There are several models that predict the risk of recurrence following resection of localised, primary gastrointestinal stromal tumour (GIST). However, assessment of calibration is not always feasible and when performed, calibration of current GIST models appears to be suboptimal. We aimed to develop a prognostic model to predict the recurrence of GIST after surgery with both good discrimination and calibration by uncovering and harnessing the non-linear relationships among variables that predict recurrence. In this observational cohort study, the data of 395 adult patients who underwent complete resection (R0 or R1) of a localised, primary GIST in the pre-imatinib era at Memorial Sloan Kettering Cancer Center (NY, USA) (recruited 1982–2001) and a European consortium (Spanish Group for Research in Sarcomas, 80 sites) (recruited 1987–2011) were used to train an interpretable Artificial Intelligence (AI)-based model called Optimal Classification Trees (OCT). The OCT predicted the probability of recurrence after surgery by capturing non-linear relationships among predictors of recurrence. The data of an additional 596 patients from another European consortium (Polish Clinical GIST Registry, 7 sites) (recruited 1981–2013) who were also treated in the pre-imatinib era were used to externally validate the OCT predictions with regard to discrimination (Harrell's C-index and Brier score) and calibration (calibration curve, Brier score, and Hosmer-Lemeshow test). The calibration of the Memorial Sloan Kettering (MSK) GIST nomogram was used as a comparative gold standard. We also evaluated the clinical utility of the OCT and the MSK nomogram by performing a Decision Curve Analysis (DCA). The internal cohort included 395 patients (median [IQR] age, 63 [54–71] years; 214 men [54.2%]) and the external cohort included 556 patients (median [IQR] age, 60 [52–68] years; 308 men [55.4%]). The Harrell's C-index of the OCT in the external validation cohort was greater than that of the MSK nomogram (0.805 (95% CI: 0.803–0.808) vs 0.788 (95% CI: 0.786–0.791), respectively). In the external validation cohort, the slope and intercept of the calibration curve of the main OCT were 1.041 and 0.038, respectively. In comparison, the slope and intercept of the calibration curve for the MSK nomogram was 0.681 and 0.032, respectively. The MSK nomogram overestimated the recurrence risk throughout the entire calibration curve. Of note, the Brier score was lower for the OCT compared to the MSK nomogram (0.147 vs 0.564, respectively), and the Hosmer-Lemeshow test was insignificant (P = 0.087) for the OCT model but significant (P < 0.001) for the MSK nomogram. Both results confirmed the superior discrimination and calibration of the OCT over the MSK nomogram. A decision curve analysis showed that the AI-based OCT model allowed for superior decision making compared to the MSK nomogram for both patients with 25–50% recurrence risk as well as those with >50% risk of recurrence. We present the first prognostic models of recurrence risk in GIST that demonstrate excellent discrimination, calibration, and clinical utility on external validation. Additional studies for further validation are warranted. With further validation, these tools could potentially improve patient counseling and selection for adjuvant therapy. The NCI SPORE in Soft Tissue Sarcoma and NCI Cancer Center Support Grants.

Anaemia complicates recovery in surgical patients. Intravenous (IV) iron supplementation shows promise in improving outcomes, but optimal timing remains uncertain. In this review, we compare the efficacy, safety, tolerability, and outcomes between preoperative and postoperative IV iron supplementation. In this systematic review and network meta-analysis, we searched PubMed, EMBASE, Cochrane Library, and Web of Science from inception to May 1, 2025, for randomised controlled trials (RCT) investigating IV iron supplementation in surgical patients either 7-30 days before surgery (preoperative) or 0-30 days after surgery (postoperative). Studies were excluded if they included patients with critical illness or prior transfusion or if iron was given outside the defined time frames or with other agents. Two reviewers independently appraised the data and extracted summary estimates from published reports. The primary outcomes were: (1) proportion of patients who received blood transfusion; (2) change between the baseline haemoglobin level and the haemoglobin level on postoperative day (POD) 7 and POD30. Data processing was conducted based on frequentist network meta-analysis. The risk of bias was assessed using the Cochrane Risk of Bias tool. The protocol is registered with PROSPERO, CRD42024533265. Among 129 identified studies, 22 RCTs with 3026 patients were included. All included studies had a low (n = 6) or moderate (n = 16) risk of bias. Compared to controls, postoperative IV iron supplementation reduced transfusion rates (RR 0.80, 95% CI 0.68-0.94; I² = 0.0%). Postoperative IV iron supplementation did not affect haemoglobin levels (MD -4.51, 95% CI -9.75 to 0.72; I² = 90.3%) at POD7 but increased haemoglobin levels (MD 5.45, 95% CI 2.70-8.20; I² = 45.5%) at POD30. In comparison, preoperative IV iron supplementation resulted in higher haemoglobin levels than postoperative supplementation at POD30 (MD 6.67, 95% CI 1.61-11.72) but did not influence transfusion rates (RR 0.91, 95% CI 0.72-1.15; I² = 0.0%). Our results suggest that postoperative IV iron supplementation reduces transfusion rates, while preoperative supplementation improves haemoglobin recovery. Clinicians may choose either strategy in an individualised, patient-centered manner. These conclusions should be interpreted with caution due to heterogeneity among included studies, limited data for subgroup analyses, and the absence of direct comparisons between preoperative and postoperative approaches. National Key Research and Development Program of China, National Natural Science Foundation of China, Beijing Natural Science Foundation, Capital's Funds for Health Improvement and Research, National High Level Hospital Clinical Research Funding, and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.

Background Metastatic melanoma to the brain carries a particularly poor prognosis that may be associated with an attenuated antitumor response in the presence of central nervous system malignancies. Thus, the development of brain metastases could theoretically accelerate cancer progression both locally and systemically. Although dysregulation of checkpoint markers, such as programmed death-ligand 1 (PD-L1), programmed cell death receptor 1 (PD-1), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), have been implicated in immune dysfunction, the exact relationship between these markers and brain tumor-mediated immune suppression remains unclear. Thus, the objective of this study was to explore whether there exists a differential expression of the above checkpoint markers in the intracranial milieu as compared to tumors in the periphery, which may shed light on the mechanism behind the diminished antitumor response. Methods We identified nine patients with extracranial melanomas and matched intracranial metastases. Formalin-fixed, paraffin-embedded slides were stained for PD-L1, PD-1, LAG-3, and TIM-3 via immunohistochemistry. Qualitative analysis was performed to assess the staining of the markers in the neoplastic and lymphocytic cells, which were the two cell lineages in each biopsy. Results Expression of PD-1 and TIM-3 between extracranial and intracranial tumoral sites was conserved. Specifically, in lymphocytes, PD-1 expression was observed in 100% of extracranial and 100% of intracranial slides, whereas TIM-3 expression was seen in 33.33% of extracranial and 33.33% of intracranial slides. Neither marker stained tumor cells, as expected. PD-L1 showed a slight variation in staining between sites, with lymphocyte staining in 100% of extracranial and 88.89% of intracranial slides, and the same percentages per site for tumor cells. The greatest variability was observed in LAG-3 lymphocyte staining, with staining in 77.78% of extracranial and 33.33% of intracranial slides. No LAG-3 staining of tumor cells was noted, as expected. Conclusion Preliminary analysis revealed the conservation of PD-L1, PD-1, LAG-3, and TIM-3 expression intra- and extracranially. This could suggest that these markers are important in maintaining an immunosuppressive phenotype at both sites. Another possibility is that this pattern of expression is associated with patients who develop brain metastasis, as this was the only subset of patients included in this study. Interestingly, LAG-3 staining of lymphocytes appeared more prominent in extracranial over intracranial tumors. Future studies should include more samples to draw out potential patterns masked by the small sample size, as well as to compare checkpoint expression in other patient groups, such as those with non-brain metastasis or those with no metastasis at all.

Background: It is debated whether primary tumor laterality (PTL) is prognostic in all patients with colorectal liver metastases (CRLM) or only those with KRAS wild-type or KRAS-mutated tumors; Methods: We systematically reviewed PubMed for studies reporting on resected CRLM originating from left-sided (LS) versus right-sided (RS) colon cancer stratified by KRAS status. Individual participant data (IPD) were used if available. Given that there are two definitions of PTL, we performed two meta-analyses for KRAS-mutated and two for wild-type patients. To assess if an interaction underlies the possible difference between the effects of PTL in KRAS-mutated vs. wild-type CRLM, we similarly performed two meta-analyses of interaction terms; Results: The meta-analyses included eight studies and 7475 patients. PTL had a prognostic association with OS in patients with wild-type tumors (HR for LS: 0.71 [0.60–0.84]), but not in those with KRAS-mutated tumors (HR: 0.99 [0.82–1.19]). This difference stemmed from a truly variable effect of PTL for each KRAS status (mutated vs. wild-type) as the meta-analysis of interaction terms showed a significant interaction between them (HR:1.38 [1.24–1.53]). Similar results were obtained when the second definition of PTL (LS to not include the rectum) was used; Conclusions: KRAS status modifies the association of tumor site with survival. Right-sided tumors are associated with worse OS only in patients with wild-type CRLM.

Surgery combined with chemotherapy and precision medicine is the only potential treatment for patients with colorectal cancer liver metastases (CRLM). The use of modern molecular biotechnology to identify suitable biomarkers is of great significance for predicting prognosis and formulating individualized treatment plans for these patients. BRAF mutations, particularly V600E, are widely believed to be associated with poor prognosis in patients with metastatic CRC (mCRC). However, it is unclear which specific factors affect the prognosis of CRLM patients with BRAF mutations. It is also unknown whether patients with resectable CRLM and BRAF mutations should undergo surgical treatment since there is an increased recurrence rate after surgery in these patients. In this review, we combined the molecular mechanism and clinical characteristics of BRAF mutations to explore the prognostic significance and potential targeted therapy strategies for patients with BRAF-mutated CRLM.