PCI after any response to initial chemotherapy significantly improved OS of ESCLC patients analyzed in this study.

No abstract

Current choices of second-line chemotherapy regimens for patients with advanced non-small-cell lung cancer (NSCLC) are extremely limited. We applied a new strategy of using nab-paclitaxel as single chemotherapy regimen in second-line setting for patients with unsuccessful first-line chemotherapy. The efficacy and safety were compared with patients who received standard second-line regimen pemetrexed. Patients with stage IIIB/IV NSCLC and unsuccessful first-line platinum-based chemotherapy were randomly divided into two arms. Arm I received pemetrexed 500 mg/m(2) intravenously (i.v.) on day 1 of 3-week cycle. Arm II received nab-paclitaxel 150 mg/m(2) i.v. on days 1 and 8 of 3-week cycle. The primary endpoint was overall survival (OS). One hundred and eleven patients were randomly assigned to receive pemetrexed (n = 56) and nab-paclitaxel (n = 55). Median OSs were 9.4 months (95% CI 7.1-12.5 months) for pemetrexed and 9.9 months (95% CI 8.2-11.9 months) for nab-paclitaxel. Median PFS was 4.6 months (95% CI 2.7-6.1 months) for pemetrexed and 5.1 months (95% CI 3.9-7.4 months) for nab-paclitaxel. While no CR was reported for either treatment, PRs + SDs were seen in 32/56 (57.1%) patients in pemetrexed arm and 36/55 (65.5%) patients in nab-paclitaxel arm. Grade 3 and grade 4 adverse events were comparable between two treatment arms. New second-line chemotherapy single-regimen nab-paclitaxel showed equivalent efficacy and toxicity profiles as pemetrexed in treating patients with NSCLC.

The majority of cancers are driven by multiple genetic alterations, but how these changes collaborate during tumorigenesis remains largely unknown. To gain mechanistic insights into tumor-promoting genetic interactions among tumor suppressor genes (TSGs), we conducted combinatorial CRISPR screening coupled with single-cell transcriptomic profiling in human mammary epithelial cells. As expected, different driver-gene alterations in mammary epithelial cells influenced the repertoire of tumor suppressor alterations capable of inducing tumor formation. More surprisingly, TSG interaction networks were comprised of numerous cliquessets of three or four genes such that each TSG within the clique showed oncogenic cooperation with all other genes in the clique. Genetic interaction profiling indicated that the predominant cooperating TSGs shared overlapping functions, rather than distinct or complementary functions.Single-cell transcriptomic profiling of CRISPR double knockouts revealed that cooperating TSGs that synergized in promoting tumorigenesis and growth factor independence showed transcriptional epistasis, whereas non-cooperating TSGs did not. These epistatic transcriptional changes, both buffering and synergistic, affected expression of oncogenic mediators and therapeutic targets, including CDK4, SRPK1 and DNMT1. Importantly, the epistatic expression alterations caused by dual inactivation of TSGs in this system, such as PTEN and TP53, were also observed in patient tumors, establishing the relevance of these findings to human breast cancer. An estimated 50% of differentially expressed genes in breast cancer are controlled by epistatic interactions. Overall, our study indicates that transcriptional epistasis is a central aspect of multigenic breast cancer progression and outlines methodologies to uncover driver gene epistatic networks in other human cancers. SIGNIFICANCEThis study provides a roadmap for moving beyond discovery and development of therapeutic strategies based on single driver gene analysis to discovery based on interactions between multiple driver genes.

Depression is associated with poorer outcomes in a wide spectrum of surgeries but the specific effects of depression in patients undergoing cervical spine surgery are unknown. This study aimed to evaluate the prevalence and impact of pre-surgical clinical depression on pain and other outcomes after surgery for cervical degenerative disc disease using a national representative database. Data of patients with cervical myelopathy and radiculopathy were extracted from the 2005–2014 US Nationwide Inpatient Sample (NIS) database. Included patients underwent anterior discectomy and fusion (ACDF). Acute or chronic post-surgical pain, postoperative complications, unfavorable discharge, length of stay (LOS) and hospital costs were evaluated. Totally 215,684 patients were included. Pre-surgical depression was found in 29,889 (13.86%) patients, with a prevalence nearly doubled during 2005–2014 in the US. Depression was independently associated with acute or chronic post-surgical pain (aOR: 1.432), unfavorable discharge (aOR: 1.311), prolonged LOS (aOR: 1.152), any complication (aOR: 1.232), respiratory complications/pneumonia (aOR: 1.153), dysphagia (aOR: 1.105), bleeding (aOR: 1.085), infection/sepsis (aOR: 1.529), and higher hospital costs (beta: 1080.640) compared to non-depression. No significant risk of delirium or venous thrombotic events was observed in patients with depression as compared to non-depression. Among patients receiving primary surgery, depression was independently associated with prolonged LOS (aOR: 1.150), any complication (aOR:1.233) and postoperative pain (aOR:1.927). In revision surgery, no significant associations were found for prolonged LOS, any complication or pain. In conclusion, in the US patients undergoing ACDF, pre-surgical clinical depression predicts post-surgical acute or chronic pain, a slightly prolonged LOS and the presence of any complication. Awareness of these associations may help clinicians stratify risk preoperatively and optimize patient care.