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1.  Does the Timing of Esophagectomy after Neoadjuvant Chemoradiation Affect Outcome? 
The Annals of thoracic surgery  2011;93(1):207-213.
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.athoracsur.2011.05.021
PMCID: PMC4041623  PMID: 21962263
Adjuvant/neoadjuvant therapy; Esophageal Cancer; Radiation Therapy; Esophageal Surgery
2.  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.
Objective
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.
Results
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.
Conclusion
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.
doi:10.1016/j.urolonc.2010.08.005
PMCID: PMC3956468  PMID: 20933444
Mediastinal neoplasms; Germ-cell neoplasms; Seminoma; Tumor markers; Resection; Outcome
3.  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.
doi:10.1158/1940-6207.CAPR-09-0265
PMCID: PMC3932797  PMID: 20651033
4.  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 
Purpose
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.
Results
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).
Conclusions
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.
doi:10.1016/j.ijrobp.2012.02.015
PMCID: PMC3923623  PMID: 22867894
IMRT; 3D-conformal radiation therapy; chemoradiation; esophageal cancer; propensity score
5.  Prognostic Impact of Radiation Therapy to the Primary Tumor in Patients With Non-small Cell Lung Cancer and Oligometastasis at Diagnosis 
Purpose
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.
Results
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.
Conclusions
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.
doi:10.1016/j.ijrobp.2012.02.054
PMCID: PMC3919541  PMID: 22503522
6.  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
7.  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.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.ejca.2012.06.020
PMCID: PMC3869451  PMID: 22853875
8.  Outcome of Trimodality-Eligible Esophagogastric Cancer Patients Who Declined Surgery after Preoperative Chemoradiation 
Oncology  2012;83(5):10.1159/000341353.
Background:
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.
Method:
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.
Results:
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.
Conclusion:
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.
doi:10.1159/000341353
PMCID: PMC3832345  PMID: 22964903
Esophageal cancer; Trimodality; Surgery; Chemoradiation; Outcomes
9.  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
10.  Tissue Platinum Concentration and Tumor Response in Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2012;30(27):3345-3352.
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1200/JCO.2011.40.8120
PMCID: PMC3438232  PMID: 22891266
11.  Primary Salivary Gland–Type Lung Cancer: Imaging and Clinical Predictors of Outcome 
OBJECTIVE
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.
MATERIALS AND METHODS
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.
RESULTS
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).
CONCLUSION
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.
doi:10.2214/AJR.12.9579
PMCID: PMC3767141  PMID: 23789697
adenoid cystic carcinoma; CT; mucoepidermoid carcinoma; PET; salivary gland tumor
12.  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.
BACKGROUND
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).
METHODS
We retrospectively reviewed the medical records of consecutive referred patients with advanced/metastatic thymoma or thymic carcinoma
RESULTS
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.
CONCLUSION
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
13.  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.
doi:10.1016/j.bcp.2012.02.010
PMCID: PMC3391570  PMID: 22387047
Drug development; Lung Cancer; STAT3; Reactive oxygen species
14.  Predicting Radiation Pneumonitis After Stereotactic Ablative Radiation Therapy in Patients Previously Treated With Conventional Thoracic Radiation Therapy 
Purpose
To determine the incidence of and risk factors for radiation pneumonitis (RP) after stereotactic ablative radiation therapy (SABR) to the lung in patients who had previously undergone conventional thoracic radiation therapy.
Methods and Materials
Seventy-two patients who had previously received conventionally fractionated radiation therapy to the thorax were treated with SABR (50 Gy in 4 fractions) for recurrent disease or secondary parenchymal lung cancer (T <4 cm, N0, M0, or Mx). Severe (grade ≥3) RP and potential predictive factors were analyzed by univariate and multivariate logistic regression analyses. A scoring system was established to predict the risk of RP.
Results
At a median follow-up time of 16 months after SABR (range, 4-56 months), 15 patients had severe RP (14 [18.9%] grade 3 and 1 [1.4%] grade 5) and 1 patient (1.4%) had a local recurrence. In univariate analyses, Eastern Cooperative Oncology Group performance status (ECOG PS) before SABR, forced expiratory volume in 1 second (FEV1), and previous planning target volume (PTV) location were associated with the incidence of severe RP. The V10 and mean lung dose (MLD) of the previous plan and the V10-V40 and MLD of the composite plan were also related to RP. Multivariate analysis revealed that ECOG PS scores of 2-3 before SABR (P=.009), FEV1 ≤65% before SABR (P=.012), V20 ≥30% of the composite plan (P=.021), and an initial PTV in the bilateral mediastinum (P=.025) were all associated with RP.
Conclusions
We found that severe RP was relatively common, occurring in 20.8% of patients, and could be predicted by an ECOG PS score of 2-3, an FEV1 ≤ 65%, a previous PTV spanning the bilateral mediastinum, and V20 ≥30% on composite (previous RT + SABR) plans. Prospective studies are needed to validate these predictors and the scoring system on which they are based.
doi:10.1016/j.ijrobp.2012.02.020
PMCID: PMC3612879  PMID: 22543216
15.  A Prospective Phase 2 Study of Surgery Followed by Chemotherapy and Radiation for Superior Sulcus Tumors 
Cancer  2011;118(2):444-451.
BACKGROUND
The optimal treatment for locally advanced superior sulcus tumors is not clear. The authors report long-term results of a trial examining the safety and efficacy of surgery followed by concurrent chemoradiation therapy for this disease.
METHODS
Thirty-two patients with resectable or marginally resectable superior sulcus tumors at The University of Texas MD Anderson Cancer Center from 1994 to 2010 were enrolled in a prospective trial. Surgery involved segmentectomy or lobectomy with en bloc resection of the involved chest wall and complete nodal staging; radiation therapy (RT) began 14 to 42 days later to a dose of 60 grays (Gy) in 50 1.2-Gy fractions if surgical margins were negative or 64.8 Gy in 54 1.2-Gy fractions if margins were positive. Two cycles of etoposide (50 mg/ m2) and cisplatin (50 mg/m2) were given during RT, and another 3 cycles were given after RT. Eleven patients underwent prophylactic cranial irradiation (PCI).
RESULTS
The protocol completion rate was 78%. Gross total resection was accomplished in all 32 patients; 28% underwent R1 resection. Operative mortality was 0%. The most common surgical complication was postoperative pneumonia (25%). At a median follow-up time of 53.4 months (range, 2–154 months), the 2-year, 5-year, and 10-year rates of locoregional control were 84%, 76%, and 76%; distant metastasis-free survival, 52%, 48%, and 48%; disease-free survival, 49%, 45%, and 45%; and overall survival, 72%, 50%, and 45%, respectively. The brain was the most common site of distant failure (n =5), but no patient who received PCI experienced brain metastasis.
CONCLUSIONS
Surgery followed by postoperative chemoradiation is safe and effective for the treatment of marginally resectable superior sulcus tumors.
doi:10.1002/cncr.26277
PMCID: PMC3465936  PMID: 21713767
Pancoast tumor; lung neoplasms; adjuvant radiotherapy; adjuvant chemotherapy; chemoradiation
16.  Predictors for Locoregional Recurrence for Clinical Stage III-N2 Non-small Cell Lung Cancer with Nodal Downstaging After Induction Chemotherapy and Surgery 
Annals of Surgical Oncology  2012;20(6):1934-1940.
Purpose
Pathologic downstaging following chemotherapy for stage III-N2 NSCLC is a well-known positive prognostic indicator. However, the predictive factors for locoregional recurrence (LRR) in these patients are largely unknown.
Methods
Between 1998 and 2008, 153 patients with clinically or pathologically staged III-N2 NSCLC from two cancer centers in the United States were treated with induction chemotherapy and surgery. All had pathologic N0-1 disease, and none received postoperative radiotherapy. LRR were defined as recurrence at the surgical site, lymph nodes (levels 1–14 including supraclavicular), or both.
Results
Median follow-up was 39.3 months. Pretreatment N2 status was confirmed pathologically (18.2 %) or by PET/CT (81.8 %). Overall, the 5-year LRR rate was 30.8 % (n = 38), with LRR being the first site of failure in 51 % (22/+99877943). Five-year overall survival for patients with LRR compared with those without was 21 versus 60.1 % (p < 0.001). Using multivariate analysis, significant predictors for LRR were pN1 disease at time of surgery (p < 0.001, HR 3.43, 95 % CI 1.80–6.56) and a trend for squamous histology (p = 0.072, HR 1.93, 95 % CI 0.94–3.98). Five-year LRR rate for pN1 versus pN0 disease was 62 versus 20 %. Neither single versus multistation N2 disease (p = 0.291) nor initial staging technique (p = 0.306) were predictors for LRR. N1 status also was predictive for higher distant recurrence (p = 0.021, HR 1.91, 95 % CI 1.1–3.3) but only trended for poorer survival (p = 0.123, HR 1.48, 95 % CI 0.9–2.44).
Conclusions
LRR remains high in resected stage III-N2 NSCLC patients after induction chemotherapy and nodal downstaging, particularly in patients with persistent N1 disease.
Electronic supplementary material
The online version of this article (doi:10.1245/s10434-012-2800-x) contains supplementary material, which is available to authorized users.
doi:10.1245/s10434-012-2800-x
PMCID: PMC3656229  PMID: 23263700
17.  Prognostic Significance of Baseline Positron Emission Tomography And Importance of Clinical Complete Response In Patients With Esophageal or Gastroesophageal Junction Cancer Treated With Definitive Chemoradiotherapy 
Cancer  2011;117(21):4823-4833.
Background
Metabolic imaging is of interest in esophageal cancer, however, the usefulness of initial standardized uptake value (iSUV) of positron emission tomography (PET) is unknown in patients with esophageal or gastroesophageal carcinoma (E-GEC) treated with definitive chemoradiotherapy. We hypothesized that iSUV would correlate with patient outcome.
Methods
We retrospectively analyzed E-GEC patients who had a baseline PET and endoscopic ultrasonography (EUS) in addition to other routine staging. All patients received definitive chemoradiotherapy. Multiple statistical methods were employed.
Results
We analyzed 209 consecutive E-GEC patients treated with definitive chemoradiation for outcome; of these 179 had baseline PET for additional analyses. The median overall survival (OS) for all patients was 20.7 months (95% confidence interval; 18.8, 26.3 months). Patients with clinical complete response (cCR) lived longer than those with
Conclusions
Our data indicate that a higher iSUV is associated with poorer OS in patients with E-GEC receiving definitive chemoradiation. Upon validation, baseline PET may become a useful stratification factor in randomized trials and for individualizing therapy.
doi:10.1002/cncr.26122
PMCID: PMC3144261  PMID: 21456015
The Annals of thoracic surgery  2012;94(3):914-920.
Background
Persistent pathologic mediastinal nodal involvement after induction chemotherapy and surgical resection is a negative prognostic factor for stage III-N2 non-small cell lung cancer patients. This population has high rates of local-regional failure and distant failure, yet the effectiveness of additional therapies is not clear. We assessed the role of consolidative therapies (postoperative radiation therapy and chemotherapy) for such patients.
Methods
In all, 179 patients with stage III-N2 non-small cell lung cancer at MD Anderson Cancer Center were treated with induction chemotherapy followed by surgery from 1998 through 2008; 61 patients in this cohort had persistent, pathologically confirmed, mediastinal nodal disease, and were treated with postoperative radiation therapy. Local-regional failure was defined as recurrence at the surgical site or lymph nodes (levels 1 to 14, including supraclavicular), or both. Overall survival was calculated using the Kaplan-Meier method, and survival outcomes were assessed by log rank tests. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing local-regional failure, distant failure, and overall survival.
Results
All patients received postoperative radiation therapy after surgery, but approximately 25% of the patients also received additional chemotherapy: 9 (15%) with concurrent chemotherapy, 4 (7%) received adjuvant sequential chemotherapy, and 2 (3%) received both. Multivariate analysis indicated that additional postoperative chemotherapy significantly reduced distant failure (hazard ratio 0.183, 95% confidence interval: 0.052 to 0.649, p = 0.009) and improved overall survival (hazard ratio 0.233, 95% confidence interval: 0.089 to 0.612, p = 0.003). However, additional postoperative chemotherapy had no affect on local-regional failure.
Conclusions
Aggressive consolidative therapies may improve outcomes for patients with persistent N2 disease after induction chemotherapy and surgery.
doi:10.1016/j.athoracsur.2012.04.088
PMCID: PMC3468148  PMID: 22819472
Introduction
We evaluated the ability of histopathologic response criteria to predict overall survival (OS) and disease-free survival (DFS) in patients with surgically resected non-small cell lung cancer (NSCLC) treated with or without neoadjuvant chemotherapy.
Methods
Tissue specimens from 358 patients with NSCLC were evaluated by pathologists blinded to the patient treatment and outcome. The surgical specimens were reviewed for various histopathologic features in the tumor including percentage of residual viable tumor cells, necrosis, and fibrosis. The relationship between the histopathologic findings and OS was assessed.
Results
The percentage of residual viable tumor cells and surgical pathologic stage were associated with OS and DFS in 192 patients with NSCLC receiving neoadjuvant chemotherapy in multivariate analysis (p = 0.005 and p = 0.01, respectively). There was no association of OS or DFS with percentage of viable tumor cells in 166 patients with NSCLC who did not receive neoadjuvant chemotherapy (p = 0.31 and p = 0.45, respectively). Long-term OS and DFS were significantly prolonged in patients who had ≤10% viable tumor compared with patients with >10% viable tumor cells (5 years OS, 85% versus 40%, p < 0.0001 and 5 years DFS, 78% versus 35%, p < 0.001).
Conclusion
The percentages of residual viable tumor cells predict OS and DFS in patients with resected NSCLC after neoadjuvant chemotherapy even when controlled for pathologic stage. Histopathologic assessment of resected specimens after neoadjuvant chemotherapy could potentially have a role in addition to pathologic stage in assessing prognosis, chemotherapy response, and the need for additional adjuvant therapies.
doi:10.1097/JTO.0b013e318247504a
PMCID: PMC3465940  PMID: 22481232
Lung cancer; Neoadjuvant chemotherapy; Histopathology
Cancer biology & therapy  2007;7(1):103-108.
Many cancers can become resistant to repeated administration of even the most effective therapeutic agents. In developing adenoviral mda-7/IL-24 (Ad-mda-7/IL-24) therapy for lung cancer, we have anticipated this potential clinical problem by attempting to identify the molecular mechanisms of Ad-mda7/IL-24 resistance in several Ad-mda7/IL-24-resistant lung cancer cell lines that we have developed. For the present study, we established four Ad-mda7-resistant cell lines by repeated selection of resistant clones of parental Ad-mda7-sensitive A549 cells: two lines (A549R1 and A549R2) resistant to both adenoviral vector and the mda-7 gene and two (A549R3 and A549R4) resistant to the therapeutic mda-7 gene only. As shown by western blot analysis of several known anti-apoptotic proteins, parental A549 and resistant A549R3 cells expressed similar levels of AKT and phosphorylated AKT (p-AKT), whereas resistant A549R3 and A549R4 cells expressed higher levels of bcl-2 and lower levels of bcl-xL than did their parental cells. As shown by flow-cytometric analysis, treating resistant A549R3 and A549R4 cells with a combination of Ad-mda7 and 17-allylamino-17-demethoxygeldanamycin (17AAG) (50 nM) for 48 hours enhanced apoptosis. Together, these in vitro findings indicate that an antiapoptotic mechanism may underlie Ad-mda7 resistance and that such resistance can be overcome by addition of 17AAG. Further investigations along these lines are warranted.
PMCID: PMC3442784  PMID: 18059175
resistant cell lines; apoptosis; MDA-7; adenovirus; gene therapy
Purpose
To analyze the toxicity and patterns of failure of proton therapy given in ablative doses for medically inoperable early-stage non-small cell lung cancer (NSCLC).
Methods and Materials
Eighteen patients with medically inoperable T1N0M0 (central location) or T2-3N0M0 (any location) NSCLC were treated with proton therapy at 87.5 Gy (relative biological effectiveness, RBE) at 2.5 Gy/fraction in this phase I/II study. All patients underwent treatment simulation with 4-dimensional (4D) computed tomography (CT); internal gross tumor volumes (iGTVs) were delineated on maximal intensity projection (MIP) images and modified by visual verification of the target volume in 10 breathing phases. The iGTV with MIP density was used to design compensators and apertures to account for tumor motion. Therapy consisted of passively scattered protons. All patients underwent repeat 4D CT simulations during treatment to assess the need for adaptive replanning.
Results
At a median follow-up time of 16.3 months (range, 4.8–36.3 months), no patient had experienced grade 4 or 5 toxicity. The most common adverse effect was dermatitis (grade 2, 67%; grade 3, 17%), followed by grade 2 fatigue (44%), grade 2 pneumonitis (11%), grade 2 esophagitis (6%), and grade 2 chest wall pain (6%). Rates of local control were 88.9%, regional lymph node failure 11.1%, and distant metastasis 27.8%. Twelve patients (67%) were still alive at the last follow-up; five had died of metastatic disease and one of preexisting cardiac disease.
Conclusions
Proton therapy to ablative doses is well tolerated and produces promising local control rates for medically inoperable early-stage NSCLC.
doi:10.1016/j.ijrobp.2010.04.049
PMCID: PMC3117089  PMID: 21251767
Proton therapy; non-small cell lung cancer; toxicity; patterns of failure
Altered microRNA (miRNA) expression has been found to promote carcinogenesis, but little is known about the role of miRNAs in esophageal cancer. In this study, we selected 10 miRNAs and analyzed their expression in 10 esophageal cancer cell lines and 158 tissue specimens using Northern blotting and in situ hybridization, respectively. We found that Let-7g, miR-21, and miR-195p were expressed in all 10 cell lines, miR-9 and miR-20a were not expressed in any of the cell lines, and miR-16-2, miR-30e, miR-34a, miR-126, and miR-200a were expressed in some of the cell lines but not others. In addition, transient transfection of miR-34a inhibited c-Met and cyclin D1 expression and esophageal cancer cell proliferation, whereas miR-16-2 suppressed RAR-β2 expression and increased tumor cell proliferation. Furthermore, we found that miR-126 expression was associated with tumor cell de-differentiation and lymph node metastasis, miR-16-2 was associated with lymph node metastasis, and miR-195p was associated with higher pathologic disease stages in patients with esophageal adenocarcinoma. Kaplan-Meier analysis showed that miR-16-2 expression and miR-30e expression were associated with shorter overall and disease-free survival in all esophageal cancer patients. In addition, miR-16-2, miR-30e, and miR-200a expression were associated with shorter overall and disease-free survival in esophageal adenocarcinoma patients; however, miR-16-2, miR-30e, and miR-200a expression was not associated with overall or disease-free survival in squamous cell carcinoma patients. Our data indicate that further evaluation of miR-30e and miR-16-2 as prognostic biomarkers is warranted in patients with esophageal adenocarcinoma. In addition, the role of miR-34a in esophageal cancer also warrants further study.
doi:10.1002/ijc.25330
PMCID: PMC2937084  PMID: 20309880
miRNA; cell viability; gene regulation; prognosis; esophageal cancer
Purpose
The role of RNA-dependent protein kinase (PKR) in antiviral defence mechanisms and in cellular differentiation, growth, and apoptosis is well known, but the role of PKR in human lung cancer remains poorly understood. To explore the role of PKR in human lung cancer, we evaluated PKR’s expression in tissue microarray specimens from both non-small cell lung cancer (NSCLC) and normal human bronchial epithelium tissue.
Experimental Design
Tissue microarray samples (TMA-1) from 231 lung cancers were stained with PKR antibody and validated on TMA-2 from 224 lung cancers. Immunohistochemical expression score was quantified by three pathologists independently. Survival probability was computed by the Kaplan-Meier method.
Results
The NSCLC cells showed lower levels of PKR expression than normal bronchial epithelium cells did. We also found a significant association between lower levels of PKR expression and lymph node metastasis. We found that loss of PKR expression is correlated with a more aggressive behavior, and that a high PKR expression predicts a subgroup of patients with a favorable outcome. Univariate and multivariate Cox proportional hazards regression models showed that a lower level of PKR expression was significantly associated with shorter survival in NSCLC patients. We further validated and confirmed that PKR to be a powerful prognostic factor in TMA-2 lung cancer (HR=0.22, P<0.0001).
Conclusions
Our findings first indicate that PKR expression is an independent prognostic variable in NSCLC patients.
doi:10.1158/1078-0432.CCR-10-0753
PMCID: PMC3070287  PMID: 20930042
PKR; Biomarker; Lung cancer
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
Purpose
We performed a study to determine if a fluorescence in-situ hybridization (FISH)-based assay using isolated peripheral blood mononuclear cells (PBMCs) with DNA probes targeting specific sites on chromosomes known to have abnormalities in Non Small Cell Lung Cancer (NSCLC) cases could detect circulating genetically abnormal cells (CACs).
Experimental Design
We evaluated 59 NSCLC cases with stage I through IV disease and 24 controls. PBMCs and matched tumors were hybridized with 2 two-color (3p22.1/CEP3 and 10q22.3 [SP-A]/CEP10) and 2 four-color (CEP3, CEP7, CEP17, and 9p21.3 [URO]) and (EGFR, c-MYC, 6p11-q11, and 5p15.2 [LAV]) FISH probes. Percentages of cytogenetically abnormal cells (CACs) in peripheral blood and in matched tumor specimens were quantified using an automated fluorescent scanner. Numbers of CACs were calculated based on the percentage of CACs (defined as PBMCs with genetic abnormalities) per mL of blood and expressed per microliter of blood.
Results
Patients with NSCLC had significantly higher numbers of CACs than did controls. Mean number of CACs ranged from 7.23±1.32/μl for deletions of 10q22.3/CEP10 to 45.52±7.49/μl for deletions of 3p22.1/CEP3. Numbers of CACs with deletions of 3p22.1, 10q22.3, and 9p21.3, and gains of URO, increased significantly from early to advanced stage of disease.
Conclusions
We have developed a sensitive and quantitative antigen-independent FISH-based test for detecting CACs in peripheral blood of patients with NSCLC which showed a significant correlation with the presence of cancer. If this pilot study can be validated in a larger study, CACs may have a role in the management of patients with NSCLC.
doi:10.1158/1078-0432.CCR-09-3358
PMCID: PMC2949278  PMID: 20651054

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