Mutations in the BRAF proto-oncogene have been shown to predict poor patient survival following curative-intent liver surgery for metastatic colorectal cancer. The aim of the present systematic ...review and meta-analysis is to evaluate the effect of mutated BRAF status (mutBRAF) on the overall (OS) and disease-free survival (DFS) in these patients.
A comprehensive literature search was performed for studies reporting outcomes of patients undergoing curative-intent surgery stratified by BRAF mutation status. Subgroup analysis was performed to evaluate whether inclusion of KRAS mutation status significantly influenced the results.
Six studies incorporating 1857 patients with known BRAF status were identified. Pooled results revealed significantly worse OS (Hazard Ratio 2.8, 95% C.I. 2.09 to 3.77) and DFS (Hazard Ratio 2.29, 95% C.I. 2.09 to 3.77) in mutBRAF patients. Subgroup analysis revealed no statistically significant impact of including KRAS status testing on the obtained results.
Patients with metastatic colorectal cancer carrying BRAF mutations have significantly worse oncologic outcomes following surgery and more aggressive disease phenotype overall.
•BRAF mutations decrease overall survival of patients with resectable colorectal liver metastases by 180%.•BRAF mutations increase the risk for disease recurrence in patients undergoing curative intent liver metastasectomy by 129%.•The effect was especially pronounced in the subgroup of patients with wild-type (versus unknown) KRAS status.•The V600E variant of BRAF mutation is likely linked to even worse outcomes.
Abstract Background Despite recent advances the pathogenesis of Crohn's disease remains incompletely understood. A variety of animal models have been utilized in an effort to provide further insights ...and develop more therapeutic options. In order to simulate, to an extent, the pathogenesis and the clinical course of the disease, TNBS induced colitis is often used. Various approaches for inducing TNBS -colitis have been described in the literature. Methods/results In this review, we sought to present the animal model of TNBS induced colitis and outline the pathogenesis, pathophysiology, clinical course and pathological characteristics of the model. Furthermore, we describe the differences among those protocols regarding types of animals and colitis induction. Data sources The MEDLINE database was thoroughly searched using the keywords: TNBS, colitis, Crohn's disease, animal model. Two investigators independently reviewed the abstracts and appropriate articles were included in this review. Additional articles were gathered and evaluated. Conclusion The aim of this study was to thoroughly present an updated review of the TNBS-induced colitis protocols that are implemented by researchers.
Precision surgery for colorectal liver metastases (CRLM) includes optimal selection of both the patient and surgery. Initial attempts of using clinical risk scores to identify patients for whom ...technically feasible surgery is oncologically futile failed. Since then, patient selection for single‐stage hepatectomy followed three distinct approaches, all of which incorporated biomarkers. The BRAF V600E mutation, the G12V KRAS variant, and the triple mutation of RAS, TP53, and SMAD4 appear to be the most promising, but none can be used in isolation to deny surgery in otherwise resectable cases. Combining biomarkers with clinicopathologic factors that predict poor prognosis may be used to select patients for surgery, but external validation and matched analyses with medically treated counterparts are needed. Patient selection for special surgical procedures (two‐stage hepatectomy TSH, Associating Liver Partition and Portal vein Ligation for staged hepatectomy ALPPS, and liver transplant LT) has been recently refined. Specifically, BRAF mutations and right‐sided laterality have been proposed as separate contraindications to LT. A similar association of right‐sided laterality, particularly when combined with RAS mutations, with very poor outcomes has been observed for ALPPS and has been suggested as a biologic contraindication. Data are scarce for TSH but RAS mutations may portend very poor survival following TSH completion. The selection of the best single‐stage hepatectomy (optimal margin and type of resection) based on biomarkers remains debated, although there is some evidence that RAS may play a significant role. Lastly, although there are currently no criteria to select among the three special techniques based on their efficacy or appropriateness in different settings, RAS mutational status may be used to select patients for TSH, while right‐sided tumor in conjunction with a RAS mutation may be a contraindication to LT and ALPPS.
Current guidelines recommend use of adjuvant imatinib therapy for many patients with gastrointestinal stromal tumours (GISTs); however, its optimal treatment duration is unknown and some patient ...groups do not benefit from the therapy. We aimed to apply state-of-the-art, interpretable artificial intelligence (ie, predictions or prescription logic that can be easily understood) methods on real-world data to establish which groups of patients with GISTs should receive adjuvant imatinib, its optimal treatment duration, and the benefits conferred by this therapy.
In this observational cohort study, we considered for inclusion all patients who underwent resection of primary, non-metastatic GISTs at the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY, USA) between Oct 1, 1982, and Dec 31, 2017, and who were classified as intermediate or high risk according to the Armed Forces Institute of Pathology Miettinen criteria and had complete follow-up data with no missing entries. A counterfactual random forest model, which used predictors of recurrence (mitotic count, tumour size, and tumour site) and imatinib duration to infer the probability of recurrence at 7 years for a given patient under each duration of imatinib treatment, was trained in the MSKCC cohort. Optimal policy trees (OPTs), a state-of-the-art interpretable AI-based method, were used to read the counterfactual random forest model by training a decision tree with the counterfactual predictions. The OPT recommendations were externally validated in two cohorts of patients from Poland (the Polish Clinical GIST Registry), who underwent GIST resection between Dec 1, 1981, and Dec 31, 2011, and from Spain (the Spanish Group for Research in Sarcomas), who underwent resection between Oct 1, 1987, and Jan 30, 2011.
Among 1007 patients who underwent GIST surgery in MSKCC, 117 were included in the internal cohort; for the external cohorts, the Polish cohort comprised 363 patients and the Spanish cohort comprised 239 patients. The OPT did not recommend imatinib for patients with GISTs of gastric origin measuring less than 15·9 cm with a mitotic count of less than 11·5 mitoses per 5 mm2 or for those with small GISTs (<5·4 cm) of any site with a count of less than 11·5 mitoses per 5 mm2. In this cohort, the OPT cutoffs had a sensitivity of 92·7% (95% CI 82·4–98·0) and a specificity of 33·9% (22·3–47·0). The application of these cutoffs in the two external cohorts would have spared 38 (29%) of 131 patients in the Spanish cohort and 44 (35%) of 126 patients in the Polish cohort from unnecessary treatment with imatinib. Meanwhile, the risk of undertreating patients in these cohorts was minimal (sensitivity 95·4% 95% CI 89·5–98·5 in the Spanish cohort and 92·4% 88·3–95·4 in the Polish cohort). The OPT tested 33 different durations of imatinib treatment (<5 years) and found that 5 years of treatment conferred the most benefit.
If the identified patient subgroups were applied in clinical practice, as many as a third of the current cohort of candidates who do not benefit from adjuvant imatinib would be encouraged to not receive imatinib, subsequently avoiding unnecessary toxicity on patients and financial strain on health-care systems. Our finding that 5 years is the optimal duration of imatinib treatment could be the best source of evidence to inform clinical practice until 2028, when a randomised controlled trial with the same aims is expected to report its findings.
National Cancer Institute.
Objective
The aim of this study was to examine if the prognostic significance of margin status in hepatectomy for colorectal cancer liver metastasis (CRLM) varies for different levels of tumor burden ...because hepatectomy indications for CRLM have been recently expanded to include patients with a higher tumor burden in whom achieving an R0 resection is difficult.
Methods
Clinicopathological variables in an exploration cohort of 290 patients receiving hepatectomy in Japan for CRLM were investigated. R0 resection was defined as a margin width > 0 mm. Tumor burden was assessed using the recently introduced Tumor Burden Score (TBS), which was calculated as TBS
2
= (maximum tumor diameter in cm)
2
+ (number of lesions)
2
. The principal findings were validated using a cohort from the United States.
Results
R1 resection rates significantly increased as TBS increased: 4/86 (4.7%) in patients with TBS < 3, 29/171 (17.0%) in patients with TBS ≥ 3 and < 9, and 9/33 (27.3%) in patients with TBS ≥ 9 (
p
< 0.001). R0 resection was significantly superior to R1 resection in patients with TBS ≥ 5; however, this was not the case for TBS ≥ 6, as confirmed by both univariate and multivariate analyses. Furthermore, prehepatectomy chemotherapy was associated with significantly improved survival for patients with TBS ≥ 8. Analysis of the validation cohort yielded similar results.
Conclusions
R0 resection appeared to have a positive impact on prognosis among patients with low tumor burden; however, this was not the case for patients with high tumor burden. As such, systemic treatment, in addition to surgery, may be central to achieving satisfactory outcomes in the latter patient population.
In patients presenting with colorectal cancer and synchronous liver metastases, the disease burden related to the liver metastasis is the driving cause of limited longevity and, eventually, risk of ...death. Surgical resection is the potentially curative treatment for colorectal cancer liver metastases. In the synchronous setting where both the liver metastases and the primary tumor are resectable with a relative low risk, the oncological surgeon and the patient may consider three potential treatment strategies. Firstly, a "staged" or a "simultaneous" surgical approach. Secondly, for a staged strategy, a 'conventional approach' will suggest removal of the primary tumor first (either colon or rectal cancer) and plan for liver surgery after recovery from the first operation. A "Liver first" strategy is prioritizing the liver resection before resection of the primary tumor. Planning a surgical trial investigating a two-organ oncological resection with highly variable extent and complexity of resection as well as the potential impact of perioperative chemo(radio)therapy makes it difficult to find the optimal primary endpoint. Here, we suggest running investigational trials with carefully chosen composite endpoints as well as embedded risk-stratification strategies to identify subgroups of patients who may benefit from simultaneous surgery.
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