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1.  Thymidylate Synthase and Folyl-polyglutamate synthase (FPGS) Are Not Clinically Useful Markers of Response to Pemetrexed [Pem] in Patients with Malignant Pleural Mesothelioma [MPM] 
Purpose
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.
Results
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.
Conclusions
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.
doi:10.1097/JTO.0b013e318283da3e
PMCID: PMC3601580  PMID: 23486267
2.  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.
doi:10.4161/cbt.13.5.19594
PMCID: PMC3367715  PMID: 22481432
non-small cell lung cancer; antiangiogenic therapy; vascular endothelial growth factor; angiogenesis; tyrosine kinase inhibitor; monoclonal antibody; chemotherapy
3.  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.
doi:10.4103/0974-777X.77304
PMCID: PMC3068588  PMID: 21572617
Arcanobacterium haemolyticum; Chorioamnionitis; Premature rupture of membranes
4.  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 
Purpose
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).
Results
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.
Conclusions
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.
doi:10.1158/1078-0432.CCR-09-1445
PMCID: PMC2826106  PMID: 19825950
Danusertib; PHA-739358; Aurora Kinase Inhibitor; phase I trial; solid tumors
5.  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
6.  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 1-6 (6)