The BRAF^V600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAF^V600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.

Pneumatosis intestinalis (PI) is a rare condition due to the presence of gas within the bowel wall; it is mainly caused by endoscopic procedures, infections and other gastrointestinal diseases. Oncological therapies have been reported to be a cause of PI as well, but their role is not clearly defined. This systematic review investigates the concurrency of PI and antitumor therapy in cancer patients, considering both solid tumors and onco-hematological ones. We performed a literature review of PubMed, Embase and the Web of Science up to September 2021 according to the PRISMA guidelines. A total of 62 papers reporting 88 different episodes were included. PI was mainly reported with targeted therapies (sunitinib and bevacizumab above all) within the first 12 weeks of treatment. This adverse event mostly occurred in the metastatic setting, but in 10 cases, it also occurred also in the neoadjuvant and adjuvant setting. PI was mostly localized in the large intestine, being fatal in 11 cases, while in the remaining cases, symptoms were usually mild, or even absent. A significant risk of PI reoccurrence after drug reintroduction was also reported (6/18 patients), with no fatal outcomes. Potential pharmacological mechanisms underlying PI pathogenesis are also discussed. In conclusion, although uncommonly, PI can occur during oncological therapies and may lead to life-threatening complications; therefore, consideration of its occurrence among other adverse events is warranted in the presence of clinical suspicion.

Background: oxaliplatin with fluoropyrimidine is a “mainstay” regarding the upfront treatment of metastatic colorectal cancer (mCRC). In contrast, the efficacy and safety of oxaliplatin-based regimens in late-care settings have been poorly reported. Methods: we identified a real-world mCRC patient cohort who were re-treated with oxaliplatin, and in which clinicopathological features were retrospectively analyzed to identify efficacy–predictive determinants (RETROX-CRC study). Results: of 2606 patients, 119 fulfilled the eligibility criteria. Oxaliplatin retreatment response rate (RR) and disease control rate (DCR) were 21.6% (CI 14.4–31.0%), and 57.8% (CI 47.7–67.4). A trend towards better RR and DCR was observed among patients who had first oxaliplatin in an adjuvant setting; a poorer outcome was observed if two or more intervening treatments were delivered. Median progression-free survival (PFS) was 5.1 months (95%CI 4.3–6.1), reducing to 4.0 months (95%CI 3.07–5.13) if oxaliplatin was readministered beyond third-line (HR 2.02; 1.25–3.25; p = 0.004). Safety data were retrieved in 65 patients (54.6%); 18.5% (12/65) and 7.7% (5/65) had G3–4 toxicities. Toxicities led to discontinuation in 34/119 (28.6%). Conclusions: oxaliplatin retreatment produced further RR in around one-fifth of patients and DCR 57.8%. Efficacy decreased in more pre-treated patients and around one-third of patients discontinued treatment due to adverse events. Translational studies improving patient selection are warranted.

Immunocytokines are an emerging class of antibody-cytokine fusion proteins combining the specificity of monoclonal antibodies with the potent immunostimulatory effects of cytokines, potentially enhancing the anti-tumor immune response while reducing systemic toxicity. We conducted a systematic review following the PRISMA guidelines. We performed a comprehensive literature search using PubMed and ClinicalTrials.gov databases. The search strategy included the terms "immunocytokine", "cytokine", "tumor", and "cancer". Filters were applied to retrieve only peer-reviewed articles and clinical trials. 25 publications were retrieved: 15 were Phase I studies; 2 Phase I/II, and 8 Phase II. Regarding ongoing clinical trials, 62 studies were included: 30 were Phase I studies, 2 Phase III, and the remaining 30 were either Phase II (n = 13) or Phase I/II (n = 17). In 50/62 trials, the primary and co-primary outcomes included safety measures, such as adverse effects, dose-limiting toxicities, and maximum tolerated dose. In both studies from literature and ongoing clinical trials, the most common target was extra-domain B (EDB) of fibronectin, and the most investigated type of cancer was melanoma. While all published studies focused on solid tumors, several ongoing trials include hematologic malignancies. Research interest in immunocytokines as a potential cancer treatment is increasing, although only limited data are currently available. Several trials, mainly in the early phase, are ongoing, paving the way for a possible broader clinical application of this class of immunotherapeutics.

Objectives: Treatment of metastatic colorectal cancer (mCRC) includes resection of liver metastases (LM), however, no validated biomarker identifies patients most likely to benefit from this procedure. This meta-analysis aimed to assess the impact of the most relevant molecular alterations in cancer-related genes of CRC (i.e., RAS, BRAF, SMAD4, PIK3CA) as prognostic markers of survival and disease recurrence in patients with mCRC surgically treated by LM resection. Methods: A systematic literature review was performed to identify studies reporting data regarding survival and/or recurrence in patients that underwent complete liver resection for CRC LM, stratified according to RAS, BRAF, PIK3CA, and SMAD4 mutational status. Hazard ratios (HRs) from multivariate analyses were pooled in the meta-analysis and various adjustment strategies for confounding factors were combined. The search was conducted in numerous databases, including MEDLINE (PubMed), Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO host), and WHO Global Index Medicus, through March 18th, 2022. Meta-analyses, editorials, letters to the editor, case reports, studies on other primary cancers, studies with primary metastatic sites other than the liver, studies lacking specific oncological outcome variables or genetic data, non-English language studies, and studies omitting residual disease data from liver metastasectomy were excluded. The remaining 47 studies were summarized in a descriptive table which outlines the key characteristics of each study and final results were graphically presented. Results: RAS mutation status was negatively associated with overall survival (OS) (HR, 1.68; 95% CI, 1.54–1.84) and recurrence free survival (RFS) (HR, 1.46; 95% CI, 1.33–1.61). A negative association was also found for BRAF regarding OS (HR, 2.64; 95% CI, 2.15–3.24) and RFS (HR, 1.89; 95% CI, 1.32–2.73) and SMAD4 regarding OS (HR, 1.93; 95% CI, 1.56–2.38) and RFS (HR, 1.95; 95% CI, 1.31–2.91). For PIK3CA only three studies were eligible and no significant association with either OS or RFS could be highlighted. Conclusion: RAS, BRAF, and SMAD4 are negatively associated with OS and RFS in patients undergoing curative liver metastasectomy from colorectal cancer. No conclusion can be drawn for PIK3CA due to the limited literature availability. These data support the integration of RAS, BRAF, and SMAD4 mutational status in the surgical decision-making for colorectal liver metastasis. Nevertheless, we have to consider several limitations, the major ones being the pooling of results from studies that evaluated patient outcomes as either disease-free survival (DFS) or RFS; the inclusion of patients with minimal residual disease and unconsidered potential confounding factors, such as variability in resectability definitions, chemotherapy use, and a potential interaction between biological markers and pre- and post-resection pharmacological treatments.