Publications by authors named "Jonathan E Dowell"

41 Publications

Predictors of prognosis of synchronous brain metastases in small-cell lung cancer patients.

Clin Exp Metastasis 2020 08 4;37(4):531-539. Epub 2020 Jun 4.

Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Patients with small cell lung cancer (SCLC) are more likely to have synchronous brain metastasis (SBM) at the time of diagnosis than patients with any other extracranial primary malignancy. We sought to identify which factors predicted an increased risk of SBM in SCLC as well as which factors affected the prognosis of these patients. 38,956 Patients in the Surveillance, Epidemiology, and End Results (SEER) database with microscopically confirmed SCLC from 2010 to 2016 were identified. 6264 (16.1%) Patients with SCLC had SBM at the time of diagnosis. In the multivariable logistic regression, disease specific factors that were predictive of SBM were primary tumor size > 7 cm (adjusted OR = 1.14, 95% CI [1.02, 1.28], p = 0.02), synchronous lung metastases, and synchronous bone metastases. Demographic specific factors predictive of increased SBM risk in this model were younger age, male sex, and race (American Indian/Alaska Native and black patients). Patients insured through Medicaid were less likely to present with SBM. In the multivariate Cox proportional hazards model, lack of insurance was the strongest predictor of mortality (adjusted HR = 1.47, 95% CI [1.26, 1.73], p < 0.001). Other factors associated with an increased risk of mortality include male sex, older age, health insurance coverage through Medicaid, synchronous liver metastasis, synchronous lung metastasis, and primary tumor size > 7 cm. In contrast, Asian patients had a lower risk of mortality. This study identifies risk factors for SBM among patients with SCLC, as well as indicators of prognosis among this patient population.
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http://dx.doi.org/10.1007/s10585-020-10040-4DOI Listing
August 2020

Efficacy and Safety of Bavituximab in Combination with Sorafenib in Advanced Hepatocellular Carcinoma: A Single-Arm, Open-Label, Phase II Clinical Trial.

Target Oncol 2019 10;14(5):541-550

Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.

Background: Bavituximab, an immunomodulator, targets phosphatidylserine (PS), a membrane lipid externalized on tumor and endothelial cells in response to sorafenib.

Objective: The objective of this phase II study was to assess the efficacy of combination bavituximab and sorafenib in advanced hepatocellular carcinoma (HCC).

Methods: In this single-arm phase II study, patients with HCC determined to be unresectable with Eastern Cooperative Oncology Group (ECOG) score ≤ 2, Child-Pugh score A/B7 received intravenous bavituximab 3 mg/kg weekly and oral sorafenib 400 mg twice daily until disease progression or intolerable toxicity. We investigated time to progression (TTP) for patients receiving combination bavituximab and sorafenib compared with that for sorafenib-only historical controls.

Results: In total, 38 patients were accrued. The median follow-up was 6.1 months. Patient characteristics were as follows: median age 61 years; male 82%; hepatitis C virus 79%; Black 39%, Hispanic 26%, White 29%; previous treatment 39%; macrovascular invasion 84%; and extrahepatic metastases 24%. The median TTP was 6.7 months (95% confidence interval [CI] 4-17). The median overall survival was 6.1 months (95% CI 5-8), and the median disease-specific survival was 8.6 months (95% CI 6-14). Two patients experienced partial responses; none had a complete response. The disease control rate was 58%. Treatment-related adverse events were observed in 63% of patients, with the most commonly reported therapy-related symptoms being diarrhea (32%), fatigue (26%), and anorexia (24%).

Conclusions: The efficacy of adding bavituximab to sorafenib for the treatment of advanced HCC was inconclusive; however, the combination regimen did not exacerbate toxicities associated with single-agent sorafenib. CLINICALTRIALS.

Gov Identifier: NCT01264705.
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http://dx.doi.org/10.1007/s11523-019-00663-3DOI Listing
October 2019

Treatment and Outcomes of Primary Pericardial Mesothelioma: A Contemporary Review of 103 Published Cases.

Clin Lung Cancer 2019 03 29;20(2):e152-e157. Epub 2018 Nov 29.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Harold C. Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX; Veterans Affairs, North Texas Health Care System, Dallas, TX. Electronic address:

Primary pericardial mesothelioma (PPM) is a rare cancer for which there is no consensus on treatment. We evaluated and summarized a large contemporary population of published PPM cases to characterize risk factors, treatment patterns, and clinical outcomes. Using Ovid and PubMed, literature published from 2000 through 2016 was searched using the terms "primary pericardial mesothelioma," "pericardial mesothelioma," and "malignant pericardial mesothelioma." We identified 6 case series and 84 case reports for a total of 103 PPM cases published from 2000 through 2016. The median age at diagnosis was 55 years, and the median overall survival was 6 months. In univariate analyses of clinical characteristics including gender, asbestos exposure, tobacco use, prior radiation exposure, histologic subtype, and metastasis and/or mediastinal spread, only the presence of metastasis and/or mediastinal spread was a significant predictor of decreased survival (P = .015). Surgery did not provide a statistically significant survival benefit (P = .12). A survival benefit was noted in those who received chemotherapy (median survival, 13 months vs. 0.5 months, P = .002), specifically chemotherapy with a platinum agent with or without pemetrexed. In multivariate analysis, only the receipt of chemotherapy was associated with improved survival. PPM remains a rare and poorly understood malignancy with unclear etiology and a poor prognosis. In this retrospective systematic review, a survival benefit was seen in patients who received chemotherapy.
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http://dx.doi.org/10.1016/j.cllc.2018.11.008DOI Listing
March 2019

Phase 1 study of ARQ 761, a β-lapachone analogue that promotes NQO1-mediated programmed cancer cell necrosis.

Br J Cancer 2018 10 15;119(8):928-936. Epub 2018 Oct 15.

Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

Background: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a β-lapachone (β-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death.

Methods: We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours (H-score ≥ 200).

Results: A total of 42 patients were treated. Median number of prior lines of therapy was 4. Maximum tolerated dose was 390 mg/m as a 2-h infusion every other week. Dose-limiting toxicity was anaemia. The most common treatment-related adverse events were anaemia (79%), fatigue (45%), hypoxia (33%), nausea (17%), and vomiting (17%). Transient grade 3 hypoxia, reflecting possible methemoglobinaemia, occurred in 26% of patients. Among 32 evaluable patients, best response was stable disease (n = 12); 6 patients had tumour shrinkage. There was a trend towards improved efficacy in NQO1-high tumours (P = 0.06).

Conclusions: ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.
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http://dx.doi.org/10.1038/s41416-018-0278-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203852PMC
October 2018

Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

JAMA Oncol 2018 Jan 11;4(1):e173501. Epub 2018 Jan 11.

Departments of Radiation Oncology, Harold C. Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center, Dallas.

Importance: Patterns-of-failure studies suggest that in metastatic non-small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited.

Objective: To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy in patients with non-progressive limited metastatic NSCLC after induction therapy led to significant improvements in progression-free survival (PFS).

Design, Setting, And Participants: This is a single-institution randomized phase 2 study of maintenance chemotherapy alone vs SAbR followed by maintenance chemotherapy for patients with limited metastatic NSCLC (primary plus up to 5 metastatic sites) whose tumors did not possess EGFR-targetable or ALK-targetable mutations but did achieve a partial response or stable disease after induction chemotherapy.

Interventions: Maintenance chemotherapy or SAbR to all sites of gross disease (including SAbR or hypofractionated radiation to the primary) followed by maintenance chemotherapy.

Main Outcomes And Measures: The primary end point was PFS; secondary end points included toxic effects, local and distant tumor control, patterns of failure, and overall survival.

Results: A total of 29 patients (9 women and 20 men) were enrolled; 14 patients (median [range] age, 63.5 [51.0-78.0] years) were allocated to the SAbR-plus-maintenance chemotherapy arm, and 15 patients (median [range] age, 70.0 [51.0-79.0] years) were allocated to the maintenance chemotherapy-alone arm. The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy-alone arm (P = .01). Toxic effects were similar in both arms. There were no in-field failures with fewer overall recurrences in the SAbR arm while those patients receiving maintenance therapy alone had progression at existing sites of disease and distantly.

Conclusions And Relevance: Consolidative SAbR prior to maintenance chemotherapy appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local therapy in limited metastatic settings.

Trial Registration: clinicaltrials.gov Identifier: NCT02045446.
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http://dx.doi.org/10.1001/jamaoncol.2017.3501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833648PMC
January 2018

Spotlight on bevacizumab and its potential in the treatment of malignant pleural mesothelioma: the evidence to date.

Onco Targets Ther 2017 7;10:2057-2066. Epub 2017 Apr 7.

Division of Hematology/Oncology, University of Texas Southwestern Medical Center.

Malignant pleural mesothelioma (MPM) is a rare, but aggressive cancer. Surgery and radiation offer limited benefit, and systemic chemotherapy remains the primary treatment modality for the majority of patients. Vascular endothelial growth factor (VEGF) and its receptor have been recognized as important players in the biology of this disease. Bevacizumab is a monoclonal antibody that binds VEGF and blocks its interaction with the VEGF receptor. Recent studies have shown benefit with the addition of bevacizumab to the combination of cisplatin and pemetrexed in MPM. This combination is now included in the National Comprehensive Cancer Network guidelines (with a category 2A recommendation) as a possible first-line treatment for unresectable MPM in appropriately selected patients. This review discusses the rationale behind the use of bevacizumab in MPM, as well as summarizes the pharmacology, efficacy, safety, and toxicity of bevacizumab across multiple trials. The use of small-molecule inhibitors of angiogenesis in the treatment of MPM is also discussed.
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http://dx.doi.org/10.2147/OTT.S113598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391166PMC
April 2017

Modern management of malignant pleural mesothelioma.

Lung Cancer (Auckl) 2016 3;7:63-72. Epub 2016 May 3.

Division of Hematology and Oncology, University of Texas Southwestern; Section of Hematology and Oncology, Veterans Affairs North Texas Healthcare System, Dallas, TX, USA.

Malignant pleural mesothelioma (MPM) is a deadly disease that produces a significant worldwide health care burden. The majority of cases are associated with prior asbestos exposure, but recent studies have identified a possible genetic predisposition in a minority of patients. Historically, obtaining a pathologic diagnosis of MPM was challenging, but with current pathological techniques, a secure diagnosis is possible in the majority of patients. Curative therapy for MPM remains elusive, and the primary treatment option for fit patients is platinum-based chemotherapy. Encouraging recent reports suggest that there may be a benefit to the addition of bevacizumab to standard chemotherapy as well as with the use of immune checkpoint inhibitors in MPM. Selected patients may be considered for aggressive surgical approaches, but there is considerable controversy regarding the true benefit of surgery and multimodality therapy in this disease.
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http://dx.doi.org/10.2147/LCTT.S83338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310692PMC
May 2016

Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer.

Lung Cancer 2015 Dec 9;90(3):534-41. Epub 2015 Oct 9.

Department of Internal Medicine (Division of Hematology-Oncology), USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, USA.

Purpose: Preclinical studies demonstrated anti-tumor efficacy of the combination of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in non-small cell lung cancer (NSCLC) models that were insensitive to erlotinib monotherapy. We therefore studied this combination in a phase 1 clinical trial in previously treated advanced NSCLC.

Methods: Romidepsin (8 or 10mg/m(2)) was administered intravenously on days 1, 8, and 15 every 28 days in combination with erlotinib (150 mg orally daily), with romidepsin monotherapy lead-in during Cycle 1. Correlative studies included peripheral blood mononuclear cell HDAC activity and histone acetylation status, and EGFR pathway activation status in skin biopsies.

Results: A total of 17 patients were enrolled. Median number of prior lines of therapy was 3 (range 1-5). No cases had a sensitizing EGFR mutation. The most common related adverse events were nausea, vomiting, and fatigue (each 82%), diarrhea (65%), anorexia (53%), and rash (41%). Dose-limiting nausea and vomiting occurred at the romidepsin 10 mg/m(2) level despite aggressive antiemetic prophylaxis and treatment. Among 10 evaluable patients, the best response was stable disease (n=7) and progressive disease (n=3). Median progression-free survival (PFS) was 3.3 months (range 1.4-16.5 months). Prolonged PFS (>6 months) was noted in a KRAS mutant adenocarcinoma and a squamous cell cancer previously progressed on erlotinib monotherapy. Romidepsin monotherapy inhibited HDAC activity, increased histone acetylation status, and inhibited EGFR phosphorylation.

Conclusions: Romidepsin 8 mg/m(2) plus erlotinib appears well tolerated, has evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population.
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http://dx.doi.org/10.1016/j.lungcan.2015.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125089PMC
December 2015

Randomized phase 2 trial of erlotinib in combination with high-dose celecoxib or placebo in patients with advanced non-small cell lung cancer.

Cancer 2015 Sep 29;121(18):3298-306. Epub 2015 May 29.

Departments of Medicine and Pathology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.

Background: Cyclooxygenase 2 (COX-2)-dependent signaling represents a potential mechanism of resistance to therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This is mediated in part through an EGFR-independent activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) by prostaglandin E2 (PGE2). PGE2 promotes downregulation of E cadherin and epithelial to mesenchymal transition. The current study investigated EGFR and COX-2 inhibition in patients with non-small cell lung cancer (NSCLC) and elevated baseline urinary metabolite of PGE2 (PGEM).

Methods: Patients with stage IIIB/IV (AJCC 6th edition) NSCLC who progressed after at least 1 line of therapy or refused standard chemotherapy were randomized to receive erlotinib and celecoxib versus erlotinib and placebo. The primary endpoint was progression-free survival (PFS) with 80% power to detect a 50% improvement with a 1-sided significance level of .2 in the intent-to-treat and elevated baseline PGEM populations. Secondary endpoints included response rate, overall survival, and evaluation of molecular markers to assess targeting COX-2-related pathways and evaluate EGFR tyrosine kinase inhibitor resistance.

Results: A total of 107 patients were enrolled with comparable baseline characteristics. Among the patients treated with celecoxib, those with wild-type EGFR were found to have an increased PFS (3.2 months vs 1.8 months; P = .03). PFS was numerically improved among patients in the intent-to-treat group who received erlotinib and celecoxib compared with those treated with erlotinib and placebo (5.4 months vs 3.5 months; P = .33) and was increased in patients in the erlotinib and celecoxib arm with elevated baseline PGEM (5.4 months vs 2.2 months; P = .15). Adverse events were similar in both treatment arms.

Conclusions: The combination of erlotinib and celecoxib did not appear to improve outcomes in an unselected population, but selection by elevated baseline PGEM led to an increase in PFS with this combination. Patients with EGFR wild-type status may benefit from the combination of erlotinib and celecoxib.
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http://dx.doi.org/10.1002/cncr.29480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864011PMC
September 2015

Phase I dose escalation trial of nitroglycerin in addition to 5-fluorouracil and radiation therapy for neoadjuvant treatment of operable rectal cancer.

Surgery 2015 Aug 9;158(2):460-5. Epub 2015 May 9.

VA North Texas Health Care System Department of Hematology Oncology, Radiation Oncology, and Surgery/University of Texas Southwestern, Department of Surgery and Radiation Oncology, Dallas, TX. Electronic address:

Background: Nitric oxide donors decreased cell survival in vitro and tumor load in vivo in models of rectal cancer subjected to ionizing radiation. Nitroglycerin (NTG) transdermal patches, added to chemotherapy, have been shown to improve outcomes in lung cancer patients.

Methods: This open-label, nonrandomized, multicohort, dose escalation, phase I trial had a primary endpoint to evaluate the safety, tolerability, feasibility, dose-limiting toxicity and maximum tolerated dose of topical NTG in addition to 5-fluorouracil and radiation therapy for neoadjuvant treatment of locoregionally advanced operable rectal cancer. The secondary endpoint was rate of pathologic complete response (pCR). Patients were assigned to 3 sequential cohorts of escalating dose levels of commercially available NTG patches (0.2, 0.4, and 0.6 mg/h), each cohort was intended to consist of 3 patients.

Results: Thirteen patients were enrolled in the trial as specified in the dose escalation protocol. They were all male with a median age of 59.4 ± 2.5 (SEM) years. The observed toxicities were mild to moderate and manageable. Four patients developed asymptomatic grade 3 lymphopenia during the chemoradiation that resolved promptly upon completion. One patient had a non-ST segment elevation MI and 1 patient developed diarrhea. None of these toxicities were attributed to NTG except for 1 patient who developed a grade 3 headache. This required an additional group of patients at the same dose and no other patient experienced headaches. pCR was 17%.

Conclusion: NTG patches are well-tolerated and it is feasible to proceed with a phase II trial at the maximum dose examined (0.6 mg/h).
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http://dx.doi.org/10.1016/j.surg.2015.04.007DOI Listing
August 2015

Upper extremity venous thrombosis in patients with cancer with peripherally inserted central venous catheters: a retrospective analysis of risk factors.

J Oncol Pract 2013 Jan;9(1):e8-12

University of Texas Southwestern Medical Center, Department of Palliative Care, Dallas, TX 75390-8889, USA.

Purpose: Peripherally inserted central catheters (PICCs) are often used in place of mediport catheters because of cost and lack of operating room time and to prevent delays in therapy. One common complication associated with their use is upper extremity venous thrombosis (UEVT). The purpose of this study was to ascertain risk factors associated with an increased risk of PICC-associated UEVT in patients with cancer.

Methods: Retrospective analysis identified 237 patients with cancer who received PICCs at the Dallas Veterans Affairs Medical Center from 2006 to 2009. We analyzed many risk factors, including PICC infection (PI), use of erythropoiesis-stimulating agents (ESAs), antiplatelet agents (APAs), treatment dose anticoagulation (TDA), and bevacizumab.

Results: Of 237 patients, 36 (15%) were found to have UEVT. Stepwise logistic regression analysis showed risk factors positively associated with UEVT were use of ESAs (odds ratio [OR], 10.66; 95% CI, 2.25 to 50.49), hospitalization (OR, 2.38; 95% CI, 1.05 to 5.39), PI (OR, 2.46; 95% CI, 1.03 to 5.86), and TDA (OR, 8.34; 95% CI, 2.98 to 23.33), whereas patients receiving APAs had a lower risk of UEVT (OR, 0.25; 95% CI, 0.07 to 0.92).

Conclusion: Specific factors significantly increase the risk of UEVT in patients with cancer with PICCs, whereas use of APAs seems to have a protective effect against UEVT. These results may aid in the development of a predictive model for identifying patients at high risk of UEVT who may benefit from APAs, as well as in determining preventive strategies for reducing the risk of PICC-associated UEVT.
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http://dx.doi.org/10.1200/JOP.2012.000595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545673PMC
January 2013

Consent timing and experience: modifiable factors that may influence interest in clinical research.

J Oncol Pract 2012 Mar 6;8(2):91-6. Epub 2011 Dec 6.

University of Texas Southwestern Medical Center, Dallas, TX.

Purpose: Low rates of participation in cancer clinical trials have been attributed to patient, institutional, and study characteristics. However, few studies have examined factors related to the consent process. We therefore evaluated the impact of consent timing and experience on markers of patient interest in research.

Methods: We performed a retrospective analysis of patients enrolled in a cancer center tissue repository. During enrollment, patients were asked if they were willing to be contacted in the future to provide medical follow-up information and/or to participate in other clinical research. We analyzed the association between patient responses to these questions and consent process factors using univariate analysis and multivariate logistic regression.

Results: Of 922 patients evaluated, 85% agreed to be contacted to provide follow-up information, and 83% agreed to be contacted to participate in future research studies. In univariate analysis, willingness to be contacted for future research was associated with consenter experience (P = .01) and had a trend toward association with the timing of enrollment in relation to diagnosis (P = .08), but it was not associated with patient sex, race, or diagnosis. In multivariate analysis, responses remained associated with consenter experience (P = .02).

Conclusion: Factors related to the consent process, including consenter experience and timing of study enrollment, are significantly associated with or have a trend toward association with markers of patient interest in clinical research. These understudied and potentially modifiable variables warrant further evaluation.
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http://dx.doi.org/10.1200/JOP.2011.000335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3457835PMC
March 2012

Hematologic malignancies associated with germ cell tumors.

Expert Rev Hematol 2012 Aug;5(4):427-37

Center for Comprehensive Cancer Care, 4117 Veterans Memorial Drive, Mount Vernon, IL 62864, USA.

Germ cell tumor (GCT)-associated hematologic malignancies present a unique challenge to hematologists and hematopathologists. As most GCTs are of gonadal origin, only a small percentage occur at extragonadal sites in the midline. Extragonadal GCTs are believed to originate from the ectopic primordial germ cells that fail to migrate to the urogenital ridge during development. An overactive KIT pathway and overexpression of genes on chromosome 12p are strongly implicated in GCT development. Approximately 54% of extragonadal GCTs are located in the anterior mediastinum. This is disproportionally high among the midline structures, presumably due to a favorable microenvironment for GCT development in the developing thymus. The mediastinal nonseminomatous GCTs have two unique features. First, they are often refractory to current treatment modality with the worst prognosis among GCTs of all sites. Second, they have a tendency to give rise to secondary hematologic neoplasia. The outcome is grave for patients with GCT-associated hematologic malignancies. As standard chemotherapy used to treat their bone marrow-derived counterparts has been ineffective, the best treatment modality to achieve long-term survival is allogeneic hematopoietic stem cell or cord blood transplant for a very limited number of cases.
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http://dx.doi.org/10.1586/ehm.12.24DOI Listing
August 2012

A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma.

Lung Cancer 2012 Sep 4;77(3):567-71. Epub 2012 Jul 4.

Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA.

Introduction: Malignant mesothelioma (MM) cells express the vascular endothelial growth factor (VEGF) receptor, and VEGF protein expression is detected in a majority of human mesothelioma biopsy specimens. Bevacizumab is a recombinant humanized monoclonal antibody that blocks the binding of VEGF to its receptor. We evaluated the addition of bevacizumab to cisplatin and pemetrexed as first-line treatment in patients with advanced, unresectable MM.

Methods: Previously untreated MM patients with advanced, unresectable disease received cisplatin (75 mg/m(2)), pemetrexed (500 mg/m(2)), and bevacizumab (15 mg/kg) intravenously every 21 days for a maximum of 6 cycles. Patients with responsive or stable disease received bevacizumab (15 mg/kg) intravenously every 21 days until progression or intolerance. The primary endpoint was progression-free survival rate at 6 months.

Results: 53 patients were enrolled at 4 centers; 52 were evaluable for this analysis. The progression-free survival rate at 6 months was 56% and the median progression-free survival was 6.9 months (95% confidence interval [CI], 5.3-7.8 months). The partial response rate was 40% and 35% of patients had stable disease. Median overall survival was 14.8 months (95% CI; 10.0-17.0 months). Grade 3/4 toxicities included neutropenia in 11%, hypertension in 6%, and venous thromboembolism in 13% of patients.

Conclusion: This trial evaluating the addition of bevacizumab to cisplatin and pemetrexed in patients with previously untreated, advanced MM failed to meet the primary endpoint of a 33% improvement in the progression-free survival rate at 6 months compared with historical controls treated with cisplatin and pemetrexed alone.
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http://dx.doi.org/10.1016/j.lungcan.2012.05.111DOI Listing
September 2012

ERCC1 expression and outcomes in head and neck cancer treated with concurrent cisplatin and radiation.

Anticancer Res 2011 Dec;31(12):4135-9

Sacred Heart Medical Oncology, Miramar Beach, FL, USA.

Background: Overexpression of excision repair cross complementing group 1 (ERCC1), a DNA repair enzyme, is associated with resistance to cisplatin.

Materials And Methods: Tissues from 73 patients with squamous cell carcinoma of the head and neck (HNSCC) who received concurrent cisplatin and radiation was analyzed immunohistochemically to determine if ERCC1 expression predicted for survival and response. Expression was scored as follows: 0=0% tumor nuclei positive, 1+=<50%, 2+=50-75% and 3+=>75%.

Results: ERCC1 expression was 0 in 0%, 1+ (14%), 2+ (42%) and 3+ (44%). In uni- and multivariate analyses, 3+ ERCC1 expression was not a significant predictor of survival or response. Median survival for the ERCC1 3+ patients was 2.9 years versus 2.1 years for the ERCC1 <3+ group (p=0.44).

Conclusion: In this retrospective review of HNSCC patients receiving concurrent cisplatin and radiation, ERCC1 expression was not a significant predictor of survival or response.
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December 2011

Incidence of isolated heparin-induced thrombocytopenia and risk of thrombosis by IgG-specific anti-PF4/heparin ELISA.

Clin Appl Thromb Hemost 2012 Mar-Apr;18(2):215-7. Epub 2011 Nov 8.

Division of Hematology/Oncology, Department of Medicine, UT Southwestern Medical Center at Dallas, TX, USA.

Unlabelled: Heparin-induced thrombocytopenia (HIT) antibodies are screened by an enzyme-linked immunosorbent assay (ELISA). Polyspecific ELISA detects anti-PF4/heparin IgG, IgA, and IgM. Recently, anti-PF4/heparin IgG ELISA has been shown to be more specific. However, the impact of using the IgG-ELISA on the incidence of isolated HIT (thrombocytopenia alone without clinically evident thrombosis) and the risk of developing subsequent thrombosis are still unknown.

Methods: A total of 492 consecutive patients with clinically suspected HIT at The University of Texas Southwestern Medical Center and affiliated hospitals were retrospectively reviewed from December 2008 to May 2010.

Results: 29 patients (6%) were diagnosed with HIT based on clinical findings and positive ELISA. 19 of the 29 patients (65%) had thrombosis at the time of diagnosis; whereas 10 of the 29 (35%) had only isolated HIT. The ten patients with isolated HIT had serial follow up for at least 3 months. 3 of 10 were treated with direct thrombin inhibitors and 5 of 10 were treated with Warfarin for at least 1 month upon discharge. None of them developed symptoms or signs of thrombosis during 3 months of follow up.

Conclusion: The incidence of isolated HIT in this study was 35%, which is significantly lower than previously reported in the literature. It is possible that some patients previously thought to have HIT by the poly-specific ELISA assay had false positive results. The improved specificity of the IgG- ELISA appears to reduce the incidence of isolated HIT which may have lower risk of subsequent thrombosis.
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http://dx.doi.org/10.1177/1076029611423389DOI Listing
July 2012

Putting lung cancer clinical trials into perspective.

Oncology (Williston Park) 2011 Jan;25(1):78, 80

Internal Medicine, Veterans Affairs North Texas Healthcare System, Dallas, Texas, USA.

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January 2011

Risk of renal failure in cancer patients with bone metastasis treated with renally adjusted zoledronic acid.

Support Care Cancer 2012 Jan 1;20(1):87-93. Epub 2011 Jan 1.

Texas Tech University Health Sciences Center (TTUHSC) School of Pharmacy, 4500 S. Lancaster Rd., Dallas, TX 75216, USA.

Purpose: The purpose of this study was to evaluate the incidence of acute renal failure (ARF) in patients with mild to moderate renal dysfunction, receiving renally adjusted zoledronic acid (ZA) and compare it to patients with normal baseline renal function, receiving standard-dose ZA.

Methods: This was a retrospective study of patients receiving ZA for the treatment of bone metastasis due to cancer. Patients were divided into two groups: (1) normal group with baseline creatinine clearance (CrCl) of greater than 60 mL/min and standard ZA dose; (2) impaired group with baseline CrCl of 30-60 mL/min and renally adjusted ZA dose. Primary endpoint of ARF was defined as an increase in serum creatinine (SCr) of 0.5 mg/dL or 1.0 mg/dL from a baseline SCr of <1.4 mg/dL or ≥ 1.4 mg/dL, respectively.

Results: In total, 1,472 evaluable doses of ZA were given to 220 patients. Of these, 184 patients were in the normal group and 36 patients in the impaired group. There were 38 patients (20.7%) who developed ARF in the normal group versus 7 patients (19.4%) in the impaired group. There was no difference in the mean time to the incidence of ARF at 6.1 months in both groups. Incidence of ARF based on CrCl (≥ 25% decline in CrCl) was similar between groups (39.1% vs. 41.7%; p = 0.78).

Conclusion: The incidence of ARF is similar between patients in the normal group and impaired group when the ZA dose is renally adjusted.
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http://dx.doi.org/10.1007/s00520-010-1067-7DOI Listing
January 2012

Predictors and impact of second-line chemotherapy for advanced non-small cell lung cancer in the United States: real-world considerations for maintenance therapy.

J Thorac Oncol 2011 Feb;6(2):365-71

Department of Internal Medicine, Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Introduction: : Recent clinical trials incorporating maintenance chemotherapy into the initial treatment of advanced non-small cell lung cancer (NSCLC) have highlighted the benefits of exposing patients to second-line therapies. We, therefore, determined the predictors and impact of second-line chemotherapy administration in a contemporary, diverse NSCLC population.

Methods: : We performed a retrospective analysis of consecutive patients diagnosed with stage IV NSCLC from 2000 to 2007 at clinical facilities associated with the University of Texas Southwestern Medical Center. Demographic, disease, treatment, and outcome data were obtained from hospital tumor registries. The association between these variables was assessed using univariate analysis and multivariate logistic regression.

Results: : A total of 406 patients in this cohort received first-line chemotherapy and were included in the analysis. Mean age was 59 years, 28% were women, and 59% were white. Among these patients, 197 (49%) received second-line chemotherapy. Among those patients who had not progressed after four to six cycles of first-line chemotherapy, 67% received second-line chemotherapy. Receipt of second-line chemotherapy was significantly associated with patient insurance type (p = 0.007), number of cycles of first-line chemotherapy (p < 0.001), and receipt of prechemotherapy palliative radiation therapy (p = 0.005) but was not associated with patient age, gender, race, histology, or year of diagnosis. In a multivariate model, second-line chemotherapy administration remained associated with insurance type (p = 0.003), number of cycles of first-line chemotherapy (p < 0.001), and receipt of prechemotherapy palliative radiation therapy (p = 0.008). The number of cycles of first-line chemotherapy and administration of second-line chemotherapy were associated with overall survival in both univariate and multivariate analyses.

Conclusions: : In this unselected, contemporary, and diverse cohort of patients with advanced NSCLC, 67% of individuals whose disease had not progressed after four to six cycles of first-line chemotherapy eventually received second-line chemotherapy. Markers of socioeconomic status, symptom burden, and response to and tolerance of first-line chemotherapy were associated with receipt of second-line chemotherapy. These factors may assist in the selection of patients most likely to benefit from maintenance chemotherapy.
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http://dx.doi.org/10.1097/JTO.0b013e3181fff142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025081PMC
February 2011

Comparison of the 5-fluorouracil-warfarin and capecitabine-warfarin drug interactions.

Pharmacotherapy 2010 Dec;30(12):1259-65

School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, Texas 75216, USA.

Study Objective: To compare the differences between the 5-fluorouracil-warfarin and capecitabine-warfarin drug interactions in patients receiving therapeutic doses of warfarin.

Design: Retrospective medical record review.

Setting: Large academic Veterans Affairs health care system.

Patients: Twenty-four patients who received concomitant therapeutic doses of warfarin and at least one dose of a fluoropyrimidine--5-fluorouracil or capecitabine--between January 2004 and May 2008.

Measurements And Main Results: The primary outcome was mean change in international normalized ratio (INR) from baseline to end of 90-day study period. Only patients who were taking warfarin before starting either fluoropyrimidine-based chemotherapy were included in the primary analysis. Of the 24 eligible patients, 15 (9 receiving 5-fluorouracil, 6 receiving capecitabine) were taking warfarin before receiving either fluoropyrimidine. No significant differences were noted in the average weekly warfarin dose or baseline INR between the 5-fluorouracil and capecitabine groups. The mean change in INR for patients taking warfarin before fluoropyrimidine use was 4.62 in the 5-fluorouracil group compared with 5.11 in the capecitabine group (p=0.87). The capecitabine group had a similar proportion of patients achieving an INR above 9 while taking warfarin compared with the 5-fluorouracil group (17% vs 22%). In those patients who required a warfarin dosage reduction, the dose was reduced by 38% and 41% in the 5-fluorouracil and capecitabine groups, respectively. No significant differences in bleeding events were reported within 90 days of concurrent use of either fluoropyrimidine with warfarin.

Conclusion: Our study suggests that in patients receiving concomitant warfarin and a fluoropyrimidine, no significant differences in INR elevation or bleeding events were noted with 5-fluorouracil compared with capecitabine.
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http://dx.doi.org/10.1592/phco.30.12.1259DOI Listing
December 2010

Retrospective analysis of the consequences of acid suppressive therapy on ketoconazole efficacy in advanced castration-resistant prostate cancer.

Ann Pharmacother 2010 Oct 14;44(10):1538-44. Epub 2010 Sep 14.

Texas Tech University Health Sciences Center, Dallas, USA.

Background: The area under the curve of a single ketoconazole dose has been shown to decrease significantly when administered with acid suppressive therapy. No published studies have examined the clinical impact of concurrent ketoconazole and acid suppressive therapy in patients with castration-resistant prostate cancer (CRPC).

Objective: To evaluate the effect of acid suppressive therapy on prostate-specific antigen (PSA) response rate in CRPC patients receiving ketoconazole.

Methods: This retrospective study evaluated CRPC patients treated with ketoconazole 3 times daily between January 1, 1999, and September 30, 2009. Patients included in the analysis had failed androgen deprivation therapy, and were subsequently initiated on ketoconazole. Response (PSA decline ≥50% maintained ≥4 weeks) was evaluated in patients receiving ketoconazole with (group 1 [G1]) or without (group 2 [G2]) concurrent acid suppressive therapy.

Results: Thirty patients (G1: 11 patients; G2: 19 patients) were included in the analysis. Mean age in G1 and G2 was 71.8 and 69.6 years, respectively. Most patients had received prior therapy with an antiandrogen (90.9% G1; 100% G2) and fewer patients received antiandrogen withdrawal therapy (27.3% G1; 21.1% G2). Median baseline PSA was 109.4 (G1) and 86.9 ng/mL (G2) (p = 0.55). Median duration of ketoconazole was 7.2 months in G1 and 5.8 months in G2 (p = 0.09). Ketoconazole adherence was 82% (G1) and 100% (G2). Median duration of concurrent acid suppressive therapy was 3.8 months (range 2.0-20.4) in G1. PSA response (72.7% and 47.4%; p = 0.26) and time to PSA response (1.2 vs 0.9 mo; p = 0.53) were statistically similar between G1 and G2, respectively. Median progression free survival was higher in G1 (11.5 vs 6.9 months in G2; p = 0.047).

Conclusions: Use of concurrent acid suppressive therapy and ketoconazole in CRPC patients did not decrease PSA response rate, and progression free survival was unexpectedly higher compared with the non-acid suppressive therapy group. Larger studies are needed to verify the clinical impact of acid suppressive therapy in combination with ketoconazole.
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http://dx.doi.org/10.1345/aph.1P225DOI Listing
October 2010

Looking beyond surveillance, epidemiology, and end results: patterns of chemotherapy administration for advanced non-small cell lung cancer in a contemporary, diverse population.

J Thorac Oncol 2010 Oct;5(10):1529-35

Department of Internal Medicine (Hematology-Oncology), Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8852, USA.

Introduction: Chemotherapy prolongs survival without substantially impairing quality of life for medically fit patients with advanced non-small cell lung cancer (NSCLC), but population-based studies have shown that only 20 to 30% of these patients receive chemotherapy. These earlier studies have relied on Medicare-linked Surveillance, Epidemiology, and End Results (SEER) data, thus excluding the 30 to 35% of lung cancer patients younger than 65 years. Therefore, we determined the use of chemotherapy in a contemporary, diverse NSCLC population encompassing all patient ages.

Methods: We performed a retrospective analysis of patients diagnosed with stage IV NSCLC from 2000 to 2007 at the University of Texas Southwestern Medical Center. Demographic, treatment, and outcome data were obtained from hospital tumor registries. The association between these variables was assessed using univariate analysis and multivariate logistic regression.

Results: In all, 718 patients met criteria for analysis. Mean age was 60 years, 58% were men, and 45% were white. Three hundred fifty-three patients (49%) received chemotherapy. In univariate analysis, receipt of chemotherapy was associated with age (53% of patients younger than 65 years versus 41% of patients aged 65 years and older; p = 0.003) and insurance type (p < 0.001). In a multivariate model, age and insurance type remained associated with receipt of chemotherapy. For individuals receiving chemotherapy, median survival was 9.2 months, compared with 2.3 months for untreated patients (p < 0.001).

Conclusions: In a contemporary population representing the full age range of patients with advanced NSCLC, chemotherapy was administered to approximately half of all patients-more than twice the rate reported in some earlier studies. Patient age and insurance type are associated with receipt of chemotherapy.
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http://dx.doi.org/10.1097/JTO.0b013e3181e9a00fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466589PMC
October 2010

Diffuse large B-cell lymphoma in a hepatitis C virus-infected patient presenting with lactic acidosis and hypoglycemia.

Am J Med Sci 2010 Feb;339(2):202-4

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA.

Non-Hodgkin lymphoma can produce a number of metabolic derangements including, in rare instances, lactic acidosis. This case illustrates an example of significant lactic acidosis and hypoglycemia secondary to diffuse large B-cell lymphoma with hepatic involvement in a patient with hepatitis C infection. A review of the literature on the occurrence of lactic acidosis and lymphoma, including the risk factors for its development and the resultant prognosis, are discussed. In addition, the evidence linking hepatitis C infection and lymphoma are reviewed.
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http://dx.doi.org/10.1097/MAJ.0b013e3181c3fdebDOI Listing
February 2010

Small cell lung cancer: are we making progress?

Am J Med Sci 2010 Jan;339(1):68-76

Hematology/Oncology, Veterans Affairs North Texas Healthcare System, Dallas, Texas, USA.

Although the incidence of small cell lung cancer (SCLC) has declined during the past 30 years, it remains a significant cause of cancer mortality in the United States and across the world. With appropriate treatment, about 20% of patients who present with limited stage SCLC can be cured of their disease. Unfortunately, the outcome for the remainder of patients is extremely poor. The only significant advance in extensive stage SCLC in the past 2 decades is the recent discovery that prophylactic cranial irradiation improves survival in those patients whose disease has responded to initial chemotherapy. Numerous attempts to enhance the antitumor effects of traditional chemotherapy for SCLC have not been successful. As the understanding of the biology of SCLC increased, a number of rational molecular targets for therapy have been identified. Although initial attempts at "targeted therapy" in SCLC have been unsuccessful, several newly identified targets hold promise and give hope that significant improvements in therapy for this challenging disease are not far away.
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http://dx.doi.org/10.1097/MAJ.0b013e3181bccef5DOI Listing
January 2010

The impact of consenter characteristics and experience on patient interest in clinical research.

Oncologist 2009 May 28;14(5):468-75. Epub 2009 Apr 28.

Division of Hematology-Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8852, USA.

Background: To explain the historically low rates of participation in cancer clinical trials, several factors have been studied. These include subject characteristics and attitudes, clinical trial availability and eligibility criteria, and physician attitudes and communication skills. However, the impact of nonphysician research personnel, who often consent patients for studies, is unclear. We therefore evaluated the association between consenter characteristics and subject interest in clinical research.

Methods: We performed a retrospective review of subjects enrolled in a university-based cancer center tissue repository. During enrollment, subjects were asked if they were willing to be contacted in the future to (a) provide medical follow-up information and (b) participate in other clinical research. We analyzed the association between responses to these questions and consenter characteristics using univariate analysis and multivariate logistic regression.

Results: In total, 181 consenters enrolled 922 subjects. The majority of subjects agreed to be contacted for follow-up (84.9%) and future research (83.1%). Subject willingness to be contacted for future research was associated with greater consenter experience in univariate and multivariate analyses. In multivariate analysis, subject willingness to be contacted for future research was associated with discordance between subject and consenter gender, but not with subject gender, race, or income, or consenter gender or race.

Conclusions: Consenter experience and subject-consenter gender discordance were associated with greater subject interest in participating in future research. The role of consenters in clinical research merits future study and should be considered in efforts to increase cancer clinical trial accrual.
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http://dx.doi.org/10.1634/theoncologist.2008-0268DOI Listing
May 2009

Phase 1/2 dose escalating study of twice-monthly pemetrexed and gemcitabine in patients with advanced cancer and non-small cell lung cancer.

J Thorac Oncol 2008 Apr;3(4):394-9

University of Minnesota Comprehensive Cancer Center, Minneapolis, Minnesota 55455, USA.

Introduction: Pemetrexed is synergistic with gemcitabine in preclinical models of non-small cell lung cancer (NSCLC). The optimal dose and utility of gemcitabine and pemetrexed was evaluated in a dose-escalating study.

Methods: The phase 1 study included patients with advanced tumors, whereas the phase 2 study included patients with locally advanced or metastatic NSCLC. Gemcitabine was infused over 30 minutes, followed by pemetrexed administered over 10 minutes on day 1 of a 14-day cycle. Treatment continued for 12 cycles or until disease progression. All patients received folic acid, Vitamin B12, and steroid prophylaxis.

Results: Maximum tolerated dose was gemcitabine 1500 mg/m, followed by pemetrexed 500 mg/m. Fifty-three patients (29 male, 24 female) were enrolled in the phase 2 study. Response rate was 20.8% (95% CI: 0.108-0.341), and the clinical benefit rate (CR + PR + SD) was 64.2%. Median time to disease progression was 4.6 months (95% CI: 2.79-6.18), median survival was 10.1 month (95% CI: 5.95-14.09, censorship = 20.75%), and 1-year survival was 41.0%. Common grade 3 or 4 adverse events (% of patients) were neutropenia (28.3%), fatigue (22.6%), and febrile neutropenia (9.4%).

Conclusions: Twice-monthly gemcitabine and pemetrexed was well tolerated, with overall survival and clinical benefit indicating disease activity in NSCLC patients.
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http://dx.doi.org/10.1097/JTO.0b013e318169cdc4DOI Listing
April 2008

Rectal GI stromal tumor mimicking a prostate mass.

J Clin Oncol 2007 Dec;25(36):5827-8

Department of Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA.

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http://dx.doi.org/10.1200/JCO.2007.13.7174DOI Listing
December 2007

A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and Caucasian cancer patients: CALGB 9871.

Clin Cancer Res 2007 Jun;13(11):3302-11

Sections of Clinical Pharmacology and Hematology/Oncology, Department of Medicine, Dartmouth Medical School, The Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA.

Purpose: Increased clearance of drugs, such as oral cyclosporine, that are CYP3A and/or ABCB1 (P-gp/MDR1) substrates was reported in African-American compared with Caucasian patients. We hypothesized that the pharmacokinetics and pharmacodynamics of docetaxel, an i.v. administered cytotoxic and substrate for CYP3A4, CYP3A5, and ABCB1, would differ between African-American and Caucasian patients.

Experimental Design: We investigated population pharmacokinetics and pharmacodynamics and the pharmacogenetics of CYP3A4, CYP3A5, and ABCB1 in African-American and Caucasian cancer patients who received docetaxel 75 or 100 mg/m(2) as a 1-h i.v. infusion. Plasma docetaxel concentrations were measured by high-performance liquid chromatography. Clinical toxicity and absolute neutrophil count (ANC) were monitored on days 8, 15, and 22 postadministration of docetaxel. Using a limited sampling strategy and nonlinear mixed-effects modeling, each patient's docetaxel clearance was estimated. Genotyping for known polymorphisms in CYP3A4, CYP3A5, and ABCB1 was done.

Results: We enrolled 109 patients: 40 African-Americans (26 males; 14 females), with a median age of 61 years (range, 29-73), and 69 Caucasians (43 males; 26 females), with a median age of 63 years (range, 38-81). There was no difference in the geometric mean docetaxel clearance between African-American patients [40.3 L/h; 95% confidence interval (95% CI), 19.3-84.1] and Caucasian patients (41.8 L/h; 95% CI, 22.0-79.7; P = 0.6). We observed no difference between African-American and Caucasian patients in the percentage decrease in ANC nor were docetaxel pharmacokinetic parameters related to the genotypes studied.

Conclusions: Docetaxel clearance and its associated myelosuppression were similar in African-American and Caucasian cancer patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-06-2345DOI Listing
June 2007

EGFR mutations and molecularly targeted therapy: a new era in the treatment of lung cancer.

Nat Clin Pract Oncol 2006 Apr;3(4):170-1

University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.

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http://dx.doi.org/10.1038/ncponc0476DOI Listing
April 2006

Epidermal growth factor receptor mutations in non-small cell lung cancer: a basic science discovery with immediate clinical impact.

Am J Med Sci 2006 Mar;331(3):139-49

Departments of Internal Medicine, University of Texas Southwestern Medical Center, and the Dallas Veterans Affairs Medical Center, Dallas, Texas 75390-8852, USA.

A large body of preclinical work suggested that the epidermal growth factor receptor (EGFR) would be a successful target for therapy against non-small cell lung cancer (NSCLC), and this led to the development of oral, selective EGFR tyrosine kinase inhibitors (TKI) that improve symptoms and survival in patients with advanced NSCLC. However, not all patients benefit from this treatment, and there has been great interest in identifying the molecular correlates that predict for response to these agents. The recent detection of somatic mutations in EGFR that predict for response to the EGFR tyrosine kinase inhibitors has excited the scientific community. This discovery has far-reaching implications, not only for lung cancer patients treated with an EGFR TKI but also for future drug development in all malignancies.
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http://dx.doi.org/10.1097/00000441-200603000-00006DOI Listing
March 2006