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1.  A nomogram that predicts pathologic complete response to neoadjuvant chemoradiation also predicts survival outcomes after definitive chemoradiation for esophageal cancer 
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.
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.
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.
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.
PMCID: PMC4294819  PMID: 25642337
Pathologic complete response (pCR); nomogram score; esophageal cancer; chemoradiation
2.  Locoregional Failure Rate After Preoperative Chemoradiation of Esophageal Adenocarcinoma and the Outcomes of Salvage Strategies 
Journal of Clinical Oncology  2013;31(34):4306-4310.
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.
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.
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.
PMCID: PMC3837091  PMID: 24145339
3.  IGFBP2/FAK pathway is causally associated with dasatinib resistance in non-small Cell Lung Cancer Cells 
Molecular cancer therapeutics  2013;12(12):10.1158/1535-7163.MCT-13-0233.
IGFBP2 expression is increased in various types of cancers, including in a subset of lung cancer patients. Because IGFBP2 is involved in signal transduction of some critical cancer related pathways, we analyzed the association between IGFBP2 and response to pathway-targeted agents in seven human non–small cell lung cancer (NSCLC) cell lines. Western blot analysis and enzyme-linked immunosorbent assay (ELISA) showed that four of the seven NSCLC cell lines analyzed expressed high levels of IGFBP2, while the remaining three had barely detectable IGFBP2. Susceptibilities of those seven cell lines to nine anticancer agents targeting to IGF1R, Src, FAK, MEK, and AKT were determined by dose-dependent cell viability assay. The results showed that high IGFBP2 levels were associated with resistance to dasatinib, and to a lesser degree to sacaratinib, but not to other agents. Ectopic IGFBP2 overexpression or knockdown revealed that changing IGFBP2 expression levels reversed dasatinib susceptibility phenotype, suggesting a causal relationship between IGFBP2 expression and dasatinib resistance. Molecular characterization revealed that FAK activation was associated with increased IGFBP2 expression and partially contributed to IGFBP2-mediated dasatinib resistance. Treatment with a combination of dasatinib and FAK inhibitor led to enhanced antitumor activity in IGFBP2-overexpressing and dasatinib-resistant NSCLC cells in vitro and in vivo. Our results demonstrated that the IGFBP2/FAK pathway is causally associated with dasatinib resistance and may be used as biomarkers for identification of dasatinib responders among lung cancer patients. Simultaneous targeting on Src and FAK will likely improve the therapeutic efficacy of dasatinib for treatment of lung cancer.
PMCID: PMC3858413  PMID: 24130049
IGFBP2; FAK; dasatinib; biomarker; chemoresistance; lung cancer
4.  EZH2 Protein Expression Associates With the Early Pathogenesis, Tumor Progression and Prognosis of Non-small Cell Lung Carcinoma 
Enhancer of zeste homolog 2 (EZH2) promotes carcinogenesis by epigenetically silencing tumor suppressor genes. We studied EZH2 expression by immunohistochemistry in a large series of non-small cell lung carcinomas (NSCLC) in association with tumor characteristics and patient outcomes.
Experimental Design
EZH2 immunohistochemistry expression was analyzed in 265 normal and premalignant bronchial epithelia, 541 primary NSCLCs [221 squamous cell carcinomas (SCCs) and 320 adenocarcinomas] and 36 NSCLCs with paired brain metastases. An independent set of 91 adenocarcinomas was also examined. EZH2 expression was statistically correlated with clinico-pathological information, and EGFR/KRAS mutation status.
EZH2 expression was significantly (P<0.0001) higher in SCCs compared to adenocarcinomas and in brain metastasis relative to matched primary tumors (P=0.0013). EZH2 expression was significantly (P<0.0001) elevated in bronchial preneoplastic lesions with increasing severity. In adenocarcinomas, higher EZH2 expression significantly correlated with younger age, cigarette smoking and higher TNM stage (P=0.02 to P<0.0001). Higher EZH2 expression in adenocarcinoma was associated with worse recurrence-free survival (RFS; P=0.025; HR 1.54) and overall survival (OS; P=0.0002; HR 1.96). Furthermore, lung adenocarcinomas with low EZH2 levels and high expression of the lineage-specific transcription factor, TTF-1, exhibited significantly improved RFS (P=0.009; HR 0.51) and OS (P=0.0011; HR 0.45) which was confirmed in the independent set of 91 adenocarcinomas.
In lung, EZH2 expression is involved in early pathogenesis of SCC and correlates with a more aggressive tumor behavior of adenocarcinoma. When EZH2 and TTF-1 expressions are considered together, they serve as a prognostic marker in patients with surgically resected lung adenocarcinomas.
PMCID: PMC3890101  PMID: 24097870
EZH2; NSCLC; lung adenocarcinoma; lung squamous cell carcinoma; bronchial preneoplasia; brain metastasis; KRAS mutations; EGFR mutations
5.  Computed Tomography RECIST Assessment of Histopathologic Response and Prediction of Survival in Patients with Resectable Non-Small Cell Lung Cancer after Neoadjuvant Chemotherapy 
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.
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.
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.
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.
PMCID: PMC3549050  PMID: 23287849
6.  Stereotactic Ablative Radiotherapy: A Potentially Curable Approach to Early-Stage Multiple Primary Lung Cancer 
Cancer  2013;119(18):3402-3410.
Surgical resection has been the standard treatment for early-stage multiple primary lung cancer (MPLC). However, a significant proportion of patients with MPLC cannot undergo surgery. We explored here the role of stereotactic ablative radiotherapy (SABR) for patients with MPLC.
We reviewed MPLC cases treated with SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions) for the second tumor. Four-dimensional CT–based planning/volumetric image-guided treatment was used for all patients. Treatment outcomes/toxicities were analyzed.
For the 101 patients treated with SABR, at a median follow-up interval of 36 months and median overall survival of 46 months, 2-year and 4-year in-field local control rates were 97.4% and 95.7%. 2- and 4-year rates of overall survival (OS) were 73.2% and 47.5% and progression-free survival (PFS) were 67.0% and 58.0%. Patients with metachronous tumors had higher OS and PFS than did patients with synchronous tumors (2-year OS 80.6% metachronous vs. 61.5% synchronous; 4-year OS 52.7% vs. 39.7%; p=0.047; 2-year PFS 84.7% vs. 49.4%; 4-year PFS 75.6% vs. 30.4%; p=0.0001). For patients whose index tumor was treated with surgery or SABR, the incidence of grade ≥3 radiation pneumonitis was 3% (2/71), but this increased to 17% (5/30) for patients whose index tumor was treated with conventional radiotherapy. Other grade ≥3 toxicities included grade 3 chest wall pain (3/101, 3%) and grade 3 skin toxicity (1/101, 1%).
SABR achieves promising long- term tumor control, survival and could be a potential curative treatment of early-stage MPLC.
PMCID: PMC3775964  PMID: 23798353
multiple primary lung cancer; synchronous tumors; metachronous tumors; stereotactic body radiotherapy; stereotactic ablative radiotherapy
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.
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%.
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%).
PMCID: PMC3796353  PMID: 21507583
Esophageal cancer; Chemotherapy; Chemoradiation; Radiation therapy; Salvage surgery
8.  Predictors of Postoperative Complications After Trimodality Therapy for Esophageal Cancer 
While trimodality therapy for esophageal cancer has improved patient outcomes, surgical complication rates remain high. The goal of this study was to identify modifiable factors associated with postoperative complications after neoadjuvant chemoradiation.
Methods and Materials
From 1998 to 2011, 444 patients were treated at our institution with surgical resection after chemoradiation. Postoperative (pulmonary, gastrointestinal [GI], cardiac, wound healing) complications were recorded up to 30 days postoperatively. Kruskal-Wallis tests and χ2 or Fisher exact tests were used to assess associations between continuous and categorical variables. Multivariate logistic regression tested the association between perioperative complications and patient or treatment factors that were significant on univariate analysis.
The most frequent postoperative complications after trimodality therapy were pulmonary (25%) and GI (23%). Lung capacity and the type of radiation modality used were independent predictors of pulmonary and GI complications. After adjusting for confounding factors, pulmonary and GI complications were increased in patients treated with 3-dimensional conformal radiation therapy (3D-CRT) versus intensity modulated radiation therapy (IMRT; odds ratio [OR], 2.018; 95% confidence interval [CI], 1.104–3.688; OR, 1.704; 95% CI, 1.03–2.82, respectively) and for patients treated with 3D-CRT versus proton beam therapy (PBT; OR, 3.154; 95% CI, 1.365–7.289; OR, 1.55; 95% CI, 0.78–3.08, respectively). Mean lung radiation dose (MLD) was strongly associated with pulmonary complications, and the differences in toxicities seen for the radiation modalities could be fully accounted for by the MLD delivered by each of the modalities.
The radiation modality used can be a strong mitigating factor of postoperative complications after neoadjuvant chemoradiation.
PMCID: PMC3786201  PMID: 23845841
9.  Preoperative chemotherapy prior to pulmonary metastasectomy in surgically resected primary colorectal carcinoma 
Oncotarget  2014;5(16):6584-6593.
The benefit of preoperative chemotherapy prior to pulmonary metastasectomy for patients with colorectal carcinoma (CRC) is unknown. Here, we identify outcomes of preoperative chemotherapy in patients with resected primary CRC who then underwent pulmonary metastasectomy.
We queried a prospective database to identify treatment characteristics. Multivariate analyses identified predictors of overall survival (OS) and progression-free survival (PFS).
229 patients underwent lung metastasectomy, of whom 115 proceeded to surgery without chemotherapy while 114 received preoperative regimen based on oxaliplatin (32%), irinotecan (46%), capecitabine (16%), or other (6%). Median PFS in preoperative chemotherapy vs. surgery alone arms were comparable (p=0.004). Patients on oxaliplatin-based therapy had an improved OS vs. an irinotecan, capecitabine, or alternate regimen (p=.019). On multivariate analysis, the irinotecan subset had a worse OS (HR 1.846; 95% CI 1.070, 3.185) vs. surgery alone arm (p=0.028). The OS of an oxaliplatin-based regimen vs. no chemotherapy was inconclusive (HR 0.57; 95% CI 0.237 to 1.389, p=0.218). Multivariate analysis demonstrated a worse PFS and OS for the male gender and an incomplete resection (R2).
Prospective trials on specific preoperative regimens and criteria for patient selection may identify a role for preoperative chemotherapy prior to a curative pulmonary metastasectomy.
PMCID: PMC4196147  PMID: 25051371
colorectal; carcinoma; neoadjuvant; chemotherapy; metastasectomy
10.  Does the Timing of Esophagectomy after Neoadjuvant Chemoradiation Affect Outcome? 
The Annals of thoracic surgery  2011;93(1):207-213.
After neoadjuvant chemoradiation (CXRT) for esophageal cancer, surgery has traditionally been recommended to be performed within 8 weeks. However, surgery is often delayed for various reasons. Data from other cancers suggests that delaying surgery may increase the pathologic complete response rate. However, there are theoretical concerns that waiting longer after radiation may lead to a more difficult operation and more complications. The optimal timing of esophagectomy after CXRT is unknown.
From a prospective database, we analyzed 266 patients with resected esophageal cancer who were treated with neoadjuvant CXRT from 2002–2008. Salvage resections were excluded from this analysis. We compared patients who had surgery within 8 weeks of CXRT and those who had surgery after 8 weeks. We used multivariable analysis to determine whether increased interval between chemoradiation and surgery was independently associated with perioperative complication, pathologic response, or overall survival.
150 patients were resected within 8 weeks and 116 were resected greater than 8 weeks after completing CXRT. Mean length of operation, intraoperative blood loss, anastomotic leak rate, and perioperative complication rate were similar for the two groups. Pathologic complete response rate and overall survival were also similar for the two groups (p=NS). In multivariable analysis, timing of surgery was not an independent predictor of perioperative complication, pathologic complete response, or overall survival.
The timing of esophagectomy after neoadjuvant CXRT is not associated with perioperative complication, pathologic response, or overall survival. It may be reasonable to delay esophagectomy beyond 8 weeks for patients who have not yet recovered from chemoradiation.
PMCID: PMC4041623  PMID: 21962263
Adjuvant/neoadjuvant therapy; Esophageal Cancer; Radiation Therapy; Esophageal Surgery
11.  Survival outcomes for men with mediastinal germ-cell tumors: The University of Texas M. D. Anderson Cancer Center experience✩ 
Urologic oncology  2010;30(6):879-885.
Primary mediastinal germ-cell tumors are rare, and the effect of newer drugs and treatment strategies in this disease on overall survival is not known. We retrospectively assessed treatment outcomes at a single institution.
Materials and methods
We identified men seen at our institution from 1998 through 2005 for mediastinal germ-cell tumors. Medical records were reviewed for patient characteristics, histology, tumor markers, treatment, and survival outcome.
Thirty-four patients met study criteria, of whom 27 had nonseminomatous germ-cell tumor (NSGCT) and 7 had pure seminoma. Eleven patients (41%) with NSGCT were alive at last contact with a median overall survival time of 33.5 months. Among 13 patients with NSGCT referred to us at initial diagnosis, 7 (54%) were alive and recurrence-free at a median follow-up of 56.5 months. Progression-free survival was associated with absence of risk factors (any histology other than endodermal sinus tumor, β-hCG > 1000 mIU/mL, or disease outside the mediastinum). For the patients whose disease progressed (n = 5) or who had been referred to us for salvage treatment (n = 14), the 3-year overall survival from the date of first progression was 23%. Conversely, patients with seminoma did uniformly well with platinum-based chemotherapy; most did not undergo radiation or surgery.
Chemotherapy given to maximum effect followed by surgical consolidation resulted in long-term progression-free survival for 54% of patients with mediastinal NSGCT. The number of risk factors present at diagnosis may be associated with survival outcome and should be studied in a larger test group.
PMCID: PMC3956468  PMID: 20933444
Mediastinal neoplasms; Germ-cell neoplasms; Seminoma; Tumor markers; Resection; Outcome
12.  Prognostic Significance of Combinations of RNA-Dependent Protein Kinase and EphA2 Biomarkers for NSCLC 
RNA-dependent protein kinase (PKR) is an independent prognostic variable in patients with non-small cell lung cancer (NSCLC). In the present study, we investigated the correlation between PKR and 25 other biomarkers for NSCLC, identified the markers that could further improve the prognostic significance of PKR, and elucidated the mechanisms of interaction between these markers and PKR.
Tissue microarray samples obtained from 218 lung cancer patients were stained with an anti-PKR antibody and antibodies against 25 biomarkers. Immunohistochemical expression was scored and used for Kaplan-Meier survival analysis. The interaction between PKR and EphA2 in NSCLC cell lines was examined.
We found that PKR was associated with EphA2 and that the prognostic information regarding NSCLC provided by the combination of PKR and EphA2 (P/E) was significantly more accurate than that provided by either marker alone. The 5-year overall survival rate in PKRlow/EphA2high patients (20%) was significantly lower than that of PKRhigh/EphA2low patients (74%), PKRhigh/EphA2high patients (55%), and PKRlow/EphA2low patients (55%) (p< 0.0001). We also found that the PKR:EphA2 (P/E) ratio was significantly associated with prognosis (p< 0.0001). Univariate and multivariate Cox analyses revealed that this P/E combination or ratio was an independent predictor of overall survival. In addition, induction of PKR expression reduced EphA2 protein expression levels in NSCLC cell lines.
PKR/EphA2 is a significant predictor of prognosis for NSCLC. PKR/EphA2 may be a promising approach to improving screening efficiency and predicting prognosis in NSCLC patients.
PMCID: PMC3573252  PMID: 23370317
PKR; EphA2; Biomarker; Lung cancer
13.  Genome-Wide Catalogue of Chromosomal Aberrations in Barrett’s Esophagus and Esophageal Adenocarcinoma: a High-Density SNP Array Analysis 
To better understand the molecular mechanisms behind esophageal adenocarcinoma (EAC) tumorigenesis, we used high-density single nucleotide polymorphism (SNP) arrays to profile chromosomal aberrations at each of the four sequential progression stages – Barrett’s metaplasia (BM), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC, in 101 patients. We observed a significant trend toward increasing loss of chromosomes with higher progression stage. For BM, LGD, HGD, and EAC, respectively, the average numbers of chromosome arms with loss per sample were 0.30, 3.21, 7.70, and 11.90 (P for trend= 4.82 × 10−7), and the mean percentages of SNPs with allele loss were 0.1%, 1.8%, 6.6%, and 17.2% (P for trend = 2.64 × 10−6). In LGD, loss of 3p14.2 (68.4%) and 16q23.1 (47.4%) was limited to narrow regions within the FHIT (3p14.2) and WWOX (16q23.1) genes, whereas loss of 9p21 (68.4%) occurred in larger regions. A significant increase in the loss of other chromosomal regions was seen in HGD and EAC; loss of 17p (47.6%) was one of the most frequent events in EAC. Many recurrent small regions of chromosomal loss disrupted single genes, including FHIT, WWOX, RUNX1, KIF26B, MGC48628, PDE4D, C20orf133, GMDS, DMD, and PARK2, most of which are common fragile site (CFS) regions in the human genome. But RUNX1 at 21q22 appeared to be a potential tumor suppressor gene in EAC. Amplifications were less frequent than losses and mostly occurred in EAC. The 8q24 (containing Myc) and 8p23.1 (containing CTSB) were the two most frequently amplified regions. In addition, a significant trend toward increasing amplification was associated with higher progression stage.
PMCID: PMC3932797  PMID: 20651033
14.  Propensity score based comparison of long term outcomes with 3D conformal radiotherapy (3DCRT) versus Intensity Modulated Radiation Therapy (IMRT) in the treatment of esophageal cancer 
Although 3DCRT is the worldwide standard for the treatment of esophageal cancers, IMRT improves dose conformality and reduces radiation exposure to normal tissues. We hypothesized that the dosimetric advantages of IMRT should translate to substantive benefits in clinical outcomes compared to 3DCRT.
Methods and Materials
Analysis was performed on 676 nonrandomized patients (3DCRT=413, IMRT=263) with stage Ib-IVa (AJCC 2002) esophageal cancers treated with chemoradiation at a single institution from 1998–2008. An inverse probability of treatment weighting (IPW) and inclusion of propensity score (treatment probability) as a covariate were used to compare overall survival (OS) time, time to local failure, and time to distant metastasis, while accounting for effects of other clinically relevant covariates. Propensity scores were estimated using logistic regression.
A fitted multivariate inverse probability weighted (IPW)-adjusted Cox model showed that OS time was significantly associated with several well-known prognostic factors, along with radiation modality (IMRT vs 3DCRT, HR=0.72, p<0.001). Compared to IMRT, 3DCRT patients had a significantly greater risk of dying (72.6% vs 52.9%, IPW log rank test: p<0.0001) and for local-regional recurrence (LRR) (p=0.0038). There was no difference in cancer-specific mortality (Gray’s test, p=0.86), or distant metastasis (p=0.99) between the two groups. An increased cumulative incidence of cardiac deaths was seen in the 3DCRT group (p=0.049), but most deaths were undocumented (5 year estimate: 11.7% in 3DCRT vs 5.4% in IMRT, Gray’s test, p=0.0029).
Overall survival, locoregional control, and non-cancer related deaths were significantly better for IMRT compared to 3DCRT. Although these results need confirmation, IMRT should be considered for the treatment of esophageal cancer.
PMCID: PMC3923623  PMID: 22867894
IMRT; 3D-conformal radiation therapy; chemoradiation; esophageal cancer; propensity score
15.  Proton Beam Therapy and concurrent chemotherapy for esophageal cancer 
Proton beam therapy (PBT) is a promising modality for the management of thoracic malignancies. We report our preliminary experience of treating esophageal cancer patients with concurrent chemotherapy (CChT) and PBT at MD Anderson Cancer Center.
This is an analysis of 62 esophageal cancer patients enrolled on a prospective study evaluating normal tissue toxicity from CChT/PBT from 2006 to 2010. Patients were treated with Passive Scattering PBT with 2 or 3 field beam arrangement using 180–250 MV protons. We used the method of Kaplan and Meier to assess time to event outcomes and compared the distributions between groups using the log-rank test.
The median follow-up time was 20.1 months for survivors. The median age was 68 years (range 38–86). Most were males (82%), had adenocarcinomas (76%) and had stage II-III disease (84%). The median radiation dose was 50.4 Gray-Equivalence (Gy(RBE)) (range 36–57.6). The most common grade 2–3 acute toxicities from CChT/PBT were esophagitis (46.8%), fatigue (43.6%), nausea (33.9%), anorexia (30.1%), and radiation dermatitis (16.1%). There were two cases of grade 2 and 3 radiation pneumonitis and two grade 5 toxicities. A total of 29 patients (46.8%) received preoperative CChT/PBT with one postoperative death. The pathologic complete response (pCR) rate for the surgical cohort was 28%, and the pCR and near CR rate (0–1% residual cells) was 50%. While there were significantly fewer local-regional recurrences in the preoperative group (3/29) as compared to the definitive CChT/PBT group (16/33) (log-rank test p=0.005), there were no differences in DM free interval or OS between the two groups.
This is the first report of patients treated with PBT/CChT for esophageal cancer. Our data suggest that this modality is associated with a few severe toxicities but the pathologic response and clinical outcomes are encouraging. Prospective comparison with more traditional approach is warranted.
PMCID: PMC3923631  PMID: 22417808
Protons; Esophageal cancer; Chemotherapy; Chemoradiation
16.  Prognostic Impact of Radiation Therapy to the Primary Tumor in Patients With Non-small Cell Lung Cancer and Oligometastasis at Diagnosis 
We investigated prognostic factors associated with survival in patients with non-small cell lung cancer (NSCLC) and oligometastatic disease at diagnosis, particularly the influence of local treatment to the primary site on prognosis.
Methods and Materials
From January 2000 through June 2011, 78 consecutive patients with oligometastatic NSCLC (<5 metastases) at diagnosis underwent definitive chemoradiation therapy (≥45 Gy) to the primary site. Forty-four of these patients also received definitive local treatment for the oligometastases. Survival outcomes were estimated using the Kaplan-Meier method, and risk factors were identified by univariate and multivariate analyses.
Univariate Cox proportional hazard analysis revealed better overall survival (OS) for those patients who received at least 63 Gy of radiation to the primary site (P=.002), received definitive local treatment for oligometastasis (P=.041), had a Karnofsky performance status (KPS) score >80 (P=.007), had a gross tumor volume ≤ 124 cm3 (P=.002), had adenocarcinoma histology (P=.002), or had no history of respiratory disease (P=.016). On multivariate analysis, radiation dose, performance status, and tumor volume retained significance (P=.004, P=.006, and P<.001, respectively). The radiation dose also maintained significance when patients with and without brain metastases were analyzed separately.
Tumor volume, KPS, and receipt of at least 63 Gy to the primary tumor are associated with improved OS in patients with oligometastatic NSCLC at diagnosis. Our results suggest that a subset of such patients may benefit from definitive local therapy.
PMCID: PMC3919541  PMID: 22503522
17.  FDG PET-CT Aids in the Preoperative Assessment of Patients with Newly Diagnosed Thymic Epithelial Malignancies 
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.
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.
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).
Focal FDG uptake cannot predict advanced thymoma but is helpful in distinguishing thymoma from thymic carcinoma, or the more aggressive thymoma, type B3.
PMCID: PMC3878071  PMID: 23446204
Thymoma; PET-CT; Masaoka-Koga
18.  A Nomogram associated with high probability of malignant nodes in the surgical specimen after trimodality therapy of patients with oesophageal cancer 
European journal of cancer (Oxford, England : 1990)  2012;48(18):10.1016/j.ejca.2012.06.020.
The presence of malignant lymph nodes in the surgical specimen (+ypNodes) after preoperative chemoradiation (trimodality) in patients with esophageal cancer (EC) portends a poor prognosis for overall survival (OS) and disease-free survival (DFS). There is not one clinical parameter that is correlated with +ypNodes. We hypothesized that a combination of clinical parameters might provide a model that would associate with the high likelihood of +ypNodes in trimodality EC patients.
We report on 293 consecutive EC patients who received trimodality therapy. A multivariate logistic regression analysis that included pretreatment and post-chmoradiation parameters was performed to identify independent variables that were used to construct a nomogram for +ypNodes in trimodality EC patients.
Of 293 patients, 91 (31.1%) had +ypNodes. In multivariable analysis, the significant factors associated with +ypNodes were: baseline T stage (odds ratio [OR], 7.145; 95% confidence interval [CI], 1.381-36.969; p=0.019), baseline N stage (OR, 2.246; 95% CI, 1.024-4.926; p=0.044), tumor length (OR, 1.178; 95% CI, 1.024-1.357; p=0.022), induction chemotherapy (OR, 0.471; 95% CI, 0.242-0.915; p=0.026), lymph metastasis by post-chemoradiation PET (OR, 2.923; 95% CI, 1.007-8.485; p=0.049) and enlarged lymph node metastasis by post-chemoradiation CT (OR, 3.465; 95% CI, 1.549-7.753; p=0.002). The nomogram after internal validation using the bootstrap method yielded a high concordance index of 0.756 (95% CI, xx-xx).
Our results suggest that the constructed nomogram highly correlates with the presence of +ypNodes and upon validation; it could prove useful in individualizing therapy for trimodality patients with EC.
PMCID: PMC3869451  PMID: 22853875
19.  KLF4 Inhibition of Lung Cancer Cell Invasion by Suppression of SPARC Expression 
Cancer biology & therapy  2010;9(7):507-513.
Krüppel-Like Factor 4 (KLF4) functions as a tumor suppressor in some cancers, but its molecular mechanism is not clear. Our recent study also showed that the expression of KLF4 is dramatically reduced in primary lung cancer tissues. To investigate the possible role of KLF4 in lung cancer, we stably transfected KLF4 into cells from lung cancer cell lines H322 and A549 to determine the cells’ invasion ability. Our results showed that ectopic expression of KLF4 extensively suppressed lung cancer cell invasion in Matrigel. This effect was independent of KLF4-mediated p21 up-regulation because ectopic expression of p21 had minimal effect on cell invasion. Our analysis of the expression of 12 genes associated with cell invasion in parental, vector-transfected, and KLF4-transfected cells showed that ectopic expression of KLF4 resulted in extensively repressed expression of secreted protein acidic and rich in cysteine (SPARC), an extracellular matrix protein that plays a role in tumor development and metastasis. Knockdown of SPARC expression in H322 and A549 cells led to suppression of cell invasion, comparable to that observed in KLF4-transfected cells. Moreover, retrovirus-mediated restoration of SPARC expression in KLF4-transfected cells abrogated KLF4-induced anti-invasion activity. Together, our results indicate that KLF4 inhibits lung cancer cell invasion by suppressing SPARC gene expression.
PMCID: PMC2902679  PMID: 20215880
KLF4; tumor invasion; lung; carcinoma; SPARC
20.  Outcome of Trimodality-Eligible Esophagogastric Cancer Patients Who Declined Surgery after Preoperative Chemoradiation 
Oncology  2012;83(5):10.1159/000341353.
For patients with localized esophageal cancer (EC) who can withstand surgery, the preferred therapy is chemoradiation followed by surgery (trimodality). However, after achieving a clinical complete response [clinCR; defined as both post-chemoradiation endoscopic biopsy showing no cancer and physiologic uptake by positron emission tomography (PET)], some patients decline surgery. The literature on the outcome of such patients is sparse.
Between 2002 and 2011, we identified 622 trimodality-eligible EC patients in our prospectively maintained databases. All patients had to be trimodality eligible and must have completed preoperative staging after chemoradiation that included repeat endoscopic biopsy and PET among other routine tests.
Out of 622 trimodality-eligible patients identified, 61 patients (9.8%) declined surgery. All 61 patients had a clinCR. The median age was 69 years (range 47–85). Males (85.2%) and Caucasians (88.5%) were dominant. Baseline stage was II (44.2%) or III (52.5%), and histology was adenocarcinoma (65.6%) or squamous cell carcinoma (29.5%). Forty-two patients are alive at a median follow-up of 50.9 months (95% CI 39.5–62.3). The 5-year overall and relapse-free survival rates were 58.1 ± 8.4 and 35.3 ± 7.6%, respectively. Of 13 patients with local recurrence during surveil-lance, 12 had successful salvage resection.
Although the outcome of 61 EC patients with clinCR who declined surgery appears reasonable, in the absence of a validated prediction/prognosis model, surgery must be encouraged for all trimodality-eligible patients.
PMCID: PMC3832345  PMID: 22964903
Esophageal cancer; Trimodality; Surgery; Chemoradiation; Outcomes
21.  Tissue Platinum Concentration and Tumor Response in Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2012;30(27):3345-3352.
Platinum resistance is a major limitation in the treatment of advanced non–small-cell lung cancer (NSCLC). Reduced intracellular drug accumulation is one of the most consistently identified features of platinum-resistant cell lines, but clinical data are limited. We assessed the effects of tissue platinum concentrations on response and survival in NSCLC.
Patients and Methods
We measured total platinum concentrations by flameless atomic absorption spectrophotometry in 44 archived fresh-frozen NSCLC specimens from patients who underwent surgical resection after neoadjuvant platinum-based chemotherapy. Tissue platinum concentration was correlated with percent reduction in tumor size on post- versus prechemotherapy computed tomography scans. The relationship between tissue platinum concentration and survival was assessed by univariate and multicovariate Cox proportional hazards regression model analysis and Kaplan-Meier analysis.
Tissue platinum concentration correlated significantly with percent reduction in tumor size (P < .001). The same correlations were seen with cisplatin, carboplatin, and all histology subgroups. Furthermore, there was no significant impact of potential variables such as number of cycles and time lapse from last chemotherapy on platinum concentration. Patients with higher platinum concentration had longer time to recurrence (P = .034), progression-free survival (P = .018), and overall survival (P = .005) in the multicovariate Cox model analysis after adjusting for number of cycles.
This clinical study established a relationship between tissue platinum concentration and response in NSCLC. It suggests that reduced platinum accumulation might be an important mechanism of platinum resistance in the clinical setting. Further studies investigating factors that modulate intracellular platinum concentration are warranted.
PMCID: PMC3438232  PMID: 22891266
22.  Insulin-Like Growth Factor Binding Protein-2 Level Is Increased in Blood of Lung Cancer Patients and Associated with Poor Survival 
PLoS ONE  2013;8(9):e74973.
We recently showed that IGFBP2 is overexpressed in primary lung cancer tissues. This study aims to determine whether IGFBP2 is elevated in blood samples of lung cancer patients and whether its level is associated with clinical outcomes.
Methodology/Principal Findings
Plasma IGFBP2 levels were determined blindly by enzyme-linked immunosorbent assay in 80 lung cancer patients and 80 case-matched healthy controls for comparison. We analyzed blood samples for IGFBP2 levels from an additional 84 patients with lung cancer and then tested for associations between blood IGFBP2 levels and clinical parameters in all 164 lung cancer patients. All statistical tests were two-sided and differences with p<0.05 were considered significant. The mean plasma concentration of IGFBP2 in lung cancer patients was significantly higher than that in healthy controls (388.12±261.00 ng/ml vs 219.30±172.84 ng/ml, p<0.001). IGFBP2 was increased in all types of lung cancer, including adenocarcinoma, squamous cell cancer, and small-cell cancer, regardless of patients’ age, sex, or smoking status. IGFBP2 levels were mildly but significantly associated with tumor size and were significantly higher in stage IV than stage I or III disease. A multivariate analysis showed that lung cancer patients whose blood IGFBP2 was higher than 160.9 ng/ml had a poor survival outcome, with a hazard ratio of 8.76 (95% CI 1.12-68.34, p=0.038 after adjustment for tumor size, pathology, and stage). The median survival time for patients with blood IGFBP2 >160.9 ng/ml is 15.1 months; whereas median survival time was 128.2 months for the patients whose blood IGFBP2 was ≤160.9 ng/ml (p =0.0002).
Blood IGFBP2 is significantly increased in lung cancer patients. A high circulating level of IGFBP2 is significantly associated with poor survival, suggesting that blood IGFBP2 levels could be a prognostic biomarker for lung cancer.
PMCID: PMC3775736  PMID: 24069370
23.  Primary Salivary Gland–Type Lung Cancer: Imaging and Clinical Predictors of Outcome 
The objective of our study was to assess whether CT features and FDG uptake of primary salivary gland–type tumors of the lung are associated with tumor type, disease stage, or survival.
CT (n = 30) and PET (n = 15) data of 30 consecutive patients with primary salivary gland–type tumors of the lung were retrospectively evaluated for tumor size, location, and homogeneity and the presence of lymphadenopathy, pleural effusions, and metastases. Maximum FDG uptake and volumetric FDG uptake of the tumors were recorded. The Wilcoxon rank sum and Fisher exact tests and univariate Cox regression were used for statistical calculations.
Compared with mucoepidermoid carcinomas, adenoid cystic carcinomas (57%) were larger (mean, 3.5 vs 2.2 cm, respectively; p = 0.03), more frequently involved the central airways (94% vs 63%; p = 0.002), and had a higher median FDG uptake (p = 0.0264). Higher FDG uptake of the primary tumor was associated with nodal tumor involvement (p = 0.05). The median overall survival times for patients with adenoid cystic carcinoma and mucoepidermoid carcinoma were 7.7 and 4.0 years, respectively. Imaging features that significantly affected overall survival included the presence of mediastinal or hilar lymphadenopathy (hazard ratio [HR], 4.33; 95% CI, 1.15–16.26; p = 0.03), suspected metastatic disease (HR, 5.10; 95% CI, 1.27– 20.47; p = 0.02), and primary tumor heterogeneity (HR, 3.46; 95% CI, 1.04–11.55; p = 0.04).
Higher FDG uptake is associated with nodal disease in patients with primary salivary gland–type tumors of the lung but is not predictive of survival, whereas CT features suggestive of advanced disease correlate with worse outcome.
PMCID: PMC3767141  PMID: 23789697
adenoid cystic carcinoma; CT; mucoepidermoid carcinoma; PET; salivary gland tumor
24.  Thymoma Patients Treated in a Phase I Clinic at MD Anderson Cancer Center: Responses to mTOR Inhibitors and Molecular Analyses 
Oncotarget  2013;4(6):890-898.
Thymomas and thymic carcinoma are rare tumors with no approved therapies. Our purpose was to analyze the molecular features and outcomes of patients referred to the Clinical Center for Targeted Therapy (Phase I Clinic).
We retrospectively reviewed the medical records of consecutive referred patients with advanced/metastatic thymoma or thymic carcinoma
Twenty-one patients were identified (median age 52 years; 10 women; median number of prior systemic therapies = 2). Six of 10 patients (60%) treated with mTOR inhibitor combination regimens achieved stable disease (SD) ≥12 months or a partial response (PR). For patients treated on mTOR inhibitor regimens (N = 10), median time to treatment failure (TTF) was 11.6 months versus 2.3 months on last conventional regimen prior to referral (p=0.024). Molecular analyses (performed by next generation sequencing in seven patients and single polymerase chain reaction (PCR)-based assays in an additional six patients) showed diverse actionable mutations: PIK3CA (1 of 12 tested; 8%); EGFR (1 of 13; 8%); RET (1 of 7; 14%); and AKT1 (1 of 7; 14%). Of two patients with PIK3CA or AKT1 mutations, one was treated with an mTOR inhibitor-based regimen and achieved 26% regression with a TTF of 17 months.
Patients with advanced/metastatic thymoma or thymic carcinoma demonstrated prolonged TTF on mTOR inhibitor-based therapy as compared to prior conventional treatment. Heterogeneity in actionable molecular aberrations was observed, suggesting that multi-assay molecular profiling and individualizing treatment merits investigation.
PMCID: PMC3757246  PMID: 23765114
advanced thymoma; mTOR inhibitors; response; targeted therapy; thymic carcinoma
25.  Antitumor activity of a novel STAT3 inhibitor and redox modulator in non-small cell lung cancer cells☆ 
Biochemical pharmacology  2012;83(10):1456-1464.
NSC-743380 is a novel STAT3 inhibitor that suppresses the growth of several NCI-60 cancer cell lines derived from different tissues and induces regression of xenograft tumors in vivo at various doses. To evaluate the antitumor activity of NSC-743380 in lung cancer cells, we analyzed the susceptibility of 50 NSCLC cell lines to this compound using cell viability assay. About 32% (16 of 50) of these cell lines were highly susceptible to this compound, with a 50% inhibitory concentration (IC50) of <1 µM. In mechanistic studies, the increased numbers of apoptotic cells as well as increased PARP cleavage showed that cytotoxic effects correlate with apoptosis induction. Treatment with NSC-743380 inhibited transcription factor STAT3 activation and induced ROS production in sensitive human lung cancer cell lines but not in resistant cells. Blocking ROS generation with the antioxidant NDGA dramatically abolished NSC-743380-induced growth suppression and apoptosis, but had minimal effect on NSC-743380-induced STAT3 inhibition, suggesting that STAT3 inhibition is not caused by ROS production. Interestingly, knockdown of STAT3 with use of shSTAT3 induced ROS generation and suppressed tumor cell growth. Moreover, scavenging ROS induced by STAT3 inhibition also diminished antitumor activity of STAT3 inhibition. In vivo administration of NSC-743380 suppressed tumor growth and p-STAT3 in lung tumors. Our results indicate that NSC-743380 is a potent anticancer agent for lung cancer and that its apoptotic effects in lung cancer cells are mediated by induction of ROS through STAT3 inhibition.
PMCID: PMC3391570  PMID: 22387047
Drug development; Lung Cancer; STAT3; Reactive oxygen species

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