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ABSTRACT: The incidence of esophageal adenocarcinoma is rapidly increasing in the western population. Despite aggressive treatment, survival after esophagectomy is suboptimal. The main objective of the present study was to evaluate the gene expression profiles in esophageal adenocarcinoma and determine their association with survival after resection.
We conducted a prospective National Institutes of Health/National Cancer Institute funded study to evaluate the prognostic significance of gene expression in patients with esophageal adenocarcinoma undergoing esophagectomy. Gene expression in tumor tissue was analyzed using high-throughput oligonucleotide arrays. The association of gene expression and overall survival was analyzed using the tail-strength statistic and Cox regression analysis. Gene signatures were constructed with semisupervised methods using principal components. A cross-validated risk score was devised by conducting 10-fold cross-validation, 100 times.
We evaluated the gene expression in 64 patients with esophageal adenocarcinoma who underwent esophagectomy. The median overall survival was 27 months (95% confidence interval 22 to not reached). After filtering, 10,214 probe sets were used for survival analysis. The tail-strength statistic for these probe sets (0.318) indicated a significant association with overall survival. Patients were classified into high- and low-risk groups, according to the gene signature. High-risk patients had a predicted median survival of 19 months, but the median was not reached for the low-risk group (P < .05). On multivariate analysis, the gene signature was independently associated with survival (hazard ratio, 2.22; P = .04).
Global gene expression levels were significantly associated with overall survival after esophagectomy. Furthermore, individual genes could be successfully combined into a strongly predictive, internally cross-validated gene signature. If validated further, these results could help direct additional clinical trials of neoadjuvant and adjuvant therapies for esophageal adenocarcinoma.
The Journal of thoracic and cardiovascular surgery 02/2013; 145(2):505-13. · 3.41 Impact Factor
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ABSTRACT: Changes in the biomarkers of host suppressor immune response were evaluated in patients with melanoma enrolled in 2 trials. Two similar cohorts of patients participating in the 2 studies were evaluated. The first (IFN/treme) tested interferon (IFN)-α2b and tremelimumab in metastatic melanoma and reported a response rate of 24%, 6.4 months median progression-free survival, and 21 months median overall survival. The second [toll-like receptor 9 (TLR)/GM] tested vaccination with MART-1, gp100, tyrosinase given with TLR-9 agonist and granulocyte-macrophage colony-stimulating factor and reported 9% response rate, median progression-free survival of 1.9 months, and median overall survival of 13.4 months. We monitored circulating T regulatory cells (T-reg) and myeloid-derived suppressor cells (MDSC) utilizing multicolor flow cytometry. In "IFN/treme," changes in circulating T-reg and MDSC were compared between baseline, day 29 (end of IFN-α induction) and day 85 (1 course). The CD4CD25hiCD39 T-reg percentage was increased most at day 85 (P=0.018) and less significantly at day 29 (P=0.09). There was a decrease in the percentage of MDSC populations taken in aggregate, which was most significant for monocytic MDSC (HLA-DR low/CD14) at day 29 (P<0.0001) and day 85 (P=0.001). In "TLR-9/GM," changes in T-reg and MDSC were compared between baseline and day 50 (4 vaccinations) and day 90 (8 vaccinations). There were no significant changes in T-reg or MDSC, except for a trend towards decreased (HLA-DR low/CD14) MDSC at day 50 (P=0.07). Therefore, IFN/treme significantly downregulated MDSC suggesting a role on the significant clinical activity observed in this trial. T-reg findings suggest that IFN/treme induced clinically significant antitumor responses by inhibiting CTLA4 suppressive effects on T effectors, and less so by affecting T-reg.
Journal of immunotherapy (Hagerstown, Md.: 1997) 11/2012; 35(9):702-10. · 3.20 Impact Factor
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ABSTRACT: EGF receptor (EGFR) is upregulated in most epithelial cancers where signaling through EGFR contributes to cancer cell proliferation and survival. The limited clinical efficacy of EGFR inhibitors suggests that identification of resistance mechanisms may identify new pathways for therapeutic targeting. STAT3 is upregulated in many cancers and activated via both EGFR-dependent and -independent pathways. In the present study, we tested the consequences of STAT3 inhibition in EGFR inhibitor-resistant head and neck squamous cell carcinoma (HNSCC) and bladder cancer models to determine whether STAT3 blockade can enhance responses to EGFR targeting.
pSTAT3 expression was assessed in human HNSCC tumors that recurred following cetuximab treatment. Cetuximab-sensitive and -resistant cell lines were treated with a STAT3 decoy to determine EC(50) concentrations and the effects on STAT3 target gene expression by Western blotting. In vivo assays included evaluation of antitumor efficacy of STAT3 decoy in cetuximab-sensitive and -resistant models followed by immunoblotting for STAT3 target protein expression.
Targeting STAT3 with a STAT3 decoy reduced cellular viability and the expression of STAT3 target genes in EGFR inhibitor resistance models. The addition of a STAT3 inhibitor to EGFR blocking strategies significantly enhanced antitumor effects in vivo. Biopsies from HNSCC tumors that recurred following cetuximab treatment showed increased STAT3 activation compared with pretreatment biopsies.
These results suggest that STAT3 activation contributes to EGFR inhibitor resistance both in HNSCC and bladder cancer where concomitant targeting of STAT3 may represent an effective treatment strategy. Clin Cancer Res; 18(18); 4986-96. ©2012 AACR.
Clinical Cancer Research 07/2012; 18(18):4986-96. · 7.74 Impact Factor
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ABSTRACT: Targeting the epidermal growth factor receptor (EGFR) using the tyrosine kinase inhibitor (TKI) erlotinib has demonstrated activity in aerodigestive tract malignancies. Co-targeting of the G-protein-coupled receptor cyclooxygenase (COX) with EGFR inhibitors has shown promise in preclinical models and early phase clinical studies.
We studied the modulation of serum proteins after neoadjuvant treatment with erlotinib with or without sulindac in head and neck cancer patients. In a prospective, randomized, double-blind clinical trial, paired serum samples were obtained before and after neoadjuvant treatment in three groups of patients (n=23 total), who were randomized to receive 7-14 consecutive days of erlotinib alone, erlotinib plus sulindac, or placebo. Two separate multiplexed ELISA systems (SearchLight™ or Luminex™) were used to measure serum biomarkers. HGF and IL-6 levels were tested on both systems, and validated using single analyte ELISAs.
Several analytes were significantly altered (generally decreased) post-treatment, in patients who received erlotinib (with or without sulindac) as well as in the placebo groups. No single analyte was differentially altered across the three treatment groups using either multiplex platform. Single HGF ELISA suggested a nonspecific decrease in all patients.
These results demonstrate the importance of a placebo group when assessing changes in expression of serum biomarkers. While multiplex platforms can provide quantitative information on a large number of serum analytes, results should be cautiously compared across platforms due to their intrinsic features. Furthermore, the dynamic range of expression of a single analyte is constrained in multiplex versus standard ELISA.
Oral Oncology 06/2012; 48(11):1136-45. · 2.86 Impact Factor
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Malabika Sen,
Sufi M Thomas,
Seungwon Kim,
Joanne I Yeh,
Robert L Ferris,
Jonas T Johnson,
Umamaheswar Duvvuri,
Jessica Lee,
Nivedita Sahu,
Sonali Joyce, [......],
Pui-Kai Li,
Lin Wang,
Simion Chiosea,
Raja R Seethala, William E Gooding,
Xiaomin Chen,
Naftali Kaminski,
Kusum Pandit,
Daniel E Johnson,
Jennifer R Grandis
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ABSTRACT: Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as "undruggable." We developed a decoy targeting STAT3 and conducted a phase 0 trial. Expression levels of STAT3 target genes were decreased in head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexaethylene glycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development. SIGNIFICANCE: This is the fi rst study of a STAT3-selective inhibitor in humans and the fi rst evidence that a transcription factor decoy can be modifi ed to enable systemic delivery. These findings have therapeutic implications beyond STAT3 to other “undruggable” targets in human cancers.
Cancer discovery. 06/2012; 2(8):694-705.
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ABSTRACT: Ineffective recognition of tumor cells by CD8+ T cells is a limitation of cancer immunotherapy. Therefore, treatment regimens that coordinately promote enhanced antitumor CD8+ T-cell activation, delivery, and target cell recognition should yield greater clinical benefit. Using an MCA205 sarcoma model, we show that in vitro treatment of tumor cells with the HSP90 inhibitor 17-DMAG results in the transient (proteasome-dependent) degradation of the HSP90 client protein EphA2 and the subsequent increased recognition of tumor cells by Type-1 anti-EphA2 CD8+ T cells. In vivo administration of 17-DMAG to tumor-bearing mice led to slowed tumor growth, enhanced/prolonged recognition of tumor cells by anti-EphA2 CD8+ T cells, reduced levels of myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment, and activation of tumor-associated vascular endothelial cells in association with elevated levels of Type-1 tumor-infiltrating lymphocytes. When combined with EphA2-specific active vaccination or the adoptive transfer of EphA2-specific CD8+ T cells, 17-DMAG cotreatment yielded a superior tumor therapeutic regimen that was capable of rendering animals free of disease. Taken together, our findings indicate that 17-DMAG functions as an immune adjuvant in the context of vaccines targeting EphA2.
Cancer Research 05/2012; 72(13):3196-206. · 7.86 Impact Factor
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Marie Reveiller,
Sayak Ghatak,
Liana Toia,
Irina Kalatskaya,
Lincoln Stein,
Mary D'Souza,
Zhongren Zhou,
Santhoshi Bandla, William E Gooding,
Tony E Godfrey,
Jeffrey H Peters
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ABSTRACT: This study aimed to identify pathways and cellular processes that are modulated by exposure of normal esophageal cells to bile and acid.
Barrett's esophagus most likely develops as a response of esophageal stem cells to the abnormal reflux environment. Although insights into the underlying molecular mechanisms are slowly emerging, much of the metaplastic process remains unknown.
We performed a global analysis of gene expression in normal squamous esophageal cells in response to bile or acid exposure. Differentially expressed genes were classified into major biological functions using pathway analysis and interaction network software. Array data were verified by quantitative PCR and western blot both in vitro and in human esophageal biopsies.
Bile modulated expression of 202 genes, and acid modulated expression of 103 genes. Genes involved in squamous differentiation formed the largest functional group (n = 45) all of which were downregulated by bile exposure. This included genes such as involucrin (IVL), keratinocyte differentiation-associated protein (KRTDAP), grainyhead-like 1 (GRHL1), and desmoglein1 (DSG1) the downregulation of which was confirmed by quantitative PCR and western blot. Bile also caused expression changes in genes involved in cell adhesion, DNA repair, oxidative stress, cell cycle, Wnt signaling, and lipid metabolism. Analysis of human esophageal biopsies demonstrated greatly reduced expression of IVL, KRTDAP, DSG1, and GRHL1 in metaplastic compared to squamous epithelia.
We report for the first time that bile inhibits the squamous differentiation program of esophageal epithelial cells. This, coordinated with induction of genes driving intestinal differentiation, may be required for the development of Barrett's esophagus.
Annals of surgery 04/2012; 255(6):1113-20. · 7.90 Impact Factor
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ABSTRACT: The effectivenes of cancer vaccines in inducing CD8(+) T-cell responses remains a challenge, resulting in a need for testing more potent adjuvants. Our objective was to determine the safety and immunogenicity of vaccination against melanoma-related antigens employing MART-1, gp100, and tysosinase paptides combined with the TLR9 agonist PF-3512676 and local granulocyte macrophage-colony stimulating factor in oil emulsion. Using continuous monitoring of safety and a 2-stage design for immunologic efficacy, 20 immune response evaluable patients were targetted. Vaccinations were given subcutaneously on days 1 and 15 per cycle (1cycle=28 d) for up to 13 cycles. Interferon-γ enzyme-linked immunosorbent spot was used as the primary assay measuring the frequency of peripheral antigen-specific CD8(+) T cells at days 50 and 90 compared with baseline (target ≥ 9/20 immunologic responses). Clinical responses were measured by Response Evaluation Criteria In Solid Tumors every 8 weeks. Twenty-two (including 20 immune response evaluable) melanoma patients were enrolled. All had American Joint Committe on Cancer stage IV (5M1a, 6M1b, 11M1c) and most had previously received therapy. Eight had previously treated brain metastases. An average of 3.5 cycles of vaccination per patient was administered. Clinical response data were available for 21 patients. There were 2 partial response and 8 stable disease lasting 2-7 months. One patient with ongoing partial response continued on treatment. At a median follow-up of 7.39 months (range, 3.22-20.47 mo), median progression-free survival was 1.9 months (90% confidence interval, 1.84-3.68) and median overall survival was 13.4 months (90% confidence interval,11.3-∞). No regimen-related grade 3/4/5 toxicities were observed. There were 9/20 patients with positive enzyme-linked immunosorbent spot at day 50 and/or day 90. Our adjuvant regimen combining PF-3512676 and granulocyte macrophage-colony stimulating factor was safe and is worthy of further testing with these or alternative peptides, potentially in combination with antibodies that target immunoregulatory checkpoints.
Journal of immunotherapy (Hagerstown, Md.: 1997) 04/2012; 35(4):359-66. · 3.20 Impact Factor
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ABSTRACT: To estimate the distribution of head and neck squamous cell carcinoma (HNSCC) recurrence after definitive chemoradiation therapy (CRT) among patients who underwent 18F-fluorodeoxyglucose positron-emission tomography and computed tomography (PET/CT) surveillance.
Retrospective review.
HNSCC patients who underwent definitive CRT from 2001 to 2008 were evaluated for recurrence with serial PET/CT. Patients were excluded if they were previously treated for recurrent disease, were treated with surgery as the primary therapeutic modality, or had inadequate clinical follow-up. Recurrence was defined by histopathologic evidence of tumor.
Three hundred eighty-eight patients were studied. Patients in whom recurrence was not detected were followed clinically and radiographically for a median of 27 months. Tumor recurrence was detected in 110 patients. For 37 patients, recurrence was heralded by clinical signs. Among the 73 asymptomatic patients who had a confirmed recurrence, disease was detected by PET/CT between 2 and 43 months, median of 6 months. Forty-five percent of observed asymptomatic recurrences were detected during the first 6 months of surveillance (95% confidence interval [CI], 34%-57%), 79% within the first 12 months (95% CI, 68%-88%), 95% within the first 24 months (95% CI, 87%-98%), and 100% within the first 48 months (95% CI, 95%-100%).
Among HNSCC patients followed with PET/CT surveillance, 95% of observed asymptomatic recurrences were detected within 24 months after completing CRT. For patients without clinical signs of recurrence, routine PET/CT surveillance beyond the first 24 months may be of limited value and may not be cost effective.
The Laryngoscope 04/2012; 122(7):1512-7. · 1.75 Impact Factor
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ABSTRACT: The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) have been implicated as therapeutic targets for head and neck squamous cell carcinoma (HNSCC). Vandetanib is a small-molecule tyrosine kinase inhibitor (TKI) with dual specificity for EGFR and VEGFR. Here we characterize the phenotypic and biochemical effects of vandetanib on various HNSCC cell lines.
In vitro models were used for studying tumor cell viability, invasion, and signaling as well as in vivo xenograft models.
Treatment with vandetanib reduced viability, invasion, and tumor growth of HNSCC cell lines. Phosphorylation levels of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) were reduced in vandetanib-treated HNSCC cells. Additionally, vandetanib abrogates EGF-induced STAT3 activity and STAT3 target gene expression.
We demonstrated that vandetanib inhibits the growth of head and neck cancer cell lines. The antitumor effects of vandetanib appear to be exerted via the EGFR inhibitory effect of the compound.
Head & Neck 02/2012; 34(9):1269-76. · 2.40 Impact Factor
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ABSTRACT: We tested the hypothesis that the combination of tremelimumab and interferon alfa-2b acting via different and possibly synergistic mechanisms would overcome tumor immune tolerance and lead to significant and durable clinical responses.
We conducted a phase II study in which patients were administered tremelimumab 15 mg/kg/course (three cycles [one cycle = 4 weeks]) intravenously every 12 weeks. High-dose interferon alfa-2b (HDI) was administered concurrently, including intravenous induction at 20 MU/m2/d for 5 d/wk for 4 weeks followed by maintenance at 10 MU/m2/d subcutaneously three times a week for 8 weeks per course. From course 2 onward, HDI maintenance was administered subcutaneously.
Thirty-seven patients with American Joint Committee on Cancer stage IV (9M1a, 6M1b, and 22M1c) were enrolled. Two patients had previously treated brain metastases. Grades 3 and 4 toxicities included neutropenia (six patients; 17%), diarrhea/colitis (four patients; 11%), liver enzyme increase (four patients; 11%), rash (four patients; 11%), fatigue (15 patients; 40%), and anxiety/depression (five patients; 14%). Response data were available for 35 patients. The best objective response rate (RR; Response Evaluation Criteria in Solid Tumors) by intention to treat was 24% (90% CI, 13% to 36%; four complete responses [CRs] and five partial responses [PRs] that lasted 6, 6, > 12, > 14, > 18, 20, > 28, 30, and > 37 months, respectively). Fourteen patients (38%) had stable disease (SD) that lasted 1.5 to 21 months. The median progression-free survival was 6.4 months (95% CI, 3.3 to 12.1 months). The median overall survival (OS) was 21 months (95% CI, 9.5 to not reached). There was a weak association between therapy-induced autoimmunity and clinical benefits (CR/PR/SD; P = .0059), baseline C-reactive protein (CRP) less than or equal to 2.7× the upper limit of normal and clinical benefits (P = .0494) and improved probability of survival (P = .0032), and baseline lymphocyte count of at least 1,000/μL and response (CR/PR; P = .0183) and clinical benefits (CR/PR/SD; P = .0255). Biomarker associations were not significant after adjustment for multiple comparisons.
HDI can be administered combined with tremelimumab with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.
Journal of Clinical Oncology 12/2011; 30(3):322-8. · 18.37 Impact Factor
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ABSTRACT: To evaluate the ability of posttreatment positron emission tomography and computed tomography (PET/CT) to predict ultimate disease status in patients with head and neck squamous cell carcinoma and known human papillomavirus (HPV) status.
Retrospective.
Single tertiary academic referral center.
Clinical and radiographic data, including HPV status, were available for 62 patients with head and neck squamous cell carcinoma who underwent treatment from 2005 to 2010.
The first posttreatment PET/CT scan, performed between 4 and 16 weeks (median, 9 weeks) after treatment, was categorized as negative, probably negative, or positive for residual disease. The PET/CT and clinical follow-up results, including disease status, were obtained every 3 months thereafter.
Among the 62 patients, 35 results (56%) were negative, 15 (24%) were probably negative, and 12 (19%) were positive. Eight of the 27 HPV-negative patients were PET/CT positive compared with 4 of the 35 HPV-positive patients (Cochran-Armitage trend test, P = .11). The median follow-up for disease-free patients was 21 months from the completion of the treatment. Disease-free survival was associated with PET/CT outcome (log-rank P < .001) and HPV status (log-rank P = .01). Using recurrence at 2 years as a reference standard, the early PET/CT scans had a specificity of 69% (95% confidence interval [CI], 46%-91%) and a negative predictive value of 79% (95% CI, 57%-99%). All PET/CT-negative HPV-positive patients (n = 6) were free of disease at 2 years, although this proportion was not statistically different from the PET/CT-negative HPV-positive patients in this small cohort.
A negative posttreatment PET/CT result may have the potential to identify patients who are at very low risk of recurrence. The HPV status may augment the predictive utility of an initial negative PET/CT result.
Archives of otolaryngology--head & neck surgery 11/2011; 137(11):1106-11. · 1.92 Impact Factor
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ABSTRACT: With an increase in the performance of laparoscopic antireflux procedures, more patients with a failed primary antireflux operation are being referred to thoracic surgeons for complex redo procedures. The objective of this study was to evaluate our results of redo antireflux surgery.
We conducted a retrospective review of patients who underwent redo surgery for failed fundoplication. The primary endpoint was failure of the redo operation; other endpoints included gastroesophageal reflux disease-health-related quality of life (HRQOL) after redo fundoplication.
A total of 275 patients (median age, 52 years; range, 17 to 88 years; men 82, women 193) underwent redo antireflux surgery. The most common pattern of failure of the initial operation was transmediastinal migration-recurrent hernia in 177 patients (64%). Redo surgery included Nissen fundoplication in 200 (73%), Collis gastroplasty in 119 (43%), and partial fundoplication in 41 (15%). There was no perioperative mortality. At a median follow-up of 39.6 months, 31 patients (11.2%) had a failure of the redo surgery, requiring reoperation. The two-year estimated probability of freedom from failure was 93% (95% confidence interval 89% to 96%). The HRQOL scores, available for 186 patients, were excellent to satisfactory in 85.5%, and poor in 14.5%.
Redo antireflux surgery can be performed safely in experienced centers with outcomes that are similar to published open results. Complete takedown and reestablishment of the normal anatomy, recognition of a short esophagus, and proper placement of the wrap are essential components of the procedure. Thoracic surgeons with significant laparoscopic and open esophageal surgical experience can perform minimally invasive, complex redo esophageal antireflux procedures safely with good results.
The Annals of thoracic surgery 07/2011; 92(3):1083-9; discussion 1089-90. · 3.74 Impact Factor
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ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is usually fatal, and innovative approaches targeting growth pathways are necessary to effectively treat this disease. Both the epidermal growth factor receptor (EGFR) and the hepatocyte growth factor (HGF)/c-Met pathways are overexpressed in HNSCC and initiate similar downstream signaling pathways. c-Met may act in consort with EGFR and/or be activated as a compensatory pathway in the presence of EGFR blockade.
Expression levels of EGFR and c-Met were determined by Western analysis in HNSCC cell lines and correlated with antitumor responses to inhibitors of these pathways.
Combining the c-Met inhibitor PF2341066 with the EGFR inhibitor gefitinib abrogated HNSCC cell proliferation, invasion, and wound healing significantly more than inhibition of each pathway alone in HNSCC cell lines. When both HGF and the EGFR ligand, TGF-α, were present in vitro, P-AKT and P-MAPK expression were maximally inhibited by targeting both EGFR and c-Met pathways, suggesting that c-Met or EGFR can compensate when phosphorylation of the other receptor is inhibited. We also showed that TGF-α can induce phosphorylation of c-Met over sixfold by 8 hours in the absence of HGF, supporting a ligand-independent mechanism. Combined targeting of c-Met and EGFR resulted in an enhanced inhibition of tumor volumes accompanied by a decreased number of proliferating cells and increased apoptosis compared with single agent treatment in vivo.
Together, these results suggest that dual blockade of c-Met and EGFR may be a promising clinical therapeutic strategy for treating HNSCC.
Clinical Cancer Research 05/2011; 17(13):4425-38. · 7.74 Impact Factor
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Amin Ismail,
Santhoshi Bandla,
Marie Reveiller,
Liana Toia,
Zhongren Zhou, William E Gooding,
Irina Kalatskaya,
Lincoln Stein,
Mary D'Souza,
Virginia R Litle,
Jeffrey H Peters,
Arjun Pennathur,
James D Luketich,
Tony E Godfrey
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ABSTRACT: Chromosomal gain at 7q21 is a frequent event in esophageal adenocarcinoma (EAC). However, this event has not been mapped with fine resolution in a large EAC cohort, and its association with clinical endpoints and functional relevance are unclear.
We used a cohort of 116 patients to fine map the 7q21 amplification using SNP microarrays. Prognostic significance and functional role of 7q21 amplification and its gene expression were explored.
Amplification of the 7q21 region was observed in 35% of tumors with a focal, minimal amplicon containing six genes. 7q21 amplification was associated with poor survival and analysis of gene expression identified cyclin-dependent kinase 6 (CDK6) as the only gene in the minimal amplicon whose expression was also associated with poor survival. A low-level amplification (10%) was observed at the 12q13 region containing the CDK6 homologue cyclin-dependent kinase 4 (CDK4). Both amplification and expression of CDK4 correlated with poor survival. A combined model of both CDK6 and CDK4 expressions is a superior predictor of survival than either alone. Specific knockdown of CDK4 and/or CDK6 by siRNAs shows that they are required for proliferation of EAC cells and that their function is additive. PD-0332991 targets the kinase activity of both molecules and suppresses proliferation and anchorage independence of EAC cells through activation of the pRB pathway.
We suggest that CDK6 is the driver of 7q21 amplification and that both CDK4 and CDK6 are prognostic markers and bona fide oncogenes in EAC. Targeting these molecules may constitute a viable new therapy for this disease.
Clinical Cancer Research 05/2011; 17(13):4513-22. · 7.74 Impact Factor
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Arjun Pennathur,
Irfan Qureshi,
Matthew J Schuchert,
Rajeev Dhupar,
Peter F Ferson, William E Gooding,
Neil A Christie,
Sebastien Gilbert,
Manisha Shende,
Omar Awais,
Joel S Greenberger,
Rodney J Landreneau,
James D Luketich
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ABSTRACT: The minimally invasive, video-assisted thoracoscopic surgical (VATS) approach to resection of the thymus is frequently practiced for benign disease; however, a VATS approach for thymoma remains controversial. The objective of the present study was to evaluate the feasibility of VATS thymectomy for the treatment of early-stage thymoma and to compare the outcomes with those after open resection.
A retrospective review of 40 patients who underwent surgical resection of early-stage thymoma during a 12-year period was conducted. Data on patient characteristics, morbidity, recurrence, and survival were collected. The primary endpoint studied was overall survival.
Of the 40 patients, 14 underwent thymectomy for stage I and 26 for stage II thymoma; 19 were men and 21 were women (median age, 64 years; range, 35-86 years). Open thymectomy was performed in 22 patients, and VATS was performed in 18. The operative mortality rate was 0%. The tumor stage and number of patients undergoing adjuvant radiotherapy were comparable in both surgical groups. The median length of hospital stay was shorter in the VATS group (3 days) than in the open group (5 days) (P = .0001). The median follow-up was 36 months. No significant differences were found in the estimated recurrence-free and overall 5-year survival rates (83%-100%) between the 2 groups.
VATS of early-stage thymoma appears safe and feasible and was associated with a shorter hospital stay. The oncologic outcomes were comparable in the open and VATS groups during intermediate-term follow-up. Additional follow-up is required to evaluate the long-term results of thoracoscopic thymectomy for early-stage thymoma.
The Journal of thoracic and cardiovascular surgery 03/2011; 141(3):694-701. · 3.41 Impact Factor
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ABSTRACT: The incidence of esophageal adenocarcinoma is rapidly increasing and is now one of the leading causes of cancer death in the western world. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of protein-encoding genes and are involved in the development, progression and prognosis of other malignancies. We hypothesized that global miRNA expression would predict survival and lymph node involvement in a cohort of surgically resected esophagus cancer patients.
The miRNA analysis was performed using a custom Affymetrix microarray with probes for 462 known human, 2,102 predicted human, 357 mouse, and 238 rat miRNAs. Expression of miRNA was evaluated in 45 primary tumors, and the association of miRNA expression with patient survival and lymph node metastasis was assessed. The prognostic impact of identified unique miRNAs was verified with quantitative reverse transcriptase polymerase chain reaction.
Our data indicate that the expression of individual human miRNA species is significantly associated with postresection patient survival. Using data from five unique miRNAs, we were further able to generate a combined miRNA expression signature that is associated with patient survival (p=0.005; hazard ratio 3.6) independent of node involvement and overall stage. The expression of three miRNAs (miR-99b and miR-199a_3p and _5p) was also associated with the presence of lymph node metastasis.
These results suggest miRNA expression profiling could provide prognostic utility in staging esophagus cancer patients and treatment planning with endoscopic and neoadjuvant therapies. The alterations of specific miRNAs may further elucidate steps in the metastatic pathway and allow for development of targeted therapy.
The Annals of thoracic surgery 03/2011; 91(5):1523-30. · 3.74 Impact Factor
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Rebecca J Leeman-Neill,
Raja R Seethala,
Shivendra V Singh,
Maria L Freilino,
Joseph S Bednash,
Sufi M Thomas,
Mary C Panahandeh, William E Gooding,
Sonali C Joyce,
Mark W Lingen,
Daniel B Neill,
Jennifer R Grandis
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ABSTRACT: Chemoprevention of head and neck squamous cell carcinoma (HNSCC), a disease associated with high mortality rates and frequent occurrence of second primary tumor (SPT), is an important clinical goal. The epidermal growth factor receptor (EGFR)-signal transducer and activator of transcription (STAT)-3 signaling pathway is known to play a key role in HNSCC growth, survival, and prognosis, thereby serving as a potential therapeutic target in the treatment of HNSCC. In the current study, the 4-nitroquinoline-1-oxide (4-NQO)-induced murine model of oral carcinogenesis was utilized to investigate the chemopreventive activities of compounds that target the EGFR-STAT3 signaling pathway. This model mimics the process of oral carcinogenesis in humans. The drugs under investigation included erlotinib, a small molecule inhibitor of the EGFR, and guggulipid, the extract of an Ayurvedic medicinal plant, which contains guggulsterone, a compound known to inhibit STAT3. Dietary administration of guggulipid failed to confer protection against oral carcinogenesis. On the other hand, the mice placed on erlotinib-supplemented diet exhibited a 69% decrease (P < 0.001) in incidence of preneoplastic and neoplastic lesions compared with mice on the control diet. Immunostaining of dysplastic lesions demonstrated modest decreases in STAT3 levels, with both drug treatments, that were not statistically significant. The results of the present study provide the basis for exploring the efficacy of erlotinib for prevention of HNSCC in a clinical setting.
Cancer Prevention Research 02/2011; 4(2):230-7. · 4.91 Impact Factor
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ABSTRACT: The aim of this study, using a retrospective chart review as the primary study design, was to determine the relative contribution of clinicopathologic risk factors versus low- and high-risk grade histologic groups to assist management of primary parotid cancers.
In all, 168 primary parotid malignancies were treated surgically at a tertiary care center from 1982 to 2005. Of these, 115 patients with complete follow-up information were further analyzed. Pathologic updating and reclassification in 28% of cases enabled comparison of tumor histology or grade with current consensus criteria. Clinical outcomes of high- and low-risk histology and grade were compared with the influence of traditional clinicopathologic risk factors.
Of 115 cases, the male:female ratio was equal and the median age was 63 years (range, 15 to 89 years). Mucoepidermoid carcinoma (n = 28) was the most common histology. The median follow-up was 44 months (range, 0–278 months). Of low-risk histology patients who underwent neck dissection 40% had pN+ disease. The median time to recurrence was not reached for low-risk tumors, compared with 29 months for high-risk tumors (p = .0001). Interestingly, extracapsular spread (ECS) and margin status were independent prognostic factors and conferred significantly greater prognostic value than histologic grade risk group. Disease-free survival (DFS) and overall survival (OS) at 5 years for the entire cohort were 51% and 57%, respectively. Risk group was a strong independent predictor of OS but not DFS.
Risk group defined by histology and grade was associated with DFS. ECS and margin status were independent predictors of DFS. Inclusion of ECS and margin status substantially improved the prediction of disease recurrence, supporting elective neck dissection and postoperative radiotherapy for high-grade tumors or low-risk histologies with positive margins or ECS.
Head & Neck 02/2011; 33(2):225-31. · 2.40 Impact Factor
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ABSTRACT: We hypothesized that bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), will potentiate the activity of pemetrexed, a multitargeted antifolate, in squamous cell carcinoma of the head and neck (SCCHN).
Patients with previously untreated, recurrent, or metastatic SCCHN were treated with pemetrexed 500 mg/m(2) and bevacizumab 15 mg/kg given intravenously every 21 days with folic acid and B(12) supplementation until disease progression. Primary end point was time-to-progression (TTP). DNA was isolated from whole blood samples for the detection of polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase (MTHFR), and VEGF.
Forty patients were enrolled. The median TTP was 5 months, and the median overall survival (OS) was 11.3 months. In 37 evaluable patients, the overall response rate was 30%, including a complete response rate of 5%, and the disease control rate was 86%. Grade 3 to 5 bleeding events occurred in six patients (15%): four were grade 3, and two were fatal. Other serious toxicities in 10% or more of patients included neutropenia (10%) and infection (12.5%). One patient died of sepsis after receiving eight cycles of therapy. For the MTHFR A1298C (rs1801131) single nucleotide polymorphisms, homozygote patients with AA had worse OS (P = .034).
The addition of bevacizumab to pemetrexed resulted in promising efficacy outcomes in SCCHN. Bleeding events were frequent but some may have been due to natural history of disease. Polymorphisms in MTHFR may offer potential for treatment individualization.
Journal of Clinical Oncology 02/2011; 29(9):1140-5. · 18.37 Impact Factor
