Emerging trends of therapy related myeloid neoplasms following modern cancer therapeutics in the United States.

Clonal hematopoiesis (CH) is a risk factor for the development of therapy-related myelodysplastic syndromes (tMDS) and acute myeloid leukemia (tAML). Adoption of targeted-immunotherapeutics since 2011, may alter the risk of CH progression to tMDS/AML. To study this, we evaluated risk of tMDS and tAML in 667 588 ≥ 1-year survivors of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma and multiple-myeloma (MM) diagnosed during: 2000-2005, 2006-2010 and 2011-2016. The risk of tMDS increased significantly after NSCLC across all time periods (Ptrend = 0.002) while tAML risk decreased from 2006-2010 to 2011-2016, coinciding with increasing use of non-chemotherapeutic agents. tAML risk after RCC decreased (Ptrend = 0.007) whereas tMDS risk did not significantly change over time. After melanoma, tMDS and tAML risks were similar to the general population. tMDS and tAML risk after MM increased from the first to second time-period, however, only risk of tMDS decreased during last period. We report diverging trends in the risk of tAML and tMDS after adoption of modern cancer therapies for specific cancers. It is imperative to further explore impact of contemporary treatment strategies on clonal evolution. Modern treatments via their discrete mechanism of actions on pre-existing CH may alter the risk of subsequent tMDS and tAML.

The Impact of Obesity on Mortality and Other Outcomes in Patients With Nonvariceal Upper Gastrointestinal Hemorrhage in the United States.

GOALS: To quantify in patients with nonvariceal upper gastrointestinal hemorrhage (NVUGIH) the relationship between obesity and mortality, disease severity, treatment modalities, and resource utilization. BACKGROUND: NVUGIH is the most common gastrointestinal emergency. STUDY: Adults with a principal diagnosis of NVUGIH were selected from the 2014 National Inpatient Sample. The primary outcome was in-hospital mortality. Secondary outcomes were hemorrhagic shock, prolonged mechanical ventilation (PMV), upper endoscopy [esophagogastroduodenoscopy (EGD)], radiologic treatment, surgery, length of hospital stay (LOS), and total hospitalization costs and charges. Confounders were adjusted for using multivariable regression analyses. RESULTS: In total, 227,480 admissions with NVUGIH were included, 11.70% of whom were obese. Obese and nonobese patients had similar odds of mortality (aOR: 0.88; 95% confidence interval [CI]: 0.69-1.12; P=0.30), EGD within 24 hours of admission (aOR: 0.95; CI: 0.89-1.01; P=0.10), radiologic treatment (aOR: 1.06; CI: 0.82-1.35; P=0.66), and surgery (aOR: 1.27; CI: 0.94-1.70; P=0.11). However, obese patients had higher odds of shock (aOR: 1.30; CI: 1.14-1.49; P<0.01), PMV (aOR: 1.39; CI: 1.18-1.62; P<0.01), undergoing an EGD (aOR: 1.27; CI: 1.16-1.40; P<0.01), needing endoscopic therapy (aOR: 1.18; CI: 1.09-1.27; P<0.01), a longer LOS (0.31 d; CI: 0.16-0.46 d; P<0.01), higher costs ($1075; CI: $636-$1514; P<0.01), and higher charges ($4084; CI: $2060-$6110; P<0.01) compared with nonobese patients. CONCLUSIONS: Obesity is not an independent predictor of NVUGIH mortality. However, obesity is associated with a more severe disease course (shock and PMV), higher rates of EGD and endoscopic therapy use, and significant increases in resource utilization (hospital LOS, total hospitalization costs, and charges).

One Step Forward, Two Steps Back: Trends in Aggressive Inpatient Care at the End of Life for Patients With Stage IV Lung Cancer.

BACKGROUND: Patients with metastatic lung cancer are treated with palliative intent. Aggressive care at the end of life is a marker of poor-quality care. National trends and factors related to aggressive inpatient care at the end of life for these patients have not been evaluated. METHODS: Patients with stage IV lung cancer and a terminal hospitalization were identified in the National Inpatient Sample database between 1998 and 2014. Longitudinal analysis was conducted to determine trends in aggressive inpatient care at the end of life and multivariate logistic regression was performed to determine associations with patient and hospital characteristics. RESULTS: A total of 412,946 patients met the inclusion criteria. From 1998 to 2014, the proportion of patients admitted to the intensive care unit (ICU) during the terminal hospitalization increased from 13.3% to 27.9% (P < .001). The ICU stay translated into a higher mean total cost of care (+$18,461; 95% CI, $17,460 to $19,463). Promisingly, palliative care encounters for terminal hospitalizations also increased during this period from 8.7% to 53.0% (P < .01) and were correlated with a decrease in aggressive care at the end of life. However, this did not offset the trend in increased ICU use; mean total costs for a terminal hospitalization increased from $14,000 to $19,500, adjusted for inflation. A multivariable model demonstrates variation by patient and hospital characteristics in aggressive care use. CONCLUSIONS: Among patients with metastatic lung cancer there has been a substantial increase in ICU use during terminal hospitalizations, resulting in high cost for the health care system.

The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers.

Brigatinib (AP26113) is a dimethylphosphine oxide group-containing tyrosine kinase inhibitor (TKI) constructed around a bisanilinopyrimidine scaffold with potent activity against the anaplastic lymphoma kinase (ALK) and several other targets. Despite the activity of first- and second-generation ALK inhibitors in advanced ALK-rearranged lung cancers, the development of acquired resistance represents an ongoing challenge. Later generation ALK inhibitors such as brigatinib are important potential tools in the management of patients with acquired resistance characterized by continued dependency on ALK. Brigatinib is active in vitro against many ALK kinase domain mutations that may mediate acquired resistance to other ALK TKIs, with reported activity (IC50 <50 nM) against ALK C1156Y, I1171S/T, V1180L, L1196M, L1152R/P, E1210K, and G1269A. In patients with ALK-rearranged lung cancers who receive brigatinib after crizotinib, substantial and durable responses and intracranial disease control can be achieved based on early-phase clinical trial data. The drug is also being explored in TKI-naïve patients. From a safety perspective, early pulmonary toxicity has been observed, prompting the decision to pursue lead-in dosing for the drug. Early data point to ALK G1202R and ALK E1210K as potential mechanisms of clinical resistance to brigatinib.