Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies. Significance: Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247

Background: The endovascular treatment of complex intracranial aneurysms, such as wide-neck aneurysms (WNAs), remains a challenge. More established endovascular techniques, which include balloon-assisted coiling, stent-assisted coiling, and flow diversion, all have their drawbacks. Intrasaccular flow disruptor devices have emerged as a useful tool for the neurointerventionalist. Methods: Here, we discuss landmark studies and provide a comprehensive, narrative review of the Woven EndoBridge (WEB; Microvention, Alisa Viejo, CA, USA), Artisse (Medtronic, Irvine, CA, USA), Contour (Stryker, Kalamazoo, MI, USA), Saccular Endovascular Aneurysm Lattice Embolization System (SEAL; Galaxy Therapeutics Inc, Milpitas, CA, USA), Medina (Medtronic, Irvine, CA, USA), and Trenza (Stryker, Kalamazoo, MI, USA) devices. Results: Intrasaccular devices have proven to be effective in treating complex aneurysms like WNAs. Conclusions: Intrasaccular flow disruptors have emerged as a new class of effective endovascular therapy, and results of ongoing clinical studies for the newer devices (e.g., SEAL and Trenza) are much anticipated.

Cerebrospinal fluid (CSF) fistulas have recently been recognized as a cause of spontaneous intracranial hypotension (SIH), predominantly presenting with headaches, especially positional headaches. Atypical presentations like tinnitus and cranial nerve symptoms have also been reported. SIH has been linked to venous sinus thrombosis; however, to our knowledge, no prior cases describe a CSF venous fistula causing SIH that leads to cerebral venous thrombosis and coma. We report a patient who developed progressive venous sinus thrombosis, leading to coma, and was found to have low intracranial pressure indicative of SIH. Invasive monitoring and imaging confirmed the low intracranial pressure, prompting a dynamic myelogram that revealed a T2/3 CSF venous fistula. The patient underwent transvenous embolization of the fistula, which resulted in the resolution of symptoms and almost immediate improvement in both venous thrombosis and intracranial hypotension. CSF venous fistulae as a cause of SIH is a recently recognized entity, with ongoing research into its treatment through transvenous embolization. Most documented cases focus on patients with headaches. This case highlights a novel presentation, emphasizing the importance of thorough diagnostic workup in patients with cerebral venous thrombosis. Early detection and treatment of this condition can lead to significant clinical improvement, including the resolution of coma.

Background: Venous sinus stenting (VSS) is a safe and effective treatment strategy for pulsatile tinnitus (PT) and idiopathic intracranial hypertension (IIH). Although complications are rare, the morbidity associated with the complications is high. Navigating through the venous sinuses poses unique challenges to the interventionalist. There is limited literature regarding device selection to maximize safety and efficiency. We report on the safety and advantages of using a balloon guide catheter (BGC) for venous access in VSS. Methods: Retrospective analysis of all patients undergoing VSS using a BGC over a three-month period. Results: A total of 22 patients were included in the analysis (median age 35; 21 female). The indication for treatment was PT in 10 patients and IIH in 12 patients. The BGC was navigated into the sigmoid and transverse sinuses, enabling successful delivery of the stent in all cases. The BGC balloon was inflated 23 times for navigating past tortuosity or obstructions, and for anchoring. There were no intraprocedural complications. Conclusions: The use of BGC in VSS is safe and feasible. BGCs have features that can be utilized to overcome the unique challenges encountered during VSS.

Purpose: Flow diverting stents are a mainstay treatment of intracranial aneurysms (IA). They rely on reduction of intra-aneurysmal blood flow velocity along with endothelialization to induce thrombus formation and promote occlusion. Patients with hematologic disorders (HDs) can have abnormal fluid dynamics and blood cell/metal interactions that can affect the mechanism of action of flow diversion (FD). We sought to determine the outcomes of patients with various HD after receiving FD treatment for IA.Materials and Methods: This retrospective chart review examined 11 patients with various HD who received FD for their IAs. HD were classified as either coagulopathies (e.g., factor deficiencies, von Willebrand disease) or hemoglobinopathies (e.g., sickle cell disease [SCD]). Patient outcomes were assessed clinically and radiographically, with radiographic outcomes based on O’Kelly-Marotta (OKM) scores from follow-up angiograms.Results: The total sample included 11 patients with 29 IAs. The median age was 50 years and 81.8% were female. All patients were on pre-procedural dual antiplatelet therapy. Out of the 29 total aneurysms, 17 were treated with FD and 15 originated from the paraophthalmic segment. Seven patients received surface modified stents. The median number of deployed stents during initial treatment was 2. The average aneurysm diameter was 5.03 mm (standard deviation: 3.88 mm). Patients with SCD were the only group to experience complications, with 2 out of 3 patients suffering a post-operative stroke. Seven patients with 8 treated aneurysms experienced complete occlusion at last follow-up with a mean time to OKMD score of 16.8 months.Conclusion: Despite a small sample size, this series raises concern for the use of FD in patients with SCD. While FD still resulted in adequate rates of aneurysm occlusion, treatment methodology must be tailored for patients with HD.

Effects of MRTX1133 in KPC/Y and subcutaneous models