTCL1, circ0000825) exerts its critical oncogenic functions by promoting complement C1q-binding protein (C1QBP)-dependent ubiquitin degradation and subsequently activating Wnt/ß-catenin signalling in laryngeal carcinoma initiation and development. Specifically, circMTCL1 was remarkably up-regulated in the paired tissues of patients with LSCC (n = 67), which predicted a worse clinical outcome. Functionally, circMTCL1 exerted oncogenic biological charactersistics by promoting cell proliferative capability and invasive and migrative abilities. Ectopic circMTCL1 augumented cell proliferation, migration, and invasion of LSCC cells, and this effect could be reversed by C1QBP knocking down in vitro and in vivo. Mechanistically, circMTCL1 directly recruited C1QBP protein by harboring the specific recognized sequence (+ 159 - + 210), thereby accelerating the translation of C1QBP expression by inhibiting its ubiquitin-proteasome-mediated degradation. Importantly, the direct interaction of C1QBP with ß-catenin protein was enhanced via suppressing the ß-catenin phosphorylation and accelerating its accumulation in cytoplasm and nucleus. CONCLUSION: Our findings manifested a novel circMTCL1-C1QBP-ß-catenin signaling axis involving in LSCC tumorigenesis and progression, which shed new light on circRNAs-ubiquitous acidic glycoprotein mediated ubiquitin degradation and provided strategies and targets in the therapeutic intervention of LSCC.

LINC01021 maintains tumorigenicity by enhancing N6-methyladenosine reader IMP2 dependent stabilization of MSX1 and JARID2: implication in colorectal cancer.

Insulin-like growth factor-2 mRNA-binding protein 2 (IGF2BP2, also known as IMP2), a novel class III N6-methyladenosine (m6A) reader, has recently gained attention due to its critical functions in recognizing and stabilizing m6A modified oncogenic transcripts. However, whether and how long non-coding RNAs (lncRNAs) facilitate IMP2's role as m6A "reader" remains elusive, particularly in colorectal cancer (CRC). Here, we demonstrated that oncogenic LINC021 specifically bound with the m6A "reader" IMP2 protein and enhanced the mRNA stability of MSX1 and JARID2 in an m6A regulatory manner during CRC tumorigenesis and pathogenesis. Specifically, a remarkable upregulation of LINC021 was confirmed in CRC cell lines and clinical tissues (n = 130). High level of LINC021acted as an independent prognostic predictor for CRC clinical outcomes. Functional assays demonstrated that LINC021 exerted its functions as an oncogene to aggravate CRC malignant phenotypes including enhanced cell proliferation, colony formation, migration capabilities, and reduced cell apoptosis. Mechanistically, LINC021 directly recognized IMP2 protein, the latter enhanced the mRNA stability of transcripts such as MSX1 and JARID2 by recognizing their m6A-modified element RGGAC. Thus, these findings uncovered an essential LINC021/IMP2/MSX1 and JARID2 signaling axis in CRC tumorigenesis, which provided profound insights into our understanding of m6A modification regulated by lncRNA in CRC initiation and progression and shed light on the targeting of this axis for CRC treatment.

Positive lymph node ratio is an index in predicting prognosis for remnant gastric cancer with insufficient retrieved lymph node in R0 resection.

The staging system of remnant gastric cancer (RGC) has not yet been established, with the current staging being based on the guidelines for primary gastric cancer. Often, surgeries for RGC fail to achieve the > 15 lymph nodes needed for TNM staging. Compared with the pN staging system, lymph node ratio (NR) may be more accurate for RGC staging and prognosis prediction. We retrospectively analyzed the data of 208 patients who underwent R0 gastrectomy with curative intent and who have ≤ 15 retrieved lymph nodes (RLNs) for RGC between 2000 and 2014. The patients were divided into four groups on the basis of the NR cutoffs: rN0: 0; rN1: > 0 and ≤ 1/6; rN2: > 1/6 and ≤ 1/2; and rN3: > 1/2. The 5-year overall survival (OS) rates for rN0, rN1, rN2, and rN3 were 84.3%, 64.7%, 31.5%, and 12.7%, respectively. Multivariable analyses revealed that tumor size (p = 0.005), lymphovascular invasion (p = 0.023), and NR (p < 0.001), but not pN stage (p = 0.682), were independent factors for OS. When the RLN count is ≤ 15, the NR is superior to pN as an important and independent prognostic index of RGC, thus predicting the prognosis of RGC patients more accurately.

Subtotal gastrectomy combined with chemotherapy: An effective therapy for patients with circumscribed Borrmann type IV gastric cancer.

BACKGROUND: Although Borrmann type IV (B-4) gastric cancer has a higher mortality rate and presents distant metastasis easily, especially peritoneal metastasis, when diagnosed, some B-4 patients were found to have no distant metastasis by preoperative detection and underwent curative surgery, which was defined as circumscribed B-4 in our study. In this study, we focused on the circumscribed B-4 patients without distant metastasis during surgery to identify factors related to prognosis and postoperative peritoneal cavity metastasis (PPCM), which is important for selecting an appropriate therapeutic strategy. AIM: To identify factors related to the prognosis and PPCM of B-4 patients. METHODS: A total of 117 B-4 patients who underwent gastrectomy between January 2005 and December 2012 were included in this study. Survival analysis was performed using Kaplan-Meier analysis and Cox multivariate models. Pearson correlation analyses were performed to identify the factors related to PPCM. All statistical analyses were performed using SPSS 20.0. RESULTS: Lymph node status, gastrectomy type, and postoperative chemotherapy were independent prognostic factors in 117 circumscribed B-4 patients. Subtotal gastrectomy combined with chemotherapy could significantly improve the long-term survival time. Six patients who were diagnosed with pN0 and received the combination therapy had a 3-year survival rate of 100% and a median survival of 77.7 mo. Even for patients with metastatic lymph nodes (n = 13), the combination therapy also increased the 3-year overall survival rate to 57.1%. In addition, positive lymph node status was the only factor (P = 0.005) correlated with PPCM in certain B-4 patients, and chemotherapy was useful for suppressing PPCM in patients with subtotal gastrectomy but not in those with total gastrectomy. CONCLUSION: Lymph node status is an independent prognostic factor for circumscribed B-4 patients. In addition, subtotal gastrectomy and postoperative chemotherapy could effectively improve prognosis and even suppress PPCM.