[show abstract][hide abstract] ABSTRACT: Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2,800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potent in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine and bortezomib showed similar inhibitory effect on cell lines and three primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy.
Cancer biology & therapy 05/2013; 14(7). · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: A growing set of quality measures is being implemented to evaluate all components of cancer care, from diagnosis through the end of life. We investigated the Quality Oncology Practice Initiative (QOPI) quality measures portfolio. Additionally, we explored the effect of quality measure type on conformance.
We performed QOPI data collections twice per year from fall 2007 through fall 2010 and spring 2012, using chart review of the Durham Veterans Administration outpatient oncology clinic. We categorized QOPI measures as nontreatment-related supportive care (NTSC), treatment-related supportive care (TSC), diagnostic, or therapeutic. Descriptive statistics and χ(2) were used to compare longitudinal conformance.
The majority of QOPI measures in spring 2012 assess processes of chemotherapy treatment (therapeutic, 54.3%; TSC, 8.7%) or diagnostic modalities (19.6%). Measures targeting NTSC are few (17.4%) but increased from three measures in fall 2007 to eight measures in spring 2012. During those 5 years, average conformance to NTSC, TSC, diagnostic, and therapeutic measures was 71.4%, 86.1%, 89.3%, and 75.4%, respectively (P < .001). Within the NTSC measures, emotional well-being and constipation assessment were least documented (41.0% and 46.3%, respectively). In spring 2012, NTSC measure conformance (75.8%) remained significantly lower than diagnostic measure conformance (91.5%; P < .001).
Most QOPI quality measures assess diagnosis or treatment processes of care and not supportive care. Aggregate conformance to the NTSC measures was lower than that of other categories. The differential conformance demonstrates the necessity of standardized documentation methods and quality improvement efforts that remain commensurate with the increasing portfolio of supportive care measures.
[show abstract][hide abstract] ABSTRACT: PURPOSEIt is unclear why racial differences exist in the frequency of surgery for lung cancer treatment. Comorbidity is an important consideration in selection of patients for lung cancer treatment, including surgery. To assess whether comorbidity contributes to the observed racial differences, we evaluated racial differences in the prevalence of comorbidity and their impact on receipt of surgery. PATIENTS AND METHODSA total of 1,314 patients (1,135 white, 179 black) in the Veterans Health Administration diagnosed with early-stage non-small-cell lung cancer in 2007 were included. The effect of comorbidity on surgery was determined by using generalized linear models with a logit link accounting for patient clustering within Veterans Administration Medical Centers.ResultsCompared with whites, blacks had greater prevalence of hypertension, liver disease, renal disease, illicit drug abuse, and poor performance status, but lower prevalence of respiratory disease. The impact of most individual comorbidities on receipt of surgery was similar between blacks and whites, and comorbidity did not influence the race-surgery association in a multivariable analysis. The proportion of blacks not receiving surgery as well as refusing surgery was greater than that among whites. CONCLUSION
Blacks had a greater prevalence of several comorbid conditions and poor performance status; however, the overall comorbidity score did not differ by race. In general, the effect of comorbidity on receipt of surgery was similar in blacks and whites. Racial differences in comorbidity do not fully explain why blacks undergo lung cancer surgery less often than whites.
Journal of Clinical Oncology 12/2012; · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: INTRODUCTION:: We sought to determine the efficacy of using both irinotecan- and etoposide-containing regimens sequentially for patients with untreated limited-stage small-cell lung cancer. METHODS:: Patients with untreated, measurable, limited-stage small-cell lung cancer with performance status 0 to 2, and adequate organ function were eligible. Treatment consisted of induction with cisplatin 30 mg/m and irinotecan 65 mg/m intravenously on day 1 and 8, every 21 days for two cycles. Beginning day 43, daily chest irradiation to 70 Gy was administered concurrently with carboplatin area under curve 5 on day 1, and etoposide 100 mg/m on days 1 to 3, every 21 days for three cycles. The primary objective was to differentiate between 45% and 60% 2-year survival. RESULTS:: Two induction cycles were delivered to 72 of 75 eligible patients (96%) and all planned treatment was delivered to 59 patients (79%). Cisplatin and irinotecan induction chemotherapy resulted in complete responses in 7% and partial responses in 64% (response rate 71%, 95% confidence interval [CI], 59%-81%). The best response to all therapy included 88% complete or partial responses (95% CI, 78%-94%). With median follow-up of 57 months, the median progression-free survival and overall survival are 12.6 (95% CI, 9.4-14.7) and 18.1 months (15.8-22.9), respectively. The 1- and 2-year survival was 69% and 31%, respectively. Frequent (>20%) grade 3 and 4 toxicities were neutropenia in 84%, hemoglobin in 36%, platelets in 51%, esophagitis in 22%, and dehydration in 24%. There were no fatal toxicities. CONCLUSIONS:: This treatment regimen of irinotecan-cisplatin induction chemotherapy followed by 70 Gy concurrent radiation and etoposide-carboplatin had tolerable toxicity but did not meet the preplanned 2-year survival target for further development.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2012; · 4.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Approximately 40,000 incident cancer cases are reported in the Veterans Affairs Central Cancer Registry (VACCR) annually (approximately 3% of U.S. cancer cases). Our objective was to provide the first comprehensive description of cancer incidence as reported in VACCR.
Data were obtained from VACCR for incident cancers diagnosed in VA. Analyses focused on 2007 data. Cancer incidence among VA patients was compared to the general U.S. cancer population.
In 2007, 97.5% of VA cancers were diagnosed among men. Approximately 78.5% of newly diagnosed patients were White, 19.0% Black, and 2.5% were another race. Median age at diagnosis was 66 years. The geographic distribution of cancer patients in VA aligns that of VA users. The most commonly diagnosed cancers were similar between VA and the U.S. male cancer population. The five most frequently diagnosed cancers among VA cancer patients were: prostate (31.8%), lung/bronchus (18.8%), colon/rectum (8.6%), urinary bladder (3.6%), and skin melanomas (3.4%). VA patients were diagnosed at an earlier stage of disease for the three most commonly diagnosed cancers--lung/bronchus, colon/rectum, and prostate--compared to the U.S. male cancer population.
Registry data indicate that incident cancers in VA in 2007 approximately mirrored those observed among U.S. men.
Military medicine 06/2012; 177(6):693-701. · 0.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have generated 3 mouse lines, each with a different mutation in the nonmuscle myosin II-A gene, Myh9 (R702C, D1424N, and E1841K). Each line develops MYH9-related disease similar to that found in human patients. R702C mutant human cDNA fused with green fluorescent protein was introduced into the first coding exon of Myh9, and D1424N and E1841K mutations were introduced directly into the corresponding exons. Homozygous R702C mice die at embryonic day 10.5-11.5, whereas homozygous D1424N and E1841K mice are viable. All heterozygous and homozygous mutant mice show macrothrombocytopenia with prolonged bleeding times, a defect in clot retraction, and increased extramedullary megakaryocytes. Studies of cultured megakaryocytes and live-cell imaging of megakaryocytes in the BM show that heterozygous R702C megakaryocytes form fewer and shorter proplatelets with less branching and larger buds. The results indicate that disrupted proplatelet formation contributes to the macrothrombocytopenia in mice and most probably in humans. We also observed premature cataract formation, kidney abnormalities, including albuminuria, focal segmental glomerulosclerosis and progressive kidney disease, and mild hearing loss. Our results show that heterozygous mice with mutations in the myosin motor or filament-forming domain manifest similar hematologic, eye, and kidney phenotypes to humans with MYH9-related disease.
[show abstract][hide abstract] ABSTRACT: To the Editor: We would like to retract our article, "A Genomic Strategy to Refine Prognosis in Early-Stage Non-Small-Cell Lung Cancer,"(1) which was published in the Journal on August 10, 2006. Using a sample set from a study by the American College of Surgeons Oncology Group (ACOSOG) and a collection of samples from a study by the Cancer and Leukemia Group B (CALGB), we have tried and failed to reproduce results supporting the validation of the lung metagene model described in the article. We deeply regret the effect of this action on the work of other investigators.
New England Journal of Medicine 03/2011; 364(12):1176. · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: The Veterans Affairs (VA) healthcare system treats approximately 3% of patients with cancer in the United States each year. We measured the quality of nonmetastatic colorectal cancer (CRC) care in VA as indicated by concordance with National Comprehensive Cancer Network practice guidelines (six indicators) and timeliness of care (three indicators).
A retrospective medical record abstraction was done for 2,492 patients with incident stages I to III CRC diagnosed between October 1, 2003, and March 31, 2006, who underwent definitive CRC surgery. Patients were treated at one or more of 128 VA medical centers. The proportion of patients receiving guideline-concordant care and time intervals between care processes were calculated.
More than 80% of patients had preoperative carcinoembryonic antigen determination (ie, stages II to III disease) and documented clear surgical margins (ie, stages II to III disease). Between 72% and 80% of patients had appropriate referral to a medical oncologist (ie, stages II to III disease), preoperative computed tomography scan of the abdomen and pelvis (ie, stages II to III disease), and adjuvant fluorouracil-based chemotherapy (ie, stage III disease). Less than half of patients with stages I to III CRC (43.5%) had a follow-up colonoscopy 7 to 18 months after surgery. The mean number of days between major treatment events included the following: 26.6 days (standard deviation [SD], 38.2; median, 20 days) between diagnosis and initiation of treatment (in stages II to III disease); 64.8 [corrected] days (SD, 54.9; median, 50 days) between definitive surgery and start of adjuvant chemotherapy (in stages II to III disease); and 444.2 [corrected] days (SD, 182.1; median, 393 days) between definitive surgery and follow-up colonoscopies (in stages I to III disease).
Although there is opportunity for improvement in the area of cancer surveillance, the VA performs well in meeting established guidelines for diagnosis and treatment of CRC.
Journal of Clinical Oncology 07/2010; 28(19):3176-81. · 18.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: SRC is an oncogene with an essential role in the invasiveness and metastasis of solid tumors including small cell lung cancer. Dasatinib is a potent inhibitor of SRC as well as other tyrosine kinases. The primary objective of this study was to determine the efficacy of second-line dasatinib in patients with chemosensitive (relapse or progression > or =90 days after completing first-line therapy) small cell lung cancer.
Patients with measurable disease; performance status 0 to 1; no more than one prior platinum-based chemotherapy regimen; and adequate hematologic, hepatic, and renal function were eligible. Dasatinib was administered orally at 70 mg twice daily continuously (1 cycle = 21 days) until disease progression or unacceptable toxicity. Response was determined after every two cycles. Patients were followed until disease progression or death. The study was prospectively designed to simultaneously discriminate between complete plus partial response rates of 5% versus 20% and progression-free survival (PFS) rates at 6 weeks of 50% versus 70.7% in 53 evaluable patients with at least 92% power. The study was to be terminated early and declared negative if 1 or less objective response and 14 or fewer instances of PFS > or =6 weeks were observed among the initial 27 patients; however, patient accrual continued while the initial 27 patients were evaluated.
Between April 2007 and December 2008, 45 patients were enrolled, but one patient never received any protocol therapy and one patient was ineligible: male/female, 17/26; white/black/unknown, 40/2/1; median age, 64 years (range, 35-84 years); and performance status 0/1, 12/31. No objective response was recorded among the 43 eligible and treated patients. Among the initial 27 patients, only 13 instances of PFS > or =6 weeks were observed. With a median follow-up time of 7.1 months, median estimated overall survival and PFS times for the 43 eligible and treated patients were 17.0 and 5.9 weeks, respectively. Common reasons for removal of patients from protocol treatment were progressive disease (65%) and adverse events (26%). Toxicity was generally mild to moderate: grade 3 events of >5% frequency included fatigue and pleural and pericardial effusions; and no grade 4 or 5 events were encountered.
Dasatinib did not reach our specified efficacy criteria in this clinical setting, and the study was terminated.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2010; 5(3):380-4. · 4.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: The hallmark of human cancer is heterogeneity, reflecting the complexity and variability of the vast array of somatic mutations acquired during oncogenesis. An ability to dissect this heterogeneity, to identify subgroups that represent common mechanisms of disease, will be critical to understanding the complexities of genetic alterations and to provide a framework to develop rational therapeutic strategies. Here, we describe a classification scheme for human breast cancer making use of patterns of pathway activity to build on previous subtype characterizations using intrinsic gene expression signatures, to provide a functional interpretation of the gene expression data that can be linked to therapeutic options. We show that the identified subgroups provide a robust mechanism for classifying independent samples, identifying tumors that share patterns of pathway activity and exhibit similar clinical and biological properties, including distinct patterns of chromosomal alterations that were not evident in the heterogeneous total population of tumors. We propose that this classification scheme provides a basis for understanding the complex mechanisms of oncogenesis that give rise to these tumors and to identify rational opportunities for combination therapies.
Proceedings of the National Academy of Sciences 03/2010; 107(15):6994-9. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: The Veterans Affairs (VA) Quality Enhancement Research Initiative (QUERI) seeks to develop partnerships between VA health services researchers and clinical managers, with the goal of designing and evaluating interventions to improve the quality of VA health care.
In the present report we describe one such initiative aimed at enhancing the continuum of colorectal cancer (CRC) care, including diagnosis, treatment and surveillance-the Colorectal Cancer Care Collaborative (C4).
We describe the process and thinking that led to two parallel quality improvement "collaboratives" that addressed (1) CRC screening and diagnostic follow-up and (2) the guideline concordance and timeliness of CRC treatment. Additionally, we discuss ongoing effort to spread lessons learned during the first stages of the project, which initially occurred at only a subset of VA facilities, throughout the VA health care system. The description of this initiative is organized around key questions that must be answered when developing, sustaining and spreading multi-component quality improvement interventions.
We conclude with a discussion of lessons learned that we believe would apply to similar initiatives elsewhere, even if they address different clinical issues in health care settings with different organizational structures.
Journal of General Internal Medicine 01/2010; 25 Suppl 1:38-43. · 3.28 Impact Factor
[show abstract][hide abstract] ABSTRACT: Immortal tumor cell lines are an important model system for cancer research, however, misidentification and cross-contamination of cell lines are a common problem. Seven chordoma cell lines are reported in the literature, but none has been characterized in detail. We analyzed gene expression patterns and genomic copy number variations in five putative chordoma cell lines (U-CH1, CCL3, CCL4, GB60, and CM319). We also created a new chordoma cell line, U-CH2, and provided genotypes for cell lines for identity confirmation. Our analyses revealed that CCL3, CCL4, and GB60 are not chordoma cell lines, and that CM319 is a cancer cell line possibly derived from chordoma, but lacking expression of key chordoma biomarkers. U-CH1 and U-CH2 both have gene expression profiles, copy number aberrations, and morphology consistent with chordoma tumors. These cell lines also harbor genetic changes, such as loss of p16, MTAP, or PTEN, that make them potentially useful models for studying mechanisms of chordoma pathogenesis and for evaluating targeted therapies.
[show abstract][hide abstract] ABSTRACT: Currently there is no effective chemotherapy for chordoma. Recent studies report co-expression of insulin-like growth factor-1 receptor (IGF1R) and its cognate ligand in chordoma, but it is unknown whether this receptor tyrosine kinase is activated in these tumours. Additionally, genetic studies have confirmed frequent deletions of chromosome 9p in chordomas, which encompasses the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus. Another gene in this region, methylthioadenosine phosphorylase (MTAP), is an essential enzyme of the purine salvage pathway and has therapeutic relevance because MTAP-deficient cells are particularly sensitive to inhibitors of de novo purine synthesis. We investigated whether these pathways might be potential therapeutic targets for chordoma. Paraffin-embedded tissue samples from 30 chordomas were analysed by immunohistochemistry for expression of the phosphorylated isoforms of IGF1R or the insulin receptor (pIGF1R/pIR) and selected downstream signalling molecules, including BCL2-associated agonist of cell death protein (BAD). Expression of CDKN2A and MTAP proteins was also assessed. Skeletal chondrosarcomas, benign notochordal cell tumours, and fetal notochord were studied for comparison. Phosphorylated IGF1R/IR was detected in 41% of chordomas, together with activated downstream signalling molecules, and pIGF1R/pIR was absent in benign notochordal cell tumours and fetal notochord. Thirty-nine per cent of chordomas were negative for MTAP immunoreactivity. Patients with pIGF1R/pIR-positive tumours showed significantly decreased median disease-free survival in multivariate survival analysis (p = 0.036), whereas phosphorylation of BAD at serine-99 was found to be associated with a favourable prognosis (p = 0.002). Approximately 40% of chordomas demonstrate evidence of activation of the IGF1R/IR signalling pathway or loss of a key enzyme in the purine salvage pathway. Aberrant signalling cascades and disrupted metabolic pathways such as these may represent opportunities for novel targeted therapeutic approaches for the treatment of chordoma.
The Journal of Pathology 12/2009; 220(5):608-17. · 7.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Using high-resolution array-CGH, we identified unique duplications of a region on 6q27 in four multiplex families with at least three cases of chordoma, a cancer of presumed notochordal origin. The duplicated region contains only the T (brachyury) gene, which is important in notochord development and is expressed in most sporadic chordomas. Our findings highlight the value of screening for complex genomic rearrangements in searches for cancer-susceptibility genes.
[show abstract][hide abstract] ABSTRACT: In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival and demonstrated no significant benefit from the addition of induction chemotherapy. The primary objective of this analysis was to dichotomize patients into prognostic groups using factors predictive of survival and to investigate whether induction chemotherapy was beneficial in either prognostic group.
A Cox proportional hazard model was used to assess the impact on survival of the following factors: (>or=70 versus <70 years), gender, race, stage (IIIB versus IIIA), hemoglobin (hgb) (<13 versus >or=13 g/dl), performance status (PS) (1 versus 0), weight loss (>or=5% versus <5%), treatment arm, and the interaction between weight loss and hgb.
Factors predictive of decreased survival were weight loss >or=5%, age >or=70 years, PS of 1, and hgb <13 g/dl (p < 0.05). Patients were classified as having >or=2 poor prognostic factors (n = 165) or <or=1 factor (n = 166). The hazard ratio (HR) for overall survival for the patients with >or=2 versus patients with <or=1 was 1.88 [95% confidence interval (CI), 1.49-2.37; p = <0.0001]; median survival times observed were 9 (95% CI, 8-11) and 18 (95% CI, 16-24) months, respectively. There was no significant difference in survival between treatment arms in patients with >or=2 factors (HR = 0.86, 95% CI, 0.63-1.17; p = 0.34) or <or=1 factor (HR = 0.97, 95% CI, 0.70-1.35; p = 0.87).
There is no evidence that induction chemotherapy is beneficial in either prognostic group.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 07/2009; 4(9):1117-25. · 4.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tumors contain oxygenated and hypoxic regions, so the tumor cell population is heterogeneous. Hypoxic tumor cells primarily use glucose for glycolytic energy production and release lactic acid, creating a lactate gradient that mirrors the oxygen gradient in the tumor. By contrast, oxygenated tumor cells have been thought to primarily use glucose for oxidative energy production. Although lactate is generally considered a waste product, we now show that it is a prominent substrate that fuels the oxidative metabolism of oxygenated tumor cells. There is therefore a symbiosis in which glycolytic and oxidative tumor cells mutually regulate their access to energy metabolites. We identified monocarboxylate transporter 1 (MCT1) as the prominent path for lactate uptake by a human cervix squamous carcinoma cell line that preferentially utilized lactate for oxidative metabolism. Inhibiting MCT1 with alpha-cyano-4-hydroxycinnamate (CHC) or siRNA in these cells induced a switch from lactate-fueled respiration to glycolysis. A similar switch from lactate-fueled respiration to glycolysis by oxygenated tumor cells in both a mouse model of lung carcinoma and xenotransplanted human colorectal adenocarcinoma cells was observed after administration of CHC. This retarded tumor growth, as the hypoxic/glycolytic tumor cells died from glucose starvation, and rendered the remaining cells sensitive to irradiation. As MCT1 was found to be expressed by an array of primary human tumors, we suggest that MCT1 inhibition has clinical antitumor potential.
Journal of Clinical Investigation 01/2009; 118(12):3930-42. · 12.81 Impact Factor