Purpose: Oncogenic mutations in KRAS have been identified in >85% of pancreatic ductal adenocarcinoma (PDAC) cases, with G12D, G12V, and G12R being the most frequent variants. Using large clinical and genomic databases, this study characterizes prognostic and molecular differences between KRAS variants, focusing on KRASG12D and KRASG12R. Experimental Design: PDAC samples were tested using DNA and RNA sequencing. The MAPK activation score and tumor microenvironment were analyzed from RNA expression data. Real-world overall survival (OS) obtained from insurance claims data was calculated from tissue collection to last contact. Significance was determined by χ2 and Fisher exact tests. Results: A total of 3,755 patients with PDAC harboring KRASG12D (n = 1,766), KRASG12V (n = 1,294), KRASG12R (n = 621), or KRASG12C (n = 74) variants were identified. Patients with G12R mutations had longer OS compared with those with G12D overall (12.7 vs. 10.1 months; P value = 0.0001), with similar trends in patients treated with gemcitabine/nab-paclitaxel (13.5 vs. 10.4 months; P value = 0.0002) or FOLFIRINOX (18.3 vs. 14.0 months; P value<0.001). ARID1A and KMT2D mutations were more frequent in the G12D subgroup. Several genes involved in glucose and glutamine metabolism were less expressed in G12R compared with G12D. PD-L1 expression was lower in G12R compared with G12D (13% vs. 19%). Conclusions: KRAS G12D tumors exhibited a distinct molecular profile compared with G12R tumors, including genes involved in the MAPK pathway, immune activation, and glucose and glutamine metabolism. Patients with G12D mutations had lower OS compared with those with G12R. Based on these data, future studies should address the KRAS mutation status and explore distinct therapeutic vulnerabilities.

BRAF-altered pancreatic cancer is an important molecular subgroup that activates the mitogen-activated protein kinase pathway and promotes tumorigenesis. This manuscript reviews the prevalence and molecular features of BRAF-driven pancreatic cancer and also explores the published data about targeted approaches for this subgroup. A review of the existing literature was undertaken through the PubMed database using the search terms BRAF mutation, BRAF fusion, BRAF deletion, mitogen-activated protein kinase pathway, and pancreatic cancer. Pathogenic BRAF variants are enriched in KRAS wild-type (WT) tumors and drive tumorigenesis in in vitro and experimental animal models. The majority of clinical cases are comprised of V600E mutations, N486-P490 deletions and fusions. Anecdotal evidence is building that KRAS-WT, BRAF-driven pancreatic cancers are sensitive either to BRAF inhibitors, MEK inhibitors, or combination strategies. Precision medicine has transformed the treatment landscape for several cancers. With increasing knowledge about molecular drivers in pancreatic cancer, it is critical to characterize each distinct subgroup and evaluate targeted approaches to improve clinical outcomes.

Aim: Cytokine release syndrome (CRS) is an infrequently described immune-related adverse event of checkpoint inhibitors (CPI). CPI-induced CRS typically presents with fevers, hemodynamic instability and organ dysfunction within 2 weeks of the last treatment cycle. Case study: We report an unusual case of delayed and severe CRS occurring postoperatively in a patient with hepatic-limited metastatic colorectal cancer who received neoadjuvant immunotherapy. After a negative workup for alternative causes, he received prolonged corticosteroid treatment with symptom resolution. Conclusion: CPI-induced CRS can mimic sepsis and clinicians should maintain a high-index of suspicion to diagnose this immune-related adverse event early and initiate appropriate treatment. As use of perioperative immunotherapy increases, the potential role of surgery to trigger CRS in this case warrants further investigation.

Liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is increasing in incidence and mortality across the globe. An improved understanding of the complex tumor microenvironment has opened many therapeutic doors and led to the development of novel pharmaceuticals targeting cellular signaling pathways or immune checkpoints. These interventions have significantly improved tumor control rates and patient outcomes, both in clinical trials and in real-world practice. Interventional radiologists play an important role in the multidisciplinary team given their expertise in minimally invasive locoregional therapy, as the bulk of these tumors are usually in the liver. The aim of this review is to highlight the immunological therapeutic targets for primary liver cancers, the available immune-based approaches, and the contributions that interventional radiology can provide in the care of these patients.

Aim: Immune-related (IR) colitis is a potentially life-threatening complication of checkpoint inhibitors. Its presentation often includes diarrhea, abdominal pain and rectal bleeding and the median time to onset is 6-10 weeks post initiation of immunotherapy. Case study: We report an unusual case of fulminant IR-colitis beginning 3 days after the first dose of dual checkpoint blockade. IR-colitis was refractory to high-dose corticosteroids and was further complicated by sigmoid diverticulum perforation. Conclusion: Early-onset IR-colitis can occur, particularly in the context of combined anti-PD1 and anti-CTLA4 blockade, and clinicians should maintain a high-index of suspicion even when timing of symptom onset is atypical. Further research is needed to elucidate risk factors for early-onset IR-colitis.