Theodore Karrison

Publications of Theodore Karrison

• Prematurity and Severity Are Associated With Toxoplasma gondii Alleles (NCCCTS, 1981-2009).

  Authors: Rima McLeod, Kenneth M Boyer, Daniel Lee, Ernest Mui, Kristen Wroblewski, Theodore Karrison, A Gwendolyn Noble, Shawn Withers, Charles N Swisher, Peter T Heydemann, Mari Sautter, Jane Babiarz, Peter Rabiah, Paul Meier, Michael E Grigg

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 04/2012;

  Background. Congenital toxoplasmosis is a severe, life-altering disease in the United States. A recently developed enzyme-linked immunosorbent assay (ELISA) distinguishes Toxoplasma gondii parasiteBackground. Congenital toxoplasmosis is a severe, life-altering disease in the United States. A recently developed enzyme-linked immunosorbent assay (ELISA) distinguishes Toxoplasma gondii parasite types (II and not exclusively II [NE-II]) by detecting antibodies in human sera that recognize allelic peptide motifs of distinct parasite types.Methods. ELISA determined parasite serotype for 193 congenitally infected infants and their mothers in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS), 1981-2009. Associations of parasite serotype with demographics, manifestations at birth, and effects of treatment were determined.Results. Serotypes II and NE-II occurred in the United States with similar proportions during 3 decades. For persons diagnosed before or at birth and treated in infancy, and persons diagnosed after 1 year of age who missed treatment in infancy, proportions were similar (P = .91). NE-II serotype was more common in hot, humid regions (P = .02) but was also present in other regions. NE-II serotype was associated with rural residence (P < .01), lower socioeconomic status (P < .001), and Hispanic ethnicity (P < .001). Prematurity (P = .03) and severe disease at birth (P < .01) were associated with NE-II serotype. Treatment with lower and higher doses of pyrimethamine with sulfadizine improved outcomes relative to those outcomes of persons in the literature who did not receive such treatment.Conclusions. Type II and NE-II parasites cause congenital toxoplasmosis in North America. NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth. Both type II and NE-II infections improved with treatment.Clinical Trials Registration. NCT00004317.

• Unrecognized ingestion of Toxoplasma gondii oocysts leads to congenital toxoplasmosis and causes epidemics in North America.

  Authors: Kenneth Boyer, Dolores Hill, Ernest Mui, Kristen Wroblewski, Theodore Karrison, J P Dubey, Mari Sautter, A Gwendolyn Noble, Shawn Withers, Charles Swisher, Peter Heydemann, Tiffany Hosten, Jane Babiarz, Daniel Lee, Paul Meier, Rima McLeod

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 12/2011; 53(11):1081-9.

  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 supportCongenital 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. Acutely infected mothers and their congenitally infected infants were evaluated, including in-person interviews concerning risks and evaluation of perinatal maternal serum samples. Fifty-nine (78%) of 76 mothers of congenitally infected infants in NCCCTS had primary infection with oocysts. Only 49% of these mothers identified significant risk factors for sporozoite acquisition. Socioeconomic status, hometown size, maternal clinical presentations, and ethnicity were not reliable predictors. Undetected contamination of food and water by oocysts frequently causes human infections in North America. Risks are often unrecognized by those infected. Demographic characteristics did not identify oocyst infections. Thus, although education programs describing hygienic measures may be beneficial, they will not suffice to prevent the suffering and economic consequences associated with congenital toxoplasmosis. Only a vaccine or implementation of systematic serologic testing of pregnant women and newborns, followed by treatment, will prevent most congenital toxoplasmosis in North America.

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

  Authors: Ezra E W Cohen, Janakiraman Subramanian, Feng Gao, Livia Szeto, Mark Kozloff, Leonardo Faoro, Theodore Karrison, Ravi Salgia, Ramaswamy Govindan, Everett E Vokes

  Clinical lung cancer. 11/2011; 13(2):123-8.

  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). PatientsThis 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). 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. 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. 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.

• The effect of thalidomide on the pharmacokinetics of irinotecan and metabolites in advanced solid tumor patients.

  Authors: Jacqueline Ramírez, Kehua Wu, Linda Janisch, Theodore Karrison, Larry K House, Federico Innocenti, Ezra E W Cohen, Mark J Ratain

  Cancer chemotherapy and pharmacology. 08/2011; 68(6):1629-32.

  Irinotecan and thalidomide are commonly administered antineoplastic drugs. Combination treatment may potentiate their antitumor effect and protect against irinotecan's intestinal toxicity. WeIrinotecan 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. The study employed a crossover design in which advanced solid tumor patients were randomized to two arms and treated with irinotecan 350 mg/m(2) intravenously (IV) every 3 weeks and thalidomide orally (p.o.) 400 mg daily. Pharmacokinetic data when irinotecan was administered as a single agent in each arm were compared to data when the two study agents were co-administered using paired t tests. Eighty percent and 90% confidence intervals for the true difference were also calculated. The differences in pharmacokinetic parameters and metabolic markers after thalidomide administration were small and unlikely to be clinically significant. With the exception of APC T (1/2), none of the upper confidence limits exceeds a 50% increase. This study did not find any clinically meaningful effects of thalidomide on the pharmacokinetics of irinotecan or its metabolites.

• RON (MST1R) is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma.

  Authors: Daniel V T Catenacci, Gustavo Cervantes, Soheil Yala, Erik A Nelson, Essam El-Hashani, Rajani Kanteti, Mohamed El Dinali, Rifat Hasina, Johannes Brägelmann, Tanguy Seiwert [......] Olufunmilayo Olopade, Theodore Karrison, Yung-Jue Bang, Woo Ho Kim, Maria Tretiakova, Everett Vokes, David A Frank, Hedy L Kindler, Heather Huet, Ravi Salgia

  Cancer biology & therapy. 07/2011; 12(1):9-46.

  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 poorlyRON (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.

• A phase II trial of gemcitabine, capecitabine, and bevacizumab in metastatic renal carcinoma.

  Authors: Elizabeth K Chung, Edwin M Posadas, Kristen Kasza, Theodore Karrison, Elizabeth Manchen, Olwen M Hahn, Walter M Stadler

  American journal of clinical oncology. 04/2011; 34(2):150-4.

  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. WeRenal 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. Following significant hematotoxicity, dosing was modified to gemcitabine 1000 mg/m (Days 1, 8), capecitabine 1000 mg twice daily (Days 1-14), and bevacizumab 15 mg/kg (Day 1) on a 21-day cycle with evaluation every 3 cycles. Primary end point was objective response rate. Twenty-nine patients were enrolled between March 2005 and May 2008. Most patients had been previously treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Seven patients (24%) had a partial response. Median overall and progression-free survival were 9.8 months (95% confidence interval: 6.2, 14.9) and 5.3 months (95% confidence interval: 3.9, 9.9), respectively. The regimen was well tolerated with hematologic toxicity, fatigue, and rash being most common. The trial was terminated early despite not meeting criteria for success or futility because of slow accrual and because the historical response rate became irrelevant with emerging data using sequential vascular endothelial growth factor therapies. Nevertheless, the observed progression-free and overall survival compare favorably to other phase II trials in this heavily pretreated population.

• Correction: CBL Is Frequently Altered in Lung Cancers: Its Relationship to Mutations in MET and EGFR Tyrosine Kinases.

  Authors: Yi-Hung Carol Tan, Soundararajan Krishnaswamy, Suvobroto Nandi, Rajani Kanteti, Sapana Vora, Kenan Onel, Rifat Hasina, Fang-Yi Lo, Essam El-Hashani, Gustavo Cervantes, Matthew Robinson, Han-Shui Hsu, Stephen C Kales, Stanley Lipkowitz, Theodore Karrison, Martin Sattler, Everett E Vokes, Yi-Ching Wang, Ravi Salgia

  PloS one. 01/2011; 6(1).

  [This corrects the article on p. e8972 in vol. 5.].

• Generation of comprehensive thoracic oncology database--tool for translational research.

  Authors: Mosmi Surati, Matthew Robinson, Suvobroto Nandi, Leonardo Faoro, Carley Demchuk, Rajani Kanteti, Benjamin Ferguson, Tara Gangadhar, Thomas Hensing, Rifat Hasina, Aliya Husain, Mark Ferguson, Theodore Karrison, Ravi Salgia

  Journal of visualized experiments : JoVE. 01/2011;

  The Thoracic Oncology Program Database Project was created to serve as a comprehensive, verified, and accessible repository for well-annotated cancer specimens and clinical data to be available toThe Thoracic Oncology Program Database Project was created to serve as a comprehensive, verified, and accessible repository for well-annotated cancer specimens and clinical data to be available to researchers within the Thoracic Oncology Research Program. This database also captures a large volume of genomic and proteomic data obtained from various tumor tissue studies. A team of clinical and basic science researchers, a biostatistician, and a bioinformatics expert was convened to design the database. Variables of interest were clearly defined and their descriptions were written within a standard operating manual to ensure consistency of data annotation. Using a protocol for prospective tissue banking and another protocol for retrospective banking, tumor and normal tissue samples from patients consented to these protocols were collected. Clinical information such as demographics, cancer characterization, and treatment plans for these patients were abstracted and entered into an Access database. Proteomic and genomic data have been included in the database and have been linked to clinical information for patients described within the database. The data from each table were linked using the relationships function in Microsoft Access to allow the database manager to connect clinical and laboratory information during a query. The queried data can then be exported for statistical analysis and hypothesis generation.

• MET and phosphorylated MET as potential biomarkers in lung cancer.

  Authors: Maria Tretiakova, April K S Salama, Theodore Karrison, Mark K Ferguson, Aliya N Husain, Everett E Vokes, Ravi Salgia

  Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer. 01/2011; 30(4):341-54.

  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 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.

• Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: The University of Chicago phase II consortium.

  Authors: Sonali M Smith, Koen van Besien, Theodore Karrison, Janet Dancey, Peter McLaughlin, Anas Younes, Scott Smith, Patrick Stiff, Eric Lester, Sanjiv Modi, L Austin Doyle, Everett E Vokes, Barbara Pro

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 11/2010; 28(31):4740-6.

  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 notDespite 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. We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas). Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis. Single-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.

• Statin use and risk of prostate cancer recurrence in men treated with radiation therapy.

  Authors: Ruchika Gutt, Nathan Tonlaar, Rangesh Kunnavakkam, Theodore Karrison, Ralph R Weichselbaum, Stanley L Liauw

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 06/2010; 28(16):2653-9.

  There has been growing interest in the potential anticancer activity of statins based on preclinical evidence of their antiproliferative, proapoptotic, and radiosensitizing properties. The primaryThere 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. In total, 691 men with prostate adenocarcinoma treated with curative-intent RT between 1988 and 2006 were retrospectively analyzed. Of those, 189 patients (27%) were using statins, either during initial consultation or during follow-up. Lipid panels were collected (n = 298) a median of 5 months before RT start. Median follow-up was 50 months after RT. Statin use was associated with improved freedom from biochemical failure (FFBF; P < .001), freedom from salvage androgen deprivation therapy (FFADT; P = .0011), and relapse-free survival (RFS; P < .001). Improved FFBF for statin users was seen in low-, intermediate-, and high-risk groups (P = .0401, P = .0331, and P = .0034, respectively). The improvement in FFBF with statin use was independent of ADT use or radiation dose. On multivariable analysis, statin use was associated with improved FFBF (P < .001) along with pretreatment prostate-specific antigen < or = 8.4 (P < .001), stage less than T2b (P = .0111), and Gleason score < 7 (P = .0098). On univariate analysis, pretreatment total cholesterol < 187 (89% v 80%; P = .0494) and low-density lipoprotein (LDL) < 110 (96% v 85%; P = .0462) were associated with improved 4-year FFBF. Statin use was associated with a significant improvement in FFBF, FFADT, and RFS in this cohort of men treated with RT for prostate cancer. The favorable effect of statins may be mediated by direct effect or via the LDL-lowering effect of these medications.

• Chorioretinal lesions in mothers of children with congenital toxoplasmosis in the National Collaborative Chicago-based, Congenital Toxoplasmosis Study.

  Authors: A Gwendolyn Noble, Paul Latkany, Jaroslaw Kusmierczyk, Marilyn Mets, Peter Rabiah, Kenneth Boyer, Jessica Jalbrzikowski, Kristen Wroblewski, Theodore Karrison, Charles N Swisher, William F Mieler, Paul Meier, Rima McLeod

  Scientia medica. 01/2010; 20(1):20-26.

  AIMS: To determine whether mothers of children with congenital toxoplasmosis have chorioretinal lesions consistent with toxoplasmosis. METHODS: Prospective cohort study. Ophthalmologists in our studyAIMS: To determine whether mothers of children with congenital toxoplasmosis have chorioretinal lesions consistent with toxoplasmosis. METHODS: Prospective cohort study. Ophthalmologists in our study have examined 173 children with congenital toxoplasmosis in a hospital outpatient setting. These children were referred to us by their primary care physicians. One hundred and thirty mothers of these children had retina examinations of both eyes at least once. Main outcome measure was lesion(s) consistent with ocular toxoplasmosis. RESULTS: Of 130 mothers examined between 1991-2005, 10 (7.7%, 95% Confidence Interval 3.8%, 13.7%) had chorioretinal lesions which likely represent resolved toxoplasmic chorioretinitis. Most of these were small peripheral chorioretinal lesions. None reactivated between 1991-2005. CONCLUSIONS: Chorioretinal lesions consistent with quiescent ocular toxoplasmosis occur in mothers of children with congenital toxoplasmosis in the United States.

• CBL is frequently altered in lung cancers: its relationship to mutations in MET and EGFR tyrosine kinases.

  Authors: Yi-Hung Carol Tan, Soundararajan Krishnaswamy, Suvobroto Nandi, Rajani Kanteti, Sapana Vora, Kenan Onel, Rifat Hasina, Fang-Yi Lo, Essam El-Hashani, Gustavo Cervantes, Matthew Robinson, Han-Shui Hsu, Stephen C Kales, Stanley Lipkowitz, Theodore Karrison, Martin Sattler, Everett E Vokes, Yi-Ching Wang, Ravi Salgia

  PloS one. 01/2010; 5(1):e8972.

  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 normalNon-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. Using archival formalin-fixed paraffin embedded (FFPE) extracted genomic DNA, we show that c-CBL mutations occur in somatic fashion for lung cancers. c-CBL mutations were not mutually exclusive of MET or EGFR mutations; however they were independent of p53 and KRAS mutations. In normal/tumor pairwise analysis, there was significant loss of heterozygosity (LOH) for the c-CBL locus (22%, n = 8/37) and none of these samples revealed any mutation in the remaining copy of c-CBL. The c-CBL LOH also positively correlated with EGFR and MET mutations observed in the same samples. Using select c-CBL somatic mutations such as S80N/H94Y, Q249E and W802* (obtained from Caucasian, Taiwanese and African-American samples, respectively) transfected in NSCLC cell lines, there was increased cell viability and cell motility. Taking the overall mutation rate of c-CBL to be a combination as somatic missense mutation and LOH, it is clear that c-CBL is highly mutated in lung cancers and may play an essential role in lung tumorigenesis and metastasis.

• Impaired Replication Dynamics at the FRA3B Common Fragile Site.

  Authors: Aparna Palakodeti, Isabelle Lucas, Yanwen Jiang, David J Young, Anthony A Fernald, Theodore Karrison, Michelle M Le Beau

  Human molecular genetics. 10/2009;

  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 DNAChromosomal 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, 2, 3, and 4, using two independent methods. In untreated cells, we detected significantly less newly-replicated DNA at FRA3B ori 1-3, as compared to 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. Based on 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.

• Phase II study of sunitinib malate in head and neck squamous cell carcinoma.

  Authors: Nicholas Choong, Mark Kozloff, David Taber, H Hu, James Wade, Percy Ivy, Theodore Karrison, Allison Dekker, Everett Vokes, Ezra Cohen

  Investigational new drugs. 09/2009;

  Background 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 ofBackground 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. Methods Patients who had received no more than two prior chemotherapy regimens were eligible and, depending on ECOG performance status (PS), were entered into either Cohort A (PS 0-1) or Cohort B (PS 2). Sunitinib was administered in 6-week cycles at 50 mg daily for 4 weeks followed by 2 weeks off. Primary endpoint for Cohort A was objective tumor response. A Simon two-stage design required twelve patients to be enrolled in the first stage and if 1 or fewer responses were observed, further study of this cohort would be terminated due to lack of treatment efficacy. Primary endpoint of Cohort B was to determine the feasibility of sunitinib in patients with ECOG performance status 2. Results Twenty-two patients were accrued (Cohort A - 15 patients, Cohort B - 7 patients). Median age in cohort A and B was 56 and 61 years, respectively. Grade 3 hematologic toxicities encountered were lymphopenia (18%), neutropenia (14%) and thrombocytopenia (5%). There was only one incidence of grade 4 hematologic toxicity which was thrombocytopenia. Fatigue and anorexia were the most common non-hematologic toxicities. Grade 3 fatigue occurred in 23% of patients. The only grade 4 non-hematologic toxicity was one incidence of gastrointestinal hemorrhage. Non-fatal hemorrhagic complications occurred in 8 patients: epistaxis (3 patients), pulmonary hemorrhage (2 patients), gastrointestinal hemorrhage (2 patients) and tumor hemorrhage (1 patient). Four patients were not evaluable for tumor response (Cohort A - 3patients, Cohort B - 1 pt). One partial response was observed in the entire study. Dose reduction was required in 5 patients (Cohort A - 3 patients for grd 3 fatigue, grd 3 mucositis and recurrent grd 3 neutropenia; Cohort B - 2 patients for grd 3 fatigue and grd 3 nausea). Median time to progression for cohort A and B were 8.4 and 10.5 weeks, respectively. Median overall survival for cohort A and B was 21 and 19 weeks, respectively. Conclusions Sunitinib had low single agent activity in SCCHN necessitating early closure of cohort A at interim analysis. Sunitinib was well tolerated in PS 2 patients. Further evaluation of single agent sunitinib in head and neck is not supported by the results of this trial.

• Ambulatory Monitoring Detects Sorafenib-Induced Blood Pressure Elevations on the First Day of Treatment.

  Authors: Michael L Maitland, Kristen E Kasza, Theodore Karrison, Kristin Moshier, Laura Sit, Henry R Black, Samir D Undevia, Walter M Stadler, William J Elliott, Mark J Ratain

  Clinical cancer research : an official journal of the American Association for Cancer Research. 09/2009;

  PURPOSE: Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective,PURPOSE: 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. EXPERIMENTAL DESIGN: Fifty-four normotensive advanced cancer patients underwent 24-hour ambulatory blood pressure monitoring before and between days 6 and 10 of sorafenib therapy. After blood pressure changes were detected among the first cohort within 10 days, ambulatory blood pressure monitoring was done during the first 24 hours of treatment for the second cohort. RESULTS: For the entire patient population, the blood pressure increase [mean systolic, +10.8 mm Hg; 95% confidence interval (95% CI), 8.6-13.0; range, -5.2 to +28.7 mm Hg; mean diastolic, +8.0 mm Hg; 95% CI, 6.3-9.7; range, -4.4 to +27.1 mm Hg] was detected between days 6 and 10 (P < 0.0001 for both) and plateaued thereafter. Variability in blood pressure change did not associate with: age, body size, sex, self-reported race, baseline blood pressure, or steady-state sorafenib plasma concentrations. In the second cohort, the blood pressure elevation was detected during the first 24 hours (mean systolic, +8.2 mm Hg; 95% CI, 5.0-11.3; mean diastolic, +6.5 mm Hg; 95% CI, 4.7-8.3; P < 0.0001 for both). CONCLUSIONS: Ambulatory blood pressure monitoring detects the blood pressure response to VEGF signaling pathway inhibition by sorafenib during the first 24 hours of treatment. The magnitude of blood pressure elevation is highly variable and unpredictable but could be important in optimizing the therapeutic index of VEGF signaling pathway inhibitor therapy. (Clin Cancer Res 2009;15(19):6250-7).

• Common fragile sites are characterized by histone hypoacetylation.

  Authors: Yanwen Jiang, Isabelle Lucas, David J Young, Elizabeth M Davis, Theodore Karrison, Joshua S Rest, Michelle M Le Beau

  Human molecular genetics. 09/2009;

  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 instabilityCommon 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 these regions.

• A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies.

  Authors: Christine M Hartford, Apurva A Desai, Linda Janisch, Theodore Karrison, Victor M Rivera, Lori Berk, John W Loewy, Hedy Kindler, Walter M Stadler, Heather L Knowles, Camille Bedrosian, Mark J Ratain

  Clinical cancer research : an official journal of the American Association for Cancer Research. 03/2009; 15(4):1428-34.

  PURPOSE: 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,PURPOSE: 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. EXPERIMENTAL DESIGN: Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule. Dose was escalated according to an accelerated titration design. Patients remained on study until disease progression as long as they tolerated the drug without significant toxicities. RESULTS: Forty-six patients were enrolled on the study. Common side effects included fatigue, anorexia, and mucositis. The maximum tolerated dose was 75 mg and mucositis was the dose-limiting toxicity. Similar to other mTOR inhibitors, deforolimus exhibited nonlinear pharmacokinetics and a prolonged half-life. Among 34 patients evaluable for response, 1 patient had a partial response, 21 patients had stable disease, and 12 had progressed. Percent change in tumor size was significantly associated with AUC (P=0.015). A significant association was also detected for maximum change in cholesterol within the first two cycles of therapy and change in tumor size (r=-0.38; P=0.029). CONCLUSIONS: Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mTOR inhibitors. Additional phase II studies are needed to determine if deforolimus is superior to other mTOR inhibitors in terms of efficacy. The change in serum cholesterol as a potential biomarker of activity should be studied further.

• A Randomized Phase 1 Study of Testosterone Replacement for Patients with Low-Risk Castration-Resistant Prostate Cancer.

  Authors: Russell Szmulewitz, Supriya Mohile, Edwin Posadas, Rangesh Kunnavakkam, Theodore Karrison, Elizabeth Manchen, Walter M Stadler

  European urology. 03/2009;

  BACKGROUND: Even in castration-resistant prostate cancer (CRPC), the androgen pathway remains biologically relevant. In preclinical models, androgen therapy for CRPC leads to growth arrest,BACKGROUND: 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. OBJECTIVE: This study sought to determine the toxicity and feasibility of a testosterone therapy in early CRPC. DESIGN, SETTING, AND PARTICIPANTS: Prostate cancer patients with progressive disease following androgen ablation, antiandrogen therapy, and withdrawal and no to minimal metastatic disease who were followed at the University of Chicago were randomized to treatment with three doses of transdermal testosterone. INTERVENTION: Patients were treated with transdermal testosterone at 2.5, 5.0, or 7.5mg/day. MEASUREMENTS: Toxicity, prostate-specific antigen (PSA), imaging, quality of life (QoL), and strength were monitored. Treatment was discontinued for significant toxicity, clinical progression, or a 3-fold increase in PSA. RESULTS AND LIMITATIONS: Fifteen men with a median age of 73 yr (range: 62-92) and a median PSA of 11.1ng/ml (range: 5.2-63.6) were treated. Testosterone increased from castrate to median concentrations of 305ng/dl, 308ng/dl, and 297ng/dl for dosages of 2.5mg/day (n=4), 5.0mg/day (n=5), and 7.5mg/day (n=5), respectively. One patient was taken off of the study at 53 wk due to grade 4 cardiac toxicity. There were no other grade 3 or 4 toxicities related to the study medication, and the grade 2 toxicities were minimal. Only one patient experienced symptomatic progression, and three (20%) patients demonstrated a decrease in PSA (largest was 43%). Median time to progression was 9 wk (range: 2-96), with no detectable difference in the three dose cohorts. There was no significant improvement in QoL, and there was a borderline statistically significant improvement in hand-grip strength with treatment. The study was limited by sample size, single arm, and variability of baseline patient characteristics. CONCLUSIONS: Testosterone is a feasible and reasonably well-tolerated therapy for men with early CRPC. A larger, randomized trial is under way to further characterize efficacy and impact on QoL measures.

• Design of Phase II cancer trials for evaluation of cytostatic/cytotoxic agents.

  Authors: Masha Kocherginsky, Ezra E W Cohen, Theodore Karrison

  Journal of biopharmaceutical statistics. 02/2009; 19(3):524-9.

  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 thereforeFor 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.