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1.  Frequency of EGFR and KRAS Mutations in Patients with Non Small Cell Lung Cancer by Racial Background: Do Disparities exist? 
Mutations in EGFR and KRAS can impact treatment decisions for patients with NSCLC. The incidence of these mutations varies, and it is unclear whether there is a decreased frequency among African Americans (AfAs).
We performed a retrospective chart review of 513 NSCLC patients undergoing EGFR and KRAS mutational analysis at the Hospital of the University of Pennsylvania between May 2008 and November 2011. Clinical and pathologic data were abstracted from the patients’ electronic medical record.
Of 497 patients with informative EGFR mutation analyses, the frequency of EGFR mutation was 13.9%. The frequency of EGFR mutations was associated with race (p<0.001) and was lower in AfA patients compared to Caucasian (C) patients but did not reach statistical significance (4.8% vs 13.7%, p=0.06). Mean Charlson Comorbidity Index and number of cigarette pack years were significantly lower in patients with EGFR mutations (p=0.01 and p<0.001, respectively). Multivariable logistic regression analysis showed a significant association between race and EGFR mutation (p=0.01), even after adjusting for smoking status (p<0.001) and gender (p=0.03). KRAS mutation (study frequency 28.1%) was not associated with race (p=0.08; p=0.51 for Afa vs C patients), but was more common among smokers (p<0.001) and females (p=0.01).
Based on multivariable analysis, even after adjusting for smoking status and gender, we found that race was statistically significantly associated with EGFR mutation, but not KRAS mutational status. To our knowledge, this is the largest single institution series to date evaluating racial differences in EGFR and KRAS mutational status among patients with NSCLC.
PMCID: PMC3749295  PMID: 23806795
EGFR; KRAS; Racial Disparity; NSCLC
2.  Determinants of Survival in Advanced Non-Small Cell Lung Cancer (NSCLC) in the Era of Targeted Therapies 
Clinical lung cancer  2013;14(5):581-591.
Molecular profiling of NSCLC samples has a profound impact on choice of therapy. It is less clear, however, whether EGFR and KRAS mutations are prognostic outside of a trial-based treatment paradigm.
We performed a retrospective chart review of 513 NSCLC patients undergoing EGFR and KRAS mutational analysis at the Hospital of the University of Pennsylvania between May 2008 and November 2011. Survival analysis was based upon the 376 patients who received systemic treatment and their survival was determined from date of initiation of systemic therapy.
The median overall survival was 30.8 months (95%CI 24.7–36.9 months). Neither EGFR mutational status (p=0.09) nor KRAS mutational status (0.69) was associated with overall survival. Female sex (p<0.001), never smoker status (p=0.01), better PS (p<0.001), lower Charlson Comorbidity Index (p<0.001) and lower age-weighted Index (p<0.001) were associated with prolonged survival. The presence of bone metastases (p=0.001) and liver metastases (p=0.004) were also associated with a shortened survival. In a multivariable regression that adjusted for stage, we demonstrated that male gender (p=0.002), worse ECOG PS (p=0.01), metastases to bone (p=0.03) and higher age-weighted co-morbidity Index (p=0.001) were independent prognostic factors for shorter survival. EGFR mutation status was not prognostic (p=0.85).
EGFR and KRAS, in our series, do not function as prognostic determinants for NSCLC.
PMCID: PMC3762923  PMID: 23827517
EGFR; KRAS; prognosis; NSCLC
3.  Thymidylate Synthase and Folyl-polyglutamate synthase (FPGS) Are Not Clinically Useful Markers of Response to Pemetrexed [Pem] in Patients with Malignant Pleural Mesothelioma [MPM] 
Thymidylate synthase (TS) is a potential predictor of outcome after pemetrexed (Pem) in patients with malignant pleural mesothelioma (MPM), and assays measuring TS levels are commercially marketed. The goal of this study was to further evaluate the value of TS and to study another potential biomarker of response, the enzyme, folyl-polyglutamate synthase (FPGS), which activates Pem intracellularly.
Patients and Methods
Levels of TS and FPGS were semi-quantitatively determined immunohistochemically using H-scores on tissue samples from 85 MPM patients receiving Pem as primary therapy. H-score was correlated with radiographic disease control rate (DCR), time to progression (TTP) and overall survival (OS). In addition, expression levels of TS and FPGS in MPM cell lines were determined using immunoblotting and correlated with their sensitivity to Pem-induced cell death.
H-scores from patients with disease control versus progressive disease showed extensive overlap. There were no significant correlations of DCR, TTP, or OS to either TS levels (p = 0.73, 0.93, and 0.59, respectively), FPGS levels (p = 0.95, 0.77 and 0.43 respectively) or the ratio of FPGS/TS using the median scores of each test as cutoffs. There was no correlation between TS or FPGS expression and chemosensitivity of mesothelioma cells to Pem in vitro.
Although previous retrospective data suggest that TS and FPGS expression might be potential markers of Pem efficacy in MPM, our data indicate these markers lack sufficient predictive value in individual patients and should not be used to guide therapeutic decisions in the absence of prospective studies.
PMCID: PMC3601580  PMID: 23486267
4.  Antiangiogenic agents in the management of non-small cell lung cancer 
Cancer Biology & Therapy  2012;13(5):247-263.
Several therapies targeting angiogenesis are currently in development for non-small cell lung cancer (NSCLC). This review discusses results of recent clinical trials evaluating chemotherapy plus antiangiogenic therapy for NSCLC. Bevacizumab, an anti-VEGF antibody, is currently approved for the treatment of advanced NSCLC in combination with carboplatin and paclitaxel. Completed phase III trials evaluating bevacizumab plus chemotherapy have shown prolonged progression-free survival; however, not all trials showed significant improvement in overall survival (OS). Phase III trials of the tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib and the vascular disrupting agent ASA404 also failed to improve OS compared with chemotherapy alone. Clinical trials are ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, cediranib, nintedanib (BIBF 1120), sunitinib, pazopanib, brivanib, ABT-869, axitinib, ABT-751 and NPI-2358; several of these agents have shown promising phase I/II results. Results from recently completed and ongoing phase III trials will determine if these newer antiangiogenic agents will be incorporated into clinical practice.
PMCID: PMC3367715  PMID: 22481432
non-small cell lung cancer; antiangiogenic therapy; vascular endothelial growth factor; angiogenesis; tyrosine kinase inhibitor; monoclonal antibody; chemotherapy
5.  Chorioamnionitis due to Arcanobacterium haemolyticum 
Clinical chorioamnionitis can result either from the ascending organisms from vagina after rupture of membranes or via the blood stream. This report describes a case of chorioamnionitis caused by Arcanobacterium haemolyticum, an unusual organism associated with this infection. A 19-year-old primigravida at 32 weeks of gestation presented with the complaints of fever, pain in the abdomen, and discharge per vaginum for the past 2 days. Watery, odorless, colorless, and discharge passing intermittently were noticed. A. haemolyticum was isolated from amniotic fluid. Upon induction, a healthy male baby weighing 1.9 kg was delivered. The patient was started on gentamicin and metronidazole for 8 days. Recovery was uneventful. The mother and baby were discharged on ninth day. Chorioamnionitis can result in significant maternal and fetal mortality and morbidity. Hence, it is important to ascertain the prompt diagnosis and treatment of suspected cases. Increase in awareness of clinicians and laboratories will reduce misdiagnosis and facilitate appropriate treatment.
PMCID: PMC3068588  PMID: 21572617
Arcanobacterium haemolyticum; Chorioamnionitis; Premature rupture of membranes
6.  A Phase I Dose-Escalation Study of Danusertib (PHA-739358) Administered as a 24-hour Infusion With and Without G-CSF in a 14-day Cycle in Patients with Advanced Solid Tumors 
This study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of the intravenous pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors.
Experimental Design
In Part 1, patients received escalating doses of danusertib (24-h infusion every 14 days) without filgrastim (G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was performed in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3).
Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose limiting toxicity in Part 1 without G-CSF. Most other adverse events were grade 1–2, occurring at doses ≥360 mg/m2 with similar incidence in parts 1 and 2. The MTD without G-CSF is 500 mg/m2. The recommended phase 2 dose (RP2D) in Part 2 with G-CSF is 750 mg/m2. Danusertib demonstrated dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18–26 hours. pH3 modulation in skin biopsies was observed at ≥500 mg/m2. One patient with refractory small cell lung cancer (1000 mg/m2 with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline.
Danusertib was well tolerated with target inhibition in skin at ≥500 mg/m2. Preliminary evidence of anti-tumor activity, including a PR and several occurrences of prolonged stable disease (SD), was seen across a variety of advanced refractory cancers. Phase II studies are ongoing.
PMCID: PMC2826106  PMID: 19825950
Danusertib; PHA-739358; Aurora Kinase Inhibitor; phase I trial; solid tumors
7.  Impact of Rituximab (Rituxan) on the Treatment of B-Cell Non-Hodgkin’s Lymphoma 
Pharmacy and Therapeutics  2010;35(3):148-157.
Non-Hodgkin’s lymphoma (NHL) is the most common hematological malignancy in adults, with B-cell lymphomas accounting for 85% of all NHLs. The most substantial advancement in the treatment of B-cell malignancies, since the advent of combination chemotherapy, has been the addition of the monoclonal anti-CD20 antibody rituximab (Rituxan). Since its initially reported single-agent activity in indolent lymphomas in 1997, the role of rituximab has expanded to cover both indolent and aggressive lymphomas.
This article focuses on the impact of rituximab on the treatment, survival, and long-term outcomes of patients with indolent and aggressive lymphomas over the past two decades.
PMCID: PMC2844047  PMID: 20442809
rituximab; non-Hodgkin’s lymphoma
8.  Rational use of cetuximab in the treatment of advanced non-small cell lung cancer 
OncoTargets and therapy  2009;2:251-260.
Lung cancer is the leading cause of mortality in the United States. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Most NSCLC patients present with loco-regionally advanced or metastatic disease where response rates are low and median overall survival approximates 8 to 10 months. Chemotherapy is the mainstay of treatment for NSCLC patients with metastatic disease. Epidermal growth factor receptor (EGFR) and family of receptors play a critical role in lung cancer tumorigenesis. Cetuximab, a monoclonal antibody that binds the EGFR, has demonstrated preclinical and clinical activity against NSCLC. This review focuses on the use of cetuximab in NSCLC.
PMCID: PMC2886327  PMID: 20616912
cetuximab; lung cancer; monoclonal antibody

Results 1-8 (8)