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1.  Impact of a Fast-Track Esophagectomy Protocol on Esophageal Cancer Patient Outcomes and Hospital Charges 
Annals of surgery  2015;261(6):1114-1123.
Objective
To evaluate the effects of a fast-track esophagectomy protocol (FTEP) on esophageal cancer patients' safety, length of hospital stay (LOS) and hospital charges.
Background
FTEP involved transferring patients to the telemetry unit instead of the surgical intensive care unit (SICU) after esophagectomy.
Methods
We retrospectively reviewed 708 consecutive patients who underwent esophagectomy for primary esophageal cancer during the 4 years before (group A; 322 patients) or 4 years after (group B; 386 patients) the institution of an FTEP. Postoperative morbidity and mortality, LOS, and hospital charges were reviewed.
Results
Compared with group A, group B had significantly shorter median LOS (12 days vs 8 days; P < 0.001); lower mean numbers of SICU days (4.5 days vs 1.2 days; P < 0.001) and telemetry days (12.7 days vs 9.7 days; P < 0.001); and lower rates of atrial arrhythmia (27% vs 19%; P = 0.013) and pulmonary complications (27% vs 20%; P = 0.016). Multivariable analysis revealed FTEP to be associated with shorter LOS (P < 0.001) even after adjustment for predictors like tumor histology and location. FTEP was also associated with a lower rate of pulmonary complications (odds ratio = 0.655; 95% confidence interval = 0.456, 0.942; P = 0.022). In addition, the median hospital charges associated with primary admission and readmission within 90 days for group B ($65,649) were lower than that for group A ($79,117; P < 0.001).
Conclusion
These findings suggest that an FTEP reduces patients' LOS, perioperative morbidity and hospital charges.
doi:10.1097/SLA.0000000000000971
PMCID: PMC4838458  PMID: 25243545
3.  Surgery is an essential component of multimodality therapy for patients with locally advanced esophageal adenocarcinoma 
Background
Experience with neoadjuvant chemoradiation (CXRT) has raised questions regarding the additional benefit of surgery after locally advanced esophageal adenocarcinoma patients achieve a clinical response to CXRT. We sought to quantify the value of surgery by comparing the overall (OS) and disease-free survival (DFS) of trimodality eligible patients treated with definitive CXRT versus CXRT followed by esophagectomy.
Methods
We identified 143 clinical stage III esophageal adenocarcinoma patients that were eligible for trimodality therapy. All patients successfully completed neoadjuvant CXRT and were considered appropriate candidates for resection. Patients that were medically inoperable were excluded. Cox regression models were used to identify significant predictors of survival.
Results
Among the 143 patients eligible for surgery after completing CXRT, 114 underwent resection and 29 did not. Poorly differentiated tumors (HR=2.041, 95% CI 1.235–3.373) and surgical resection (HR=0.504, 95% CI 0.283–0.899) were the only independent predictors of OS. Patients treated with surgery had a 50% and 54% risk reduction in overall and cancer-specific mortality, respectively. Median OS (41.2 months vs. 20.3 months, p=0.012) and DFS (21.5 months vs. 11.4 months, p=0.007) were significantly improved with the addition of surgery compared to definitive CXRT.
Conclusions
Surgery provides a significant survival benefit to trimodality-eligible esophageal adenocarcinoma patients with locally advanced disease.
doi:10.1007/s11605-013-2223-4
PMCID: PMC4998180  PMID: 23715646
esophageal adenocarcinoma; trimodality therapy; neoadjuvant chemoradiation; esophagectomy; selective surgery
4.  A PHASE II STUDY OF A PACLITAXEL-BASED CHEMORADIATION REGIMEN WITH SELECTIVE SURGICAL SALVAGE FOR RESECTABLE LOCOREGIONALLY ADVANCED ESOPHAGEAL CANCER: INITIAL REPORTING OF RTOG 0246 
Purpose
The strategy of definitive chemoradiation with selective surgical salvage in locoregionally advanced esophageal cancer was evaluated in a Phase II trial in Radiation Therapy Oncology Group (RTOG)-affiliated sites.
Methods and Materials
The study was designed to detect an improvement in 1-year survival from 60% to 77.5% (α= 0.05; power = 80%). Definitive chemoradiation involved induction chemotherapy with 5-fluorouracil (5-FU) (650 mg/mg2/day), cisplatin (15 mg/mg2/day), and paclitaxel (200 mg/mg2/day) for two cycles, followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fraction) and daily 5-FU (300 mg/mg2/day) with cisplatin (15 mg/mg2/day) over the first 5 days. Salvage surgical resection was considered for patients with residual or recurrent esophageal cancer who did not have systemic disease.
Results
Forty-three patients with nonmetastatic resectable esophageal cancer were entered from Sept 2003 to March 2006. Forty-one patients were eligible for analysis. Clinical stage was ≥T3 in 31 patients (76%) and N1 in 29 patients (71%), with adenocarcinoma histology in 30 patients (73%). Thirty-seven patients (90%) completed induction chemotherapy followed by concurrent chemoradiation. Twenty-eight patients (68%) experienced Grade 3+ nonhematologic toxicity. Four treatment-related deaths were noted. Twenty-one patients underwent surgery following definitive chemoradiation because of residual (17 patients) or recurrent (3 patients) esophageal cancer,and 1 patient because of choice. Median follow-up of live patients was 22 months, with an estimated 1-year survival of 71%.
Conclusions
In this Phase II trial (RTOG 0246) evaluating selective surgical salvage after definitive chemoradiation in locoregionally advanced esophageal cancer, the hypothesized 1-year RTOG survival rate (77.5%) was not achieved (1 year, 71%; 95% confidence interval< 54%–82%).
doi:10.1016/j.ijrobp.2011.01.043
PMCID: PMC3796353  PMID: 21507583
Esophageal cancer; Chemotherapy; Chemoradiation; Radiation therapy; Salvage surgery
5.  Cost-Effectiveness of Stereotactic Radiation, Sublobar Resection, and Lobectomy for Early Non-Small Cell Lung Cancers in Older Adults 
Journal of geriatric oncology  2015;6(4):324-331.
Objectives
Stereotactic ablative radiation (SABR) is a promising alternative to lobectomy or sublobar resection for early lung cancer, but the value of SABR in comparison to surgical therapy remains debated. We examined the cost-effectiveness of SABR relative to surgery using SEER-Medicare data.
Materials&Methods
Patients age≥66 years with localized (<5 cm) non-small cell lung cancers diagnosed from 2003-2009 were selected. Propensity score matching generated cohorts comparing SABR with either sublobar resection or lobectomy. Costs were determined via claims. Median survival was calculated using the Kaplan-Meier method. Incremental cost-effectiveness ratios (ICERs) were calculated and cost-effectiveness acceptability curves (CEACs) were constructed from joint distribution of incremental costs and effects estimated by non-parametric bootstrap.
Results
In comparing SABR to sublobar resection, 5-year total costs were $55,120 with SABR vs. $77,964 with sublobar resection (P<0.001) and median survival was 3.6 years with SABR vs. 4.1 years with sublobar resection (P=0.95). The ICER for sublobar resection compared to SABR was $45,683/life-year gained, yielding a 46% probability that sublobar resection is cost-effective. In comparing SABR to lobectomy, 5-year total costs were $54,968 with SABR vs. $82,641 with lobectomy (P<0.001) and median survival was 3.8 years with SABR vs. 4.7 years with lobectomy (P=0.81). The ICER for lobectomy compared to SABR was $28,645/life-year gained, yielding a 78% probability that lobectomy is cost-effective.
Conclusion
SABR is less costly than surgery. While lobectomy may be cost-effective compared to SABR, sublobar resection is less likely to be cost-effective. Assessment of the relative value of SABR versus surgical therapy requires further research.
doi:10.1016/j.jgo.2015.05.002
PMCID: PMC4536110  PMID: 26094172
6.  Accumulation of RNA-dependent protein kinase (PKR) in the nuclei of lung cancer cells mediates radiation resistance 
Oncotarget  2016;7(25):38235-38242.
We have previously demonstrated that radiation induced cell death in PKR (−/−) deficient mouse embryo fibroblasts (MEFs) but not in PKR (+/+) wild type MEFs. Our study indicated that PKR can also be involved in survival pathways following radiation therapy through activation of the AKT survival pathways in these MEFs is mediated in part through PKR. The role of PKR on radiation sensitivity in cancer cells has not been evaluated. In this study, we demonstrated that radiation treatment causes nuclear translocation of PKR in human lung cancer cells. The transduction of lung cancer cells with a dominant negative adenoviral PKR vector blocks nuclear translocation of PKR and leads to the reversal of radiation resistance. Plasmid transduction of lung cancer cells with nuclear targeted wild type PKR vectors also increased radiation resistance. This effect is selectively abrogated by plasmid transduction of dominant negative PKR vectors which restore radiation sensitivity. These findings suggest a novel role for PKR in lung cancer cells as a mediator of radiation resistance possibly through translocation of the protein product to the nucleus.
doi:10.18632/oncotarget.9428
PMCID: PMC5122385  PMID: 27203671
lung cancer; PKR; radiation sensitivity
7.  Importance of Surveillance and Success of Salvage Strategies After Definitive Chemoradiation in Patients With Esophageal Cancer 
Journal of Clinical Oncology  2014;32(30):3400-3405.
Purpose
Patients with esophageal carcinoma (EC) who are treated with definitive chemoradiotherapy (bimodality therapy [BMT]) experience frequent relapses. In a large cohort, we assessed the timing, frequency, and types of relapses during an aggressive surveillance program and the value of the salvage strategies.
Patients and Methods
Patients with EC (N = 276) who received BMT were analyzed. Patients who had surgery within 6 months of chemoradiotherapy were excluded to reduce bias. We focused on local relapse (LR) and distant metastases (DM) and the salvage treatment of patients with LR only. Standard statistical methods were applied.
Results
The median follow-up time was 54.3 months (95% CI, 48.4 to 62.4). First relapses included LR only in 23.2% (n = 64), DM with or without LR in 43.5% (n = 120), and no relapses in 33.3% (n = 92) of patients. Final relapses included no relapses in 33.3%, LR only in 14.5%, DM only in 15.9%, and DM plus LR in 36.2% of patients. Ninety-one percent of LRs occurred within 2 years and 98% occurred within 3 years of BMT. Twenty-three (36%) of 64 patients with LR only underwent salvage surgery, and their median overall survival was 58.6 months (95% CI, 28.8 to not reached) compared with those patients with LR only who were unable to undergo surgery (9.5 months; 95% CI, 7.8 to 13.3).
Conclusion
Unlike in patients undergoing trimodality therapy, for whom surveillance/salvage treatment plays a lesser role,1 in the BMT population, approximately 8% of all patients (or 36% of patients with LR only) with LRs occurring more than 6 months after chemoradiotherapy can undergo salvage treatment, and their survival is excellent. Our data support vigilant surveillance, at least in the first 24 months after chemotherapy, in these patients.
doi:10.1200/JCO.2014.56.7156
PMCID: PMC4195852  PMID: 25225435
8.  Relationship between tumor size and survival in non-small cell lung cancer (NSCLC): an analysis of the Surveillance, Epidemiology, and End Results (SEER) registry 
INTRODUCTION
Tumor size is a known prognostic factor for early stage non-small cell lung cancer (NSCLC), but its significance in node-positive and locally invasive NSCLC has not been extensively characterized. We queried the Surveillance, Epidemiology and End Results (SEER) database to evaluate the prognostic value of tumor size for early stage as well as node-positive and locally invasive NSCLC.
METHODS
Patients in SEER registry with NSCLC diagnosed between 1998 and 2003 were analyzed. Tumor size was analyzed as a continuous variable. Other demographic variables included age, gender, race, histology, primary tumor extension, node status and primary treatment modality (surgery vs radiation). The Kaplan-Meier method was used to estimate overall survival (OS). Cox proportional hazard model was used to evaluate whether tumor size was an independent prognostic factor.
RESULTS
52,287 eligible patients were subgrouped based on tumor extension and node status. Tumor size had a significant effect on OS in all subgroups defined by tumor extension or node status. In addition, tumor size also had statistically significant effect on OS in 15 of 16 subgroups defined by tumor extension and nodal status after adjustment for other clinical variables. Our model incorporating tumor size had significantly better predictive accuracy than our alternative model without tumor size.
CONCLUSIONS
Tumor size is an independent prognostic factor, for early stage as well as node positive and locally invasive disease. Prediction tools, such as nomograms, incorporating more detailed information not captured in detail by the routine TNM classification, may improve prediction accuracy of OS in NSCLC.
doi:10.1097/JTO.0000000000000456
PMCID: PMC4368494  PMID: 25590605
Non-small cell lung cancer; Tumor Size; Survival; SEER
9.  Distribution of Resistant Esophageal Adenocarcinoma in the Resected Specimens of Clinical Stage III Patients After Chemoradiation: Its Clinical Implications 
Oncology  2015;89(2):65-69.
Background
We have limited knowledge of the geographic distribution of resistant EAC in the resected specimen and its clinical importance can be enormous.
Method
We selected patients with baseline stage III EAC who had chemoradiation followed by surgery, and had residual EAC (resistant cases only). Outcomes were correlated with various endpoints (% of resistant EAC, anatomic distribution).
Results
100 clinical stage III patients were studied. 90% had an R0 resection. 99% had either moderate or poorly differentiated EAC. 12% had >50% residual cancer, 31% had 11–50% residual cancer, 53% had 1–10% residual cancer, and 3% had positive nodes only. Each compartment was frequently involved: mucosa/submucosa=66%, muscularis propria=76%, serosa=62%, and all=35%. Lack of EAC (meaning response) was observed in mucosa/submucosa (34%), muscularis propria (24%), serosa (38%), and nodes (42%). Although the endoscopic biopsies prior to surgery had no EAC in 79% of patients, in the surgical specimen, however, resistant EAC was frequent (66%) in mucosa/submucosa.
Conclusion
Contrary to our belief that resistant EAC would be frequent in the nodes, our data show that its distribution is heterogeneous and unpredictable. Most importantly, the post-chemoradiation biopsies are misleading and a decision to delay/avoid surgery based on negative biopsies can be detrimental for the patients.
doi:10.1159/000371889
PMCID: PMC4498973  PMID: 25765719
Esophageal adenocarcinoma; chemoradiation; surgery; treatment decisions
10.  Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer 
Cancer letters  2014;357(1):179-185.
Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies.
doi:10.1016/j.canlet.2014.11.024
PMCID: PMC4301580  PMID: 25444907
Lung cancer; Gene mutations; Tumor models; Patient-derived xenografts; Biomarkers
11.  Pathologic response after neoadjuvant chemotherapy in resectable non-small cell lung cancers: proposal for the use of “major pathologic response” as a surrogate endpoint 
The Lancet. Oncology  2014;15(1):e42-e50.
Improvements in outcomes for patients with resectable lung cancers have plateaued. Clinical trials in this disease using overall survival as the primary endpoint require a decade or longer to complete, are expensive, and limit innovation. A surrogate for survival, such as pathologic response to neoadjuvant chemotherapy, has the potential to improve the efficiency of trials and expedite advances. ≤10% residual viable tumor following neoadjuvant chemotherapy, termed here major pathologic response meets criteria for a surrogate: it strongly associates with improved survival, is reflective of treatment impact, and captures the magnitude of the treatment benefit on survival. We support the incorporation of major pathologic response as a surrogate endpoint for survival in future trials for resectable lung cancers. Additional prospective studies are needed to confirm the validity and reproducibility of major pathologic response within individual histologic and molecular subgroups and with novel therapeutics.
doi:10.1016/S1470-2045(13)70334-6
PMCID: PMC4734624  PMID: 24384493
12.  Lobectomy, Sublobar Resection, and Stereotactic Radiation for Early-Stage Non-Small Cell Lung Cancers in the Elderly 
JAMA surgery  2014;149(12):1244-1253.
Importance
The incidence of early-stage non-small cell lung cancers among the elderly is expected to rise dramatically due to demographic trends and CT screening. However, no modern trials have compared the most commonly delivered treatments.
Objective
To determine clinical characteristics and survival outcomes associated with the three most commonly utilized definitive therapies for early-stage NSCLC in the elderly population.
Design, Setting, and Participants
The Surveillance, Epidemiology, and End Results–Medicare–linked database was used to determine the baseline characteristics and outcomes of 9,093 patients with early-stage, node-negative NSCLC who underwent definitive treatment with lobectomy, sublobar resection, or stereotactic ablative radiation between 2003 and 2009.
Main Outcomes and Measures
Overall survival and lung-cancer specific survival were compared using Medicare claims through December 2012. Both proportional hazards regression and propensity score matching (PSM) were used to adjust outcomes for key patient, tumor, and practice environment factors.
Results
The median age was 75 years, and treatment distribution was as follows: Lobectomy (79.4%), sublobar resection (16.5%), and SABR (4.2%). Unadjusted 90-day mortality was highest for lobectomy (4.0%) followed by sublobar resection (3.7%, P=0.79) and SABR (1.3%, P=0.008). At three years, unadjusted mortality was lowest for lobectomy (25.0%), followed by sublobar resection (35.3%, P<0.001) and SABR (45.1%, P<0.001). Proportional hazards regression demonstrated that sublobar resection was associated with worse overall survival (Adjusted hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.20–1.44) and lung-cancer specific survival (HR 1.50; 95%CI 1.29–1.75) compared to lobectomy. PSM analysis reiterated these findings. In proportional hazards regression, SABR was associated with better overall survival than lobectomy in the first 6 months after diagnosis (HR 0.45; 95%CI 0.27–0.75), but worse survival thereafter (HR 1.66; 95%CI 1.39–1.99). PSM analysis of well-matched SABR and lobectomy cohorts demonstrated similar overall survival in the two groups (HR 1.01; 95%CI 0.74–1.38).
Conclusions
Lobectomy was associated with better outcomes than sublobar resection in elderly patients with early-stage NSCLC. Propensity-score matching suggests that SABR may be a good option among patients with very advanced age and multiple comorbidities.
doi:10.1001/jamasurg.2014.556
PMCID: PMC4401470  PMID: 25321323
13.  Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells 
Oncotarget  2015;7(3):3548-3558.
Auranofin, a gold complex that has been used to treat rheumatoid arthritis in clinics and has documented pharmacokinetic and safety profiles in humans, has recently been investigated for its anticancer activity in leukemia and some solid cancers. However, auranofin's single agent activity in lung cancer is not well characterized. To determine whether auranofin has single agent activity in lung cancer, we evaluated auranofin's activity in a panel of 10 non-small cell lung cancer (NSCLC) cell lines. Cell viability analysis revealed that auranofin induced growth inhibition in a subset of NSCLC cell lines with a half maximal inhibitory concentration (IC50) below 1.0 μM. Treatment with auranofin elicited apoptosis and necroptosis in auranofin-sensitive cell lines. Moreover, the susceptibility of NSCLC cells to auranofin was inversely correlated with TXNRD1 expression in the cells. Transient transfection of the TXNRD1-expressing plasmid in auranofin-sensitive Calu3 cells resulted in partial resistance, indicating that high TXNRD level is one of causal factors for resistance to auranofin. Further mechanistic characterization with proteomic analysis revealed that auranofin inhibits expression and/or phosphorylation of multiple key nodes in the PI3K/AKT/mTOR pathway, including S6, 4EBP1, Rictor, p70S6K, mTOR, TSC2, AKT and GSK3. Ectopic expression of TXNRD1 partially reversed auranofin-mediated PI3K/AKT/mTOR inhibition, suggesting that TXNRD1 may participate in the regulation of PI3K/AKT/mTOR pathway. Administration of auranofin to mice with xenograft tumors derived from NSCLC cells significantly suppressed tumor growth without inducing obvious toxic effects. Our results demonstrated feasibility of repurposing auranofin for treatment of lung cancer.
doi:10.18632/oncotarget.6516
PMCID: PMC4823126  PMID: 26657290
lung cancer; drug repurposing; anticancer agent; biomarkers
14.  Locoregional Failure Rate After Preoperative Chemoradiation of Esophageal Adenocarcinoma and the Outcomes of Salvage Strategies 
Journal of Clinical Oncology  2013;31(34):4306-4310.
Purpose
The primary purpose of surveillance of patients with esophageal adenocarcinoma (EAC) and/or esophagogastric junction adenocarcinoma after local therapy (eg, chemoradiotherapy followed by surgery or trimodality therapy [TMT]) is to implement a potentially beneficial salvage therapy to overcome possible morbidity/mortality caused by locoregional failure (LRF). However, the benefits of surveillance are not well understood. We report on LRFs and salvage strategies in a large cohort.
Patients and Methods
Between 2000 and 2010, 518 patients with EAC who completed TMT were analyzed for the frequency of LRF over time and salvage therapy outcomes. Standard statistical techniques were used.
Results
For 518 patients, the median follow-up time was 29.3 months (range, 1 to 149 months). Distant metastases (with or without LRF) occurred in 188 patients (36%), and LRF only occurred in 27 patients (5%). Eleven of 27 patients had lumen-only LRF. Most LRFs (89%) occurred within 36 months of surgery. Twelve patients had salvage chemoradiotherapy, but only five survived more than 2 years. Four patients needed salvage surgery, and three who survived more than 2 years developed distant metastases. The median overall survival of 27 patients with LRF was 17 months, and 10 patients (37%) survived more than 2 years. Thus, only 2% of all 518 patients benefited from surveillance/salvage strategies.
Conclusion
Our surveillance strategy, which is representative of many others currently being used, raises doubts about its effectiveness and benefits (along with concerns regarding types and times of studies and costs implications) to patients with EAC who have LRF only after TMT. Fortunately, LRFs are rare after TMT, but the salvage strategies are not highly beneficial. Our data can help develop an evidence-based surveillance strategy.
doi:10.1200/JCO.2013.51.7250
PMCID: PMC3837091  PMID: 24145339
15.  Prodrug oncrasin-266 improves the stability, pharmacokinetics, and safety of NSC-743380 
Bioorganic & medicinal chemistry  2014;22(19):5234-5240.
Through synthetic lethality screening of isogenic cell lines with and without the oncogenic KRAS gene and through lead compound optimization, we recently developed a novel anticancer agent designated NSC-743380 (oncrasin-72) that has promising in vitro and in vivo anticancer activity in a subset of cancer cell lines, including KRAS-mutant cancer cells. However, NSC-743380 tends to form dimers, which dramatically reduces its anticancer activity. To improve the physicochemical properties of NSC-743380, we synthesized a prodrug of NSC-743380, designated oncrasin-266, by modifying NSC-743380 with cyclohexylacetic acid and evaluated its in vitro and in vivo properties. Oncrasin-266 spontaneously hydrolyzed in phosphate-buffered saline in a time-dependent manner and was more stable than NSC-743380 in powder or stock solutions. In vivo administration of oncrasin-266 in mice led to the release of NSC-743380 which improved the pharmacokinetics of NSC-743380. Tissue distribution analysis revealed that oncrasin-266 was deposited in liver, whereas released NSC-743380 was detected in liver, lung, kidney, and subcutaneous tumor. Oncrasin-266 was better tolerated in mice at a higher dose level treatment (150–300mg/kg, i.p.) than the parent agent was, suggesting that the prodrug reduced the acute toxicity of the parent agent. Our results demonstrated that the prodrug strategy could improve the stability, pharmacokinetic properties, and safety of NSC-743380.
doi:10.1016/j.bmc.2014.08.006
PMCID: PMC4172508  PMID: 25182964
Cancer; drug development; prodrug; synthetic lethality
16.  Selective Antitumor Activity of Ibrutinib in EGFR-Mutant Non–Small Cell Lung Cancer Cells 
Ibrutinib, which irreversibly inhibits Bruton tyrosine kinase, was evaluated for antitumor activity in a panel of non–small cell lung cancer (NSCLC) cell lines and found to selectively inhibit growth of NSCLC cells carrying mutations in the epidermal growth factor receptor (EGFR) gene, including T790M mutant and erlotinib-resistant H1975 cells. Ibrutinib induced dose-dependent inhibition of phosphor-EGFR at both Y1068 and Y1173 sites, suggesting ibrutinib functions as an EGFR inhibitor. Survival was analyzed by Kaplan–Meier estimation and log-rank test. All statistical tests were two-sided. In vivo study showed that ibrutinib statistically significantly suppressed H1975 tumor growth and prolonged survival of the tumor bearing mice (n = 5 per group). The mean survival times for solvent- and erlotinib-treated mice were both 17.8 days (95% confidence interval [CI] = 14.3 to 21.3 days), while the mean survival time for ibrutinib-treated mice was 29.8 days (95% CI = 26.0 to 33.6 days, P = .008). Our results indicate that ibrutinib could be a candidate drug for treatment of EGFR-mutant NSCLC, including erlotinib-resistant tumors.
doi:10.1093/jnci/dju204
PMCID: PMC4200057  PMID: 25214559
17.  Computed Tomography RECIST Assessment of Histopathologic Response and Prediction of Survival in Patients with Resectable Non-Small Cell Lung Cancer after Neoadjuvant Chemotherapy 
Introduction
This study’s objectives were to determine whether tumor response measured by CT and evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) correlated with overall survival (OS) in patients with non-small cell lung cancer (NSCLC) after neoadjuvant chemotherapy and surgical resection.
Methods
We measured primary tumor size on CT before and after neoadjuvant chemotherapy in 160 NSCLC patients who underwent surgical resection. The relationship between CT-measured response (RECIST) and histopathologic response (≤10% viable tumor) and OS were assessed by Kaplan Meier survival, univariable and multivariable Cox proportional hazards regression.
Results
There was a statistically significant association between CT-measured response (RECIST) and OS (p=0.03). However, histopathologic response was a stronger predictor of OS (p=0.002), with a more pronounced separation of the survival curves when compared to CT-measured response. In multivariable Cox regression analysis, only pathologic stage and histopathologic response were significant predictors of OS. A 41% overall discordance rate was noted between CT RECIST response and histopathologic response. CT RECIST classified as non-responders a subset of patients with histopathologic response (8/30 pts, 27%) who demonstrated prolonged survival after neoadjuvant chemotherapy.
Conclusion
We were unable to show that CT RECIST is a reliable predictor of OS in patients with NSCLC undergoing surgical resection after neoadjuvant chemotherapy. The failure of CT RECIST to predict long-term outcome may be due to the inability of CT imaging to consistently identify patients with histopathologic response. CT RECIST may have only a limited role as an efficacy endpoint after neoadjuvant chemotherapy in patients with resectable NSCLC.
doi:10.1097/JTO.0b013e3182774108
PMCID: PMC3549050  PMID: 23287849
18.  Genetic variation in the TNF/TRAF2/ASK1/p38 kinase signaling pathway as markers for postoperative pulmonary complications in lung cancer patients 
Scientific Reports  2015;5:12068.
Post-operative pulmonary complications are the most common morbidity associated with lung resection in non-small cell lung cancer (NSCLC) patients. The TNF/TRAF2/ASK1/p38 kinase pathway is activated by stress stimuli and inflammatory signals. We hypothesized that genetic polymorphisms within this pathway may contribute to risk of complications. In this case-only study, we genotyped 173 germline genetic variants in a discovery population of 264 NSCLC patients who underwent a lobectomy followed by genotyping of the top variants in a replication population of 264 patients. Complications data was obtained from a prospective database at MD Anderson. MAP2K4:rs12452497 was significantly associated with a decreased risk in both phases, resulting in a 40% reduction in the pooled population (95% CI:0.43–0.83, P = 0.0018). In total, seven variants were significant for risk in the pooled analysis. Gene-based analysis supported the involvement of TRAF2, MAP2K4, and MAP3K5 as mediating complications risk and a highly significant trend was identified between the number of risk genotypes and complications risk (P = 1.63 × 10−8). An inverse relationship was observed between association with clinical outcomes and complications for two variants. These results implicate the TNF/TRAF2/ASK1/p38 kinase pathway in modulating risk of pulmonary complications following lobectomy and may be useful biomarkers to identify patients at high risk.
doi:10.1038/srep12068
PMCID: PMC4499815  PMID: 26165383
19.  FDG PET-CT Aids in the Preoperative Assessment of Patients with Newly Diagnosed Thymic Epithelial Malignancies 
Introduction
Advanced thymoma (stage III and IV) is difficult to detect by computed tomography (CT), yet it is important to distinguish between early (stage I and II) and advanced disease before surgery, as patients with locally advanced tumors require neoadjuvant chemotherapy to enable effective resection. This study assessed whether the amount of fluorodeoxyglucose (FDG) uptake can predict advanced thymoma and whether it can separate thymoma from thymic cancer.
Methods
We retrospectively reviewed FDG positron emission tomography (PET)-CT scans of 51 consecutive newly diagnosed patients with thymic epithelial malignancy. PET-CT findings documented were focal FDG activity: SUVmax, SUVmean, SUVpeak and total body volumetric standardized uptake value (SUV) measurements. These were correlated with Masaoka-Koga staging and WHO classification. Wilcoxon rank-sum tests were used to assess association between SUV and pathological stage, cancer type, and classification.
Results
Among the study patients, 37 had thymoma, 12 thymic carcinoma, and 2 thymic carcinoid. Higher focal FDG uptake was seen in patients with type B3 thymoma than in those with type A, AB, B1, or B2 thymoma (p<0.006). Uptake was higher in patients with thymic carcinoma or carcinoid than in those with thymoma (p<0.0003), with more variable associations with volumetric SUV measurements. There was no significant association observed between higher focal FDG uptake and advanced-stage disease in thymoma patients (p>0.09), though greater FDG-avid tumor volume was significantly associated with advanced disease (p<0.03).
Conclusions
Focal FDG uptake cannot predict advanced thymoma but is helpful in distinguishing thymoma from thymic carcinoma, or the more aggressive thymoma, type B3.
doi:10.1097/JTO.0b013e3182835549
PMCID: PMC3878071  PMID: 23446204
Thymoma; PET-CT; Masaoka-Koga
20.  Predictive biomarkers in precision medicine and drug development against lung cancer 
The molecular characterization of various cancers has shown that cancers with the same origins, histopathologic diagnoses, and clinical stages can be highly heterogeneous in their genetic and epigenetic alterations that cause tumorigenesis. A number of cancer driver genes with functional abnormalities that trigger malignant transformation and that are required for the survival of cancer cells have been identified. Therapeutic agents targeting some of these cancer drivers have been successfully developed, resulting in substantial improvements in clinical symptom amelioration and outcomes in a subset of cancer patients. However, because such therapeutic drugs often benefit only a limited number of patients, the successes of clinical development and applications rely on the ability to identify those patients who are sensitive to the targeted therapies. Thus, biomarkers that can predict treatment responses are critical for the success of precision therapy for cancer patients and of anticancer drug development. This review discusses the molecular heterogeneity of lung cancer pathogenesis; predictive biomarkers for precision medicine in lung cancer therapy with drugs targeting epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 receptor tyrosine kinase (ROS1), and immune checkpoints; biomarkers associated with resistance to these therapeutics; and approaches to identify predictive biomarkers in anticancer drug development. The identification of predictive biomarkers during anticancer drug development is expected to greatly facilitate such development because it will increase the chance of success or reduce the attrition rate. Additionally, such identification will accelerate the drug approval process by providing effective patient stratification strategies in clinical trials to reduce the sample size required to demonstrate clinical benefits.
doi:10.1186/s40880-015-0028-4
PMCID: PMC4593363  PMID: 26134262
Precision medicine; Personalized therapy; Epidermal growth factor receptor (EGFR); Anaplastic lymphoma kinase (ALK); Immunotherapy; Biomarkers; Drug development
21.  Copper Transporter CTR1 Expression and Tissue Platinum Concentration in Non-Small Cell Lung Cancer 
Background
Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue platinum concentration in NSCLC specimens was significantly associated with reduced tumor response. Furthermore, low expression of the copper transporter CTR1, a transporter of platinum uptake was associated with poor clinical outcome following platinum-based therapy in NSCLC patients. We investigated the relationship between tissue platinum concentrations and CTR1 expression in NSCLC specimens.
Methods
We identified paraffin-embedded NSCLC tissue blocks of known tissue platinum concentrations from 30 patients who underwent neoadjuvant platinum-based chemotherapy at MD Anderson Cancer Center. Expression of CTR1 in tumors and normal adjacent lung specimens was determined by immunohistochemistry with adequate controls.
Results
Tissue platinum concentration significantly correlated with tumor response in 30 patients who received neoadjuvant platinum-based chemotherapy (P<0.001). CTR1 was differentially expressed in NSCLC tumors. A subset of patients with undetectable CTR1 expression in their tumors had reduced platinum concentrations (P=0.058) and tumor response (P=0.016) compared to those with any level of CTR1 expression. We also observed that African Americans had significantly reduced CTR1 expression scores (P=0.001), tissue platinum concentrations (P=0.009) and tumor shrinkage (P=0.016) compared to Caucasians.
Conclusions
To our best knowledge this is the first study investigating the function of CTR1 in clinical specimens. CTR1 expression may be necessary for therapeutic efficacy of platinum drugs, consistent with previous preclinical studies. A prospective clinical trial is necessary to develop CTR1 into a potential biomarker for platinum drugs.
doi:10.1016/j.lungcan.2014.04.005
PMCID: PMC4090351  PMID: 24792335
22.  RNA-dependent protein kinase (PKR) depletes nutrients, inducing phosphorylation of AMP-activated kinase in lung cancer 
Oncotarget  2015;6(13):11114-11124.
We have demonstrated that RNA-dependent protein kinase (PKR) and its downstream protein p-eIF2α are independent prognostic markers for overall survival in lung cancer. In the current study, we further investigate the interaction between PKR and AMPK in lung tumor tissue and cancer cell lines. We examined PKR protein expression in 55 frozen primary lung tumor tissues by Western blotting and analyzed the association between PKR expression and expresson of 139 proteins on tissue samples examined previously by Reverse Phase Protein Array (RPPA) from the same 55 patients. We observed that biomarkers were either positively (phosphorylated AMP-activated kinaseT172 [p-AMPK]) or negatively (insulin receptor substrate 1, meiotic recombination 11, ATR interacting protein, telomerase, checkpoint kinase 1, and cyclin E1) correlated with PKR. We further confirmed that induction of PKR with expression vectors in lung cancer cells causes activation of the AMPK protein independent of the LKB1, TAK1, and CaMKKβ pathway. We found that PKR causes nutrient depletion, which increases AMP levels and decreases ATP levels, causing AMPK phosphorylation. We further demonstrated that inhibiting AMPK expression with compound C or siRNA enhanced PKR-mediated cell death. We next explored the combination of PKR and p-AMPK expression in NSCLC patients and observed that expression of p-AMPK predicted a poor outcome for adenocarcinoma patients with high PKR expression and a better prognosis for those with low PKR expression. These findings were consistent with our in vitro results. AMPK might rescue cells facing metabolic stresses, such as ATP depletion caused by PKR. Our data indicate that PKR causes nutrient depletion, which induces the phosphorylation of AMPK. AMPK might act as a protective response to metabolic stresses, such as nutrient deprivation.
PMCID: PMC4484443  PMID: 25798539
PKR; AMPK; nutrient depletion; lung cancer
23.  Influence of Preoperative Radiation Field on Postoperative Leak Rates in Esophageal Cancer Patients after Trimodality Therapy 
Introduction
Postoperative morbidities, such as anastomotic leaks, are common after trimodality therapy (chemoradiation followed by surgery) for esophageal cancer. We investigated for factors associated with an increased incidence of anastomotic leaks.
Methods
Data from 285 esophageal cancer patients treated from 2000–2011 with trimodality therapy was analyzed. Anastomotic location relative to preoperative radiation field was assessed using postoperative computed tomographic imaging. Logistic regression was used to evaluate for factors associated with any or clinically relevant (CR) (≥ grade 2) leaks.
Results
Overall anastomotic leak rate was 11% (31/285), and CR leak rate was 6% (17/285). Multivariable analysis identified body mass index (BMI) (OR 1.09, 95%CI 1.00–1.17; OR 1.11, 95%CI 1.01–1.22), three-field surgery (OR 10.01, 95%CI 3.83–26.21; OR 4.83, 95%CI 1.39–16.71), and within radiation field (“in-field”) anastomosis (OR 5.37, 95%CI 2.21–13.04; OR 8.63, 95%CI 2.90–25.65) as independent predictors of both all grade and CR leaks, respectively. While patients with distal esophageal tumors and Ivor-Lewis surgery had the lowest incidence of all grade (6.5%) and CR leaks (4.2%), most of the leaks were associated with the anastomosis constructed within the field of radiation (in-field: 39% and 30% versus out-of-field: 2.6% and 1.0%, respectively, for total and CR leaks, p<0.0001, Fisher’s Exact test).
Conclusions
Esophagogastric anastomosis placed within the preoperative radiation field was a very strong predictor for anastomotic leaks in esophageal cancer patients treated with trimodality therapy, among other factors. Surgical planning should include a critical evaluation of the preoperative radiation fields to ensure proper anastomotic placement after chemoradiation therapy.
doi:10.1097/JTO.0000000000000100
PMCID: PMC3989552  PMID: 24736077
Anastomotic leaks; Esophagectomy; Radiation; Esophageal Cancer; Trimodality Therapy
24.  Prediction of survival in resected non-small cell lung cancer using a protein-expression based risk model: Implications for personalized chemoprevention and therapy 
Purpose
Patients with resected non-small cell lung cancer (NSCLC) are at risk for recurrence of disease but we do not have tools to predict which patients are at highest risk. We set out to create a risk model incorporating both clinical data and biomarkers.
Methods
We assembled a comprehensive database with archival tissues and clinical follow-up from patients with NSCLC resected between 2002-2005. Twenty-one proteins identified from our preclinical studies as related to lung carcinogenesis were investigated, including pathways related to metabolism, DNA repair, inflammation and growth factors. Expression of proteins was quantified using immunohistochemistry. Immunohistochemistry was chosen because it is widely available and can be performed on formalin-fixed paraffin-embedded specimens. Cox models were fitted to estimate effects of clinical factors and biomarkers on recurrence free survival (RFS) and overall survival (OS).
Results
370 patients are included in our analysis. With median follow-up of 5.3 years, median overall survival is 6.4 years. 209 cases with recurrence or death were observed. Multicovariate risk models for RFS and OS were developed including relevant biomarkers, age and stage. Increased expression of pAMPK, pmTOR, EpCAM, and CASK were significant (p<0.05) predictors for favorable RFS; insulin receptor, CXCR2, and IGF1R predicted for unfavorable RFS. Significant (p<0.05) predictors for favorable OS include pAMPK, pmTOR, and EpCAM; CXCR2 and FEN1 predicted unfavorable OS.
Conclusions
We have developed a comprehensive risk model predictive for recurrence in our large retrospective database, which is one of the largest reported series of resected NSCLC.
doi:10.1158/1078-0432.CCR-13-1959
PMCID: PMC4018222  PMID: 24366692
Lung cancer; biomarkers; risk modeling
25.  A nomogram that predicts pathologic complete response to neoadjuvant chemoradiation also predicts survival outcomes after definitive chemoradiation for esophageal cancer 
Background
Pathologic complete response (pCR) to neoadjuvant chemoradiation for esophageal cancer is associated with improved outcomes. We evaluated whether a nomogram designed to predict who would have a pCR after trimodality therapy could also predict outcome after definitive chemoradiation.
Methods
Patients in this retrospective, single-institution analysis had received chemoradiation without surgery for esophageal cancer from 1998 through 2010; 333 such patients had complete information on all variables required for the pCR nomogram: sex; T status (by endoscopic sonography); tumor grade; tumor avidity on positron emission tomography (PET); and esophagogastroduodenoscopy (EGD)-directed biopsy results after chemoradiation. We used multivariate Cox regression to test potential associations between clinical outcomes [overall survival (OS), locoregional recurrence, and distant metastasis] and patient or treatment factors and the pCR nomogram score; the component variables of the nomogram were not reintroduced into the multivariate analysis.
Results
The median follow-up time for all patients (median age 66 years) was 18.2 months (30.7 months for those alive at the time of analysis). Patients with nomogram scores ≤125 (median for all patients) had significantly worse outcomes than patients with scores >125: median OS time 19.7 vs. 48.2 months; disease-free survival (DFS) time 6.1 vs. 31.1 months; locoregional failure-free survival time 17.7 months vs. not reached; and distant metastasis-free survival time 11.7 months vs. not reached (all P<0.001). Multivariate Cox regression analysis indicated that nomogram score independently predicted each survival outcome, along with other patient and disease factors.
Conclusions
The pCR nomogram score predicted survival outcomes in patients receiving definitive chemoradiation for esophageal cancer. Although this nomogram requires further validation, it may prove useful for stratifying patients for clinical trials designed to intensify treatments for patients at the highest risk of relapse.
doi:10.3978/j.issn.2078-6891.2014.054
PMCID: PMC4294819  PMID: 25642337
Pathologic complete response (pCR); nomogram score; esophageal cancer; chemoradiation

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