Citations

Objective: This study is a comprehensive review of the clinical pharmacology, pharmacokinetics, efficacy, safety, and clinical applicability of amivantamab-vmjw for metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutation. Data Synthesis: The literature search to identify clinical trials returned only the CHRYSALIS phase 1 study. In a phase I trial, amivantamab-vmjw was associated with an overall response rate (ORR) of 40% (95% CI, 29–51) in the EGFR exon20ins NSCLC patient population (n = 81) after platinum-based chemotherapy. There were 3 complete responses (CRs) and 29 partial responses (PRs). The median duration of response (DOR) was 11.1 months (95% CI, 6.9—not reached; NR). The median progression-free survival (PFS) was 8.3 months (95% CI, 6.5–10.9), and overall survival (OS) was 22.8 months (95% CI, 14.6—NR). Application to Clinical Practice: This review summarizes the pharmacology, clinical evidence, and use of amivantamab-vmjw for patients with locally advanced or metastatic NSCLC with EGFR exon20ins mutation. Conclusion: The FDA approval of amivantamab-vmjw, the first bispecific antibody to target the exon20ins mutation, represents an important advancement in the treatment of patients with NSCLC with limited effective treatment options. The initial findings of the CHRYSALIS trial demonstrate an overall tumor response benefit with an acceptable safety profile.

Abstract Background Myocardial injury after non-cardiac surgery (MINS), based on measurement of troponin T, is associated with perioperative major adverse cardiovascular events (MACE). We therefore determined the high-sensitivity troponin I (hsTnI) thresholds associated with 30 day MACE after non-cardiac surgery. Methods We performed a nested biobank cohort study of 4553 patients from the Vascular Events in Non-Cardiac Surgery Patients Cohort Evaluation (VISION) Study. We measured hsTnI (ADVIA Centaur® hsTnI assay) on postoperative days 1 to 3 in patients ≥45 years undergoing non-cardiac surgery. An iterative Cox proportional hazard model determined peak postoperative hsTnI thresholds independently associated with MACE (i.e., death, myocardial infarction occurring on postoperative day 4 or after, non-fatal cardiac arrest, or congestive heart failure) within 30 days after surgery. Results MACE occurred in 89/4545 (2.0%) patients. Peak hsTnI values of <75 ng/L, 75 ng/L to <1000 ng/L, and ≥1000 ng/L were associated with 1.2% (95% CI, 0.9–1.6), 7.1% (95% CI, 4.8–10.5), and 25.9% (95% CI, 16.3–38.4) MACE, respectively. Compared to peak hsTnI <75 ng/L, values 75 ng/L to <1000 ng/L and ≥1000 ng/L were associated with adjusted hazard ratios (aHR) of 4.53 (95% CI, 2.75–7.48) and 16.17 (95% CI, 8.70–30.07), respectively. MACE was observed in 9% of patients with peak hsTnI ≥75 ng/L vs 1% in patients with peak hsTnI <75 ng/L (aHR 5.76; 95% CI, 3.64–9.11). A peak hsTnI ≥75 ng/L was associated with MACE in the presence (aHR 9.35; 95% CI, 5.28–16.55) or absence (aHR 3.99; 95% CI, 2.19–7.25) of ischemic features of myocardial injury. Conclusion A peak postoperative hsTnI ≥75 ng/L was associated with >5-fold increase in the risk of 30 days MACE compared to levels <75 ng/L. This threshold could be used for MINS diagnosis when the ADVIA Centaur hsTnI assay is used. Clinicaltrials.gov Registration Number: NCT00512109.

Background and Objectives: Peroxisome proliferator activated receptor-gamma agonists, such as pioglitazone (PIO) enhanced hematoma resolution and improved functional recovery in our animal model of intracerebral hemorrhage (ICH). We conducted a translational Phase II randomized, controlled clinical trial to determine the maximum tolerated dose (MTD) of PIO in patients with spontaneous ICH and to explore the rate of hematoma resolution and clinical outcome. Methods: Patients with spontaneous ICH within 24 hours of symptom onset were randomly allocated 1:1 to placebo or PIO. Patients received escalating doses of PIO daily for three days, followed by a 30mg maintenance dose for the duration of treatment. Duration of treatment was when 75% of the ICH had resolved as determined by serial MRI or 10 weeks of treatment, whichever occurred first. The primary safety outcome was mortality at Day 14. Secondary measures of safety include any mortality, symptomatic cerebral edema, congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Secondary measures of efficacy include hematoma resolution and clinical outcome. The MTD was determined using the Continual Reassessment Method. Results: From March 2009 to April 2013, 84 patients (42 PIO, 42 control) were enrolled into 11 dose tiers, with a planned range from 0.1-2.0 mg/kg/d. Table 1 demonstrates preliminary baseline and clinical characteristics of patients by treatment group. Overall, 2/84 patients died within 2 weeks after ICH; however mortality rate never exceeded prespecified criteria. The study will be complete in October 2013 and the treatment team remains blinded to treatment allocation. Secondary outcomes by treatment group and the MTD of PIO will be reported. Conclusions: We have completed the treatment phase of the SHRINC Trial. Long term follow-up is on-going. These results will provide the foundation for an efficacy trial evaluating PIO as a potential treatment for patients with spontaneous ICH.

Objective: To review the new indication of cyclin-dependent kinase (CDK4/6) inhibitor abemaciclib for the adjuvant treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−), axillary lymph node (LN) positive early breast cancer (EBC) at high risk of recurrence and a Ki-67 ≥20%. Data Sources: A literature search was performed through PubMed, ClinicalTrials.gov, and Food and Drug Administration (FDA) website (February 1, 2018, to December 23, 2021) to identify relevant information. Study Selection and Data Extraction: Human and animal studies related to pharmacology, pharmacokinetics, efficacy, and safety of abemaciclib were identified. Data Synthesis: Addition of abemaciclib to standard of care endocrine therapy (ET) for patients with high-risk clinicopathologic features and Ki-67 ≥20% demonstrated 30% reduction in the risk of developing invasive disease and distant recurrence. At 15.5 months, abemaciclib + ET demonstrated a significant improvement in invasive disease-free survival (IDFS) vs ET alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.93, P = 0.01). At 27 months, IDFS benefit was maintained (HR, 0.70; 95% CI, 0.59-0.82, P < 0.0001). Diarrhea occurred in more than 80% of patients in the abemaciclib arm. Relevance to Patient Care and Clinical Practice: This review describes the clinical applicability of adjuvant abemaciclib for patients with HR+, HER2− EBC at high risk for recurrence. Conclusion: Adjuvant abemaciclib significantly reduces the risk for early development of invasive disease and distant recurrence in patients with HR+, HER2− node positive EBC. Longer follow-up is needed to determine the impact of adjuvant abemaciclib on late disease recurrence and survival outcomes.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Background The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm—the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. Results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.

Introduction- Graft-versus-host disease (GVHD) is a major complicating factor in determining morbidity and mortality following allogeneic stem cell transplant. To prevent GVHD, our institution administers calcineurin inhibitors and low doses of methotrexate (MTX) (5-15 mg/m2) on days +1, +3, +6, +11 for GVHD prophylaxis. While MTX is an efficacious agent in preventing GVHD, one of the undesirable adverse effects, which can be a dose limiting toxicity, is mucositis. Proton pump inhibitors (PPIs) are used for the treatment of gastroesophageal reflux disease, pyrosis, and/or peptic ulcer disease. PPIs have been shown to inhibit the ATP-binding cassette drug transporter Breast Cancer Resistance Protein's (BCRP/ABCG2) ability to excrete methotrexate into the urine in a concentration-dependent manner. Delayed excretion of methotrexate can lead to adverse events such as renal impairment, increased severity of mucositis, and increased infection rates. High dose MTX, defined as 500mg/m2 or more, has been shown to have delayed excretion when administered concomitantly with PPIs. The purpose of this retrospective, single center study is to assess the clinical outcomes of patients receiving low dose MTX and PPIs compared to MTX and no PPI for GVHD prophylaxis. Patients and Methods- A single-site institutional review board exempt retrospective analysis of patients 18 years of age or older who underwent allogeneic stem cell transplantation from 2013 to 2018 at our institution. Only patients that received methotrexate for GVHD prophylaxis were included. Cases were identified from clinical databases at our institution and were divided into two cohorts, those on PPIs, and those not on PPIs (no-PPI). Chart review was performed for the clinical variables of interest. The primary endpoint was grade of mucositis in each cohort. Secondary endpoints were total parenteral nutrition (TPN) use, need for patient controlled analgesia (PCA), leucovorin use, time to engraftment of absolute neutrophil count (ANC) and hospital length of stay (LOS). Lab values for analysis were assessed at admission and days +1/+5/+15. Results- 284 cases were identified, 119 (42%) patients were on a PPI at the time of MTX administration. The median age of patients on PPI was younger than those not on PPI (60 vs 54 p <0.0001). There were no differences in sex, BSA, conditioning regimen intent (ie myeloablative vs reduced intensity), dose of MTX, degree of match, or stem cell source. Elevation in serum creatinine and liver function tests were similar in both cohorts prior to and during MTX administration. Patients on PPI had a higher incidence of grade 1-4 mucositis compared to no-PPI (Table 1) and a higher percentage of grade 3-4 mucositis (Figure 1). Patients on PPIs had a higher incidence of TPN use, need for PCA, but no increase in hospital LOS. Patients on PPI had higher use of leucovorin than those not on PPI (81.2% vs 58.2% p <0.0001). Use of PPI did not increase the time of ANC engraftment. Conclusions- The concurrent use of PPIs and MTX was associated with a higher incidence and severity of mucositis. PPIs were also shown to increase the need for PCA, and TPN. PPI use did not increase the average length of hospitalization. This study was limited by retrospective review. Grading of mucositis was based on clinician assessment and documentation. While the indications for PPI were not readily known, this study raises the question if PPIs should be discontinued or patients transitioned to a histamine blocker prior to MTX administration to improve severity of mucositis and reduce costs associated with TPN/PCA use. Additional studies are needed in order to further characterize the association of PPI with MTX and its impact on clinical outcomes. Disclosures No relevant conflicts of interest to declare.