Patients 80 years or older account for 14% (70 years or older accounted for 47%) of all lung cancers, are less likely to be subjected to surgery or radiation, and have inferior outcomes when compared with younger patients.

Background The discovery of distinct subsets of non-small cell lung cancer (NSCLC) characterized by activation of driver oncogenes has greatly impacted personalized therapy. We hypothesized that the dominant oncogene in NSCLC would be associated with distinct patterns of metastatic spread in NSCLC at the time of diagnosis. Methods 209 consecutive patients with stage IV non-squamous NSCLC with an EGFR mutation (N=39), KRAS mutation (N=49), ALK gene rearrangement (N=41), or wild-type for all three (triple negative, N=80) were included. The percentage of patients with metastatic disease at a given site was compared between each molecular cohort (EGFR, KRAS, or ALK) and the triple negative cohort. Results ALK gene rearrangement was significantly associated with pericardial disease (OR=4.61, 95% CI 1.30, 16.37, p=0.02) and pleural disease (OR=4.80, 95% CI 2.10, 10.97, p<0.001). Patients with ALK gene rearrangements (OR=5.50, 95% CI 1.76, 17.18, p= 0.003) and patients with EGFR mutations (OR=5.17, 95% CI 1.63, 16.43, p= 0.006) were predisposed to liver metastasis compared to the triple negative cohort. No molecular cohort had a predisposition to pulmonary nodules, adrenal, bone, or brain metastasis compared to the triple negative cohort. The mean number of metastatic disease sites in patients within the ALK rearranged cohort was significantly greater than the triple negative cohort (mean = 3.6 sites vs. 2.5 sites, p<0.0001). Conclusion The results support the hypothesis that the dominant molecular oncogenes in NSCLC are associated with different biological behaviors manifesting as distinct patterns of metastatic spread at the time of diagnosis.

Hypothesis To explore whether the progression-free survival (PFS) with pemetrexed differs between anaplastic lymphoma kinase (ALK)-positive and other major molecular subtypes of non-small cell lung cancer. Methods In an ALK-enriched population, patients with metastatic non-small cell lung cancer were screened by ALK fluorescence in situ hybridization and for epidermal growth factor receptor (EGFR) and KRAS mutations. Triple-tested, pemetrexed-treated patients (monotherapy or combination therapy) were identified and PFS with pemetrexed captured retrospectively. Results Eighty-nine eligible cases were identified (19 ALK fluorescence in situ hybridization positive, 12 EGFR mutant, 21 KRAS mutant, and 37 triple negatives). Eighty-three cases (93%) were adenocarcinomas, two were adenosquamous, one squamous, and three had large cell histology. None of the ALK-positive patients had received crizotinib before pemetrexed. Pemetrexed was first-line therapy in 48% (72% as platinum-based combinations). Median PFS (95% confidence interval) data were EGFR mutant (5.5 months; 1–9), KRAS mutant (7 months; 1.5–10), ALK positive (9 months; 3–12), and triple negative (4 months; 3–5). In a multivariate analysis adjusting for line of therapy, mono- versus platinum and nonplatinum combination therapy, age, sex, histology, and smoking status, the only variable associated with prolonged PFS on pemetrexed was ALK+ (hazard ratio = 0.36 [95% confidence interval: 0.17– 0.73], p = 0.0051). Conclusions In this exploratory analysis, ALK-positive patients have a significantly longer PFS on pemetrexed compared with triple-negative patients, whereas EGFR or KRAS mutant patients do not. This information should be considered when sizing randomized studies in ALK-positive patients that involve pemetrexed. Pemetrexed should also be prioritized as a cytotoxic to explore further in patients with known ALK-positive disease.

IntroductionPlatelets arise as cytoplasmic fragments from megakaryocytes in the bone marrow. Thus they are anucleate, but retain megakaryocyte-derived cytoplasmic pre-mRNA, at least some of which is spliced into mRNA and translated into protein in response to external stimulation through surface receptor activation and outside-in signaling. [1][2][3] Previously unrecognized synthetic capabilities of platelets have recently emerged and the profi le of proteins released by activated platelets (the "secretome") has been well characterized. 4Prior studies have shown that the platelet transcriptome correlates well with platelet proteomic data, demonstrating that transcriptional analysis is relevant to the study of platelet biology, and can likely provide insights into platelet function and the mechanisms of platelet disorders. In one study, platelet proteomic data correlated well with the transcriptome, with 69% of secreted proteins detectable at the mRNA level.5 Using microarray analysis, Gnatenko et al reported that approximately 2,000 transcripts (13-17% of probed genes) are present in unstimulated platelets and concluded that evaluating the platelet transcriptome will be useful for identifying proteins that regulate normal and pathologic platelet functions. 6Platelets play a major role in the metastatic dissemination of tumor cells in vivo .7-10 Because of the leaky vasculature of angiogenic tumors, platelets are in contact with tumor cells and are therefore able to secrete multiple factors upon activation. 11Numerous tumor cell lines (e.g. MDA-MB-231 breast cancer cells) interact with platelets and stimulate platelet aggregation in vitro . 12Th e requirement of platelets for murine lung metastasis to occur has been long recognized and antibody-induced thrombocytopenia has been shown to markedly reduce the number and volume of metastasis associated with Lewis lung carcinoma, CT26 colon adenocarcinoma, and B16 amelanotic melanoma. 13Platelets facilitate metastasis through multiple mechanisms. [11][12][13][14][15] Tumor cell survival in the circulation is helped when they nest within platelet aggregates-this shields them from natural killer cell-mediated cell death and the eff ects of vascular shear stress. Platelets facilitate adhesion of blood-borne cancer cells to endothelium through selectins, along with transmigration at metastatic sites where they also enhance angiogenesis and release growth factors such as PDGF that have been shown to act as a mitogenic stimulus. While these observations are well accepted, the detailed mechanisms behind them remains uncertain. 16In this study, we sought to identify the relationship between platelet gene expression and lung cancer metastasis and surprisingly found near universal downregulated expression of the 200 genes with the most altered expression. Th ese genetic fi ndings further support the long-held view that platelet function is signifi cantly altered in the presence of cancer metastasis and that screening employing the tools outlined here may form the basis of an ef...

Summary Clinical trials have shown the high anti‐myeloma activity of the proteasome inhibitor bortezomib. The present study examined the activity of bortezomib combined with PXD101, a histone deacetylase inhibitor, against multiple myeloma (MM) and osteoclastogenesis. Treatment of myeloma cell lines with combinations of bortezomib and PXD101 led to synergistic inhibition of proliferation and induction of cell death. The combination significantly decreased the viability of primary human CD138+ myeloma cells but not of bone marrow mononuclear cells. Further studies showed a dose‐dependent activation of caspases‐3, ‐8 and ‐9 and nuclear fragmentation in myeloma cells. Bortezomib/PXD101 treatment markedly triggered reactive oxygen species (ROS) generation that was accompanied by p53, H2A.X and p38–mitogen‐activated protein kinase phosphorylation. ROS generation could be blocked by the free radical scavenger N‐acetyl‐l‐cysteine. The combination of bortezomib and PXD101 also resulted in synergistic inhibition of osteoclast formation. In conclusion, bortezomib and PXD101 have different molecular targets. The combination induces cell death in myeloma cells via ROS‐mediated DNA damage and also inhibits osteoclastogenesis. Therefore, this study provides the rationale for the clinical evaluation of bortezomib combined with PXD101 in patients with MM.