Intravenous subdissociative-dose ketamine versus morphine for acute geriatric pain in the Emergency Department: A randomized controlled trial

Study objective

We compare the analgesic efficacy and safety of subdissociative intravenous-dose ketamine (SDK) versus morphine in geriatric Emergency Department (ED) patients.

Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors

Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.     

Searching for prognostic biomarkers for small renal masses in the urinary proteome

Renal cell carcinoma (RCC) is frequently diagnosed incidentally as an early-stage small renal mass (SRM; pT1a, ≤4 cm). Overtreatment of patients with benign or clinically indolent SRMs is increasingly common and has resulted in a recent shift in treatment recommendations. There are currently no available biomarkers that can accurately predict clinical behavior. Therefore, we set out to identify early biomarkers of RCC progression. We employed a quantitative label-free liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) proteomics approach and targeted parallel-reaction monitoring to identify and validate early, noninvasive urinary biomarkers for RCC-SRMs. In total, we evaluated 115 urine samples, including 33 renal oncocytoma (≤4 cm) cases, 30 progressive and 26 nonprogressive clear cell RCC (ccRCC)-SRM cases, in addition to 26 healthy controls. We identified six proteins, which displayed significantly elevated expression in clear cell RCC-SRMs (ccRCC-SRMs) relative to healthy controls. Proteins C12ORF49 and EHD4 showed significantly elevated expression in ccRCC-SRMs compared to renal oncocytoma (≤4 cm). Additionally, proteins EPS8L2, CHMP2A, PDCD6IP, CNDP2 and CEACAM1 displayed significantly elevated expression in progressive relative to nonprogressive ccRCC-SRMs. A two-protein signature (EPS8L2 and CCT6A) showed significant discriminatory ability (areas under the curve: 0.81, 95% CI: 0.70–0.93) in distinguishing progressive from nonprogressive ccRCC-SRMs. Patients (Stage I–IV) with EPS8L2 and CCT6A mRNA alterations showed significantly shorter overall survival (p = 1.407 × 10⁻⁶) compared to patients with no alterations. Our in-depth proteomic analysis identified novel biomarkers for early-stage RCC-SRMs. Pretreatment characterization of urinary proteins may provide insight into early RCC progression and could potentially help assign patients to appropriate management strategies.     

Current and emerging pharmacotherapy for emergency management of preeclampsia

Introduction: Preeclampsia is a disease specific to pregnancy characterised by new onset hypertension with maternal organ dysfunction and/or fetal growth restriction. It remains a major cause of maternal and perinatal morbidity and mortality. For fifty years, antihypertensives have been the mainstay of treating preeclampsia, reducing maternal morbidity and mortality. With increased knowledge of the mechanisms underlying the disease has come opportunities for novel therapies that complement antihypertensives by protecting the maternal vasculature.

Areas covered: In this review, the authors consider, in detail, the antihypertensives commonly used today in the emergency care of women with severe preeclampsia. They also review less common anti-hypertensive agents and discuss the role of magnesium sulphate in the management of preeclampsia and the prevention of eclampsia. Finally, they explore novel therapeutics for the acute management of preeclampsia.

Expert opinion: The rapid control of maternal hypertension will, and must, remain the mainstay of emergency treatment for women with severe preeclampsia. The role of magnesium sulphate as a primary prevention for eclampsia is context dependant and should not displace a focus on correcting blood pressure safely. The exploration of novel adjuvant therapies will likely allow us to prolong pregnancy longer and improve perinatal outcomes safely for the mother.