Background: Approximately 5.0–24.2% of colorectal cancers (CRCs) have inactivating mutations in SMAD4, making it one of the frequently mutated genes in CRC. We thus carried out a comprehensive system review and meta-analysis investigating the prognostic significance and clinicopathological features of SMAD4 gene mutation in CRC patients. Methods: A detailed literature search was conducted in PubMed, Web of Science and Embase databases to study the relationship between SMAD4 mutations and the demographic and clinicopathological characteristics in CRC patients. The hazard ratios (HRs) with 95% confidence intervals (CI) were used to evaluate the effect of SMAD4 mutations on overall survival (OS) and progression-free survival (PFS)/recurrence-free survival (RFS). Results: Ten studies enrolling 4394 patients were eligible for inclusion. Data on OS were available from 5 studies and data on PFS/RFS were available from 3 studies. Comparing SMAD4-mutated CRC patients with SMAD4 wild-type CRC patients, the summary HR for OS was 1.46 (95% CI 1.28–1.67, P = 0.001), the summary HR for PFS/RFS was 1.59 (95% CI 1.14–2.22, P = 0.006). In terms of clinicopathology parameters, 9 studies have data that can be extracted, SMAD4 mutations were associated with tumor location (odds ratio [OR] = 1.15, colon/rectum, 95% CI 1.01–1.31, P = 0.042), TNM stage (OR = 1.28, stage IV/I–III, 95% CI 1.03–1.58, P = 0.025), lymph node metastasis (OR = 1.42, N1 + N2/N0, 95% CI 1.20–1.67, P < 0.001), mucinous differentiation (OR = 2.23, 95% CI 1.85–2.70, P < 0.001) and rat sarcoma viral oncogene homolog (RAS) mutation status (OR = 2.13, 95% CI 1.37–3.34, P = 0.001). No connection was found with age, gender, tumor grade, microsatellite instability status and b-viral oncogene homolog B1 mutation status. Besides, publication bias was not observed in any study. Conclusions: This meta-analysis suggests that SMAD4 mutation was associated with OS, PFS/RFS, and clinicopathological parameters, including tumor site, disease stage, RAS status, lymph node metastasis and mucinous differentiation. Our meta-analysis indicated that SMAD4 mutations could predict the poor prognosis and aggressive clinicopathological characteristics of CRC. More large-sample cohort studies are needed to confirm this conclusion. Since SMAD4 mutations are closely related to RAS mutations, their relationship warrants further investigation.

Drug therapy, including chemotherapy, targeted therapy, immunotherapy, and endocrine therapy, stands as the foremost therapeutic approach for contemporary human malignancies. However, increasing drug resistance during antineoplastic therapy has become a substantial barrier to favorable outcomes in cancer patients. To enhance the effectiveness of different cancer therapies, an in-depth understanding of the unique mechanisms underlying tumor drug resistance and the subsequent surmounting of antitumor drug resistance is required. Recently, F-box and WD Repeat Domain-containing-7 (FBXW7), a recognized tumor suppressor, has been found to be highly associated with tumor therapy resistance. This review provides a comprehensive summary of the underlying mechanisms through which FBXW7 facilitates the development of drug resistance in cancer. Additionally, this review elucidates the role of FBXW7 in therapeutic resistance of various types of human tumors. The strategies and challenges implicated in overcoming tumor therapy resistance by targeting FBXW7 are also discussed.

Purpose: Thrombocytopenia is among the most common chemotherapy-related hematologic toxicities. We aim to determine the predictors of oxaliplatin chemotherapy-induced thrombocytopenia in patients with gastrointestinal tumors to guide the clinic. Methods: Clinical data of 750 patients with a malignant gastrointestinal tumor were included as the primary cohort. Basic clinical data, serological indices, and anthropometric indices of these patients were collected. According to the presence or absence of CIT, univariate analysis was performed to identify significant factors for multivariate analysis. In R language software, nomogram was constructed based on the results of multi-factor analysis, and the calibration curve and ROC curve were drawn. Results: Univariate analysis identified 17 factors as closely related to CIT occurrence, namely age, lymph node metastasis (N) stage, metastasis (M) stage, lung metastasis, other site metastasis, chemotherapy regimen, course of treatment, total dose of oxaliplatin, AST, albumin, neutrophils, monocytes, baseline platelets, transferrin, natural killer (NK) cell, phase angle, and SMI (P < 0.10). The binary logistic multivariate regression analysis revealed five independent risk factors for developing CIT (P < 0.05), including the M stage, total dose of oxaliplatin, albumin, baseline thrombocyte count, and NK cell. Based on the results of multivariate logistic regression analysis, R software was used to establish a nomogram model. The calibration curve shows that the combined predictor has good consistency. The area under the ROC curve was 0.877 and the best cut-off value was 0.3579613 (sensitivity, 78.9%; specificity, 81.8%), which showed the better prediction efficiency. Conclusion: The total dose of oxaliplatin, M stage, albumin, baseline platelet count, and NK cell was independent risk factors for CIT. The sequentially constructed histogram model had a good predictive effect on the risk of thrombocytopenia caused by oxaliplatin chemotherapy in patients with gastrointestinal malignancies.

F-box and WD repeat domain-containing 7 (FBXW7), formerly known as hCdc4, hAGO Fbw7, or SEL10, plays a specific recognition function in SCF-type E3 ubiquitin ligases. FBXW7 is a well-established cancer suppressor gene that specifically controls proteasomal degradation and destruction of many key oncogenic substrates. The FBXW7 gene is frequently abnormal in human malignancies especially in gastrointestinal cancers. Accumulating evidence reveals that mutations and deletions of FBXW7 are participating in the occurrence, progression and treatment resistance of human gastrointestinal cancers. Considering the current therapeutic challenges faced by gastrointestinal cancers, elucidating the biological function and molecular mechanism of FBXW7 can provide new perspectives and references for future personalized treatment strategies. In this review, we elucidate the key molecular mechanisms by which FBXW7 and its substrates are involved in gastrointestinal cancers. Furthermore, we discuss the consequences of FBXW7 loss or dysfunction in tumor progression and underscore its potential as a prognostic and therapeutic biomarker. Lastly, we propose potential therapeutic strategies targeting FBXW7 to guide the precision treatment of gastrointestinal cancers.

Purpose Thrombocytopenia is among the most common chemotherapy-related hematologic toxicities. We aim to determine the predictors of oxaliplatin chemotherapy-induced thrombocytopenia (CIT) in patients with gastrointestinal tumors to guide the clinic. Methods Clinical data of 750 patients with a malignant gastrointestinal tumor were included as the primary cohort. Basic clinical data, serological indices, and anthropometric indices of these patients were collected. Grouped based on the presence or absence of CIT, univariate analysis was performed to identify significant factors related to chemotherapy-induced thrombocytopenia. Based on the results of multi-factor analysis, a nomogram was constructed using R language programing and its fitness was evaluated using the calibration curve and ROC curve. Results Univariate analysis identified 20 factors as closely related to CIT occurrence. The binary logistic multivariate regression analysis revealed five independent risk factors for developing CIT (P < 0.05): the M stage, total dose of oxaliplatin, albumin, baseline thrombocyte count, and natural killer (NK) cell count. The calibration curve of the monogram shows that the combined predictors had good consistency. A better prediction efficiency was observed with the ROC curve of 0.877 with the cut-off value of 0.3579613 (with sensitivity of 78.9% and specificity, 81.8%). Conclusion The total dose of oxaliplatin, M stage, albumin, baseline platelet count, and NK cell count were independent risk factors for CIT.

Objective: To comprehensively assess the association of pretreatment systemic immune-inflammation index (SII) with the prognosis of gastric cancer patients. Methods: PubMed, Web of Science, Embase, and the Cochrane Library were searched to select studies exploring the association of SII with the overall survival (OS), progression-free survival (PFS) or recurrence-free survival (RFS) of gastric cancer. We pooled the hazard ratios (HRs) with 95% confidence intervals (CIs) using a random-effects model. Robustness was assessed by sensitivity analyses, and publication bias was evaluated using funnel plots and Egger’s regression test. Results: A total of 61 studies involving 66 cohorts and 31,608 patients were included in this meta-analysis, with most studies adopting a retrospective design and only one prospective study enrolled. Elevated pretreatment SII was significantly correlated with inferior OS (HR = 1.48, 95% CI: 1.36–1.62), PFS (HR = 1.43, 95% CI: 1.30–1.58), and RFS (HR = 1.38, 95% CI: 1.09–1.76). Subgroup analyses demonstrated that the magnitude of the prognostic association varied across treatment modalities and geographic regions. Conclusion: In conclusion, we found that elevated pretreatment SII is a potential biomarker for adverse prognosis in gastric cancer patients. However, since nearly all included studies were retrospective and only one was a prospective study, our findings support the prognostic value of SII, but prospective validation is required before routine clinical implementation. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420261321880.