Transcriptomic Profiling of Plasma Extracellular Vesicles Enables Reliable Annotation of the Cancer-Specific Transcriptome and Molecular Subtype.

Longitudinal monitoring of patients with advanced cancers is crucial to evaluate both disease burden and treatment response. Current liquid biopsy approaches mostly rely on the detection of DNA-based biomarkers. However, plasma RNA analysis can unleash tremendous opportunities for tumor state interrogation and molecular subtyping. Through the application of deep learning algorithms to the deconvolved transcriptomes of RNA within plasma extracellular vesicles (evRNA), we successfully predicted consensus molecular subtypes in patients with metastatic colorectal cancer. Analysis of plasma evRNA also enabled monitoring of changes in transcriptomic subtype under treatment selection pressure and identification of molecular pathways associated with recurrence. This approach also revealed expressed gene fusions and neoepitopes from evRNA. These results demonstrate the feasibility of using transcriptomic-based liquid biopsy platforms for precision oncology approaches, spanning from the longitudinal monitoring of tumor subtype changes to the identification of expressed fusions and neoantigens as cancer-specific therapeutic targets, sans the need for tissue-based sampling. SIGNIFICANCE: The development of an approach to interrogate molecular subtypes, cancer-associated pathways, and differentially expressed genes through RNA sequencing of plasma extracellular vesicles lays the foundation for liquid biopsy-based longitudinal monitoring of patient tumor transcriptomes.

Management of DOAC-related bleeding in cancer patients: a single center-case series.

Venous thromboembolism (VTE) and stroke carry significant mortality and morbidity in cancer patients. Direct oral anticoagulants (DOACs) have been demonstrated to be effective for the treatment of VTE and prevention of stroke in atrial fibrillation (AF). Bleeding rates are variable and are based on the cancer type and the patient's specific risk factors. There are approved specific antidotes for DOAC-associated bleeding. Other strategies are available for bleeding reversal, including the use of prothrombin complex concentrate (PCC). No randomized studies have compared head-to-head the efficacy and safety of reversal agents. We aim to examine the safety and effectiveness of hemostatic agents in cancer patients with DOAC-related major bleeding. A retrospective chart review study of patients at MD Anderson Cancer Center with DOAC-related major bleeding between 2014 and 2019. Bleeding severity and clinical hemostasis were described based on ISTH guidelines and the Sarode criteria, respectively. The rates of thrombotic complications and mortality at 30-day from the index bleeding event were described. We identified 23 patients with DOAC-related major bleeding; 14 patients received PCC and 9 patients received andexanet alfa. The most common sites of bleeding were the gastrointestinal tract and intracranial. Effective hemostasis and 30-day mortality were similar to reported results from other reports of outcomes of reversal agents for DOAC related-bleeding in non-cancer patients. One patient in each treatment group experienced a thrombotic event. Further larger scale studies are needed to confirm our findings in cancer patients.

MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer.

Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selecti-vity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study. SIGNIFICANCE: PRMT5 was identified as a synthetic lethal target for MTAP del cancers; however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ∼10% of patients with cancer with this biomarker. See related commentary by Mulvaney, p. 2310. This article is featured in Selected Articles from This Issue, p. 2293.

The impact of regional STEMI systems on protocol use and quality improvement initiatives in community hospitals without cardiac catheterization laboratories.

Study objective: Since the 1990s, national guidelines have recommended hospitals develop STEMI treatment protocols and monitor quality. A 2003 survey of Minnesota hospitals without cardiac catheterization laboratories (CCL) found <2/3 had STEMI protocols, <50% had a quality assessment (QA) process, and protocols in existence were incomplete. We evaluated temporal changes in STEMI processes in relationship to changes in mortality. Design setting and participants: Follow-up surveys were mailed to emergency departments at 108 Minnesota hospitals without CCL. Results: Among 87% of responding hospitals, 89% had formal protocols or guidelines for STEMI management compared to 63% in 2003 (p < 0.001). In 2010, 67% of hospitals had triage/transfer criteria and 15% of hospitals used protocols for transfer decisions, compared to only 8% (p < 0.001) and 1% (p = 0.098), respectively, in 2003. The percentage of hospitals transferring patients with STEMI from the emergency department increased from 23% in 2003 to 56% in 2010 (p < 0.001). During this time, age-adjusted acute MI mortality rate in Minnesota decreased 33% and was more pronounced in areas with regional STEMI systems. Conclusions: Since 2003, utilization of STEMI guidelines, protocols, and standing orders in Minnesota hospitals without CCL has markedly improved with <10% of hospitals lacking specific STEMI management protocols. The majority of hospitals routinely transfer patients with STEMI for primary PCI and have comprehensive QA processes. This improvement was stimulated by regional STEMI systems, further supporting the current class I recommendation for STEMI systems of care in current guidelines. The decline in Minnesota STEMI mortality paralleled the growth of regional STEMI systems.

Comprehensive Clinical and Molecular Characterization of KRAS G12C-Mutant Colorectal Cancer.

PURPOSE: KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS: We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS: Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION: PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

Clinical Characteristics and Outcomes of STEMI Patients With Cardiogenic Shock and Cardiac Arrest.

OBJECTIVES: This study sought to compare the clinical characteristics and long-term outcomes of patients with ST-segment elevation myocardial infarction (STEMI) with and without cardiogenic shock (CS) or cardiac arrest (CA) before percutaneous coronary intervention (PCI). BACKGROUND: Patients with STEMI complicated by CS or CA are underrepresented in STEMI registries. METHODS: Consecutive patients with STEMI or new left bundle branch block within 24 h of symptom onset were included in a regional STEMI program comprising a PCI center (Minneapolis Heart Institute at Abbott Northwestern Hospital), 11 hospitals <60 miles from PCI center (zone 1), and 19 hospitals 60 to 210 miles from PCI center (zone 2). No patients were excluded. Patients were stratified based on the presence (+) or absence (-) of CS or CA before PCI. Patients with CA were further classified based on initial rhythm. Primary outcomes were in-hospital and 5-year mortality. RESULTS: Between March 2003 and December 2014, 4,511 STEMI patients were included in the regional program, including 398 (9%) with CS and 499 (11%) with CA. Hospital mortality was: CS+ and CA+, 44%; CS+ and CA-, 23%; CS- and CA+, 19%; and CS- and CA-, 2% (p < 0.001). The 5-year survival probability for CS+ and CA+ patients was 0.69 (95% confidence interval: 0.61 to 0.76) and 0.89 (95% confidence interval: 0.84 to 0.93), respectively (p < 0.01). Compared with patients with shockable rhythms, CA patients with nonshockable rhythms had significantly lower odds of survival at hospital discharge and at 5 years (both p < 0.001). CONCLUSIONS: The combination of CS and CA significantly increases short-term mortality in patients with STEMI. After 5 years of follow-up, CS patients remained at high risk of fatal events, whereas the prognosis of CA patients was determined by initial rhythm at presentation.

Satisfaction with emergent transfer for percutaneous coronary interventions on patients with ST-segment-elevation myocardial infarction and their families.

BACKGROUND: Transfer for primary percutaneous coronary intervention (PCI) is superior to fibrinolysis if performed in a timely manner but frequently requires dislocation of patients and their families from their local community. Although patient satisfaction is increasingly viewed as an important quality indicator, there are no data on how emergent transfer for PCI affects patients with ST-segment-elevation myocardial infarction and their families. METHODS AND RESULTS: The Minneapolis Heart Institute's Level 1 Regional ST-Segment-Elevation Myocardial Infarction program is designed to facilitate emergent transfer for PCI in patients with ST-segment-elevation myocardial infarction from 31 rural and community hospitals. To determine the effect of emergent transfer, questionnaires were given to 152 patients and their families who survived to hospital discharge with a 65.8% response rate (mean age, 63.9 years; 29% women). Ninety-five percent of patients felt the reasons and process of transfer were well explained, and 97% felt transfer for care was necessary. Despite this, 15% of patients would have preferred to stay in their local hospital. The majority of the families felt the transfer process (88%) and family member's condition (94%) were well explained. Although 99% felt it was necessary for their family member to be transferred for specialized care, 11% of families still would have preferred that their family members remain at the local community hospital. CONCLUSIONS: Our results suggest that ST-segment-elevation myocardial infarction patients and families can be informed, even in time-critical situations, about the transfer process for PCI and understand the need for specialized care. Still, a significant minority would prefer to stay at their local hospital, despite acknowledging transfer for PCI provided optimal care.

Impact of age on treatment and outcomes in ST-elevation myocardial infarction.

OBJECTIVES: We hypothesized that older patients in a regional ST-elevation myocardial infarction (STEMI) transfer program would attain comparable treatment to younger patients. BACKGROUND: Older patients have been either excluded or underrepresented in STEMI clinical trials. Observational studies suggest that these patients are less likely to receive adjunctive pharmacologies and reperfusion therapy-thrombolysis or percutaneous coronary intervention (PCI)-and therapy is frequently delayed. METHODS: We identified a consecutive series of 2,262 STEMI patients (March 2003-December 2008) who either presented or were transferred to Abbott Northwestern Hospital for PCI (<65 years [n = 1285], 65-74 years [n = 436], 75-84 years [n = 381], and ≥85 years [n = 160]). Main outcome measures included time-to-reperfusion therapy, adjunctive medications received, and all-cause mortality. RESULTS: Overall time-to-reperfusion therapy was similar across age strata-94 minutes (<65 years), 101 minutes (65-74 years), 106 minutes (75-84 years), and 103 minutes (≥85 years). No difference in adjunctive antiplatelet or anticoagulant medications was seen at hospital admission, and only slight differences in standard post-myocardial infarction medication use were seen by age at hospital discharge. Age was an independent predictor of in-hospital and yearly mortality up to 5 years (1-year mortality 3.4% [<65 years], 9.2% [65-74 years], 15.2% [75-84 years], and 28.9% [≥85 years]; P < .0001). CONCLUSIONS: Older patients receive similar care to younger patients when treated in a regional STEMI transfer program. Although all-cause mortality in the elderly is increased, the absolute rates are lower than previously established. Our data suggest primary PCI (including transfer) can be applied to all appropriate STEMI patients, regardless of age.