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1.  Lung Volume Measurements as a Surrogate Marker for Patient Response in Malignant Pleural Mesothelioma 
Introduction
The purpose of this study was to investigate continuous changes in three distinct response assessment methods during treatment as a marker of response for mesothelioma patients. Linear tumor thickness measurements, disease volume measurements, and lung volume measurements (a physiological correlate of disease volumes) were investigated in this study.
Methods
Serial CT scans were obtained during the course of clinically standard chemotherapy for 61 patients. For each of the 216 CT scans the aerated lung volumes were segmented using a fully automated method, and the pleural disease volume was segmented using a semi-automated method. Modified RECIST linear thickness measurements were acquired clinically. Diseased (ipsilateral) lung volumes were normalized by the respective contralateral lung volumes to account for differences in inspiration between scans for each patient. Relative changes in each metric from baseline were tracked over the course of follow-up imaging. Survival modeling was performed using Cox proportional hazards models with time-varying covariates.
Results
Median survival from pre-treatment baseline imaging was 12.7 months. A negative correlation was observed between measurements of lung volume and disease volume, and a positive correlation was observed between linear thickness measurements and disease volume. As continuous numerical parameters, all three response assessment methods were significant imaging biomarkers of patient prognosis in independent survival models.
Conclusions
Analysis of trajectories of linear thickness measurements, disease volume measurements, and lung volume measurements during chemotherapy for patients with mesothelioma indicates that increasing linear thickness, increasing disease volume, and decreasing lung volume are all significantly and independently associated with poor patient prognosis.
doi:10.1097/JTO.0b013e31828354c8
PMCID: PMC3597989  PMID: 23486268
2.  Optimization of Response Classification Criteria for Patients with Malignant Pleural Mesothelioma 
Introduction
Response assessment metrics play an important role in clinical trials and routine patient management. For patients with malignant pleural mesothelioma (MPM), the standard for response assessment is image-based measurements of tumor thickness made according to the modified RECIST (Response Evaluation Criteria in Solid Tumors) protocol. To classify tumor response, changes in tumor thickness are compared with the standard RECIST −30% and +20% cut-points for partial response (PR) and progressive disease (PD), respectively, which are not specific to MPM. The purpose of this work is to optimize the correlation between tumor response and patient survival by assessing the validity of existing response criteria in MPM, and proposing alternative criteria.
Methods
CT measurements of tumor thickness were acquired at baseline and throughout treatment for 78 patients undergoing standard of care chemotherapy. Overall survival was correlated with best response and first follow-up response using Harrell’s C statistic. The response criteria for PD and PR were each varied in 1% increments to obtain the optimal classification criteria. The performance was cross-validated using a leave-one-out approach.
Results
Median survival was 14.9 months. The performance of the standard RECIST criteria in correlating response with survival was 0.778, while the optimized performance was obtained with criteria of −64% for PR and +50% for PD, yielding a performance of 0.855. After cross-validation, this performance was slightly reduced to 0.829.
Conclusions
New tumor response classification criteria were obtained for patients with MPM. These criteria improve the correlation between image-based response and patient survival.
doi:10.1097/JTO.0b013e318269fe21
PMCID: PMC3473122  PMID: 23059782
3.  Immunological effects of the TGFβ-blocking antibody GC1008 in malignant pleural mesothelioma patients 
Oncoimmunology  2013;2(8):e26218.
We evaluated a neutralizing anti-TGFβ antibody (GC1008) in cancer patients with malignant pleura mesothelioma (MPM). The goal of this study was to assess immunoregulatory effects in relation to clinical safety and clinical response. Patients with progressive MPM and 1–2 prior systemic therapies received GC1008 at 3mg/kg IV over 90 min every 21 d as part of an open-label, two-center Phase II trial. Following TGFβ blockade therapy, clinical safety and patient survival were monitored along with the effects of anti-TGFβ antibodies on serum biomarkers and peripheral blood mononuclear cells (PBMC). Although designed as a larger trial, only 13 patients were enrolled when the manufacturer discontinued further development of the antibody for oncology indications. All participants tolerated therapy. Although partial or complete radiographic responses were not observed, three patients showed stable disease at 3 mo. GC1008 had no effect in the expression of NK, CD4+, or CD8+ T cell activating and inhibitory markers, other than a decrease in the expression of 2B4 and DNAM-1 on NK cells. However, serum from 5 patients showed new or enhanced levels of antibodies against MPM tumor lysates as measured by immunoblotting. Patients who produced anti-tumor antibodies had increased median overall survival (OS) (15 vs 7.5 mo, p < 0.03) compared with those who did not. To our knowledge, these data represent the first immune analysis of TGFβ- blockade in human cancer patients.
doi:10.4161/onci.26218
PMCID: PMC3812201  PMID: 24179709
GC1008; anti-TGFβ antibody; antibody therapy; clinical trial; immunotherapy; malignant mesothelioma
4.  Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma 
Journal of Clinical Oncology  2012;30(20):2509-2515.
Purpose
Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM.
Patients and Methods
Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m2 on days 1 and 8 every 21 days, cisplatin 75 mg/m2 every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression.
Results
One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater.
Conclusion
The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM.
doi:10.1200/JCO.2011.41.5869
PMCID: PMC3397785  PMID: 22665541
5.  Does Health-Related Quality of Life Improve for Advanced Pancreas Cancer Patients Who Respond to Gemcitabine? Analysis of a Randomized Phase III Trial of the Cancer and Leukemia Group B (CALGB 80303) 
Context
Gemcitabine for advanced pancreas cancer (APC) is palliative and prognosis is poor, making health-related quality of life (HRQOL) particularly important.
Objectives
We evaluated HRQOL with the EuroQol EQ-5D™, in patients with APC participating in Cancer and Leukemia Group B (CALGB) 80303, a multicenter, double-blind, randomized trial comparing overall survival (OS) between two treatment arms, gemcitabine with bevacizumab, or gemcitabine with placebo.
Methods
A consecutive subsample of patients was invited to complete the EQ-5D surveys. Because neither clinical nor HRQOL outcomes differed based on study arm, analyses were pooled. Changes in mean scores from baseline to eight weeks and the prognostic value of the EQ-5D were evaluated.
Results
Mean index scores remained stable (0.78 at baseline [n=267], 0.79 at eight weeks [n=186], P-value=0.34, Wilcoxon signed rank test), attributable to a modest deterioration of physical function domain scores coincident with small improvements in pain and anxiety/depression scores. A small decline in visual analogue scale (VAS) scores was observed (70.7 vs. 68.2, P-value=0.026). HRQOL changes within chemotherapy response strata revealed stable index scores, but a trend of worsened physical function among patients with disease progression compared with those with stable or improved disease. VAS scores trended downward over time irrespective of chemotherapy response status, with a statistically meaningful deterioration in patients who progressed (68.9 vs. 64.4, P-value=0.029). Baseline scores from both EQ-5D scales were significant predictors of OS in Cox proportional hazard models.
Conclusion
Response to gemcitabine treatment in APC is not associated with appreciable improvement of global HRQOL. Small improvements in pain and mood are observed despite progressive functional decline. Those who respond to gemcitabine may experience a slight slowing of functional deterioration.
doi:10.1016/j.jpainsymman.2011.09.001
PMCID: PMC3658140  PMID: 22104618
Advanced pancreas cancer; gemcitabine; quality of life
6.  Cetuximab is Associated With Excessive Toxicity When Combined With Bevacizumab Plus mFOLFOX6 in Metastatic Colorectal Carcinoma 
Clinical colorectal cancer  2010;9(5):290-296.
Background
The bevacizumab-cetuximab combination has shown promising activity in chemotherapy-refractory metastatic colorectal cancer (mCRC). We sought to determine the safety and efficacy of cetuximab added to bevaci-zumab plus standard mFOLFOX6 (modified 5-fluorouracil [5-FU]/leucovorin/oxaliplatin) as first-line therapy for mCRC.
Patients and Methods
Sixty-six patients received cetuximab (400 mg/m2 loading dose, then 250 mg/m2 weekly intravenously [I.V.]) plus bevacizumab 5 mg/kg and mFOLFOX6 chemotherapy every 2 weeks. The primary endpoint was toxicity.
Results
The most common grade 3–4 events included diarrhea (14%), fatigue (14%), neuropathy (12%), venous thrombosis (9%), acneiform rash (8%), and desquamation (8%). A protocol-defined prohibitive adverse event occurred in 4 patients (6%), including 2 treatment-associated deaths. Thirty-seven patients (56%) discontinued therapy before disease progression because of either toxicity (n = 19; 29%) or patient withdrawal (n = 18; 27%). Twenty-eight of 37 patients (76%) who discontinued therapy before disease progression did so because of cetuximab-associated toxicity.
Conclusion
Although the addition of cetuximab to bevacizumab plus mFOLFOX6 was not associated with excessive life-threatening toxicity, many patients discontinued therapy because of cetuximab-associated toxicity. Taken together with the results of recently reported phase III trials, cetuximab should not be used concurrently with bevacizumab and infusional 5-FU, leucovorin, and oxaliplatin chemotherapy for the treatment of mCRC.
doi:10.3816/CCC.2010.n.042
PMCID: PMC3623373  PMID: 21208843
KRAS mutation; Oxaliplatin; Vascular endothelial growth factor
7.  Phase II study of dasatinib in patients with previously treated malignant mesothelioma (Cancer and Leukemia Group B 30601): a brief report 
Journal of Thoracic Oncology  2012;7(4):755-759.
Introduction
We conducted a phase II trial of dasatinib in malignant mesothelioma (MM) patients to evaluate its toxicity and efficacy as a second-line treatment.
Material and Methods
Patients with unresectable MM and no symptomatic effusions were given dasatinib 70 mg twice daily as part of a 28-day cycle. We also measured plasma VEGF and PDGFβ and serum CSF-1 and mesothelin-related protein at baseline and during therapy.
Results
Forty-six patients were enrolled in this study. Fifty percent of the first 12 patients enrolled experienced ≥ grade 3 treatment-related adverse events, and therefore, the starting dose was reduced to 50 mg twice daily. Grade 3 and 4 toxicities included fatigue (11%) and pleural effusion (9%). The overall disease control rate was 32.6%, and PFS at 24 weeks was 23% (95% CI: 13.5%, 40.0%). Survival was markedly longer in patients with lower pre-treatment CSF-1 levels and in patients whose CSF-1 levels decreased from baseline during therapy.
Discussion
Single-agent dasatinib has no activity in MM and is associated with pulmonary toxicities that prohibit its use in an unselected MM population.
doi:10.1097/JTO.0b013e318248242c
PMCID: PMC3308128  PMID: 22425926
dasatinib; mesothelioma; SRC kinase
8.  Identification of Potential Prognostic Biomarkers in Patients with Untreated, Advanced Pancreatic Cancer from a Phase III Trial (CALGB 80303) 
Cancer  2011;118(2):571-578.
BACKGROUND
Patients with advanced stage adenocarcinoma of the pancreas have a poor prognosis. The identification of prognostic and/or predictive biomarkers may help stratify patients so that therapy can be individualized.
METHODS
Serum samples from patients enrolled in the CALGB 80303 Phase III trial, “Randomized Study of Gemcitabine with Versus without Bevacizumab in Patients with Locally Advanced or Metastatic Adenocarcinoma of the Pancreas” were used to discover novel biomarkers. For the discovery phase, 40 sera were selected based on length of survival and type of therapy, and subjected to LC-MS/MS analysis. The top features (proteins) were then further selected for validation by ELISA.
RESULTS
Quantitation by nano-LC-MS/MS resulted in 1452 peptides mapping to 156 proteins across all 40 samples, 92 of which had 2 or more peptides. After curation of the data we selected one putative prognostic protein, alpha-1 antichymotrypsin (AACT), and two putative predictive proteins, histidine-rich glycoprotein (HRG) and complement factor H (CFH) for validation by ELISA. AACT was found to be negatively correlated with overall survival (τ = −0.30 (−0.38, −0.22); p<0.00001). There was no evidence for interaction with bevacizumab and HRG, but there was some evidence for a weak positive correlation of HRG with overall survival (τ = 0.11 (0.03, 0.19); p<0.01). CFH was found to be neither a predictive nor a prognostic factor for overall survival.
CONCLUSION
AACT may be a useful prognostic marker in patients with advanced stage pancreatic carcinoma, although additional validation studies are needed.
doi:10.1002/cncr.26270
PMCID: PMC3184330  PMID: 21713765
pancreatic neoplasms; prognosis; biological markers; bevacizumab; alpha 1-antichymotrypsin
9.  Three-Dimensional Stereoscopic Volume Rendering of Malignant Pleural Mesothelioma 
International Surgery  2012;97(1):65-70.
Our objective was to investigate the application of three-dimensional (3D) stereoscopic volume rendering with perceptual colorization on preoperative imaging for malignant pleural mesothelioma. At present, we have prospectively enrolled 6 patients being considered for resection of malignant pleural mesothelioma that have undergone a multidetector-row computed tomography (CT) scan of the chest. The CT data sets were volume rendered without preprocessing. The resultant 3D rendering was displayed stereoscopically and used to provide information regarding tumor extent, morphology, and anatomic involvement. To demonstrate this technique, this information was compared with the corresponding two-dimensional CT grayscale axial images from two of these patients. Three-dimensional stereoscopic reconstructions of the CT data sets provided detailed information regarding the local extent of tumor that could be used for preoperative surgical planning. Three-dimensional stereoscopic volume rendering for malignant pleural mesothelioma is a novel approach. Combined with our innovative perceptual colorization algorithm, stereoscopic volumetric analysis potentially allows for the accurate determination of the extent of pleural mesothelioma with results difficult to duplicate using grayscale, multiplanar CT images.
doi:10.9738/CC66.1
PMCID: PMC3723194  PMID: 23102002
Mesothelioma; Imaging; Lung cancer; Diagnosis; Computed tomography; CAT scan; Imaging
10.  Personalized Colon Cancer Care in 2010 
Seminars in oncology  2011;38(2):284-308.
Colon cancer therapies have improved patient outcomes significantly over the last decades in both the adjuvant and metastatic settings. With the introduction of a number of novel agents, both traditional chemotherapies and biologically targeted agents, the need to identify subgroups that are likely and not likely to respond to a particular treatment regimen is paramount. This will allow patients who are likely to benefit to receive optimal care, while sparing those unlikely to benefit from unnecessary toxicity and cost. With the identification of several novel biomarkers and a variety of technologies to interrogate the genome, we are already able to rapidly study patient tumor or blood samples and normal tissues to generate a large dataset of aberrations within the cancer. How to digest this complex information to obtain accurate, reliable, and meaningful results that will allow us to provide truly personalized care for colon cancer patients is just starting to be addressed. In this article, we briefly review the history of colon cancer treatment, with an emphasis on current clinical standards that incorporate a ‘personalized medicine’ approach. We then review strategies which will potentially improve our ability to individualize therapy in the future.
doi:10.1053/j.seminoncol.2011.01.001
PMCID: PMC3065981  PMID: 21421118
11.  Quantitative Measurement of Lung Re-Expansion in Malignant Pleural Mesothelioma Patients Undergoing Pleurectomy/Decortication 
Academic radiology  2010;18(3):294-298.
Rationale and Objectives
Malignant pleural mesothelioma (MPM) is a neoplasm that grows circumferentially along the pleura. The tumor and concurrent pleural effusion may reduce lung function by restricting or preventing lung expansion. The purpose of this study was to provide objective evidence that pleurectomy/decortication (P/D) allows trapped lung to re-expand, quantify the re-expansion based on computed tomography (CT) scans, and investigate whether the expansion persists after surgery.
Materials and Methods
A database of 12 patients demonstrating unilateral MPM was collected. Each patient underwent a pre-surgical CT scan, surgical debulking by P/D, and two post-surgical CT scans (at one and four months). The lung volume was measured in each scan using an automated algorithm and compared for each patient across time.
Results
An increase in the ipsilateral post-surgical lung volume was observed for 10 of 12 patients (83%) one month after surgery. The median ipsilateral volume increase was 44% relative to the pre-surgical ipsilateral volume and 21% relative to the contralateral volume. A statistically significant change in ipsilateral lung volume was not observed between 1 -month and 4-month post-surgical scans, implying that the volume improvement persisted months after surgery.
Conclusions
Debulking of MPM with P/D substantially increased the ipsilateral lung volume relative to both the pre-surgical, ipsilateral volume and the contralateral lung volume. This improvement persisted months after surgery.
doi:10.1016/j.acra.2010.10.009
PMCID: PMC3075578  PMID: 21145765
12.  A Cancer and Leukemia Group B Phase II Study of Sunitinib Malate in Patients with Previously Treated Metastatic Pancreatic Adenocarcinoma (CALGB 80603) 
The Oncologist  2010;15(12):1310-1319.
This paper reports a trial performed by a National Cancer Institute–funded cooperative group evaluating the antitumor efficacy and safety of sunitinib malate in patients with previously treated pancreas adenocarcinoma.
Background.
The Cancer and Leukemia Group B (CALGB) conducted a phase II study evaluating sunitinib in patients with progressive metastatic pancreas adenocarcinoma following prior gemcitabine-based therapy (trial CALGB 80603; ClinicalTrials.gov identifier, NCT00397787). The primary endpoint was to determine the disease control rate (DCR) as measured by the Response Evaluation Criteria in Solid Tumors (complete response, partial response [PR], and stable disease) at 6 weeks.
Patients and Methods.
Patients aged ≥18 years with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2 and with progressive pancreas adenocarcinoma following treatment with gemcitabine were eligible. Sunitinib was dosed at 50 mg orally days 1–28, every 42 days (1 cycle). The statistical plan called for a three-stage design. A DCR ≥15% was considered worthy of further study.
Results.
In total, 77 patients were enrolled. Forty-two (54.6%) enrollees were male. The median age was 65 years. The ECOG performance status score distribution was: 0, 39%; 1, 50%; 2, 11%. The DCR was 21.6%; one patient (1.4%) had a PR and 15 patients (20.3%) had stable disease as their best response. The progression-free survival time was 1.31 months (95% confidence interval [CI] 1.25–1.38 months) and overall survival time was 3.68 months (95% CI, 3.06–4.24 months).
Conclusions.
The study met its primary endpoint; however sunitinib had minimal activity and moderate toxicity in a population of gemcitabine-refractory pancreas adenocarcinoma patients. For future studies, limiting enrollment to patients with an ECOG performance status score of 0–1 is recommended.
doi:10.1634/theoncologist.2010-0152
PMCID: PMC3227926  PMID: 21148613
Sunitinib; Phase II; Refractory; Pancreas adenocarcinoma; CALGB 80603
13.  Role of protein kinase C β and vascular endothelial growth factor receptor in malignant pleural mesothelioma: Therapeutic implications and the usefulness of Caenorhabditis elegans model organism 
Purpose:
To examine the role of both protein kinase C (PKC)-β and vascular endothelial growth factor receptor (VEGFR)-2 in malignant pleural mesothelioma (MPM) using respective inhibitors, enzastaurin and KRN633.
Materials and Methods:
MPM cell lines, control cells, and a variety of archived MPM tumor samples were used to determine the protein expression levels of PKC-β, VEGFR-2, VEGF, and p-AKT. Effects of enzastaurin and KRN633 on phosphorylation status of key signaling molecules and viability of the mesothelioma cells were determined. The common soil nematode, Caenorhabditis elegans, was treated with enzastaurin to determine its suitability to screen for highly potent kinase inhibitors.
Results:
PKC-β1, PKC-β2 and VEGFR-2/KDR were overexpressed in MPM cell lines and MPM tumor tissues. Enzastaurin treatment resulted in significant loss in viability of VEGF induced cell proliferation; however, the effect of KRN633 was much less. Enzastaurin also dramatically decreased the phosphorylation of PKC-β, its downstream target p-AKT, and surprisingly, the upstream VEGFR-2. The combination of the two drugs at best was additive and similar results were obtained with respect to cell viability. Treatment of C. elegans with enzastaurin resulted in clear phenotypic changes and the worms were hypermotile with abnormal pattern and shape of eggs, suggesting altered fecundity.
Conclusions:
PKC-β1 and VEGFR-2 are both excellent therapeutic targets in MPM. Enzastaurin was better at killing MPM cells than KRN633 and the combination lacked synergy. In addition, we show here that C. elegans can be used to screen for the next generation inhibitors as treatment with enzastaurin resulted in clear phenotypic changes that could be assayed.
doi:10.4103/1477-3163.77274
PMCID: PMC3049271  PMID: 21383961
Enzastaurin; KRN633; malignant pleural mesothelioma; PKC-β; VEGFR-2
14.  Randomized Phase II Study of Gemcitabine Administered at a Fixed Dose Rate or in Combination With Cisplatin, Docetaxel, or Irinotecan in Patients With Metastatic Pancreatic Cancer: CALGB 89904 
Journal of Clinical Oncology  2009;27(33):5506-5512.
Purpose
The relative value of gemcitabine-based combination chemotherapy therapy and prolonged infusions of gemcitabine in patients with advanced pancreatic cancer remains controversial. We explored the efficacy and toxicity of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in a multi-institutional, randomized, phase II study.
Patients and Methods
Patients with metastatic pancreatic cancer were randomly assigned to one of the following four regimens: gemcitabine 1,000 mg/m2 on days 1, 8, and 15 with cisplatin 50 mg/m2 on days 1 and 15 (arm A); gemcitabine 1,500 mg/m2 at a rate of 10 mg/m2/min on days 1, 8, and 15 (arm B); gemcitabine 1,000 mg/m2 with docetaxel 40 mg/m2 on days 1 and 8 (arm C); or gemcitabine 1,000 mg/m2 with irinotecan 100 mg/m2 on days 1 and 8 (arm D). Patients were observed for response, toxicity, and survival.
Results
Two hundred fifty-nine patients were enrolled onto the study, of whom 245 were eligible and received treatment. Anticipated rates of myelosuppression, fatigue, and expected regimen-specific toxicities were observed. The overall tumor response rates were 12% to 14%, and the median overall survival times were 6.4 to 7.1 months among the four regimens.
Conclusion
Gemcitabine/cisplatin, fixed dose rate gemcitabine, gemcitabine/docetaxel, and gemcitabine/irinotecan have similar antitumor activity in metastatic pancreatic cancer. In light of recent negative randomized studies directly comparing several of these regimens with standard gemcitabine, none of these approaches can be recommended for routine use in patients with this disease.
doi:10.1200/JCO.2009.22.1309
PMCID: PMC2792952  PMID: 19858396
15.  Multicenter Phase II Trial of Neoadjuvant Pemetrexed Plus Cisplatin Followed by Extrapleural Pneumonectomy and Radiation for Malignant Pleural Mesothelioma 
Journal of Clinical Oncology  2009;27(18):3007-3013.
Purpose
Neoadjuvant pemetrexed plus cisplatin was administered, followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation (RT), to assess the feasibility and efficacy of trimodality therapy in stage I to III malignant pleural mesothelioma.
Patients and Methods
Requirements included stage T1-3 N0-2 disease, no prior surgical resection, adequate organ function (including predicted postoperative forced expiratory volume in 1 second ≥ 35%), and performance status 0 to 1. Patients received pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 for four cycles. Patients without disease progression underwent EPP followed by RT (54 Gy). The primary end point was pathologic complete response (pCR) rate.
Results
Seventy-seven patients received chemotherapy. All four cycles were administered to 83% of patients. The radiologic response rate was 32.5% (95% CI, 22.2 to 44.1). Fifty-seven patients proceeded to EPP, which was completed in 54 patients. Three pCRs were observed (5% of EPP). Forty of 44 patients completed irradiation. Median survival in the overall population was 16.8 months (95% CI, 13.6 to 23.2 months; censorship, 33.8%). Patients completing all therapy had a median survival of 29.1 months and a 2-year survival rate of 61.2%. Radiologic response of complete or partial response was associated with a median survival of 26.0 months compared with 13.9 months for patients with stable disease or progressive disease (P = .05).
Conclusion
This multicenter trial showed that trimodality therapy with neoadjuvant pemetrexed plus cisplatin is feasible with a reasonable long-term survival rate, particularly for patients who completed all therapy. Radiologic response to chemotherapy, but not sex, histology, disease stage, or nodal status, was associated with improved survival.
doi:10.1200/JCO.2008.20.3943
PMCID: PMC3646305  PMID: 19364962
16.  A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours 
Purpose
To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose.
Methods
R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1–5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmaco-kinetic studies.
Results
Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma.
Conclusions
The recommended phase II doses are 850–1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes.
doi:10.1016/j.ejca.2008.05.018
PMCID: PMC2731567  PMID: 18650079
Pharmacokinetics; Phase I; Quinoxaline; R(+)XK469; XK469
17.  Protein kinase C beta (PKCβ) in malignant pleural mesothelioma 
Anti-cancer drugs  2008;19(9):841-848.
Purpose
Malignant pleural mesothelioma (MPM) is a disease with few therapeutic options. Protein kinase C beta (PKCß) is involved in important cellular functions. Enzastaurin (LY317615.HCl) is a novel inhibitor of PKC in clinical development.
Experimental Design
MPM cell lines (7) and patient tumor tissues (24) were evaluated for expression of PKCß by immunoblotting and immunohistochemistry, respectively. In-vitro cell-growth assays were performed with enzastaurin with or without cisplatin. Cell migration was evaluated with the wound healing assay. Downstream signaling (survival and focal adhesion pathways) was studied by immunobloting for related molecules in the presence of phorbol-ester with or without enzastaurin.
Results
Expression for PKCß1 was seen in all cases, with a mean integrated optical density (IOD) of 152.5 (standard deviation = 95.47, n=24), whereas PKCß2 expression was less intense, with a mean IOD of 11.45 (standard deviation = 16.27, n=21). There was a trend toward lower overall survival among patients expressing above-median PKCß1 (p=.064), but not PKCß2. Robust expression of PKCß1 and low expression of PKCß2 was observed in MPM cell lines. Treatment of MPM cell lines with enzastaurin revealed IC50 of 5 μM, and strong synergism was observed when combined with cisplatin. Wound healing assay revealed that treatment of H2461 cells with enzastaurin reduced migration by 59.2 %. Enzastaurin treatment led to disruption of F-actin architecture. Downstream signaling showed reduced phosphorylation of: AKT, FAK, p130Cas, S6 ribosomal protein and paxillin.
Conclusions
PKCß1 was expressed in the majority of MPM samples. Enzastaurin has pre-clinical activity against MPM, and exhibited synergism with cisplatin. PKCß inhibition in MPM might be able to reduce the invasiveness of MPM by affecting cytoskeletal function.
doi:10.1097/CAD.0b013e32830ce506
PMCID: PMC2605682  PMID: 18765998
malignant pleural mesothelioma; protein kinase C; receptor tyrosine kinase; therapy
18.  A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303 
Background and Aims
CALGB 80303 was a randomized, phase III study in advanced pancreatic cancer patients treated with gemcitabine plus either bevacizumab or placebo. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS) using overall survival (OS) as the endpoint.
Methods
DNA from 351 patients was genotyped for >550,000 single nucleotide polymorphisms (SNPs). Associations between OS and SNPs were investigated using the log-linear two-way multiplicative Cox proportional-hazards model. The subset of 294 genetically European patients was used for the primary analysis.
Results
A nonsynonymous SNP in IL17F (rs763780, H161R) and an intronic SNP in strong linkage disequilibrium (rs7771466) were associated with OS using genome-wide criteria (p≤10−7). Median OS was significantly shorter (p 2.61×10−8) for the rs763780 heterozygotes (3.1 months, 95% CI 2.3–4.3) as compared to the patients without this variant (6.8 months, 5.8–7.3). After adjustment by stratification factors, the p value for the association was 9.51×10−7.
Conclusions
The variant 161R form of interleukin-17F is a natural antagonist of the anti-angiogenic effects of wild-type 161H interleukin-17F, and angiogenesis may play an important role in the metastatic spread of pancreatic cancer. In this preliminary study, we hypothesize that the angiogenesis potential of pancreatic cancers in patients with variant interleukin-17F is higher than that of tumors in patients with wild-type interleukin-17F, conferring worse prognosis. This exploratory GWAS may provide the foundation for testing the biology and clinical effects of novel genes and their heritable variants through mechanistic and confirmatory studies in pancreatic cancer.
doi:10.1158/1078-0432.CCR-11-1387
PMCID: PMC3412624  PMID: 22142827
GWAS; pharmacogenetics; bevacizumab; pancreatic cancer; gemcitabine
19.  Utilisation of a thoracic oncology database to capture radiological and pathological images for evaluation of response to chemotherapy in patients with malignant pleural mesothelioma 
BMJ Open  2012;2(5):e001620.
Objective
An area of need in cancer informatics is the ability to store images in a comprehensive database as part of translational cancer research. To meet this need, we have implemented a novel tandem database infrastructure that facilitates image storage and utilisation.
Background
We had previously implemented the Thoracic Oncology Program Database Project (TOPDP) database for our translational cancer research needs. While useful for many research endeavours, it is unable to store images, hence our need to implement an imaging database which could communicate easily with the TOPDP database.
Methods
The Thoracic Oncology Research Program (TORP) imaging database was designed using the Research Electronic Data Capture (REDCap) platform, which was developed by Vanderbilt University. To demonstrate proof of principle and evaluate utility, we performed a retrospective investigation into tumour response for malignant pleural mesothelioma (MPM) patients treated at the University of Chicago Medical Center with either of two analogous chemotherapy regimens and consented to at least one of two UCMC IRB protocols, 9571 and 13473A.
Results
A cohort of 22 MPM patients was identified using clinical data in the TOPDP database. After measurements were acquired, two representative CT images and 0–35 histological images per patient were successfully stored in the TORP database, along with clinical and demographic data.
Discussion
We implemented the TORP imaging database to be used in conjunction with our comprehensive TOPDP database. While it requires an additional effort to use two databases, our database infrastructure facilitates more comprehensive translational research.
Conclusions
The investigation described herein demonstrates the successful implementation of this novel tandem imaging database infrastructure, as well as the potential utility of investigations enabled by it. The data model presented here can be utilised as the basis for further development of other larger, more streamlined databases in the future.
doi:10.1136/bmjopen-2012-001620
PMCID: PMC3488720  PMID: 23103606
Basic Sciences
20.  Sphingosine Kinase 1 Is Required for Mesothelioma Cell Proliferation: Role of Histone Acetylation 
PLoS ONE  2012;7(9):e45330.
Background
Malignant pleural mesothelioma (MPM) is a devastating disease with an overall poor prognosis. Despite the recent advances in targeted molecular therapies, there is a clear and urgent need for the identification of novel mesothelioma targets for the development of highly efficacious therapeutics.
Methodology/Principal Findings
In this study, we report that the expression of Sphingosine Kinase 1 (SphK1) protein was preferentially elevated in MPM tumor tissues (49 epithelioid and 13 sarcomatoid) compared to normal tissue (n = 13). In addition, we also observed significantly elevated levels of SphK1 and SphK2 mRNA and SphK1 protein expression in MPM cell lines such as H2691, H513 and H2461 compared to the non-malignant mesothelial Met5 cells. The underlying mechanism appears to be mediated by SphK1 induced upregulation of select gene transcription programs such as that of CBP/p300 and PCAF, two histone acetyl transferases (HAT), and the down regulation of cell cycle dependent kinase inhibitor genes such as p27Kip1 and p21Cip1. In addition, using immunoprecipitates of anti-acetylated histone antibody from SphK inhibitor, SphK-I2 treated Met5A and H2691 cell lysates, we also showed activation of other cell proliferation related genes, such as Top2A (DNA replication), AKB (chromosome remodeling and mitotic spindle formation), and suppression of p21 CIP1 and p27KIP1. The CDK2, HAT1 and MYST2 were, however, unaffected in the above study. Using SphK inhibitor and specific siRNA targeting either SphK1 or SphK2, we also unequivocally established that SphK1, but not SphK2, promotes H2691 mesothelioma cell proliferation. Using a multi-walled carbon nanotubes induced peritoneal mesothelioma mouse model, we showed that the SphK1−/− null mice exhibited significantly less inflammation and granulamatous nodules compared to their wild type counterparts.
Conclusions/Significance
The lipid kinase SphK1 plays a positive and essential role in the growth and development of malignant mesothelioma and is therefore a likely therapeutic target.
doi:10.1371/journal.pone.0045330
PMCID: PMC3444486  PMID: 23028939
21.  RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma 
Cancer Biology & Therapy  2011;12(1):9-46.
RON (MST1R) is one of two members of the MET receptor tyrosine kinase family, along with parent receptor MET. RON has a putative role in several cancers, but its expression and function is poorly characterized in gastroesophageal adenocarcinoma. A recognized functional role of MET tyrosine kinase in gastroesophageal cancer has led to early phase clinical trials using MET inhibitors, with unimpressive results. Therefore, the role of RON in gastroesophageal cancer, as well as its role in cooperative signaling with MET and as a mechanism of resistance to MET inhibition, was studied in gastroesophageal tissues and cell lines. By IHC, RON was highly overexpressed in 74% of gastroesophageal samples (n = 94) and overexpression was prognostic of poor survival (p = 0.008); RON and MET co-expression occurred in 43% of samples and was prognostic of worst survival (p = 0.03). High MST1R gene copy number by quantitative polymerase chain reaction and confirmed by fluorescence in situ hybridization and/or array comparative genomic hybridization, was seen in 35.5% (16/45) of cases. High MST1R gene copy number correlated with poor survival (p = 0.01), and was associated with high MET and ERBB2 gene copy number. a novel somatic MST1R juxtamembrane mutation R1018G was found in 11% of samples. RON signaling was functional in cell lines, activating downstream effector STAT3, and resulted in increased viability over controls. RON and MET co-stimulation assays led to enhanced malignant phenotypes over stimulation of either receptor alone. Growth inhibition as evidenced by viability and apoptosis assays was optimal using novel blocking monoclonal antibodies to both ROn and MET, versus either alone. SU11274, a classic MET small molecule tyrosine kinase inhibitor, blocked signaling of both receptors and proved synergistic when combined with STAT3 inhibition (combination index <1). These preclinical studies define RON as an important novel prognostic marker and therapeutic target for gastroesophageal cancer warranting further investigation.
doi:10.4161/cbt.12.1.15747
PMCID: PMC3149873  PMID: 21543897
RON; MST1R; MET; MSP; HGF; STAT3; stomach cancer; gastroesophageal adenocarcinoma; R1018G mutation

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