DeepBTS: Prediction of Recurrence-free Survival of Non-small Cell Lung Cancer Using a Time-binned Deep Neural Network.

Accurate prediction of non-small cell lung cancer (NSCLC) prognosis after surgery remains challenging. The Cox proportional hazard (PH) model is widely used, however, there are some limitations associated with it. In this study, we developed novel neural network models called binned time survival analysis (DeepBTS) models using 30 clinico-pathological features of surgically resected NSCLC patients (training cohort, n = 1,022; external validation cohort, n = 298). We employed the root-mean-square error (in the supervised learning model, s- DeepBTS) or negative log-likelihood (in the semi-unsupervised learning model, su-DeepBTS) as the loss function. The su-DeepBTS algorithm achieved better performance (C-index = 0.7306; AUC = 0.7677) than the other models (Cox PH: C-index = 0.7048 and AUC = 0.7390; s-DeepBTS: C-index = 0.7126 and AUC = 0.7420). The top 14 features were selected using su-DeepBTS model as a selector and could distinguish the low- and high-risk groups in the training cohort (p = 1.86 × 10-11) and validation cohort (p = 1.04 × 10-10). When trained with the optimal feature set for each model, the su-DeepBTS model could predict the prognoses of NSCLC better than the traditional model, especially in stage I patients. Follow-up studies using combined radiological, pathological imaging, and genomic data to enhance the performance of our model are ongoing.

Discovery of N-(1-Acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as Covalent Inhibitors of KRASG12C.

KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. KRAS p.G12C, which occurs in approximately 14% of lung adenocarcinomas, 3-5% of colorectal cancers, and low levels in other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery of a class of novel, potent, and selective covalent inhibitors of KRASG12C identified through a custom library synthesis and screening platform called Chemotype Evolution and structure-based design. Identification of a hidden surface groove bordered by H95/Y96/Q99 side chains was key to the optimization of this class of molecules. Best-in-series exemplars exhibit a rapid covalent reaction with cysteine 12 of GDP-KRASG12C with submicromolar inhibition of downstream signaling in a KRASG12C-specific manner.

The neutrophil-to-lymphocyte ratio prechemotherapy and postchemotherapy as a prognostic marker in metastatic gastric cancer.

BACKGROUND/AIMS: Markers of inflammation have been associated with outcomes in various cancers. The purpose of this study was to evaluate whether systemic inf lammatory markers and their f luctuations can predict survival and chemotherapy response in patients with metastatic gastric cancer (mGC). METHODS: We retrospectively reviewed the records of 502 patients who received first-line palliative chemotherapy for mGC between 2007 and 2013. The neutrophil-to-lymphocyte ratio (NLR) and modified Glasgow prognostic score (mGPS) were assessed before and after chemotherapy to evaluate their association with survival. The NLR values were categorized into two groups based on a cut-off value of 3; mGPS values were classified as high versus low. RESULTS: High prechemotherapy NLR was significantly associated with poor overall survival on univariate analysis (p = 0.002). On multivariate analysis, high prechemotherapy NLR (hazard ratio, 1.43; p < 0.001) was an independent prognostic factor for poor overall survival. However, the prechemotherapy mGPS was not significantly associated with survival. Continuously high NLR or a shift to high NLR postchemotherapy was associated with poor chemotherapy response as well as survival, while NLR reduction was associated with a good response (linear by linear association, p < 0.001) and a favorable prognosis. CONCLUSION: Prechemotherapy NLR can be used as a prognostic factor in mGC, while the postchemotherapy NLR value may predict the chemotherapeutic response and prognosis. In contrast, mGPS has limited prognostic utility in mGC.

Clinical Significance of Discordance between Carcinoembryonic Antigen Levels and RECIST in Metastatic Colorectal Cancer.

PURPOSE: The purpose of this study was to investigate the prognostic implications of carcinoembryonic antigen (CEA) levels that are inconsistent with Response Evaluation Criteria in Solid Tumor (RECIST) responses in metastatic colorectal cancer patients. MATERIALS AND METHODS: We retrospectively evaluated 360 patients with at least one measurable lesion who received first-line palliative chemotherapy. CEA-response was defined as CEA-complete response (CR; CEA normalization), CEA-partial response (PR; ≥ 50% decrease in CEA levels), CEA-progressive disease (PD; ≥ 50% increase in CEA levels), and CEA-stable disease (SD; non-CR/PR/PD). Overall survival (OS) and progression-free survival (PFS) were evaluated according to CEA-response. RESULTS: In RECIST-PR patients, poorer CEA-response was associated with disease progression at the subsequent evaluation. In RECIST-SD patients, CEA-CR and -PR were associated with lower disease progression rates than CEA-PD at the subsequent evaluation. Correlations between survival outcome and CEA-response in same-category RECIST patients were assessed. In RECIST-PR patients, discordant CEA-response (CEA-PD/SD) was associated with poorer survival than CEA-CR/PR (median OS and PFS, 44.0 and 15.4 [CEA-CR], 28.9 and 12.5 [CEA-PR], 21.0 and 9.8 [CEA-SD], and 13.0 and 7.0 [CEA-PD] months, respectively; all p < 0.001). In RECIST-SD patients, favorable CEA-response produced better survival (median OS and PFS, 26.8 and 21.0 [CEA-CR], 21.0 and 11.0 [CEA-PR], 16.1 and 8.2 [CEA-SD], and 12.2 and 6.0 [CEA-PD] months, respectively; all p < 0.001). RECIST-PD patients with CEA-CR showed longer OS than those with CEA-PD. Multivariate analysis demonstrated that discordant CEA-response is a powerful prognostic factor for RECIST-PR and RECIST-SD patients. CONCLUSION: Among patients of the same RECIST-response categories, CEA-response patterns are significantly prognostic and strongly predictive of subsequent evaluation outcomes.

Clinical significance of changes in systemic inflammatory markers and carcinoembryonic antigen levels in predicting metastatic colorectal cancer prognosis and chemotherapy response.

AIM: Metastatic colorectal cancer (mCRC) is associated with poor prognosis, and biomarkers are required for predicting survival and chemotherapy response. This study aimed to evaluate the significance of changes in systemic inflammatory markers and carcinoembryonic antigen (CEA) levels in predicting mCRC prognosis and chemotherapy response. METHODS: In this retrospective study, 503 patients who received first-line palliative chemotherapy for mCRC between 2008 and 2014 at a tertiary hospital in Korea were evaluated. Changes in neutrophil-to-lymphocyte ratio (NLR) and modified Glasgow prognostic score (mGPS) were divided into low-to-low, high-to-low, low-to-high and high-to-high groups. The CEA response was defined as CEA-complete response (CEA normalization), CEA-partial response (≥50% decrease in CEA levels), CEA-progressive disease (≥50% increase in CEA levels) and CEA-stable disease. Overall survival (OS) and progression-free survival (PFS) were evaluated according to NLR, mGPS and CEA levels. RESULTS: High prechemotherapy NLR, mGPS and CEA levels independently predicted poor survival and chemotherapy response. Continuously high NLR or change to high NLR was also associated with poor OS and PFS; however, continuously low NLR or reduced NLR showed good prognosis. CEA response was also an independent prognostic marker for OS and PFS. High NLR and mGPS were correlated with elevated CEA levels. CONCLUSION: Inflammatory marker levels were significantly associated with CEA levels. The prechemotherapy levels of systemic inflammatory markers and CEA were associated with OS or PFS. The change patterns in NLR and CEA levels can be utilized as prognostic and predictive markers for chemotherapy response.

Is the AIMS65 score useful in predicting outcomes in peptic ulcer bleeding?

AIM: To evaluate the applicability of AIMS65 scores in predicting outcomes of peptic ulcer bleeding. METHODS: This was a retrospective study in a single center between January 2006 and December 2011. We enrolled 522 patients with upper gastrointestinal haemorrhage who visited the emergency room. High-risk patients were regarded as those who had re-bleeding within 30 d from the first endoscopy as well as those who died within 30 d of visiting the Emergency room. A total of 149 patients with peptic ulcer bleeding were analysed, and the AIMS65 score was used to retrospectively predict the high-risk patients. RESULTS: A total of 149 patients with peptic ulcer bleeding were analysed. The poor outcome group comprised 28 patients [male: 23 (82.1%) vs female: 5 (10.7%)] while the good outcome group included 121 patients [male: 93 (76.9%) vs female: 28 (23.1%)]. The mean age in each group was not significantly different. The mean serum albumin levels in the poor outcome group were slightly lower than those in the good outcome group (P = 0.072). For the prediction of poor outcome, the AIMS65 score had a sensitivity of 35.5% (95%CI: 27.0-44.8) and a specificity of 82.1% (95%CI: 63.1-93.9) at a score of 0. The AIMS65 score was insufficient for predicting outcomes in peptic ulcer bleeding (area under curve = 0.571; 95%CI: 0.49-0.65). CONCLUSION: The AIMS65 score may therefore not be suitable for predicting clinical outcomes in peptic ulcer bleeding. Low albumin levels may be a risk factor associated with high mortality in peptic ulcer bleeding.

Discovery of a novel series of potent and orally bioavailable phosphoinositide 3-kinase γ inhibitors.

The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kγ revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.

Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists.

A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.

Design, synthesis, and evaluation of 2-aryl-7-(3',4'-dialkoxyphenyl)-pyrazolo[1,5-a]pyrimidines as novel PDE-4 inhibitors.

Described herein is design, synthesis, and biological evaluation of novel series of 2-aryl-7-(3',4'-dialkoxyphenyl)-pyrazolo[1,5-a]pyrimidines acting as inhibitors of type 4 phosphodiesterase (PDE4) which is known as a good target for the treatment of asthma and COPD. For this purpose, structure optimization was conducted with the aid of structure-based drug design using the known X-ray crystallography. Also, biological effects of these compounds on the target enzyme were evaluated by using in vitro assays, leading to the potent and selective PDE-4 inhibitor (IC(50)<10nM).