Multimodality therapy improves survival in elderly patients with locally advanced non-small cell lung cancer—A retrospective analysis

ObjectivesConcurrent combined modality therapy is optimal treatment for patients with stage III non-small cell lung cancer (NSCLC) and is given with curative intent. However, elderly patients (≥ 75) are often undertreated, despite good performance status (PS). This study evaluated the treatment, outcomes and survival in elderly patients with stage III NSCLC versus patients < 75 years old.Materials and MethodsA retrospective review of data from the Lung Cancer Registry at Mayo Clinic Arizona (MCA) was conducted. Patients with newly diagnosed stage III NSCLC from 1998 to 2006 were analyzed for type of therapy and outcomes.ResultsThree hundred and eighty-nine patients with newly diagnosed stage III NSCLC were identified from 1998 to 2006. Two hundred and forty-three (62%) patients were < 75 years old, and 146 patients (38%) were ≥ 75 years old. Among 374 eligible patients, 45% of patients < 75 years old received combined chemoradiation therapy vs. only 21% of patients ≥ 75 years old (p < 0.0001). The median survival in the < 75 age group was 14.5 months vs. 10.1 months in the ≥ 75 age group (p = 0.0014). In the < 75 age group, median survival was 15.0 months in patients who received combined modality treatment vs. 14.1 months in the other treatments group (p = 0.02). In the elderly group, median survival was 19.9 months in the combined modality group vs. 7.8 months in the other treatments group (p = 0.0048).ConclusionOur results confirm that older patients are less likely to receive optimal therapy, regardless of functional status. Prospective studies are desperately needed to help improve management of the burgeoning geriatric oncology population.     

Deciphering the immuno-pathological role of FLT,and evaluation of a novel dual inhibitor of topoisomerases and mutant-FLT3 for treating leukemia

Acute myeloid leukemia (AML) is a type of leukemia with an aggressive phenotype, that commonly occurs in adults and with disappointing treatment outcomes. Genetic alterations were implicated in the etiology of cancers and form the basis for defining patient prognoses and guiding targeted therapies. In the present study, we leveraged bulk and single-cell RNA sequencing datasets from AML patients to determine the clinical significance of Fms-related receptor tyrosine kinase 3 (FLT3) alterations on the T-cell phenotype and immune response of AML patients. Subsequently, we evaluated the therapeutic potential of Lwk-n019, a novel small-molecule derivative of thiochromeno[2,3-c]quinolin-12-one. Our results suggested that FLT3 plays an important role in the progression, aggressive phenotype, and worse immune response of patients. An FLT3 mutation was associated with dysfunctional T-cell phenotypes, and high risk and shorter survival of AML patients. Our findings further suggested that the aggressiveness of AML and the prognostic role of FLT3 are associated with the co-occurrence of NPM1 and DNMT3A mutations. Lwk-n019 demonstrated dose-dependent anticancer activities against various leukemia cancer cell lines. Lwk-n019 demonstrated highly selective kinase inhibitory activities against the wild-type FLT3 (D835V) and mutant FLT3 (internal tandem duplication (ITD), D835V) with >95% and 99% inhibitory levels, respectively. Moreover, the compound demonstrated the best binding constant (Kd value) of 0.77 µM against FLT3 (ITD, 835V). In addition, Lwk-n019 significantly inhibited the activities of both the topoisomerase I (TOPI) and TOPII enzymes, with higher TOPI inhibitory activity than camptothecin, a clinical inhibitor. While the jejunum, duodenum, cecum, and colon were prime sites of absorption, Lwk-n019 achieved maximum concentration (Cmax), Vd, blood/plasma ratio, time to maximum concentration (Tmax), area under the receiver operating concentration curve (AUC)_(0-24), and AUC_(0-∞) values of 0.665 µg/mL, 5.21 Vc, L/kg, 1.5 h, 6634.7, and 6909.2, respectively. In conclusion, Lwk-n019 demonstrated anticancer activities via multi-target inhibition of TOPs and kinases with high inhibition preference for mutant ITD-FLT3. The present pioneer study provides a basis for advanced optimization of drug potency, selectivity, specificity, and other properties desired of anticancer drug leads. Studies are ongoing to determine the full therapeutic properties of Lwk-n019 and the detailed mechanisms of FLT3 in TOP inhibition.