Effects of Subcutaneous Methylnaltrexone on Morphine-induced Peripherally Mediated Side Effects: a Double-blind Randomized Placebo-controlled Trial

The Journal of Pharmacology and Experimental Therapeutics. Jan, 2002  |  Pubmed ID: 11752106

Methylnaltrexone, the first peripheral opioid receptor antagonist, has the potential to prevent or reverse opioid-induced peripherally mediated side effects without affecting analgesia. In previous human trials, we demonstrated that intravenous methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time. We also observed that the compound decreased some of the morphine-induced troublesome subjective effects. However, the effects of subcutaneous methylnaltrexone, a more convenient route of administration, have not been evaluated. In this controlled trial, we evaluated the efficacy of subcutanous methylnaltrexone in antagonizing morphine-induced delay in oral-cecal transit time. In addition, opioid-induced unpleasant subjective effects and pharmacokinetics were studied. We observed that in the first group (n = 6) morphine (0.05 mg/kg intravenously) increased the transit time from a baseline level of 85 +/- 20.5 min to 155 +/- 27.9 min (mean +/- S.D., P < 0.01). After 0.1 mg/kg subcutaneous methylnaltrexone plus morphine, the transit time reduced to 110 +/- 41.0 min. In the second group (n = 6), morphine increased the transit time from a baseline level of 98 +/- 49.1 min to 140 +/- 58.2 min (P < 0.01). After 0.3 mg/kg subcutaneous methylnaltrexone plus morphine, the transit time reduced to 108 +/- 59.6 min (P < 0.05 compared with placebo plus morphine). In addition, subcutaneous methylnaltrexone significantly decreased morphine-induced subjective rating changes. Pharmacokinetic data after subcutaneous drug injection were compared to the data obtained from previous intravenous and oral administrations. Our results suggest that subcutaneous methylnaltrexone may have clinical utility in treating opioid-induced constipation and reducing opioid-induced unpleasant subjective symptoms.

Sizes of Ruptured and Unruptured Aneurysms in Relation to Their Sites and the Ages of Patients

Journal of Neurosurgery. Jan, 2002  |  Pubmed ID: 11794606

The authors explore the risk of rupture in aneurysms categorized by size.

Data Management and Statistical Methods Used in the Analysis of Balanced Chromosome Abnormalities in Therapy-related Myelodysplastic Syndromes and Therapy-related Acute Leukemia: Report from an International Workshop

Genes, Chromosomes & Cancer. Apr, 2002  |  Pubmed ID: 11921270

Evaluation of the Direct Antiglobulin (Coombs') Test for Identifying Newborns at Risk for Hemolysis As Determined by End-tidal Carbon Monoxide Concentration (ETCOc); and Comparison of the Coombs' Test with ETCOc for Detecting Significant Jaundice

Journal of Perinatology : Official Journal of the California Perinatal Association. Jul-Aug, 2002  |  Pubmed ID: 12082466

First, to determine the sensitivity, specificity, and positive predictive value (PPV) of the direct antiglobulin test (DAT) for significant hemolysis in the neonate, as referenced to end-tidal carbon monoxide, the criterion standard for estimating the rate of hemolysis; and second, to evaluate the predictive value of the two procedures for significant jaundice.

Isoimmunization is Unlikely to Be the Cause of Hemolysis in ABO-incompatible but Direct Antiglobulin Test-negative Neonates

Pediatrics. Jul, 2002  |  Pubmed ID: 12093957

It is stated that the direct antiglobulin (Coombs') test (DAT) may be negative in ABO hemolytic disease of the newborn. Thus, significant jaundice in neonates who are A-B incompatible with their mothers but DAT test negative is often attributed to isoimmunization and another diagnosis is not sought. We wished to determine the rate of bilirubin production, as an objective measure of hemolysis, in 2 groups of DAT-negative neonates--ABO-compatible and ABO-incompatible--and in DAT-positive ABO-incompatible neonates.

Troxacitabine in Patients with Refractory Leukemia

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Aug, 2002  |  Pubmed ID: 12149312

Determination of the Optimal Modulatory Dose of O6-benzylguanine in Patients with Surgically Resectable Tumors

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Aug, 2002  |  Pubmed ID: 12171878

O6-benzylguanine (BG) provides a means to effectively inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) and increase the chemotherapeutic effectiveness of chloroethylating and methylating agents in preclinical and clinical studies. Two different doses of BG have been reported as the optimal biochemical modulatory dose for patients (i.e., 100 and 120 mg/m2). The objective of our study was to compare these doses by measuring AGT in surgically removed specimens after treatment with BG.

Mitogen-activated Protein Kinase Kinase 4 (MKK4) Acts As a Metastasis Suppressor Gene in Human Ovarian Carcinoma

Cancer Research. Nov, 2002  |  Pubmed ID: 12438272

Despite improvements in chemotherapy and the recognition that aggressive surgical cytoreduction is beneficial, the majority of patients diagnosed with ovarian cancer will die as a result of metastatic disease. The molecular changes associated with acquisition of metastatic ability in ovarian cancer are poorly understood. We hypothesize that metastasis suppressor gene inactivation or down-regulation plays a role in ovarian cancer progression. Mitogen-activated protein kinase kinase 4 (MKK4), a member of the stress-activated protein kinase signaling cascade, has been identified recently as a metastasis-suppressor gene. An immunohistochemical approach was taken to test the possibility that MKK4 dysregulation occurs during the development of clinical ovarian cancer metastases. MKK4 expression was evaluated in normal and metastatic ovarian tissues. Normal ovarian epithelial cells showed high intensity staining for MKK4, whereas metastatic tissues showed a statistically significant decrease in expression. These results support a role for MKK4 dysregulation in the development of clinical disease. A functional approach was taken to test the ability of MKK4 to suppress metastatic colonization, the process whereby disseminated cancer cells lodge and grow at a secondary site in vivo. The SKOV3ip.1 human ovarian cancer cell line was chosen for these studies because it lacks endogenous MKK4 expression but retains both upstream and downstream components of the signaling cascade of MKK4. Ectopic expression of MKK4 in these cells, when injected into female SCID mice, suppressed the number of overt metastatic implants by nearly 90%. Furthermore, MKK4 expression increased the life span of the animals by 70%. Taken together, these data support a role for MKK4 in the suppression of metastatic colonization in ovarian cancer.

Predictors of Emergency Medical Services Utilization by Elders

Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. Jan, 2003  |  Pubmed ID: 12511315

Elders (age > or = 65 years) frequently use emergency medical services (EMS) for care. Understanding reasons for EMS use by elders may allow better management of EMS demand. To the best of the authors' knowledge, no studies have identified patient characteristics associated with EMS use by elders. This study aimed to identify patient attributes associated with elder EMS users.

Clinical-cytogenetic Associations in 306 Patients with Therapy-related Myelodysplasia and Myeloid Leukemia: the University of Chicago Series

Blood. Jul, 2003  |  Pubmed ID: 12623843

Therapy-related myelodysplasia and myeloid leukemia (t-MDS/t-AML) is a distinctive clinical syndrome occurring after exposure to chemotherapy (CT) or radiotherapy (RT). We report findings on 306 consecutive patients referred to our institution with morphologic review and cytogenetic analyses. Since 1972, 141 males and 165 females with a median age of 51 years (range, 3-83 years) at primary diagnosis and 58 years (range, 6-86 years) at secondary diagnosis were analyzed. Patients had been administered various cytotoxic agents, including alkylating agents (240 patients, 78%) and topoisomerase 2 inhibitors (115 patients, 39%). One hundred twenty-one (40%) had undergone CT alone, 43 (14%) had undergone RT alone, and 139 (45%) had undergone both modalities. At diagnosis of t-MDS/t-AML, 282 (92%) had clonal abnormalities involving chromosome 5 (n = 63), chromosome 7 (n = 85), chromosomes 5 and 7 (n = 66), recurring balanced rearrangements (n = 31), other clonal abnormalities (n = 39), or normal karyotype (n = 24). Abnormalities of chromosome 5, 7, or both accounted for 76% of all cases with an abnormal karyotype. Seventeen patients acquired t-MDS/t-AML after autologous stem cell transplantation, but no unique pattern of cytogenetic abnormalities was observed. Shorter latency was observed for patients with balanced rearrangements (median, 28 vs 67 months; P <.0001). Patients with acute leukemia were more likely to have balanced rearrangement than those with myelodysplasia (28% vs 4%; P <.0001). Median survival time after diagnosis of t-MDS/t-AML was 8 months; survival at 5 years was less than 10%. These data confirm and extend previous associations between clinical, morphologic, and cytogenetic findings in t-MDS/t-AML.

The Aspect Ratio (dome/neck) of Ruptured and Unruptured Aneurysms

Journal of Neurosurgery. Sep, 2003  |  Pubmed ID: 12959428

In this retrospective study the authors examined the aspect ratio (AR; the maximum dimension of the dome/width of the neck of an aneurysm) and compared the distribution of this ratio in a group of ruptured and unruptured aneurysms. A similar comparison was performed in relation to the maximum dimension of the aneurysm alone. The authors sought to evaluate the utility of these measures for differentiating ruptured and unruptured aneurysms.

A Group Sequential, Response-adaptive Design for Randomized Clinical Trials

Controlled Clinical Trials. Oct, 2003  |  Pubmed ID: 14500050

There has been considerable methodological research on response-adaptive designs for clinical trials but they have seldom been used in practice. The many reasons for this are summarized in an article by Rosenberger and Lachin, but the two main reasons generally cited are logistical difficulties and the potential for bias due to selection effects, "drift" in patient characteristics or risk factors over time, and other sources. Jennison and Turnbull consider a group sequential, response-adaptive design for continuous outcome variables that partially addresses these concerns while at the same time allowing for early stopping. The key advantage of a group sequential approach in which randomization probabilities are kept constant within sequential groups is that a stratified analysis will eliminate bias due to drift. In this article we consider binary outcomes and an algorithm for altering the allocation ratio that depends on the strength of the accumulated evidence. Specifically, patients are enrolled in groups of size n(Ak), n(Bk), k=1, 2, ...K, where n(Ak), n(Bk) are the sample sizes in treatment arms A and B in sequential group k. Patients are initially allocated in a 1:1 ratio. After the kth interim analysis, if the z-value comparing outcomes in the two treatment groups is less than 1.0 in absolute value, the ratio remains 1:1; if the z-value exceeds 1.0, the next sequential group is allocated in the ratio R(1) favoring the currently better-performing treatment; if the z-statistic exceeds 1.5, the allocation ratio is R(2), and if the z-value exceeds 2.0, the allocation ratio is R(3). If the O'Brien-Fleming monitoring boundary is exceeded the trial is terminated. Group sample-sizes are adjusted upward to maintain equal increments of information when allocation ratios exceed one. The z-statistic is derived from a weighted log-odds ratio stratified by sequential group. Simulation studies and theoretical calculations were performed under a variety of scenarios and allocation rules. Results indicate that the method maintains the nominal type I error rate even when there is substantial drift in the patient population. When a true treatment difference exists, a modest reduction in the number of patients assigned to the inferior treatment arm can be achieved at the expense of smaller increases in the total sample size relative to a nonadaptive design. Limitations, such as the impact of delays in observing outcomes, are discussed, as well as areas for further research. We conclude that responsive adaptive designs may be useful for some purposes, particularly in the presence of large treatment effects, although allowing early stopping minimizes the benefits. If such a design is undertaken, the randomization and analysis should be stratified in order to avoid bias due to time trends.

Long-term Functional Results After Ileal Pouch Anal Restorative Proctocolectomy for Ulcerative Colitis: a Prospective Observational Study

Annals of Surgery. Sep, 2003  |  Pubmed ID: 14501509

To document functional results in patients treated with an ileal pouch anal anastomosis (IPAA).

Prognostic Factors for Survival with Gemcitabine Plus 5-fluorouracil Based Regimens for Metastatic Renal Cancer

The Journal of Urology. Oct, 2003  |  Pubmed ID: 14501711

Combination gemcitabine and 5-fluorouracil (5-FU) may have activity in metastatic renal cell cancer. To identify patient subgroups most likely to benefit and compare survival to that in previously described patient series long-term survival as a function of known and suspected prognostic variables was determined.

Factors Associated with the Development of Vasospasm After Planned Surgical Treatment of Aneurysmal Subarachnoid Hemorrhage

Journal of Neurosurgery. Oct, 2003  |  Pubmed ID: 14567598

The goal of this study was to determine factors associated with the development of symptomatic vasospasm among patients with aneurysmal subarachnoid hemorrhage (SAH) who participated in the randomized, double-blind, placebo-controlled trials of tirilazad between 1991 and 1997.

A Phase II Trial of Suramin Monthly X 3 for Hormone-refractory Prostate Carcinoma

Cancer. Jan, 2004  |  Pubmed ID: 14692025

The goal of the current study was to determine the prostate-specific antigen (PSA) and objective response rates and the pharmacokinetics associated with a monthly x 3 one-hour infusion of suramin in 58 patients with hormone-refractory prostate carcinoma.

Microarray Analysis Reveals Glucocorticoid-regulated Survival Genes That Are Associated with Inhibition of Apoptosis in Breast Epithelial Cells

Cancer Research. Mar, 2004  |  Pubmed ID: 14996737

Activation of the glucocorticoid receptor (GR) results in diverse physiological effects depending on cell type. For example, glucocorticoids (GC) cause apoptosis in lymphocytes but can rescue mammary epithelial cells from growth factor withdrawal-induced death. However, the molecular mechanisms of GR-mediated survival remain poorly understood. In this study, a large-scale oligonucleotide screen of GR-regulated genes was performed. Several of the genes that were found to be induced 30 min after GR activation encode proteins that function in cell survival signaling pathways. We also demonstrate that dexamethasone pretreatment of breast cancer cell lines inhibits chemotherapy-induced apoptosis in a GR-dependent manner and is associated with the transcriptional induction of at least two genes identified in our screen, serum and GC-inducible protein kinase-1 (SGK-1) and mitogen-activated protein kinase phosphatase-1 (MKP-1). Furthermore, GC treatment alone or GC treatment followed by chemotherapy increases both SGK-1 and MKP-1 steady-state protein levels. In the absence of GC treatment, ectopic expression of SGK-1 or MKP-1 inhibits chemotherapy-induced apoptosis, suggesting a possible role for these proteins in GR-mediated survival. Moreover, specific inhibition of SGK-1 or MKP-1 induction by the introduction of SGK-1- or MKP-1-small interfering RNA reversed the anti-apoptotic effects of GC treatment. Taken together, these data suggest that GR activation in breast cancer cells regulates survival signaling through direct transactivation of genes that encode proteins that decrease susceptibility to apoptosis. Given the widespread clinical administration of dexamethasone before chemotherapy, understanding GR-induced survival mechanisms is essential for achieving optimal therapeutic responses.

Genetic Variants in the UDP-glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Apr, 2004  |  Pubmed ID: 15007088

Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation.

Strong Synergy Between Mutant Ras and HPV16 E6/E7 in the Development of Primary Tumors

Oncogene. May, 2004  |  Pubmed ID: 15077191

E6/E7 oncogenes of high-risk human papilloma virus (HPV) subtypes are essential for the development of certain types of cancers. However, these oncogenes are insufficient to transform normal cells into an immortalized or malignant state. Mutant Ha-ras cooperates with E6/E7 of HPV subtype 16 in transformation of cells in vitro and may contribute to some HPV-associated cancers in humans. This study investigates whether HPV16 E6/E7 and v-Ha-ras synergize in vivo. FVB/n mice transgenic for v-Ha-ras gene (R+) were crossed with transgenic C57BL/6 mice that harbor E6/E7 of HPV16 (E+). Beginning at about 3 months of age, the bitransgenic E(+)R(+)(C57BL/6 x FVB/n) F1 mice developed mouth, eye and ear tumors. By 6 months, the prevalence of these types of mouth, eye and ear tumors was 100, 71 and 79% respectively in the E(+)R+ mice. Most tumors grew progressively until the mice had to be killed. The median times for the appearance of the first mouth, eye and ear tumor were 3.6, 4.3 and 4.2 months, respectively. For the two singly transgenic groups of mice, the prevalence of mouth, eye and ear tumors was 0, 0 and 6% (E(-)R+) and 0, 0 and 0% (E(+)R-), respectively, and the median time to first tumor was greater than 12 months for singly transgenic mice (E(-)R+, E(+)R-). Thus, a remarkable synergy occurred between the v-Ha-ras and HPV16 E6/E7 oncogenes in the development of primary tumors in mice.

9-Aminocamptothecin (9-AC) Given As a 120-hour Continuous Infusion in Patients with Advanced Adenocarcinomas of the Stomach and Gastroesophageal Junction: A Phase II Trial of the University of Chicago Phase II Consortium

Investigational New Drugs. Aug, 2004  |  Pubmed ID: 15122080

9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin derivative that demonstrated broad activity in pre-clinical studies. In vitro, greater anti-tumor efficacy can be achieved with prolonged administration. A minor response was observed in gastric cancer in a phase I study. We conducted a phase II study of 9-AC in 15 patients with previously untreated metastatic gastric cancer and adenocarcinoma of the gastroesophageal junction. 9-AC was administered at a dose of 25 microg/m(2)/h over 120 hours (3000 microg/m(2) over 5 days) on two consecutive weeks every 21 days. Fourteen patients were evaluable for response. There were no objective responses. Three patients had stable disease lasting a median of 3.4 months (range 1.6-4.3 months). Median time to progression was 1.4 months; median survival was 5.2 months. Grade 3 neutropenia developed in 20% of patients, and anemia in 7%. Grade 3 nausea and fatigue each developed in 7% of patients. We conclude that 9-AC given by 120-hour continuous infusion demonstrates no clinical activity in patients with metastatic gastric cancer.

A Randomized Phase II Trial of the Antiangiogenic Agent SU5416 in Hormone-refractory Prostate Cancer

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. May, 2004  |  Pubmed ID: 15161690

To assess the activity of the antiangiogenic agent and VEGFR2 inhibitor SU5416 in hormone-refractory prostate cancer. Patients and Methods: Thirty-six chemotherapy naïve patients were randomized to treatment with SU5416 (145 mg/m(2)) and dexamethasone premedication or dexamethasone alone. Patients in the control arm could cross over to experimental therapy after progression. Prostate-specific antigen (PSA) was measured every 2 weeks, and radiological evaluation was performed every 8 weeks. In vitro assessment of SU5416 on PSA secretion was assessed in the LNCaP cell line. Baseline serum basic fibroblast growth factor and plasma vascular endothelial growth factor (VEGF) were explored as prognostic factors.

Brief Communication: American Ginseng Reduces Warfarin's Effect in Healthy Patients: a Randomized, Controlled Trial

Annals of Internal Medicine. Jul, 2004  |  Pubmed ID: 15238367

People using prescription medication often concurrently take herbal supplements. In a case report, the anticoagulant effect of warfarin decreased after patients consumed ginseng.

Fetal Loss Associated with Excess Thyroid Hormone Exposure

JAMA : the Journal of the American Medical Association. Aug, 2004  |  Pubmed ID: 15304465

Maternal hypothyroidism and hyperthyroidism have deleterious effects on the outcome of pregnancy. While the effects of thyroid hormone (TH) deprivation on the fetus, independently from that on the mother, can be studied in infants with congenital hypothyroidism, this is not the case in those with fetal thyrotoxicosis.

The Human BCL6 Transgene Promotes the Development of Lymphomas in the Mouse

Proceedings of the National Academy of Sciences of the United States of America. Sep, 2004  |  Pubmed ID: 15375218

BCL6, a gene on chromosome 3, band q27, encodes a zinc finger transcriptional repressor that is needed for germinal center formation and has been implicated in the pathogenesis of some human lymphomas when it is mutated or involved in chromosomal rearrangements. To explore further the mechanisms of action of BCL6 in lymphomagenesis, we developed a transgenic mouse model mimicking a common translocation, the t(3, 14)(q27;q32), in human lymphomas. The transgenic mice develop normally and express the transgenic BCL6 protein constitutively in lymphocytes. A small fraction of the animals develop B and T cell lymphomas after a long latency period, but the incidence is dramatically enhanced following administration of N-ethyl-N-nitrosourea, a carcinogen that induces DNA mutations. The N-ethyl-N-nitrosourea-induced lymphomas spread widely, were exclusively T cell, expressed the BCL6 protein, and occurred only in the transgenic mice. Because BCL6 expression has been reported in a number of T cell tumors as well as in the more commonly occurring B cell lymphomas in humans, our transgenic mice provide a model for the study of human lymphomas.

Dose-ranging Pharmacodynamic Study of Tipifarnib (R115777) in Patients with Relapsed and Refractory Hematologic Malignancies

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Dec, 2004  |  Pubmed ID: 15570084

Tipifarnib, an orally bioavailable inhibitor of farnesyl transferase, has activity in hematologic malignancies, but the dose required to achieve the proposed biologic end point, inhibition of farnesylation, is unknown.

Role of Glutathione and Nucleotide Excision Repair in Modulation of Cisplatin Activity with O6-benzylguanine

Cancer Chemotherapy and Pharmacology. Apr, 2005  |  Pubmed ID: 15723259

Modulation of platinating agent cytotoxicity has important clinical implications as a result of their widespread use in the treatment of many different cancers. O6-Benzylguanine (BG) enhances the cytotoxicity of cisplatin against several human tumor lines. The purpose of our work was to elucidate whether BG affects pathways prior to DNA damage (i.e., glutathione, GSH) or following DNA damage (i.e., nucleotide excision repair, NER).

Tolerability, Gut Effects, and Pharmacokinetics of Methylnaltrexone Following Repeated Intravenous Administration in Humans

Journal of Clinical Pharmacology. May, 2005  |  Pubmed ID: 15831777

Previous studies have shown that a single dose of methylnaltrexone, a unique peripheral opioid antagonist, reverses opioid-induced gut hypomotility in humans. Because repeated drug doses are likely to be needed to treat patients with opioid-induced or postsurgical bowel dysfunction, the authors have now examined the safety, pharmacological activity, and pharmacokinetics of a multiple-dose regimen of methylnaltrexone, administered as 12 consecutive intravenous doses (0.3 mg/kg every 6 hours) in 12 healthy subjects. Steady state was achieved rapidly, and after repeated dosing for 3 days, methylnaltrexone decreased oral-cecal transit time from a pretreatment baseline value of 101.3 +/- 29.4 min (mean +/- SD) to 82.5 +/- 20.7 min. Maximum observed plasma concentrations, measured 5 minutes postdose, were 538 +/- 237 and 675 +/- 180 ng/mL after doses 1 and 2, respectively. Based on 6-hour sampling periods, the plasma half-life, 2.5 +/- 0.5 and 2.9 +/- 0.9 hours following the 1st and 12th doses, respectively, was unchanged at steady state. There was essentially no accumulation of methylnaltrexone, based on the ratio of AUC values after doses 12 and 1. This study showed that repeated administration of intravenous methylnaltrexone is well tolerated in humans, with no significant adverse events or changes in opioid subjective ratings and no clinically noteworthy alterations in pharmacokinetics. The observation of a significant reduction in the gut transit time after repeated administration of methylnaltrexone to these opioid-naive volunteers suggests that endogenous opioids modulate human gut motility.

Progression of Barrett's Metaplasia to Adenocarcinoma is Associated with the Suppression of the Transcriptional Programs of Epidermal Differentiation

Cancer Research. Apr, 2005  |  Pubmed ID: 15833844

We did expressional profiling on 24 paired samples of normal esophageal epithelium, Barrett's metaplasia, and esophageal adenocarcinomas. Matching tissue samples representing the three different histologic types were obtained from each patient undergoing esophagectomy for adenocarcinoma. Our analysis compared the molecular changes accompanying the transformation of normal squamous epithelium with Barrett's esophagus and adenocarcinoma in individual patients rather than in a random cohort. We tested the hypothesis that expressional profiling may reveal gene sets that can be used as molecular markers of progression from normal esophageal epithelium to Barrett's esophagus and adenocarcinoma. Expressional profiling was done using U133A GeneChip (Affymetrix), which represent approximately two thirds of the human genome. The final selection of 214 genes permitted the discrimination of differential gene expression of normal esophageal squamous epithelium, Barrett's esophagus, and adenocarcinoma using two-dimensional hierarchical clustering of selected genes. These data indicate that transformation of Barrett's esophagus to adenocarcinoma is associated with suppression of the genes involved in epidermal differentiation, including genes in 1q21 loci and corresponding to the epidermal differentiation complex. Correlation analysis of genes concordantly expressed in Barrett's esophagus and adenocarcinoma revealed 21 genes that represent potential genetic markers of disease progression and pharmacologic targets for treatment intervention. PCR analysis of genes selected based on DNA array experiments revealed that estimation of the ratios of GATA6 to SPRR3 allows discrimination among normal esophageal epithelium, Barrett's dysplasia, and adenocarcinoma.

Phase II Trial of Bevacizumab Plus Gemcitabine in Patients with Advanced Pancreatic Cancer

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Nov, 2005  |  Pubmed ID: 16258101

Vascular endothelial growth factor (VEGF) plays a key role in the biology and prognosis of pancreatic cancer. Inhibitors of VEGF suppress the growth of pancreatic cancer in preclinical models. The objectives of this phase II study were to assess the response rate and overall survival of pancreatic cancer patients who received gemcitabine with the recombinant humanized anti-VEGF monoclonal antibody bevacizumab.

Gene Expression Profiles in Acute Myeloid Leukemia with Common Translocations Using SAGE

Proceedings of the National Academy of Sciences of the United States of America. Jan, 2006  |  Pubmed ID: 16418266

Identification of the specific cytogenetic abnormality is one of the critical steps for classification of acute myeloblastic leukemia (AML) which influences the selection of appropriate therapy and provides information about disease prognosis. However at present, the genetic complexity of AML is only partially understood. To obtain a comprehensive, unbiased, quantitative measure, we performed serial analysis of gene expression (SAGE) on CD15(+) myeloid progenitor cells from 22 AML patients who had four of the most common translocations, namely t(8;21), t(15;17), t(9;11), and inv(16). The quantitative data provide clear evidence that the major change in all these translocation-carrying leukemias is a decrease in expression of the majority of transcripts compared with normal CD15(+) cells. From a total of 1,247,535 SAGE tags, we identified 2,604 transcripts whose expression was significantly altered in these leukemias compared with normal myeloid progenitor cells. The gene ontology of the 1,110 transcripts that matched known genes revealed that each translocation had a uniquely altered profile in various functional categories including regulation of transcription, cell cycle, protein synthesis, and apoptosis. Our global analysis of gene expression of common translocations in AML can focus attention on the function of the genes with altered expression for future biological studies as well as highlight genes/pathways for more specifically targeted therapy.

A Randomized Phase II Trial of Interleukin-2 in Combination with Four Different Doses of Bryostatin-1 in Patients with Renal Cell Carcinoma

Investigational New Drugs. Mar, 2006  |  Pubmed ID: 16514482

Bryostatin-1 is a PKC modulator with direct anti-tumor activity and immunomodulatory properties. We combined different doses of Bryostatin-1 with IL-2 to determine effects on clinical response rate and T cell phenotype in patients with advanced kidney cancer.

Outcome of Treatment for Congenital Toxoplasmosis, 1981-2004: the National Collaborative Chicago-Based, Congenital Toxoplasmosis Study

Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. May, 2006  |  Pubmed ID: 16619149

Without treatment, congenital toxoplasmosis has recurrent, recrudescent, adverse outcomes. Long-term follow-up of infants with congenital toxoplasmosis treated throughout their first year of life with pyrimethamine and sulfadiazine has not been reported.

A Phase II Trial of Perifosine, an Oral Alkylphospholipid, in Recurrent or Metastatic Head and Neck Cancer

Cancer Biology & Therapy. Jul, 2006  |  Pubmed ID: 16760642

Novel, effective therapies are warranted in the management of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Perifosine is an oral alkylphospholipid that inhibits AKT phosphorylation and has shown preclinical antitumor activity in head and neck cancer cell lines and xenografts.

Impact of Visual Impairment on Measures of Cognitive Function for Children with Congenital Toxoplasmosis: Implications for Compensatory Intervention Strategies

Pediatrics. Aug, 2006  |  Pubmed ID: 16864640

The purpose of this work was to determine whether visual impairment caused by toxoplasmic chorioretinitis is associated with impaired performance of specific tasks on standardized tests of cognitive function. If so, then we worked to determine whether there are patterns in these difficulties that provide a logical basis for development of measures of cognitive function independent of visual impairment and compensatory intervention strategies to facilitate learning for such children.

Studies in Hemolysis in Glucose-6-phosphate Dehydrogenase-deficient African American Neonates

Clinica Chimica Acta; International Journal of Clinical Chemistry. Mar, 2006  |  Pubmed ID: 16188248

The role of hemolysis in the mechanism and prediction of hyperbilirubinemia was contrasted between glucose-6-phosphate dehydrogenase (G-6-PD)-deficient and -normal African American neonates.

Design of Phase II Cancer Trials Using a Continuous Endpoint of Change in Tumor Size: Application to a Study of Sorafenib and Erlotinib in Non Small-cell Lung Cancer

Journal of the National Cancer Institute. Oct, 2007  |  Pubmed ID: 17895472

The primary objective of phase II cancer clinical trials is to determine whether a new regimen has sufficient activity to warrant further study, with activity generally defined as tumor shrinkage. However, oncology drug development has been limited by high rates of failure (lack of efficacy) in subsequent phase III testing. This high failure rate may reflect the process by which antineoplastic agents are usually evaluated in phase II trials, i.e., via single-arm studies in which the primary efficacy measure is the proportion of patients who achieve a complete or partial response to the treatment. This design may efficiently eliminate truly ineffective therapy but may not reliably indicate whether subsequent phase III testing is warranted.

Continuous Bayesian Adaptive Randomization Based on Event Times with Covariates by Cheung Et Al., Statistics in Medicine 2006; 25:55-70

Statistics in Medicine. Jul, 2007  |  Pubmed ID: 17163577

Therapy-related Myelodysplastic Syndrome: Morphologic Subclassification May Not Be Clinically Relevant

American Journal of Clinical Pathology. Feb, 2007  |  Pubmed ID: 17210514

In practice, cases of therapy-related myelodysplastic syndrome (t-MDS) are often classified according to morphologic schemes used for de novo MDS. However, there are few data addressing the appropriateness of such classification. We studied 155 patients with therapy-related acute myeloid leukemia (t-AML)/t-MDS to determine whether subclassification by the World Health Organization (WHO) criteria for de novo MDS provides prognostic information in t-MDS. In addition, we assessed whether cytogenetic stratification by the International Prognostic Scoring System (IPSS) guidelines or karyotypic complexity was prognostically important. We found no differences in median survival times among patients classified into the different WHO subgroup of MDS or according to their bone marrow blast percentage; our results indicate a uniformly poor outcome in t-MDS regardless of morphologic classification. However, significant survival differences correlated with cytogenetic stratification according to IPSS guidelines and/or karyotypic complexity. We found only a borderline difference in median survival of patients with an initial t-MDS diagnosis compared with patients with an initial t-AML diagnosis.

Testing the Wrong Hypothesis in Phase II Oncology Trials: There is a Better Alternative

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Feb, 2007  |  Pubmed ID: 17289865

A Phase II Study of Ixabepilone (BMS-247550) in Metastatic Renal-cell Carcinoma

Cancer Biology & Therapy. Apr, 2007  |  Pubmed ID: 17457044

Ixabepilone (BMS-247550) is a semi-synthetic analog of epothilone B that has been characterized as a microtubule stabilizing agent with a mechanism of action distinct from taxanes. Suggestion of activity in renal cell carcinoma (RCC) has been seen in early clinical studies.

Whole Blood Viscosity and Arterial Thrombotic Events in Patients with Systemic Lupus Erythematosus

Arthritis and Rheumatism. Jun, 2007  |  Pubmed ID: 17530685

To determine if whole blood viscosity (WBV), a rheologic variable contributing to risk of myocardial infarction and stroke in the general population, is elevated in patients with systemic lupus erythematosus (SLE), particularly SLE patients with a history of thrombotic or atherothrombotic events. Because the high rates of arterial and venous thrombosis in lupus cannot be explained by traditional risk factors, elevated WBV may be an easily measurable nontraditional risk factor to identify SLE patients at high risk for thrombotic events.

Safety and Tolerability of Ganoderma Lucidum in Healthy Subjects: a Double-blind Randomized Placebo-controlled Trial

The American Journal of Chinese Medicine. 2007  |  Pubmed ID: 17597499

Ganoderma lucidum is a herbal medicine commonly used in oriental countries as a remedy for treating various medical conditions. In this controlled study, we evaluated the safety and tolerance of oral administration of Ganoderma lucidum in 16 human volunteers who received 2 grams of the extract or placebo twice daily for 10 consecutive days. During the study, information from subjective questionnaires were obtained, electrocardiograms, complete blood counts, blood chemistry analysis and urinalysis were performed. In addition, blood tests reflecting immunity were done. Our data showed that compared to placebo group, no adverse effects were observed after the extract intake. Although there were no obvious changes in CD4, CD8, and CD19 levels after the extract, CD56 cell count increased during the study and returned to baseline 10 days after the herbal intake. However, due to relatively high variability and small sample size, this CD56 increase did not achieve statistical significance, and remains to be re-evaluated in the future. It appears that an additional long-term safety and tolerance trial with herbal dose-escalating design is warranted.

Critical Evaluation of Diagnostic Aids for the Detection of Oral Cancer

Oral Oncology. Jan, 2008  |  Pubmed ID: 17825602

Historically, the screening of patients for signs of oral cancer and precancerous lesions has relied upon the conventional oral examination. A variety of commercial diagnostic aids and adjunctive techniques are available to potentially assist in the screening of healthy patients for evidence of otherwise occult cancerous change or to assess the biologic potential of clinically abnormal mucosal lesions. This manuscript systematically and critically examines the literature associated with current oral cancer screening and case-finding aids or adjuncts such as toluidine blue, brush cytology, tissue reflectance and autofluorescence. The characteristics of an ideal screening test are outlined and the authors pose several questions for clinicians and scientists to consider in the evaluation of current and future studies of oral cancer detection and diagnosis. Although the increased public awareness of oral cancer made possible by the marketing of recently-introduced screening adjuncts is commendable, the tantalizing implication that such technologies may improve detection of oral cancers and precancers beyond conventional oral examination alone has yet to be rigorously confirmed.

Reproducibility and Sources of Variability in Radiographic Texture Analysis of Densitometric Calcaneal Images

Journal of Clinical Densitometry : the Official Journal of the International Society for Clinical Densitometry. Apr-Jun, 2008  |  Pubmed ID: 18158263

Radiographic texture analysis (RTA) is a computerized analysis of the spatial pattern of radiographic images used as a way of evaluating bone structure. We have shown that RTA performed on high-resolution heel images obtained using a portable densitometer differentiates subjects with and without osteoporotic fractures. In the present study, short-term precision of RTA was examined on densitometric heel images obtained from 33 subjects scanned 8 times each, with 3 observers placing a region of interest (ROI) 3 times on each image. The long-term precision was examined on images obtained from 10 subjects 3 times on each of 3 days separated by 1 week, with 2 observers placing an ROI on each image. The RTA features examined included the root mean square (RMS) variation, a measure of the contrast between the light and dark areas of the image, the first moment of the power spectrum, a measure of the spatial frequency of the trabecular pattern, and Minkowski fractal (MINK), a measure of roughness/smoothness of the trabecular pattern. The precision of the RTA features expressed as coefficient of variation ranged between the lowest of 0.5-0.7% for MINK and the highest of 14-16% for RMS. The short- and long-term precision was similar, and was not significantly influenced by repositioning and rescanning, or by ROI placement by the same or different observers. Significant sources of variability of RTA were the between-subject differences and differences between regions of the heel, but not differences due to repositioning, rescanning in the same position, or ROI placement by the same or different observers. We conclude that technical aspects of image acquisition and processing are adequate to allow further development of RTA of the densitometric images for clinical application as a method for noninvasive assessment of bone structure.

Phase I Study of the Ribonucleotide Reductase Inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in Combination with High Dose Cytarabine in Patients with Advanced Myeloid Leukemia

Investigational New Drugs. Jun, 2008  |  Pubmed ID: 18217206

This Phase I dose escalation study was based on the hypothesis that the addition of 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) to cytarabine would enhance cytarabine cytotoxicity. The primary objective of the study was to establish the maximum tolerated dose of 3-AP when given in combination with a fixed dose of cytarabine.

Successful Autologous Stem Cell Collection in Patients with Chronic Myeloid Leukemia in Complete Cytogenetic Response, with Quantitative Measurement of BCR-ABL Expression in Blood, Marrow, and Apheresis Products

Leukemia & Lymphoma. Mar, 2008  |  Pubmed ID: 18297531

Imatinib mesylate is the initial therapy of choice for chronic myeloid leukemia in chronic phase (CML-CP), but in some patients, the disease becomes resistant to imatinib. Autologous stem cell transplantation using cells collected while in complete cytogenetic response (CCyR) may represent a therapeutic option for these patients. We mobilized and collected autologous CD34(+) stem cells from 20 CML-CP patients in CCyR, 19 of whom were taking imatinib, and measured BCR-ABL expression in the apheresis products, blood and bone marrow using real-time quantitative PCR (RQ-PCR). Stem cells were mobilized with G-CSF 10 microg/kg daily for 5 days. In patients whose initial collection was <2x10(6) CD34(+) cells/kg, G-CSF dose was increased to 10 microg/kg twice daily on the second attempt, and imatinib was held for 14 days if a third attempt was necessary. All 20 patients successfully mobilized the target yield of 2 to 5x10(6) CD34(+) cells/kg; 16 reached target yield with the first mobilization. The median number of CD34(+) cells collected was 4.4 (range, 2.0 - 8.4)x10(6)/kg in a median of 3 (range, 2 - 6) apheresis days. Of 17 patients whose stem cell products were evaluable by RQ-PCR, 11 (65%) had >or=1 daily product with undetectable BCR-ABL; 4 of these (24%) had no detectable BCR-ABL in any apheresis products. BCR-ABL expression in apheresis products was correlated with levels of expression in the blood and marrow prior to mobilization. No patient has yet required transplantation. With median follow-up of 18 months, all patients remain in CCyR and 9 of 16 (54%) have undetectable BCR-ABL in the most recent blood and marrow sample.

Pharmacogenomic and Pharmacokinetic Determinants of Erlotinib Toxicity

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2008  |  Pubmed ID: 18309947

To assess the pharmacogenomic and pharmacokinetic determinants of skin rash and diarrhea, the two primary dose-limiting toxicities of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib.

IFN-gamma- and TNF-dependent Bystander Eradication of Antigen-loss Variants in Established Mouse Cancers

The Journal of Clinical Investigation. Apr, 2008  |  Pubmed ID: 18317595

Tumors elicit antitumor immune responses, but over time they evolve and can escape immune control through various mechanisms, including the loss of the antigen to which the response is directed. The escape of antigen-loss variants (ALVs) is a major obstacle to T cell-based immunotherapy for cancer. However, cancers can be cured if both the number of CTLs and the expression of antigen are high enough to allow targeting of not only tumor cells, but also the tumor stroma. Here, we showed that IFN-gamma and TNF produced by CTLs were crucial for the elimination of established mouse tumors, including ALVs. In addition, both BM- and non-BM-derived stromal cells were required to express TNF receptors and IFN-gamma receptors for the elimination of ALVs. Although IFN-gamma and TNF were not required by CTLs for perforin-mediated killing of antigen-expressing tumor cells, the strong inference is that tumor antigen-specific CTLs must secrete IFN-gamma and TNF for destruction of tumor stroma. Therefore, bystander killing of ALVs may result from IFN-gamma and TNF acting on tumor stroma.

A Phase I and Pharmacokinetic Study of the Quinoxaline Antitumour Agent R(+)XK469 in Patients with Advanced Solid Tumours

European Journal of Cancer (Oxford, England : 1990). Aug, 2008  |  Pubmed ID: 18650079

To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose.

Modeling Major Lung Resection Outcomes Using Classification Trees and Multiple Imputation Techniques

European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery. Nov, 2008  |  Pubmed ID: 18760930

Modeling of operative risks associated with major lung resection is potentially inaccurate and inefficient because of incomplete observations for predictor variables (covariates). Missing values do not usually occur randomly, potentially introducing an important source of bias in modeling. Deletion of cases with missing data also results in loss of precision. The current study analyzes incomplete variables as potential predictors of outcomes after major lung resection using imputation techniques.

Dynamic Contrast-enhanced Magnetic Resonance Imaging Pharmacodynamic Biomarker Study of Sorafenib in Metastatic Renal Carcinoma

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Oct, 2008  |  Pubmed ID: 18824708

Sorafenib is an antiangiogenic agent with activity in renal cancer. We conducted a randomized trial to investigate dynamic contrast magnetic resonance imaging (DCE-MRI) as a pharmacodynamic biomarker.

Erlotinib and Bevacizumab in Patients with Recurrent or Metastatic Squamous-cell Carcinoma of the Head and Neck: a Phase I/II Study

The Lancet Oncology. Mar, 2009  |  Pubmed ID: 19201650

Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab.

A Phase I Trial to Determine the Safety, Tolerability, and Maximum Tolerated Dose of Deforolimus in Patients with Advanced Malignancies

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Feb, 2009  |  Pubmed ID: 19228743

This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied.

A Randomized Phase 1 Study of Testosterone Replacement for Patients with Low-risk Castration-resistant Prostate Cancer

European Urology. Jul, 2009  |  Pubmed ID: 19282098

Even in castration-resistant prostate cancer (CRPC), the androgen pathway remains biologically relevant. In preclinical models, androgen therapy for CRPC leads to growth arrest, apoptosis, and tumor shrinkage.

Design of Phase II Cancer Trials for Evaluation of Cytostatic/cytotoxic Agents

Journal of Biopharmaceutical Statistics. 2009  |  Pubmed ID: 19384693

For experimental anticancer agents that may have both cytostatic and cytotoxic effects, assessment of response rates alone may not capture the full impact of the treatment. Oncologists are therefore interested in assessing both response and stable disease rates in early phase clinical trials of such therapies. We describe the design of a single-arm, Phase II clinical trial for the simultaneous evaluation of objective response and stable disease (lack of early tumor progression) rates using standard RECIST criteria. Demonstration of a sufficiently high rate for either of these endpoints will lead to rejection of the null hypothesis and a conclusion that the treatment warrants further study. A design is chosen that satisfies the desired type I error constraint and has sufficient statistical power at several selected points within the alternative hypothesis space using a restricted search algorithm. An early stopping rule for lack of efficacy is incorporated. The method is illustrated by the design of a Phase II clinical trial in head and neck cancer.

What Does It Cost Physician Practices to Interact with Health Insurance Plans?

Health Affairs (Project Hope). Jul-Aug, 2009  |  Pubmed ID: 19443477

Physicians have long expressed dissatisfaction with the time they and their staffs spend interacting with health plans. However, little information exists about the extent of these interactions. We conducted a national survey on this subject of physicians and practice administrators. Physicians reported spending three hours weekly interacting with plans; nursing and clerical staff spent much larger amounts of time. When time is converted to dollars, we estimate that the national time cost to practices of interactions with plans is at least $23 billion to $31 billion each year.

Frequency of Failure to Inform Patients of Clinically Significant Outpatient Test Results

Archives of Internal Medicine. Jun, 2009  |  Pubmed ID: 19546413

Failing to inform a patient of an abnormal outpatient test result can be a serious error, but little is known about the frequency of such errors or the processes for managing results that may reduce errors.

Common Fragile Sites Are Characterized by Histone Hypoacetylation

Human Molecular Genetics. Dec, 2009  |  Pubmed ID: 19717471

Common fragile sites (CFSs) represent large, highly unstable regions of the human genome. CFS sequences are sensitive to perturbation of replication; however, the molecular basis for the instability at CFSs is poorly understood. We hypothesized that a unique epigenetic pattern may underlie the unusual sensitivity of CFSs to replication interference. To examine this hypothesis, we analyzed chromatin modification patterns within the six human CFSs with the highest levels of breakage, and their surrounding non-fragile regions (NCFSs). Chromatin at most of the CFSs analyzed has significantly less histone acetylation than that of their surrounding NCFSs. Trichostatin A and/or 5-azadeoxycytidine treatment reduced chromosome breakage at CFSs. Furthermore, chromatin at the most commonly expressed CFS, the FRA3B, is more resistant to micrococcal nuclease than that of the flanking non-fragile sequences. These results demonstrate that histone hypoacetylation is a characteristic epigenetic pattern of CFSs, and chromatin within CFSs might be relatively more compact than that of the NCFSs, indicating a role for chromatin conformation in genomic instability at CFSs. Moreover, lack of histone acetylation at CFSs may contribute to the defective response to replication stress characteristic of CFSs, leading to the genetic instability characteristic of this regions.

Ambulatory Monitoring Detects Sorafenib-induced Blood Pressure Elevations on the First Day of Treatment

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Oct, 2009  |  Pubmed ID: 19773379

Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective, single-center, cohort study characterized ambulatory blood pressure monitoring as an early pharmacodynamic biomarker of VEGF signaling pathway inhibition by sorafenib.

Impaired Replication Dynamics at the FRA3B Common Fragile Site

Human Molecular Genetics. Jan, 2010  |  Pubmed ID: 19815620

Chromosomal common fragile sites (CFSs) are genetically unstable regions of the genome that are induced by conditions that impair DNA replication. In this report, we show that treatment with the DNA polymerase inhibitor, aphidicolin (APH), slows the replication rate throughout S phase. To investigate the unusual sensitivity of CFSs to APH-induced replication stress, we examined replication dynamics within a 50 kb region of the most frequently expressed CFS, FRA3B. We mapped four origins of replication, ori 1-4, using two independent methods. In untreated cells, we detected significantly less newly replicated DNA at FRA3B ori 1-3, as compared with three control origins located within non-fragile regions (NCFSs). In APH-treated cells, all FRA3B and control origins tested were active; however, there was a significant increase of nascent strand DNA at the control origins and, to a lesser extent, at the FRA3B ori 1-3. On the basis of these observations and the theoretical modeling of the nascent strand abundance assay developed in this study, we hypothesize that CFS origins may be less efficient, and that APH treatment slows replication fork movement near these origins to a greater extent, resulting in impaired DNA replication and, ultimately, leading to the genetic instability characteristic of CFSs.

Neoplasms with Schwannian Differentiation Express Transcription Factors Known to Regulate Normal Schwann Cell Development

International Journal of Surgical Pathology. Dec, 2010  |  Pubmed ID: 20034979

A number of transcription factors have been identified as important in guiding normal Schwann cell development. This study used immunohistochemistry on tissue arrays to assess the expression of some of these transcription factors (Sox5, Sox9, Sox10, AP-2α, Pax7, and FoxD3) on 76 schwannomas, 105 neurofibromas, and 34 malignant peripheral nerve sheath tumors (MPNSTs). Sox9 and Sox10 were found to be widely expressed in all tumor types. FoxD3 reactivity was stronger and more frequently found in schwannomas and MPNSTs than neurofibromas. AP-2α was positive in 31% to 49% of all tumors, but strong reactivity was limited to MPNSTs and schwannomas. Pax7 and Sox5 expression was restricted to subsets of MPNSTs. Statistical analysis showed significant differences between the 3 tumor types in the expression of these markers. No differences were found in the analyzed tumor subgroups, including schwannomas of different sites, schwannomas with or without NF2 association, neurofibromas of different types, or sporadic versus NF1-associated MPNSTs. These results suggest that the transcription factors that guide normal Schwann cell development also play a role in the biology of neoplastic cells with Schwannian differentiation. FoxD3, AP-2α, Pax7, and Sox5 are upregulated in MPNSTs compared with neurofibromas and may be markers of malignant transformation. Screening the expression of FoxD3, Sox9, and Sox10 on 23 cases of other spindle-cell proliferations that may be considered in the differential diagnosis of MPNST, including synovial sarcoma and spindle cell melanoma, suggests that these 3 are helpful markers of Schwannian differentiation in the context of diagnosing MPNSTs.

CBL is Frequently Altered in Lung Cancers: Its Relationship to Mutations in MET and EGFR Tyrosine Kinases

PloS One. 2010  |  Pubmed ID: 20126411

Non-small cell lung cancer (NSCLC) is a heterogeneous group of disorders with a number of genetic and proteomic alterations. c-CBL is an E3 ubiquitin ligase and adaptor molecule important in normal homeostasis and cancer. We determined the genetic variations of c-CBL, relationship to receptor tyrosine kinases (EGFR and MET), and functionality in NSCLC.

Statin Use and Risk of Prostate Cancer Recurrence in Men Treated with Radiation Therapy

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Jun, 2010  |  Pubmed ID: 20421534

There has been growing interest in the potential anticancer activity of statins based on preclinical evidence of their antiproliferative, proapoptotic, and radiosensitizing properties. The primary objective of this study was to determine whether statin use is associated with improved clinical outcomes in patients treated with radiotherapy (RT) for prostate cancer.

Temsirolimus Has Activity in Non-mantle Cell Non-Hodgkin's Lymphoma Subtypes: The University of Chicago Phase II Consortium

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Nov, 2010  |  Pubmed ID: 20837940

Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas.

Phase II Study of Sunitinib Malate in Head and Neck Squamous Cell Carcinoma

Investigational New Drugs. Oct, 2010  |  Pubmed ID: 19649772

Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor of RET, VEGFR, PDGFR, and c-KIT. We conducted a phase II trial to evaluate the tolerability and efficacy of sunitinib in metastatic and/or recurrent SCCHN patients.

Outcomes in Black Patients with Early Breast Cancer Treated with Breast Conservation Therapy

International Journal of Radiation Oncology, Biology, Physics. Feb, 2011  |  Pubmed ID: 20434849

The race-specific impact of prognostic variables for early breast cancer is unknown for black patients undergoing breast conservation.

A Phase II Trial of Gemcitabine, Capecitabine, and Bevacizumab in Metastatic Renal Carcinoma

American Journal of Clinical Oncology. Apr, 2011  |  Pubmed ID: 20395787

Renal cancer is resistant to most DNA and DNA repair targeted chemotherapy; although moderate response rates to nucleotide analog based therapy have been reported. Bevacizumab also has activity. We thus performed a phase II trial of gemcitabine, capecitabine, and bevacizumab in patients with metastatic renal cancer.

RON (MST1R) is a Novel Prognostic Marker and Therapeutic Target for Gastroesophageal Adenocarcinoma

Cancer Biology & Therapy. Jul, 2011  |  Pubmed ID: 21543897

RON (MST1R) is one of two members of the MET receptor tyrosine kinase family, along with parent receptor MET. RON has a putative role in several cancers, but its expression and function is poorly characterized in gastroesophageal adenocarcinoma. A recognized functional role of MET tyrosine kinase in gastroesophageal cancer has led to early phase clinical trials using MET inhibitors, with unimpressive results. Therefore, the role of RON in gastroesophageal cancer, as well as its role in cooperative signaling with MET and as a mechanism of resistance to MET inhibition, was studied in gastroesophageal tissues and cell lines. By IHC, RON was highly over-expressed in 74% of gastroesophageal samples (n=94), and over-expression was prognostic of poor survival (p=0.008); RON and MET co-expression occurred in 43% of samples and was prognostic of worst survival (p=0.03). High MST1R gene copy number by quantitative polymerase chain reaction, and confirmed by fluorescence in situ hybridization and/or array comparative genomic hybridization, was seen in 35.5% (16/45) of cases. High MST1R gene copy number correlated with poor survival (p=0.01), and was associated with high MET and ERBB2 gene copy number. A novel somatic MST1R juxtamembrane mutation R1018G was found in 11% of samples. RON signaling was functional in cell lines, activating downstream effector STAT3, and resulted in increased viability over controls. RON and MET co-stimulation assays led to enhanced malignant phenotypes over stimulation of either receptor alone. Growth inhibition as evidenced by viability and apoptosis assays was optimal using novel blocking monoclonal antibodies to both RON and MET, versus either alone. SU11274, a classic MET small molecule tyrosine kinase inhibitor, blocked signaling of both receptors, and proved synergistic when combined with STAT3 inhibition (combination index < 1). These preclinical studies define RON as an important novel prognostic marker and therapeutic target for gastroesophageal cancer warranting further investigation.

Proteomic Characterization of Non-small Cell Lung Cancer in a Comprehensive Translational Thoracic Oncology Database

Journal of Clinical Bioinformatics. Feb, 2011  |  Pubmed ID: 21603121

In recent years, there has been tremendous growth and interest in translational research, particularly in cancer biology. This area of study clearly establishes the connection between laboratory experimentation and practical human application. Though it is common for laboratory and clinical data regarding patient specimens to be maintained separately, the storage of such heterogeneous data in one database offers many benefits as it may facilitate more rapid accession of data and provide researchers access to greater numbers of tissue samples.

The Effect of Thalidomide on the Pharmacokinetics of Irinotecan and Metabolites in Advanced Solid Tumor Patients

Cancer Chemotherapy and Pharmacology. Dec, 2011  |  Pubmed ID: 21861128

Irinotecan and thalidomide are commonly administered antineoplastic drugs. Combination treatment may potentiate their antitumor effect and protect against irinotecan's intestinal toxicity. We investigated whether thalidomide can modulate the pharmacokinetics of irinotecan and metabolites.

Unrecognized Ingestion of Toxoplasma Gondii Oocysts Leads to Congenital Toxoplasmosis and Causes Epidemics in North America

Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. Dec, 2011  |  Pubmed ID: 22021924

Congenital toxoplasmosis presents as severe, life-altering disease in North America. If mothers of infants with congenital toxoplasmosis could be identified by risks, it would provide strong support for educating pregnant women about risks, to eliminate this disease. Conversely, if not all risks are identifiable, undetectable risks are suggested. A new test detecting antibodies to sporozoites demonstrated that oocysts were the predominant source of Toxoplasma gondii infection in 4 North American epidemics and in mothers of children in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS). This novel test offered the opportunity to determine whether risk factors or demographic characteristics could identify mothers infected with oocysts.

Targeted and Cytotoxic Therapy in Coordinated Sequence (TACTICS): Erlotinib, Bevacizumab, and Standard Chemotherapy for Non-Small-Cell Lung Cancer, A Phase II Trial

Clinical Lung Cancer. Nov, 2011  |  Pubmed ID: 22100149

BACKGROUND: This trial focused on optimally combining existing targeted therapies and cytotoxic chemotherapy in the treatment of unselected patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients with previously untreated advanced-stage nonsquamous NSCLC were eligible for this trial. In module A, patients received up to 4 cycles of erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks. Patients then received carboplatin (AUC = 6), paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg for 4 cycles in module B. Patients who did not have progressive disease in module A received maintenance erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks in module C. RESULTS: Forty-eight patients were enrolled in this multicenter phase II trial. Most patients were male (62.5%) and white (77.1%) with stage IV disease (93.8%) and adenocarcinoma histologic type (66.7%). The overall response rate in module A was 10.4%, in module B it was 15.1%, and in module C it was 5.5%. The study achieved its primary endpoint, with a nonprogression rate of 45.8% in module A. The median overall survival (OS) was 12.6 months. CONCLUSION: The novel systemic therapy regimen is feasible in patients with advanced NSCLC. However there is no further role for developing this regimen in unselected patients with NSCLC.

MET and Phosphorylated MET As Potential Biomarkers in Lung Cancer

Journal of Environmental Pathology, Toxicology and Oncology : Official Organ of the International Society for Environmental Toxicology and Cancer. 2011  |  Pubmed ID: 22181983

This study aimed to investigate the expression and prognostic role of the receptor tyrosine kinase MET, phosphorylated MET, and the ligand hepatocyte growth factor (HGF) in patients with lung cancer. This retrospective study included 129 patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) with available tumor tissue and survival data. MET, pMET, and HGF expression were assessed using immunohistochemistry. MET, pMET, and HGF were more highly expressed in tumor tissue when compared to the adjacent lung parenchyma. A specific localization pattern was also evident: membranous, cytoplasmic, and nuclear patterns of expression were seen for MET, pMET, and HGF. In addition, high expression of two specific forms of phosphorylated MET--cytoplasmic expression of Y1003 and nuclear expression of Y1365--appeared to correlate with a worse overall survival (P = .016; hazard ratio [HR], 1.86; 95% confidence interval [95% CI], 1.12- 3.07; and P = .034; HR, 1.70; 95% CI, 1.04-2.78, respectively). In summary, MET, pMET, and HGF are highly expressed in both NSCLC and SCLC. Specific forms of pMET may serve as potential biomarkers in lung cancer.

Relationship of Type II Diabetes and Metformin Use to Ovarian Cancer Progression, Survival, and Chemosensitivity

Obstetrics and Gynecology. Jan, 2012  |  Pubmed ID: 22183212

To estimate whether metformin use by ovarian cancer patients with type II diabetes was associated with improved survival.

Resampling Phase III Data to Assess Phase II Trial Designs and Endpoints

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Jan, 2012  |  Pubmed ID: 22287601

PURPOSE: The best phase II design and endpoint for growth inhibitory agents is controversial. We simulated phase II trials by resampling patients from a positive (sorafenib vs. placebo; TARGET) and a negative (AE941 vs. placebo) phase III trial in metastatic renal cancer to compare the ability of various designs and endpoints to predict the known results.EXPERIMENTAL DESIGN: 770 and 259 patients from TARGET and the AE 941 trial, respectively, were resampled (5,000 replicates) to simulate phase II trials with alpha = 0.10 (one-sided). Designs/endpoints: single arm, two-stage with response rate (RR) by RECIST (37 patients); and randomized, two arm (20-35 patients/arm) with RR by RECIST, mean log ratio of tumor sizes (log ratio), PFS rate at 90 days (PFS-90), and overall PFS.RESULTS: Single arm trials were positive with RR by RECIST in 55% and 1% of replications for sorafenib and AE 941, respectively. Randomized trials versus placebo with 20 patients per arm were positive with RR by RECIST in 55% and 7%, log ratio in 88% and 25%, PFS-90 in 64% and 15%, and overall PFS in 69% and 9% of replications for sorafenib and AE 941, respectively. CONCLUSIONS: Compared with the single arm design and the randomized design comparing PFS, the randomized phase II design with the log ratio endpoint has greater power to predict the positive phase III result of sorafenib in renal cancer, but a higher false positive rate for the negative phase III result of AE 941.

A Phase I Study of Continuous Infusion Cilengitide in Patients with Solid Tumors

Investigational New Drugs. Apr, 2012  |  Pubmed ID: 20839028

Background: Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3-5 h with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion cilengitide. Methods: Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 h after infusion bag change. Results: Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40 mg/h. Toxicities were limited to grade ≤2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached. Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and the steady-state concentration increased proportionally with dose. Conclusions: Cilengitide can be safely administered as a continuous infusion at doses up to at least 40 mg/h, which represents the maximum feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are linear and consistent with the results obtained using a twice weekly infusion.