Immunotherapy has significantly changed the treatment paradigm for solid tumors, with immune checkpoint inhibitors now established in the management of many malignancies. Despite initial success, durable responses remain limited to a subset of patients, often less than 30%, due to both intrinsic and acquired resistance mechanisms. These challenges have prompted the development of next-generation immunotherapies. Recent efforts have expanded the scope of immunotherapy beyond PD-1/PD-L1 and CTLA-4 inhibition, focusing on new immune targets currently under investigation in early phase clinical trials. These include novel immune checkpoint inhibitors, immunomodulators targeting the tumor microenvironment, and bispecific antibodies. This review provides a comprehensive overview of emerging immune targets currently being investigated in early drug development, discussing their mechanisms of action, preliminary clinical outcomes, and potential future directions.

Purpose Early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before the age of 50 years, is increasing worldwide and represents a growing clinical and public health challenge. Whether EOCRC constitutes a biologically distinct entity remains uncertain, and current diagnostic and therapeutic strategies are largely extrapolated from late-onset disease. Methods This narrative review summarizes recent evidence on EOCRC biology, diagnosis, and management, focusing on molecular and genomic features, tumor microenvironment, exposome-related factors, diagnostic pathways, treatment paradigms, and emerging strategies for early detection. We critically examine the gap between biological insights and real-world clinical practice and outline priorities for future research. Results EOCRC displays a heterogeneous molecular landscape that substantially overlaps with late-onset colorectal cancer. Although advances in multiomics profiling, liquid biopsy, and microbiome research have improved biological understanding, these findings have not yet translated into EOCRC-specific diagnostic or therapeutic approaches. Diagnosis remains delayed due to age-based screening paradigms and symptom misattribution, resulting in advanced-stage presentation. Younger patients frequently receive intensified treatment despite limited age-specific evidence and insufficient attention to long-term toxicity, fertility, and survivorship. Conclusion EOCRC underdiagnosis is likely multifactorial. While limitations in biological knowledge and diagnostic tools may play a role, the discrepancy between current paradigms and the age-specific risk profiles of younger patients likely represents an important contributing factor. Progress will require biology-informed, risk-adapted screening strategies and EOCRC-focused clinical research.

Generalized lymphatic anomaly (GLA) is an infrequent multiorgan disease characterized by the presence of abnormal proliferation of lymphatic vessels. The diagnosis requires histological confirmation, and the treatment is controversial. We are presenting a case of a 28-year-old male patient who was diagnosed with an extragonadal mediastinal nonseminomatous germ cell tumor. He underwent chemotherapy, and during this treatment, radiologic findings evidenced lytic lesions. Multiple biopsies were performed, which revealed the presence of abnormal lymphatic vessels, characteristic of GLA. There are different etiologies of osteolytic lesions, and on some occasions, they mimic a tumoral entity. The clinical suspicion of GLA is the first step in approaching the diagnosis, particularly in young adult patients.

Background/Objectives: The BRAF-mutation is a poor prognostic factor in colorectal cancer (CRC). There is a need for real-world data in low-middle-income countries regarding clinical characteristics, outcomes, and treatment strategies. This study aims to describe progression-free survival (PFS) and in the first- and second-line setting and sequences of treatment regimens. Methods: We retrospectively analyze patients from ten oncology centers in Argentina, diagnosed with BRAF^V600E-mutated advanced CRC between January 2014 and July 2023. Results: A total of 161 patients with metastatic CRC and BRAF^V600E-mutation. The median age was 58.5 (IQR 47–69), and 21.7% were MMR-deficient (dMMR). Of these patients, 93.8% received first-line treatment. With a median follow-up of 23 months (95% CI 16.5–33.4 months), the median PFS was 9 months (95% CI 7.4–10.5 months). The most common regimen in first line setting was doublet chemotherapy plus anti-VEGF for 49% of the patients. Twenty-six percent of the patients received BRAF inhibitors in the second-line setting, with a median PFS of 5.2 months (95% CI 4.9—NR); the overall response rate (ORR) was 10.5%. Conclusions: This study represents, to the best of our knowledge, the largest published real-world cohort of BRAF^V600E-mutated CRC in Latin America. The heterogeneity of the treatments reflects the existence of barriers to access to high-cost drugs in our country. Cooperative efforts are needed to understand the particular characteristics of this subgroup of patients.

Oxaliplatin, a key agent used for managing metastatic colorectal cancer (mCRC), is often discontinued due to cumulative toxicity. Its reintroduction in later treatment lines remains a common clinical practice, despite the absence of robust prospective trials supporting this therapeutic strategy. This study aimed to evaluate the efficacy of oxaliplatin rechallenge in refractory mCRC and to identify patient characteristics predictive of improved outcomes with this approach. We retrospectively analyzed patients treated with oxaliplatin in the third- or fourth-line setting at Vall d’Hebron Hospital between 2015 and 2021. Outcomes included overall response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS). Patients achieving median PFS >6 months were classified as best-responders. Factors affecting PFS were analyzed with a Cox regression model. Amplicon-seq analysis of 61 genes was carried out using Illumina technology. Of 735 patients receiving third- or fourth-line treatment, 102 (14%) received oxaliplatin retreatment (69% in third line; 31% in fourth line). Median PFS was 4.0 months (95% CI 3.29-5.03 months), with an ORR of 12% and DCR of 39%. Twenty-eight patients (27%) were best-responders. Predictors of efficacy included response to first-line oxaliplatin, planned oxaliplatin discontinuation, and an oxaliplatin-free interval of at least 22.0 months. No significant associations were identified between molecular alterations and prognostic subgroups. Oxaliplatin-based reintroduction therapy is a viable strategy in mCRC, particularly for patients with a favorable prior response and prolonged oxaliplatin-free intervals. However, identifying more precise biomarkers is essential to improve patient selection and maximize treatment efficacy.

Background/Objectives: BRAF-mutation is a poor prognostic factor in colorectal cancer (CRC). There is a need for real-world data in low-middle-income countries regarding clinical characteristics, outcomes, and treatment strategies. This study aims to describe progression free survival (PFS) and overall survival (OS) in the first-line setting, and sequences of treatment regimens. Methods: We retrospective analyze patients from ten oncology centers in Argentina, diagnosed with BRAFV600E-mutated advanced CRC between January 2014 and July 2023. Results: A total of 161 patients with metastatic CRC and BRAFV600E-mutation. The median age was 58.5 (IQR 47-69) and 21.7% were MMR-deficient (dMMR). 93.8% of the patients received first-line treatment. With a median follow-up of 23 months (95% CI 16.5 - 33.4 months), the median OS was 20.6 months (95% CI 18.4 - 29 months) and PFS 9 months (95% CI 7.4 - 10.5 months). The most common regimen was doublet chemotherapy plus anti-VEGF in 49%. 26% received BRAF inhibitors in second line setting. Conclusions: This study represents, to the best of our knowledge, the largest published real-world cohort of BRAFV600E-mutated CRC in Latin America. The heterogeneity in treatments reflect the existence of barriers to access high-cost drugs in our country. Cooperative efforts are needed to understand the particular characteristics of this subgroup of patients.