Publications by authors named "Jonathan Dowell"

67 Publications

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021.

J Natl Compr Canc Netw 2021 03 2;19(3):254-266. Epub 2021 Mar 2.

Mayo Clinic Cancer Center.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.
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http://dx.doi.org/10.6004/jnccn.2021.0013DOI Listing
March 2021

UKCAT and medical student selection in the UK - what has changed since 2006?

BMC Med Educ 2020 Sep 5;20(1):292. Epub 2020 Sep 5.

University of Dundee, Dundee, UK.

Background: The United Kingdom Clinical Aptitude Test (UKCAT) is an aptitude test used since 2006 within selection processes of a consortium of UK medical and dental schools. Since 2006, student numbers have increased in medical training and schools now have an increased focus on widening access. A growing evidence base has emerged around medical student selection (Patterson et al., Med Educ 50:36-60, 2016) leading to changes in practice. However, whilst some papers describe local selection processes, there has been no overview of trends in selection processes over time across Universities. This study reports on how the use of the UKCAT in medical student selection has changed and comments on other changes in selection processes.

Methods: Telephone interviews were conducted annually with UKCAT Consortium medical schools. Use of the UKCAT was categorised and data analysed to identify trends over time.

Results: The number of schools using the UKCAT to select applicants for interview has risen, with cognitive test results contributing significantly to outcomes at this stage at many universities. Where schools use different weighted criteria (Factor Method), the UKCAT has largely replaced the use of personal statements. Use of the test at offer stage has also increased; the most significant use being to discriminate between applicants at a decision borderline. A growing number of schools are using the UKCAT Situational Judgement Test (SJT) in selection. In 2018, all but seven (out of 26) schools made some adjustment to selection processes for widening access applicants. Multiple Mini Interviews (MMIs) are now used by the majority of schools. Whilst medical student numbers have increased over this time, the ratio of applicants to places has fallen. The probability of applicants being invited to interview or receiving an offer has increased.

Conclusions: More medical schools are using the UKCAT in undergraduate selection processes in an increasing number of ways and with increasing weight compared with 2007. It has replaced the use of personal statements in all but a few Consortium medical schools. An increased focus on academic attainment and the UKCAT across medical schools may be leading to the need for schools to interview and make offers to more applicants.
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http://dx.doi.org/10.1186/s12909-020-02214-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487558PMC
September 2020

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

A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer.

Invest New Drugs 2020 10 3;38(5):1588-1597. Epub 2020 Apr 3.

Medical Oncology Department, Vall d´Hebron University Hospital/Vall d´Hebron Institute of Oncology, Passeig de la Vall d'Hebron 119-129, Barcelona, 08035, Spain.

Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m) or S-1 (30 mg/m). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71-1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80-2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016.
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http://dx.doi.org/10.1007/s10637-020-00930-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497678PMC
October 2020

Osimertinib in Pulmonary Manifestations: Two Case Reports and Review of the Literature.

In Vivo 2020 Jan-Feb;34(1):315-319

Veterans Affairs North Texas Healthcare System, Dallas, TX and Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX, U.S.A.

Osimertinib is an oral, irreversible epidermal growth factor receptor inhibitor that is associated with various pulmonary manifestations including transient asymptomatic pulmonary opacities (TAPOs) and pneumonitis. We present a case of a 61-year-old female with Stage IV lung adenocarcinoma, who developed bilateral ground glass opacities on her chest-computed tomography (CT) three months after initiating osimertinib. Her imaging findings were thought to represent lymphangitic carcinomatosis responding to chemotherapy rather than drug induced toxicity, and she was continued on osimertinib. Conversely, we present a second case of a 57-year-old female with Stage IV lung adenocarcinoma who developed osimertinib-induced pneumonitis and was successfully rechallenged with osimertinib and glucocorticoids. These cases, described herein, illustrate examples of the range of pulmonary manifestations of osimertinib, as well as the safety of rechallenging patients with osimertinib and glucocorticoids following the development of pneumonitis.
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http://dx.doi.org/10.21873/invivo.11776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984067PMC
June 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

Cellular stress mechanisms of prenatal maternal stress: Heat shock factors and oxidative stress.

Neurosci Lett 2019 09 9;709:134368. Epub 2019 Jul 9.

Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA, USA; Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA, USA; Iowa Neuroscience Institute, Iowa City, IA, USA. Electronic address:

Development of the brain prenatally is affected by maternal experience and exposure. Prenatal maternal psychological stress changes brain development and results in increased risk for neuropsychiatric disorders. In this review, multiple levels of prenatal stress mechanisms (offspring brain, placenta, and maternal physiology) are discussed and their intersection with cellular stress mechanisms explicated. Heat shock factors and oxidative stress are closely related to each other and converge with the inflammation, hormones, and cellular development that have been more deeply explored as the basis of prenatal stress risk. Increasing evidence implicates cellular stress mechanisms in neuropsychiatric disorders associated with prenatal stress including affective disorders, schizophrenia, and child-onset psychiatric disorders. Heat shock factors and oxidative stress also have links with the mechanisms involved in other kinds of prenatal stress including external exposures such as environmental toxicants and internal disruptions such as preeclampsia. Integrative understanding of developmental neurobiology with these cellular and physiological mechanisms is necessary to reduce risks and promote healthy brain development.
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http://dx.doi.org/10.1016/j.neulet.2019.134368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053403PMC
September 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

Beyond 'health and safety' - the challenges facing students asked to work outside of their comfort, qualification level or expertise on medical elective placement.

BMC Med Ethics 2018 07 20;19(1):74. Epub 2018 Jul 20.

University of Birmingham, Birmingham, UK.

Background: On elective students may not always be clear about safeguarding themselves and others. It is important that placements are safe, and ethically grounded. A concern for medical schools is equipping their students for exposure to and response to uncomfortable and/or unfamiliar requests in locations away from home, where their comfort and safety, or that of the patient, may be compromised. This can require legal, ethical, and/or moral reasoning on the part of the student. The goal of this article is to establish what students actually encounter on elective, to inform better preparing students for safe and ethical medical placements. We discuss the implications of our findings, which are arguably applicable to other areas of graduate training, e.g. first medical roles post-qualification.

Method: An anonymised survey exploring clinical and ethical dilemmas on elective was issued across 3 years of returning final year elective medical students. Questions included the prevalence and type of potentially unsafe scenarios encountered, barriers to saying 'no' in unsafe situations, perceived differences between resource poor and developed world settings and the degree to which students refused or consented to participation in events outside of the 'norms' of their own training experience.

Results: Three hundred seventy-nine students participated. 45% were asked to do something "not permissible" at home. 27% were asked to do something they felt "uncomfortable" with, often an invasive clinical task. Half asked to do something not usually permissible were "comfortable". 48% felt it more acceptable to bypass guidelines in developing settings. 27% refused an offer outside their experience.

Conclusion: Of interest are reasons for "going along with" uncomfortable invitations, e.g. "emergency", self-belief in 'capability' and being 'more qualified' than host-personnel. This "best pair of hands available" merits scrutiny. Adverse scenarios were not exclusive to developing settings. We discuss preparing students for decision-making in new contexts, and address whether 'home' processes are too inflexible to prepare students for 'real' medical life? Ethical decision-making and communicating reluctance should be included in elective preparation.
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http://dx.doi.org/10.1186/s12910-018-0307-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053783PMC
July 2018

TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer.

J Clin Invest 2018 06 7;128(6):2500-2518. Epub 2018 May 7.

Department of Neurology and Neurotherapeutics.

Although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is effective only in a subset of non-small cell lung cancer (NSCLC) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. TNF is a major mediator of inflammation-induced cancer. We find that a rapid increase in TNF level is a universal adaptive response to EGFR inhibition in NSCLC, regardless of EGFR status. EGFR signaling actively suppresses TNF mRNA levels by inducing expression of miR-21, resulting in decreased TNF mRNA stability. Conversely, EGFR inhibition results in loss of miR-21 and increased TNF mRNA stability. In addition, TNF-induced NF-κB activation leads to increased TNF transcription in a feed-forward loop. Inhibition of TNF signaling renders EGFRwt-expressing NSCLC cell lines and an EGFRwt patient-derived xenograft (PDX) model highly sensitive to EGFR inhibition. In EGFR-mutant oncogene-addicted cells, blocking TNF enhances the effectiveness of EGFR inhibition. EGFR plus TNF inhibition is also effective in NSCLC with acquired resistance to EGFR inhibition. We suggest concomitant EGFR and TNF inhibition as a potentially new treatment approach that could be beneficial for a majority of lung cancer patients.
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http://dx.doi.org/10.1172/JCI96148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983340PMC
June 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

Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial.

Int J Radiat Oncol Biol Phys 2015 Sep 9;93(1):72-81. Epub 2015 May 9.

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Purpose: Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC.

Methods And Materials: Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiation therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy.

Results: Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥ 3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥ 3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥ 3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P = .24). The median overall survival was 6 months with no significant differences between dose levels (P = .59).

Conclusions: Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long-term safety and efficacy of this therapy are warranted.
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http://dx.doi.org/10.1016/j.ijrobp.2015.05.004DOI Listing
September 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

A phase 1 safety study of veliparib combined with cisplatin and etoposide in extensive stage small cell lung cancer: A trial of the ECOG-ACRIN Cancer Research Group (E2511).

Lung Cancer 2015 Jul 8;89(1):66-70. Epub 2015 May 8.

The Winship Cancer Institute of Emory University, Atlanta, GA, United States.

Objectives: Veliparib (V) potentiated therapeutic efficacy of cisplatin (C) and etoposide (E) in preclinical models of SCLC. We conducted this phase 1 study to establish the safety of the combination in human subjects.

Materials And Methods: The study employed the 3+3 dose escalation design to establish the safety and recommended phase 2 dose (RP2D) of V when combined with fixed doses of C (75 mg/m(2) on day 1) and E (100mg/m(2) on days 1-3) in a 21-day cycle. The starting dose of V was 60 mg (bid days 1-7) with plan to escalate to 100mg (days 1-7) or de-escalate to 40 mg (days 1-7) depending on the dose limiting toxicity (DLT) experience during cycle 1. Patients with treatment-naïve, extensive stage SCLC were included.

Results: The study enrolled 9 patients: M/F (4/5); median age (60); White/African American (8/1). V was tolerated at the 60 mg (DLT in 0 of 3 patients) and 100mg dose (DLT in 1 of 6 patients; grade 5 cardiac failure). Veliparib at 100mg in combination with standard doses of C and E was established as the RP2D. Grades 3-5 adverse events irrespective of attribution during cycle 1 included: dehydration (1), diarrhea (1), fatigue (1), febrile neutropenia (1), heart failure (1), leukopenia (6), lymphopenia (1), nausea (2), neutropenia (8), respiratory failure (1), and thrombocytopenia (2). Investigator-assessed efficacy outcome in 7 evaluable patients were stable disease in 2/7 (28.6%), partial response in 4/7 (57.1%), and complete response in 1/7 (14.3%) patients.

Conclusions: This study demonstrated the safety of combining veliparib with cisplatin and etoposide in previously untreated SCLC patients.
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http://dx.doi.org/10.1016/j.lungcan.2015.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539011PMC
July 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

Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer.

J Clin Oncol 2014 Dec 27;32(34):3824-30. Epub 2014 Oct 27.

Puneeth Iyengar, Zabi Wardak, Irma Smith, Chul Ahn, David E. Gerber, Jonathan Dowell, Randall Hughes, Ramzi Abdulrahman, Hak Choy, Robert Timmerman, University of Texas Southwestern Medical Center, Dallas, TX; Brian D. Kavanagh, D. Ross Camidge, Laurie E. Gaspar, Robert C. Doebele, and Paul A. Bunn, University of Colorado School of Medicine, Aurora, CO.

Purpose: Patients with stage IV non-small-cell lung cancer (NSCLC) who progress through first-line therapy have poor progression-free survival (PFS) and overall survival (OS), most commonly failing in original sites of gross disease. Cytoreduction with stereotactic body radiation therapy (SBRT) may help systemic agents delay relapse.

Patients And Methods: Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression. After erlotinib commencement, SBRT with equipotent fractionation was delivered to all sites of disease. PFS, OS, and other end points were evaluated.

Results: Twenty-four patients (13 men and 11 women) with a median age of 67 years (range, 56-86 years) were enrolled with median follow-up of 11.6 months. All patients had progressed through platinum-based chemotherapy. A total of 52 sites were treated with 16 of 24 patients receiving SBRT to more than one site. Lung parenchyma was most often irradiated. Median PFS was 14.7 months, and median OS was 20.4 months. Most patients progressed in new distant sites with only three of 47 measurable lesions recurring within the SBRT field. Two grade 3 toxicities were radiation related. Zero of 13 patients tested were positive for an EGFR mutation.

Conclusion: Use of SBRT with erlotinib for unselected patients with stage IV NSCLC as a second- or subsequent line therapy resulted in dramatic changes in patterns of failure, was well tolerated, and resulted in high PFS and OS, substantially greater than historical values for patients who only received systemic agents.
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http://dx.doi.org/10.1200/JCO.2014.56.7412DOI Listing
December 2014

Impact of comorbidity on initial treatment and overall survival in elderly head and neck cancer patients.

Anticancer Res 2014 Oct;34(10):5543-6

University of Texas Southwestern Medical Center, Veterans Affairs North Texas Healthcare System, Dallas, TX, U.S.A.

Background: Comorbidity is a determinant of treatment selection and survival in various cancers including head and neck cancer (HNC) and is often associated with a higher utilization of non-curative intent treatment.

Patients And Methods: In this retrospective study we analyzed 182 consecutively treated HNC patients >65 years old at the Dallas Veterans Affairs Medical Center from January 2000-June 2007. Comorbidity was assessed with the Charlson Comorbidity Index (CCI). Treatment was classified as curative vs. non-curative intent.

Results: Median overall survival was 883 days. Patients with a CCI score 0-2 had non-significant higher rate of curative intent treatment than patients with CCI score >2 (83.8% vs. 74.6%, p=0.13). In multivariate analysis, only stage had significant prognostic importance (hazard ratio (HR) 1.66; 95% confidence interval (CI) 1.29-2.14; p<0.0005). In separate multivariate analyses of patients treated with surgery or chemoradiation, CCI was not a significant predictor of survival with HR of 0.88 (95% CI 0.69-1.11; p=0.29) and 1.13 (95% CI 0.83-1.53; p=0.44), respectively.

Conclusion: In our elderly HNC population, CCI was not an independent predictor of selection of curative intent treatment or overall survival.
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October 2014

Predictive validity of the UK clinical aptitude test in the final years of medical school: a prospective cohort study.

BMC Med Educ 2014 Apr 23;14:88. Epub 2014 Apr 23.

School of Medicine, University of Dundee, The Mackenzie Building, Kirsty Semple Way, Dundee DD2 4BF, UK.

Background: The UK Clinical Aptitude Test (UKCAT) was designed to address issues identified with traditional methods of selection. This study aims to examine the predictive validity of the UKCAT and compare this to traditional selection methods in the senior years of medical school. This was a follow-up study of two cohorts of students from two medical schools who had previously taken part in a study examining the predictive validity of the UKCAT in first year.

Methods: The sample consisted of 4th and 5th Year students who commenced their studies at the University of Aberdeen or University of Dundee medical schools in 2007. Data collected were: demographics (gender and age group), UKCAT scores; Universities and Colleges Admissions Service (UCAS) form scores; admission interview scores; Year 4 and 5 degree examination scores. Pearson's correlations were used to examine the relationships between admissions variables, examination scores, gender and age group, and to select variables for multiple linear regression analysis to predict examination scores.

Results: Ninety-nine and 89 students at Aberdeen medical school from Years 4 and 5 respectively, and 51 Year 4 students in Dundee, were included in the analysis. Neither UCAS form nor interview scores were statistically significant predictors of examination performance. Conversely, the UKCAT yielded statistically significant validity coefficients between .24 and .36 in four of five assessments investigated. Multiple regression analysis showed the UKCAT made a statistically significant unique contribution to variance in examination performance in the senior years.

Conclusions: Results suggest the UKCAT appears to predict performance better in the later years of medical school compared to earlier years and provides modest supportive evidence for the UKCAT's role in student selection within these institutions. Further research is needed to assess the predictive validity of the UKCAT against professional and behavioural outcomes as the cohort commences working life.
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http://dx.doi.org/10.1186/1472-6920-14-88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008381PMC
April 2014

The UKCAT-12 study: educational attainment, aptitude test performance, demographic and socio-economic contextual factors as predictors of first year outcome in a cross-sectional collaborative study of 12 UK medical schools.

BMC Med 2013 Nov 14;11:244. Epub 2013 Nov 14.

UCL Medical School, University College London, Gower Street, London WC1E 6BT, UK.

Background: Most UK medical schools use aptitude tests during student selection, but large-scale studies of predictive validity are rare. This study assesses the United Kingdom Clinical Aptitude Test (UKCAT), and its four sub-scales, along with measures of educational attainment, individual and contextual socio-economic background factors, as predictors of performance in the first year of medical school training.

Methods: A prospective study of 4,811 students in 12 UK medical schools taking the UKCAT from 2006 to 2008 as a part of the medical school application, for whom first year medical school examination results were available in 2008 to 2010.

Results: UKCAT scores and educational attainment measures (General Certificate of Education (GCE): A-levels, and so on; or Scottish Qualifications Authority (SQA): Scottish Highers, and so on) were significant predictors of outcome. UKCAT predicted outcome better in female students than male students, and better in mature than non-mature students. Incremental validity of UKCAT taking educational attainment into account was significant, but small. Medical school performance was also affected by sex (male students performing less well), ethnicity (non-White students performing less well), and a contextual measure of secondary schooling, students from secondary schools with greater average attainment at A-level (irrespective of public or private sector) performing less well. Multilevel modeling showed no differences between medical schools in predictive ability of the various measures. UKCAT sub-scales predicted similarly, except that Verbal Reasoning correlated positively with performance on Theory examinations, but negatively with Skills assessments.

Conclusions: This collaborative study in 12 medical schools shows the power of large-scale studies of medical education for answering previously unanswerable but important questions about medical student selection, education and training. UKCAT has predictive validity as a predictor of medical school outcome, particularly in mature applicants to medical school. UKCAT offers small but significant incremental validity which is operationally valuable where medical schools are making selection decisions based on incomplete measures of educational attainment. The study confirms the validity of using all the existing measures of educational attainment in full at the time of selection decision-making. Contextual measures provide little additional predictive value, except that students from high attaining secondary schools perform less well, an effect previously shown for UK universities in general.
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http://dx.doi.org/10.1186/1741-7015-11-244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827332PMC
November 2013

Construct-level predictive validity of educational attainment and intellectual aptitude tests in medical student selection: meta-regression of six UK longitudinal studies.

BMC Med 2013 Nov 14;11:243. Epub 2013 Nov 14.

UCL Medical School, University College London, Gower Street, London WC1E 6BT, UK.

Background: Measures used for medical student selection should predict future performance during training. A problem for any selection study is that predictor-outcome correlations are known only in those who have been selected, whereas selectors need to know how measures would predict in the entire pool of applicants. That problem of interpretation can be solved by calculating construct-level predictive validity, an estimate of true predictor-outcome correlation across the range of applicant abilities.

Methods: Construct-level predictive validities were calculated in six cohort studies of medical student selection and training (student entry, 1972 to 2009) for a range of predictors, including A-levels, General Certificates of Secondary Education (GCSEs)/O-levels, and aptitude tests (AH5 and UK Clinical Aptitude Test (UKCAT)). Outcomes included undergraduate basic medical science and finals assessments, as well as postgraduate measures of Membership of the Royal Colleges of Physicians of the United Kingdom (MRCP(UK)) performance and entry in the Specialist Register. Construct-level predictive validity was calculated with the method of Hunter, Schmidt and Le (2006), adapted to correct for right-censorship of examination results due to grade inflation.

Results: Meta-regression analyzed 57 separate predictor-outcome correlations (POCs) and construct-level predictive validities (CLPVs). Mean CLPVs are substantially higher (.450) than mean POCs (.171). Mean CLPVs for first-year examinations, were high for A-levels (.809; CI: .501 to .935), and lower for GCSEs/O-levels (.332; CI: .024 to .583) and UKCAT (mean = .245; CI: .207 to .276). A-levels had higher CLPVs for all undergraduate and postgraduate assessments than did GCSEs/O-levels and intellectual aptitude tests. CLPVs of educational attainment measures decline somewhat during training, but continue to predict postgraduate performance. Intellectual aptitude tests have lower CLPVs than A-levels or GCSEs/O-levels.

Conclusions: Educational attainment has strong CLPVs for undergraduate and postgraduate performance, accounting for perhaps 65% of true variance in first year performance. Such CLPVs justify the use of educational attainment measure in selection, but also raise a key theoretical question concerning the remaining 35% of variance (and measurement error, range restriction and right-censorship have been taken into account). Just as in astrophysics, 'dark matter' and 'dark energy' are posited to balance various theoretical equations, so medical student selection must also have its 'dark variance', whose nature is not yet properly characterized, but explains a third of the variation in performance during training. Some variance probably relates to factors which are unpredictable at selection, such as illness or other life events, but some is probably also associated with factors such as personality, motivation or study skills.
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http://dx.doi.org/10.1186/1741-7015-11-243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827328PMC
November 2013

Predictive validity of the Dundee multiple mini-interview.

Med Educ 2013 Jul;47(7):717-25

Division of Clinical and Population Sciences and Education, University of Dundee, Dundee, UK.

Context: The multiple mini-interview (MMI) is the primary admissions tool used to assess non-cognitive skills at Dundee Medical School. Although the MMI shows promise, more research is required to demonstrate its transferability and predictive validity, for instance, relative to other UK pre-admissions measures.

Methods: Applicants were selected for interview based on a combination of measures derived from the Universities and Colleges Admissions Service (UCAS) form (academic achievement, medical experience, non-academic achievement and references) and the UK Clinical Aptitude Test (UKCAT) in 2009 and 2010. Candidates were selected into medical school according to a weighted combination of the UKCAT, the UCAS form and MMI scores. Examination scores were matched for 140 and 128 first- and second-year students, respectively, who took the 2009 MMIs, and 150 first-year students who took the 2010 MMIs. Pearson's correlations were used to test the relationships between pre-admission variables, examination scores and demographic variables, namely gender and age. Statistically significant correlations were adjusted for range restrictions and were used to select variables for multiple linear regression analysis to predict examination scores.

Results: Statistically significant correlations ranged from 0.18 to 0.34 and 0.23 to 0.50 unrestricted. Multiple regression confirmed that MMIs remained the most consistent predictor of medical school assessments. No scores derived from the UCAS form correlated significantly with examination scores.

Conclusions: This study reports positive findings from the largest undergraduate sample to date. The MMI was the most consistent predictor of success in early years at medical school across two separate cohorts. UKCAT and UCAS forms showed minimal or no predictive ability. Further research in this area appears worthwhile, with longitudinal studies, replication of results from other medical schools and more detailed analysis of knowledge, skills and attitudinal outcome markers.
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http://dx.doi.org/10.1111/medu.12193DOI Listing
July 2013

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

Improving student selection using multiple mini-interviews with multifaceted Rasch modeling.

Acad Med 2013 Feb;88(2):216-23

Medical School, University of Dundee, Scotland, United Kingdom.

Purpose: The authors report multiple mini-interview (MMI) selection process data at the University of Dundee Medical School; staff, students, and simulated patients were examiners and investigated how effective this process was in separating candidates for entry into medical school according to the attributes measured, whether the different groups of examiners exhibited systematic differences in their rating patterns, and what effect such differences might have on candidates' scores.

Method: The 452 candidates assessed in 2009 rotated through the same 10-station MMI that measured six noncognitive attributes. Each candidate was rated by one examiner in each station. Scores were analyzed using Facets software, with candidates, examiners, and stations as facets. The computer program calculated fair average scores that adjusted for examiner severity/leniency and station difficulty.

Results: The MMI reliably (0.89) separated the candidates into four statistically distinct levels of noncognitive ability. The Rasch measures accounted for 31.69% of the total variance in the ratings (candidates 16.01%, examiners 11.32%, and stations 4.36%). Students rated more severely than staff and also had more unexpected ratings. Adjusting scores for examiner severity/leniency and station difficulty would have changed the selection outcomes for 9.6% of the candidates.

Conclusions: The analyses highlighted the fact that quality control monitoring is essential to ensure fairness when ranking candidates according to scores obtained in the MMI. The results can be used to identify examiners needing further training, or who should not be included again, as well as stations needing review. "Fair average" scores should be used for ranking the candidates.
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http://dx.doi.org/10.1097/ACM.0b013e31827c0c5dDOI Listing
February 2013

Vemurafenib: targeted inhibition of mutated BRAF for treatment of advanced melanoma and its potential in other malignancies.

Drugs 2012 Dec;72(17):2207-22

VA North Texas Health Care System, Dallas, TX 75216, USA.

Vemurafenib is the first molecularly targeted therapy to be licensed in the US and Europe for treatment of advanced melanoma. Its mechanism of action involves selective inhibition of the mutated BRAF V600E kinase that leads to reduced signalling through the aberrant mitogen-activated protein kinase (MAPK) pathway. Its efficacy is restricted to melanomas carrying the BRAF V600E mutation, which is seen in approximately 50% of all melanomas. In a randomized phase III trial, it was superior to dacarbazine in first-line treatment of advanced melanoma, with an overall response rate (ORR) of 48% (95% CI 42, 45), an estimated 6-month progression-free survival (PFS) of 5.3 versus 1.6 months (hazard ratio [HR] 0.26; 95% CI 0.20, 0.33; p < 0.001) and a statistically superior 12-month overall survival (OS) rate of 55% versus 43% (HR 0.62 [95% CI 0.49, 0.77]). Vemurafenib is generally well tolerated, but its use can be associated with development of cutaneous neoplasms such as squamous cell carcinoma (SCC) and keratoacanthoma (KA). These lesions can be excised safely without the need for withholding the drug or reducing its dose. Mechanisms of resistance to vemurafenib do not involve development of secondary mutations in the BRAF kinase domain, but may be related to BRAF V600E over-amplification, bypassing mechanisms via upregulation and overexpression of other components in the MAPK signalling cascade or activation of alternative pathways with potential to enhance cell growth, proliferation and survival. Clinical trials to test the efficacy of vemurafenib in combination with immunomodulatory agents, such as ipilimumab, and MAPK kinase (MEK) inhibitors, such as GDC-0973, in the treatment of advanced melanoma are currently underway. Also under investigation is the use of vemurafenib in other solid tumours with BRAF mutations, such as papillary thyroid cancer.
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http://dx.doi.org/10.2165/11640870-000000000-00000DOI Listing
December 2012

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