bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurotrophic Roles of the Beta‐Thymosins in the Development and Regeneration of the Nervous System
Authors: SUN WOONG , KIM HYUN
Published: October 2007

Abstract:  Beta‐thymosins (Tβs) are polypeptides abundant in the cytosol, nucleus, and extracellular space of many cell types. In the nervous system, the expression of Tβs is regulated during the development of the central nervous system and following neuronal insults in cell‐type and brain‐region dependent manners, which may be related to the function of Tβs in the growth and regeneration of the nervous system. Supporting such a proposition, overexpression of Tβs in neurons has been shown to modify the axonal branches in vivo and neurite branches in vitro. These neurite‐modifying functions have been suggested to be due to the activity of Tβs to bind actin. In addition, we recently observed that Tβs suppressed the apoptotic neuronal death in chick embryos, and these functions might be mediated by the extracellularly secreted form(s) of Tβs. These results suggest that Tβs play neurotrophic roles in the neuroprotection and neuronal growth/regeneration via their cytosolic actin‐remodeling activity and extracellular antiapoptotic activity. Even though further verification is required, we also observed that Tβ15 was translocated into the injured neuronal nuclei, and this event appeared to be an eliminatory process of the injured cells. Therefore, treatment with Tβs or their related peptides appear to be beneficial for neuronal diseases by preventing neuronal death or promoting neuronal regeneration.
Adhesive and Proteolytic Phenotype of Migrating Endothelial Cells Induced by Thymosin β‐4
Authors: CIERNIEWSKI CZESLAW S. , MALINOWSKI MARIUSZ , BEDNAREK RADOSLAW , CIERNIEWSKA‐CIESLAK ALEKSANDRA
Published: October 2007

Abstract: The early stages of angiogenesis are usually accompanied by the occurrence of vascular leakage, and the deposition of fibrin in extravascular spaces. Initially, the fibrin network acts as a sealing matrix, but later on also as a scaffolding for invading endothelial cells. This process is induced by angiogenic growth factors, particularly by vascular endothelial growth factor (VEGF). Angiogenesis involves proteolytic activities, in particular cell‐bound urokinase/plasmin and matrix metalloproteinase (MMPs) activities that modulate the fibrin structure and affect adhesion and migration of endothelial cells. Recent data show that formation of new vessels may be stimulated by thymosin β‐4 (Tβ‐4), but it is still not clear whether Tβ‐4 alone is angiogenic or the angiogenic potential of Tβ‐4 is mediated by VEGF. In this report to further characterize Tβ‐4 angiogenic activity, we produced its mutants that were deprived of the N‐terminal tetrapeptide AcSDKP (Tβ‐4(AcSDKPT/4A)), the actin‐binding sequence KLKKTET (Tβ‐4(KLKKTET/7A)) and with the nuclear localization sequence damaged by a point mutation Lys16Ala (Tβ‐4(K16A)). Then we tested their activity to induce expression and release of MMPs as well as plasminogen activators inhibitor type‐1 (PAI‐1). We also analyzed their effect on migration and proliferation of endothelial cells in three‐dimensional (3D) fibrin matrix as well as on their ability to stimulate the outgrowth of human endothelial cells in capillary‐like tubular structures. Our data demonstrate that increased intracellular expression of Tβ‐4 and its mutants is necessary and sufficient to induce PAI‐1 gene expression in endothelial cells. Similarly, they stimulate expression and release of MMP‐1, ‐2, and ‐3. As evaluated by using specific inhibitors to these MMPs, they modified specifically the structure of fibrin and thus facilitated migration of endothelial cells. To sum up, our data show that the mechanism by which Tβ‐4 induced transition of endothelial cells from quiescent to proangiogenic phenotype is characterized by increased expression of PAI‐1 and MMPs did not require the presence of the N‐terminal sequence AcSDKP, and depended only partially on its ability to bind G‐actin or to enter the nucleus.
Function of Prothymosin α in Chromatin Decondensation and Expression of Thymosin β‐4 Linked to Angiogenesis and Synaptic Plasticity
Authors: GÓMEZ‐MÁRQUEZ JAIME
Published: October 2007

Abstract:  Prothymosin α (ProTα) is an abundant highly acidic protein found in the nuclei of virtually all mammalian cells. The expression of this protein is increased in proliferating mammalian cells. However, the function of this molecule is still controversial. Here I present a model explaining the role of this protein in chromatin decondensation through its interaction with histone H1. β‐thymosins are a family of small actin‐binding peptides widely distributed in eukaryotic cells. Here I will focus on thymosin β‐4, the most abundant member of this family. In particular, I will discuss its expression in the mammalian development of cardiovascular and nervous systems as well as its implications in neuronal plasticity.
Determination of Thymosin β4 and Protein in Human Wound Fluid after Abdominal Surgery
Authors: BODENDORF S. , BORN G. , HANNAPPEL E.
Published: October 2007

Abstract:  Wound fluids were collected up to 60 h after abdominal surgery. Immediately after obtaining the wound fluid by Robinson drainage, wound fluid was centrifuged to remove blood cells and inflammatory cells. The concentration of total protein as well as of thymosin β4 was determined in the cell‐free supernatant solution. Total protein concentration decreased from about 50 g/L to 30 g/L within 60 h after surgery. After surgery we observed a concentration of up to 20 mg thymosin β4 per liter decreasing to about 1 mg/L with time. Neither thymosin β10 nor oxidized thymosin β4 was detected in human wound fluid.
Signaling Pathways Leading to the Activation of IKK and MAPK by Thymosin α1
Authors: PENG XIAO , ZHANG PING , WANG XIN , CHAN JUSTIN , ZHU MINGWEI , JIANG MEISHENG , TUTHILL CYNTHIA , WAN YINSHENG , DRAGOI ANA MARIA , CHU WEN‐MING
Published: October 2007

Abstract:  Thymosin alpha 1 (Tα1) has therapeutic potential in the treatment of infectious diseases and cancer. However, the exact molecular pathways for Tα1 action are not fully understood. We found that Tα1 induces the production of interleukin‐6 (IL‐6), IL‐10, and IL‐12 in murine bone marrow‐derived macrophages (BMDMs) through IKK and MAPK pathways. Tα1 triggers the activation of AP‐1 and the phosphorylation of JNK and p38. Inhibition of p38 impairs IL‐6 production in response to Tα1. Further, TRAF6 is involved in the activation of JNK and IRAK4 is involved for the activation of IKK and PKCζ in a Tα1‐induced system. Loss of IRAK4 largely blocked induction of IL‐6. Thus, our studies define early signal events that are critical for the Tα1‐induced immune responses.
Identification and Characterization of Thymosin β‐4 in Chicken Macrophages Using Whole Cell MALDI‐TOF
Authors: KANNAN LAKSHMI , RATH NARAYAN C. , LIYANAGE ROHANA , LAY JACKSON O.
Published: October 2007

Abstract:  The aim of the study was to determine chicken monocyte‐ and granulocyte‐associated peptides and proteins using “whole cell” matrix‐assisted laser desorption/ionization‐time–of–flight mass spectrometry (MALDI‐TOF MS) and to characterize the peptides based on their abundance. The mass spectra showed a prominent peak at m/z 4963 in monocytes/macrophages but not in the granulocytes. Subsequent purification and characterization of the m/z 4963 peptide from an avian macrophage cell line HTC, revealed it to be thymosin β‐4 (Tβ‐4), an actin‐modulating peptide. HTC cells when treated with bacterial lipopolysaccharide and peptidoglycan to determine the modulation of Tβ‐4 gene expression or its secretion, showed no changes.
Thymosin β4 Is Not Always the Main β‐Thymosin in Mammalian Platelets
Authors: HUFF THOMAS , MÜLLER CHRISTIAN S. G. , HANNAPPEL EWALD
Published: October 2007

Abstract:  β‐thymosins constitute a family of highly conserved 5‐kDa polypeptides. Thymosin β4, the most abundant member of this family, is expressed in most mammalian cell types and is regarded as the main intracellular G‐actin sequestering peptide. In addition to this important intracellular function several other activities have been attributed to this peptide. Thymosin β4 is released from human platelets and cross‐linked to fibrin after activation of platelets with thrombin. While in most mammalian tissues thymosin β4 is accompanied by a second member of this peptide family, in human platelets only thymosin β4 is present. To elucidate if it is common to mammalian platelets that only one β‐thymosin is present, we analyzed platelets from several mammals for their β‐thymosin content. In human platelets only thymosin β4 could be detected, whereas in bovine platelets thymosin β9, which is normally the minor β‐thymosin in bovine tissues, was identified as the main β‐thymosin. In rabbit platelets, thymosin β4 is not simply replaced by the most homologous thymosin β4Ala, as might be expected from sequence homology. Thymosin β4Ala and thymosin β10 were found, but thymosin β10 is present in about 2.5‐fold higher amounts. Because thymosin β4Ala possesses about threefold higher affinity to G‐actin, compared to thymosin β4, β10, and β9, we suggest that expression of β‐thymosins is triggered by functional requirements and not sequence homology.
IFN‐α and Novel Strategies of Combination Therapy for Cancer
Authors: BRACCI LAURA , PROIETTI ENRICO , BELARDELLI FILIPPO
Published: October 2007

Abstract:  Interferons‐alpha (IFN‐α) are a group of cytokines belonging to type I IFN family, which exert multiple biological effects, including antiviral and antitumor activities in patients with defined types of cancer and viral diseases. Early studies in mouse tumor models have shown the importance of host immune mechanisms in the generation of a long‐lasting antitumor response after type I IFN treatment. Recent studies have revealed new immunomodulatory effects of IFN‐α, including activities on T cells and dendritic cells (DCs), which may explain the immune correlates frequently observed in some categories of cancer patients responding to IFN‐α therapy. Of note, new knowledge has recently been generated on the mechanisms of action of some chemotherapeutic agents, such as cyclophosphamide (CTX), on cells of the immune system, whose effects can now be exploited for the design of more effective combination therapies. On the whole, the new strategies based on IFN‐α include the in vivo use of these cytokines as immune adjuvants of cancer vaccines, their in vitro use to generate highly active DC‐based vaccines, and the combination of certain chemotherapy regimens with IFN‐α‐adjuvanted cancer vaccines.
Neuroprotective Effects of Thymosin β4 in Experimental Models of Excitotoxicity
Authors: POPOLI PATRIZIA , PEPPONI RITA , MARTIRE ALBERTO , ARMIDA MONICA , PÈZZOLA ANTONELLA , GALLUZZO MARIANGELA , DOMENICI M. ROSARIA , POTENZA ROSA LUISA , TEBANO M. TERESA , MOLLINARI CRISTIANA , MERLO DANIELA , GARACI ENRICO
Published: October 2007

Abstract:  The aim of this study was to evaluate the possible neuroprotective effects of thymosin β4 in different models of excitotoxicity. The application of thymosin β4 significantly attenuated glutamate‐induced toxicity both in primary cultures of cortical neurons and in rat hippocampal slices. In in vivo experiments, the intracerebroventricular administration of thymosin β4 significantly reduced hippocampal neuronal loss induced by kainic acid. These results show that thymosin β4 induced a protective effect in models of excitotoxicity. The mechanisms underlying such an effect, as well as the real neuroprotective potential of thymosin β4, are worthy of further investigations.
Immunopharmacology of Thymosin α1 and Cytokine Synergy
Authors: NAYLOR PAUL H. , QUADRINI KAREN , GARACI ENRICO , RASI GUIDO , HADDEN JOHN W.
Published: October 2007

Abstract:  Thymosin α1 (Tα1) is a 28 amino acid biologically active protein cleaved from positions 2–29 of a precursor protein, prothymosin α. Since its discovery, Tα1 has been administered to animals and humans in a wide variety of settings and its pharmacologic effects are to enhance cellular immunity. Tα1 administration is highly effective in settings where irradiation, chemotherapy, tumor burden, or immune senescence have caused a reduction of T cell number and/or function. Recent in vitro studies, including the one reported here, suggest that Tα1 may act via pathways commonly used by various cytokines. This raises the possibility that Tα1 and cytokines may have synergistic activity through potentiation of cytokine activity by Tα1. Improved control of tumor growth when tumor‐bearing mice were treated with Tα1 and high doses of IL‐2 has been previously reported. We extended those studies with the Lewis lung carcinoma mouse model using IRX‐2, a natural well‐defined biologic containing multiple cytokines, in combination with Tα1 (IRX‐3). Although IRX‐2 was effective alone (using doses that contain significantly less IL‐2 than in most typical studies), adding Tα1 led to significant improvement in survival of the tumor‐bearing mice. Based on these observations, the immunopharmacology of Tα1 predicts an important clinical role for Tα1 in the restoration of cellular immune activity when used in combination with cytokines. Patients who experience immune suppression due to the presence of tumor, irradiation, and/or chemotherapy or aging of the host would most benefit from this treatment combination.
Structure, Function, and Evolution of the β‐Thymosin/WH2 (WASP‐Homology2) Actin‐Binding Module
Authors: CARLIER MARIE‐FRANCE , HERTZOG MAUD , DIDRY DOMINIQUE , RENAULT LOUIS , CANTRELLE FRANÇOIS‐XAVIER , VAN HEIJENOORT CARINE , KNOSSOW MARCEL , GUITTET ERIC
Published: October 2007

Abstract:  β‐thymosins are acknowledged G‐actin sequesterers. However, in the recent years, the conserved β‐thymosins/WH2 actin‐binding module, has been identified in a large number of proteins that all interact with actin and play diverse functions in cell motility. The functional evolution of the WH2 domain has been approached by a combination of structural and biochemical methods, using thymosin β4 (Tβ4) and Ciboulot, a 3 β‐thymosin repeat protein from Drosophila as models. Ciboulot binds actin like Tβ4 but promotes actin assembly like profilin. The first repeat of Ciboulot (D1) has the profilin function of the whole protein. The crystal structure of Ciboulot‐actin shows that the major interaction with G‐actin lies in the N‐terminal amphipathic helix of D1. By point mutagenesis the sequestering activity of Tβ4 can be changed into a profilin activity. (1H, 15N)‐NMR studies show that the functional switch from inhibition to promotion of actin assembly is linked to a change in the dynamics of interaction of the central and C‐terminal regions of the WH2 domain with subdomains 1 and 2 of G‐actin. Further systematic mutagenesis studies have been performed by engineering a series of chimeras of Ciboulot and Tβ4. Proteins displaying either profilin function or enhanced sequestering activity compared to Tβ4 have been characterized. The results provide insight into the structural basis for the regulation of the multiple functions of the WH2 domain.
Influence of Prothymosin‐α on HIV‐1 Target Cells
Authors: MOSOIAN AREVIK , TEIXEIRA AVELINO , BURNS COLIN S. , KHITROV GREGORY , ZHANG WEIJIA , GUSELLA LUCA , KLOTMAN PAUL , KLOTMAN MARY
Published: October 2007

Abstract:  The important role of CD8+ T cells in controlling HIV‐1 infection through the innate as well as the adaptive immune system is well established. In addition to the major histocompatibility complex (MHC)‐dependent cytotoxic activity of CD8+ T cells, they produce soluble factors that suppress HIV‐1 replication in an MHC‐independent manner. Several of those factors have been identified, including β‐chemokines, Rantes, MIP‐1α, MIP‐1β, and MDC. We previously identified that prothymosin alpha (ProTα) in the conditioned medium of HVS transformed CD8+ T cells was a potent inhibitor of HIV‐1 replication following proviral integration. In this report we further characterize the anti‐HIV‐1 activity of ProTα by demonstrating its target‐cell specificity, distinction from additional inhibitors of HIV‐1 transcription in CD8+ T cell supernatants, as well as the differential regulation of host cell antiviral genes that could impact HIV‐1 replication. These genes include a number of transcription factors as well IFN‐α‐inducible genes including PKR, IRF1, and Rantes, in the absence of induction of IFN‐α. These data suggest that the anti‐HIV‐1 activity of ProTα is mediated through the modulation of a number of genes that have been reported to suppress HIV‐1 replication including the dysregulation of transcription factors and the induction of PKR and Rantes mRNA.
Thymosin Alpha 1
Authors: GARACI ENRICO , FAVALLI CARTESIO , PICA FRANCESCA , SINIBALDI VALLEBONA PAOLA , TERESA PALAMARA ANNA , MATTEUCCI CLAUDIA , PIERIMARCHI PASQUALE , SERAFINO ANNALUCIA , MASTINO ANTONIO , BISTONI FRANCESCO , ROMANI LUIGINA , RASI GUIDO
Published: October 2007

Abstract:  After the initial dramatic effects, observed in a Lewis lung carcinoma animal model, using a combination of thymosin alpha 1 (Tα1) and interferon (IFN) after cyclophosphamide, a number of other preclinical models in mice (Friend erythroleukemia and B16 melanoma) and in rats (DHD/K12 colorectal cancer liver metastasis) have confirmed the efficacy of the combination therapy with Tα1 and either IFN or IL‐2 plus chemotherapy. These results provided the scientific foundation for the first clinical trials using Tα1 in combination with BRMs and/or chemotherapy. Pivotal trials in advanced non‐small cell lung cancer (NSCLC) and melanoma with Tα1 and IFN‐α low doses after cis‐platinum or dacarbazine produced the first evidence of the high potentiality of this approach in the treatment of human cancer.
The combination of Tα1 and IFN‐α was also used in patients affected by chronic B and C hepatitis including IFN‐nonresponders and infected by precore mutants or genotype 1b. Further studies demonstrated additional biological activities clarifying the mechanism of action of Tα1, partially explaining the synergism with IFN. It has been shown the capacity of activating infected dendritic cells through Toll‐like receptor signaling, thus influencing the inflammation balance, and of increasing the expression of tumor, viral, and major histocompatibility complex (MHC) I antigens. Dose–response studies suggested the possibility of improving the efficacy of this molecule reducing the overall toxic. Based on these information two clinical trials are ongoing: a large phase II on advanced melanoma patients treated with Tα1 at different doses after dacarbazine and a phase III one, on IFN‐resistant hepatitis C virus (HCV) patients treated with a triple combination (IFN, ribavirin, and Tα1).
Identification and Quantification of Thymosin β4 in Human Saliva and Tears
Authors: BADAMCHIAN MAHNAZ , DAMAVANDY ALI A. , DAMAVANDY HADI , WADHWA SONAL D. , KATZ BARRETT , GOLDSTEIN ALLAN L.
Published: October 2007

Abstract:  Thymosin β4 (Tβ4) is a ubiquitous, naturally occurring, 43‐amino acid peptide that takes part in several biological activities including angiogenesis, inhibition of inflammation, wound healing, chemotaxis, and endothelial cell migration. Recent studies also indicate that Tβ4 accelerates corneal wound healing and downregulates several proinflamatory chemokines and cytokines. In this study, we sought to determine whether Tβ4 is naturally occurring in human tears and other human bodily fluids, such as saliva. Tear and saliva samples were analyzed by EIA to identify and quantify the amount of Tβ4 present. Around 10–20 samples were collected from each of three different age groups: 15–20, 25–35, and >50 years old with n= 30 and n= 60 for tears and saliva, respectively. Exclusion criteria included the use of any topical ophthalmic or topical oral medication and/or history of ocular or oral surgery within the past 6 months. Tears were collected from both eyes using Schirmer's strips. Saliva samples were collected in sterile tubes and were then centrifuged to remove solid particles. Tβ4 was found in tear and saliva samples in all age groups. The concentrations ranged from 0.5–7 μg/mL in tears and 0.2–3.6 μg/mL in saliva. In both fluids, Tβ4 concentration varied with age and appeared to peak at ages 25–35 years. Studies are in progress to determine if Tβ4 levels in saliva and tears demonstrate a circadian rhythm during a 24‐h period, as well as to confirm that they vary with age and to explore if they vary with diseased states. This is the first study to report the presence of Tβ4 in human tears and saliva. This finding raises the possibility that Tβ4 acts as an endogenous agent contributing to the rapid healing of corneal and oral wounds. Considering that Tβ4 facilitates reepithelialization and modulates anti‐inflammatory mediators, Tβ4 could potentially be used therapeutically in the treatment of (a) ocular surface disease and injury of eye and (b) various oral disorders, such as periodontal disease.
Pressure Ulcers
Authors: FRANCIS GODSCHALK MICHAEL
Published: October 2007

Abstract:  Pressure ulcers occur in up to 14% of acute hospitalizations. They cause pain, decreased quality of life, increased morbidity, and prolonged hospitalizations. Treatment includes pain control, nutritional support, relieving pressure, removing devitalized tissue, and by using dressings and medications, providing an environment in which healing can occur. Even with optimal treatment, pressure ulcers may take months to heal. Thymosin β4 is being investigated as a treatment for pressure ulcers. Thymosin β4 has wound healing and anti‐inflammatory properties. It is thought to exert its therapeutic effect through promotion of keratinocyte and endothelial cell migration, increased collagen deposition, and stimulation of angiogenesis. A study in a rat full‐thickness wound model showed that treatment with thymosin β4 increased collagen deposition and angiogenesis and stimulated keratinocyte migration and reepithelialization. If thymosin β4 decreases healing time, this would represent a significant advance in the treatment of pressure ulcers.
Development of Thymosin β4 for Treatment of Patients with Ischemic Heart Disease
Authors: CROCKFORD DAVID
Published: October 2007

Abstract:  Thymosin beta 4 (Tβ4) is a highly conserved, 43‐amino acid acidic peptide (pI 4.6) that was first isolated from bovine thymus tissue over 25 years ago. It is present in most tissues and cell lines and is found in high concentrations in blood platelets, neutrophils, macrophages, and other lymphoid tissues. Tβ4 has numerous physiological functions, the most prominent of which being the regulation of actin polymerization in mammalian nucleated cells and with subsequent effects on actin cytoskeletal organization, necessary for cell motility, organogenesis, and other important cellular events. Recently, Tβ4 was shown to be expressed in the developing heart and found to stimulate migration of cardiomyocytes and endothelial cells, promote survival of cardiomyocytes (Nature, 2004), and most recently to play an essential role in all key stages of cardiac vessel development: vasculogenesis, angiogenesis, and arteriogenesis (Nature 2006). These results suggest that Tβ4 may have significant therapeutic potential in humans to protect myocardium and promote cardiomyocyte survival in the acute stages of ischemic heart disease. RegeneRx Biopharmaceuticals, Inc. is developing Tβ4 for the treatment of patients with acute myocardial infarction (AMI). Such efforts presented will include the formulation, development, and manufacture of a suitable drug product for use in the clinic, the performance of nonclinical pharmacology and toxicology studies, and the implementation of a phase 1 clinical protocol to assess the safety, tolerability, and the pharmacokinetics of Tβ4 in healthy volunteers. A phase 2 proof of principle clinical trial in AMI patients is in the planning stage and will not be presented at this time.
Phase II Study of Low-Dose Paclitaxel and Cisplatin in Combination With Split-Course Concomitant Twice-Daily Reirradiation in Recurrent Squamous Cell Carcinoma of the Head and Neck: Results of Radiation Therapy Oncology Group Protocol 9911
Authors: Langer Corey J. , Harris Jonathan , Horwitz Eric M. , Nicolaou Nicos , Kies Merrill , Curran Walter , Wong Stuart , Ang Kian
Published: October 2007

Purpose

Recurrent squamous cell carcinoma of the head and neck (SCCHN) or new second primary tumor (SPT) in a previous radiation field, if not curable by surgery or radiation, is almost always fatal. Chemotherapy alone yields a median survival time (MST) of no more than 10 months and 1-year overall survival (OS) of 35% at best. Concurrent reirradiation and chemotherapy is an alternative strategy.

Patients and Methods

Eligibility for Radiation Therapy Oncology Group (RTOG) protocol 9911 stipulated recurrent SCCHN or SPT in a previous radiation field. Patients received twice-daily radiation (1.5 Gy per fraction bid × 5 days every 2 weeks ×4), plus cisplatin 15 mg/m2 intravenously (IV) daily × 5 and paclitaxel 20 mg/m2 IV daily × 5 every 2 weeks ×4. Granulocyte colony-stimulated factor was administered days 6 through 13 of each 2-week cycle.

Results

One hundred five patients were enrolled from March 2000 through June 2003; 23% had SPT. Oropharynx (40%) and oral cavity (27%) were the predominant primary sites. Median prior radiation dose was 65.4 Gy. Seventy-four percent of patients completed chemotherapy. Grade 4 or worse acute toxicity occurred in 28%, grade 4 or worse acute hematologic toxicity in 21%. Eight treatment-related deaths (8%) occurred: five in the acute setting, three late (including two carotid hemorrhages). MST was 12.1 months, with estimated 1- and 2-year OS rates of 50.2% and 25.9%.

Conclusion

Despite a high incidence of grade 5 toxicity, 1- and 2-year OS rates for split-course bid radiation therapy and concurrent cisplatin/paclitaxel exceed results generally seen with chemotherapy alone.
Prediagnosis Smoking, Obesity, Insulin Resistance, and Second Primary Cancer Risk in Male Cancer Survivors: National Health Insurance Corporation Study
Authors: Min Park Sang , Kyung Lim Min , Won Jung Kyu , Ae Shin Soon , Yoo Keun-Young , Ho Yun Young , Yul Huh Bong
Published: October 2007

Purpose

Smoking, obesity, and insulin resistance are well-known risk factors for cancer, yet few epidemiology studies evaluate their role as risk factors for a second primary cancer (SPC).

Patients and Methods

We identified 14,181 men with a first cancer from the National Health Insurance Corporation Study cohort. We obtained data on fasting glucose level, body mass index (BMI), and smoking history from an enrollment interview (1996). We obtained SPC incidence data for 1996 through 2002 from the Korean Central Cancer Registry. We used the standard Poisson regression model to estimate the age- and multivariate-adjusted relative risk (RR) for SPCs in relation to smoking history, BMI, and insulin resistance before diagnosis.

Results

We observed 204 patients with SPC. The overall age-standardized incidence rate of SPC was 603.2 occurrences per 100,000 person-years, which was about 2.3 times higher than that of first cancer in the general male population. Multivariate regression revealed that lung (RR, 3.69; 95% CI, 1.35 to 10.09) and smoking-related (RR, 2.02; 95% CI, 1.02 to 4.03) SPCs were significantly associated with smoking. Obese patients (BMI ≥ 25 kg/m2) had significantly elevated RRs for colorectal (RR, 3.45; 95% CI, 1.50 to 7.93) and genitourinary (RR, 3.61; 95% CI, 1.36 to 9.54) SPCs. Patients with a fasting serum glucose concentration ≥ 126 mg/dL had a higher RR for hepatopancreatobiliary (RR, 3.33; 95% CI, 1.33 to 8.37) and smoking-related (1.93; 95% CI, 1.01 to 3.68) SPCs.

Conclusion

Prediagnosis smoking history, obesity, and insulin resistance were risk factors for several SPCs. These findings suggest that more thorough surveillance and screening for SPCs is needed for the cancer survivors with these risk factors.
Predicting Treatment Response of Malignant Gliomas to Bevacizumab and Irinotecan by Imaging Proliferation With [18F] Fluorothymidine Positron Emission Tomography: A Pilot Study
Authors: Chen Wei , Delaloye Sibylle , Silverman Daniel H.S. , Geist Cheri , Czernin Johannes , Sayre James , Satyamurthy Nagichettiar , Pope Whitney , Lai Albert , Phelps Michael E. , Cloughesy Timothy
Published: October 2007

Purpose

Evaluation of treatment effects in malignant brain tumors is challenging because of the lack of reliable response predictors of tumor response. This study examines the predictive value of positron emission tomography (PET) using [18F] fluorothymidine (FLT), an imaging biomarker of cell proliferation, in patients with recurrent malignant gliomas treated with bevacizumab in combination with irinotecan.

Patients and Methods

Patients with recurrent malignant gliomas treated with biweekly cycles of bevacizumab and irinotecan were prospectively studied with FLT-PET at baseline, after 1 to 2 weeks, and after 6 weeks from start of treatment. A more than 25% reduction in tumor FLT uptake as measured by standardized uptake value was defined as a metabolic response. FLT responses were compared with response as shown by magnetic resonance imaging (MRI) and patient survival.

Results

Twenty-one patients were included, and 19 were assessable for metabolic response evaluation with FLT-PET. There were nine responders (47%) and 10 nonresponders (53%). Metabolic responders survived three times as long as nonresponders (10.8 v 3.4 months; P = .003), and tended to have a prolonged progression-free survival (P = .061). Both early and later FLT-PET responses were more significant predictors of overall survival (1 to 2 weeks, P = .006; 6 weeks, P = .002), compared with the MRI responses (P = .060 for both 6-week and best responses).

Conclusion

FLT-PET as an imaging biomarker seems to be predictive of overall survival in bevacizumab and irinotecan treatment of recurrent gliomas. Whether FLT-PET performed as early as 1 to 2 week after starting treatment is as predictive as the study indicates at 6 weeks warrants further investigation.
Comparison of Menopausal Symptoms During the First Year of Adjuvant Therapy With Either Exemestane or Tamoxifen in Early Breast Cancer: Report of a Tamoxifen Exemestane Adjuvant Multicenter Trial Substudy
Authors: Jones Stephen E. , Cantrell James , Vukelja Svetislava , Pippen John , O'Shaughnessy Joyce , Blum Joanne L. , Brooks Robert , Hartung Nicole L. , Negron Angel G. , Richards Donald A. , Rivera Ragene , Holmes Frankie Ann , Chittoor Sreeni , Whittaker Thomas L. , Bordelon James H. , Ketchel Steven J. , Davis Jennifer C. , Ilegbodu Des , Kochis Jean , Asmar Lina
Published: October 2007

Purpose

Hormonal breast cancer treatment increases menopausal symptoms in women. This study investigated differences between the symptoms associated with either adjuvant tamoxifen or exemestane.

Patients and Methods

Ten common symptoms were assessed by self-report questionnaire administered to 1,614 consecutive patients at baseline and every 3 months during the first year of a double-blind, randomized trial of postmenopausal women with early hormone receptor–positive breast cancer. Symptoms were categorized as none, mild, moderate, or severe. A hot flash score was calculated at each time point. Symptoms were analyzed by repeated-measures analysis of variance. Each time period was tested repeatedly against the baseline; an overall P value was assigned for each reported symptom.

Results

Compliance was excellent, with 7,286 questionnaires analyzed. Baseline symptom prevalence ranged from 2% (vaginal bleeding) to 60% to 70% (bone/muscle aches and low energy). There were no significant differences in vaginal bleeding, mood alteration, or low energy. Patients receiving tamoxifen had significantly more vaginal discharge (P < .0001). Exemestane patients reported more bone/muscle aches (P < .0001), vaginal dryness (P = .0004), and difficulty sleeping (P = .03). In both groups, the hot flash score peaked at 3 months and decreased thereafter. At 12 months, patients receiving tamoxifen had a significantly higher mean hot flash score (P = .03), with daily hot flashes increasing from baseline by 33% compared with a 7% increase from baseline with exemestane.

Conclusion

At 12 months, exemestane was associated with fewer hot flashes and less vaginal discharge than tamoxifen, but with more vaginal dryness, bone/muscle aches, and difficulty sleeping. Symptoms were common in both groups.
Evaluation of Alternate Size Descriptors for Dose Calculation of Anticancer Drugs in the Obese
Authors: Sparreboom Alex , Wolff Antonio C. , Mathijssen Ron H.J. , Chatelut Etienne , Rowinsky Eric K. , Verweij Jaap , Baker Sharyn D.
Published: October 2007

Purpose

Despite the rising prevalence of obesity, there is paucity of information describing how doses of anticancer drugs should be adjusted in clinical practice. Here, we assessed the pharmacokinetics of eight anticancer drugs in adults and evaluated the potential utility of alternative weight descriptors in dose calculation for the obese.

Patients and Methods

A total of 1,206 adult cancer patients were studied, of whom 162 (13.4%) were obese (body mass index ≥ 30). Pharmacokinetic parameters were calculated using noncompartmental analysis, and compared between lean (body mass index ≤ 25) and obese patients.

Results

The absolute clearance of cisplatin, paclitaxel, and troxacitabine was significantly increased in the obese (P < .023), but this was not observed for carboplatin, docetaxel, irinotecan, or topotecan (P < .17). For doxorubicin, the systemic clearance was statistically significantly reduced in obese women (P = .013), but not in obese men (P = .52). Evaluation of alternate weight descriptors for dose calculation in the obese, including predicted normal weight, lean body mass, (adjusted) ideal body weight, and the mean of ideal and actual body weight, indicated that, for most of the evaluated drugs, weight scalars used to calculate body-surface area should consider actual body weight regardless of size.

Conclusion

The results suggest that a number of widely used empiric strategies for dose adjustments in obese patients, including a priori dose reduction or dose capping, should be discouraged.
High Interleukin-15 Expression Characterizes Childhood Acute Lymphoblastic Leukemia With Involvement of the CNS
Authors: Cario Gunnar , Izraeli Shai , Teichert Anja , Rhein Peter , Skokowa Julia , Möricke Anja , Zimmermann Martin , Schrauder Andre , Karawajew Leonid , Ludwig Wolf-Dieter , Welte Karl , Schünemann Holger J. , Schlegelberger Brigitte , Schrappe Martin , Stanulla Martin
Published: October 2007

Purpose

Applying current diagnostic methods, overt CNS involvement is a rare event in childhood acute lymphoblastic leukemia (ALL). In contrast, CNS-directed therapy is essential for all patients with ALL because without it, the majority of patients eventually will experience relapse. To approach this discrepancy and to explore potential distinct biologic properties of leukemic cells that migrate into the CNS, we compared gene expression profiles of childhood ALL patients with initial CNS involvement with the profiles of CNS-negative patients.

Patients and Methods

We evaluated leukemic gene expression profiles from the bone marrow of 17 CNS-positive patients and 26 CNS-negative patients who were frequency matched for risk factors associated with CNS involvement. Results were confirmed by real-time quantitative polymerase chain reaction analysis and validated using independent patient samples.

Results

Interleukin-15 (IL-15) expression was consistently upregulated in leukemic cells of CNS-positive patients compared with CNS-negative patients. In multivariate analysis, IL-15 expression levels greater than the median were associated with CNS involvement compared with expression equal to or less than the median (odds ratio [OR] = 10.70; 95% CI, 2.95 to 38.81). Diagnostic likelihood ratios for CNS positivity were 0.09 (95% CI, 0.01 to 0.65) for the first and 6.93 (95% CI, 2.55 to 18.83) for the fourth IL-15 expression quartiles. In patients who were CNS negative at diagnosis, IL-15 levels greater than the median were associated with subsequent CNS relapse compared with expression equal to or less than the median (OR = 13.80; 95% CI, 3.38 to 56.31).

Conclusion

Quantification of leukemic IL-15 expression at diagnosis predicts CNS status and could be a new tool to further tailor CNS-directed therapy in childhood ALL.
Capecitabine Plus Erlotinib in Gemcitabine-Refractory Advanced Pancreatic Cancer
Authors: Kulke Matthew H. , Blaszkowsky Lawrence S. , Ryan David P. , Clark Jeffrey W. , Meyerhardt Jeffrey A. , Zhu Andrew X. , Enzinger Peter C. , Kwak Eunice L. , Muzikansky Alona , Lawrence Colleen , Fuchs Charles S.
Published: October 2007

Purpose

The addition of either capecitabine or erlotinib to gemcitabine in the first-line treatment of advanced pancreatic cancer is associated with modest improvements in overall survival. We evaluated an oral regimen of capecitabine and erlotinib in patients with advanced pancreatic cancer who had experienced treatment failure with standard first-line therapy with gemcitabine.

Patients and Methods

Thirty patients with gemcitabine-refractory metastatic pancreatic cancer were treated with capecitabine, administered at a dose of 1,000 mg/m2 twice daily for 2 weeks, followed by a 1-week break. All patients also received erlotinib 150 mg daily. Patients were observed for evidence of response, toxicity, and survival. EGFR mutational status was assessed in available tumor blocks.

Results

Treatment with capecitabine and erlotinib in gemcitabine-refractory patients was associated with an overall objective radiologic response rate of 10% and a median survival duration of 6.5 months. In addition, 17% of the treated patients experienced decreases in tumor marker (CA 19-9) levels of more than 50% from baseline. Common toxicities included diarrhea, skin rash, fatigue, and hand-foot syndrome. EGFR mutations were detected in two of five available tumors; no association between treatment response and EGFR mutational status was evident.

Conclusion

The combination of capecitabine and erlotinib is active in patients with gemcitabine-refractory pancreatic cancer. This regimen may represent an acceptable treatment option in patients who experience treatment failure with standard first-line therapy with gemcitabine or for whom gemcitabine may not be an appropriate first-line treatment option.
Long-Term Survival Associated With Complete Resection After Induction Chemotherapy in Stage IIIA (N2) and IIIB (T4N0-1) Non–Small-Cell Lung Cancer Patients: The Spanish Lung Cancer Group Trial 9901
Authors: Garrido Pilar , González-Larriba José Luis , Insa Amelia , Provencio Mariano , Torres Antonio , Isla Dolores , Sanchez José Miguel , Cardenal Felipe , Domine Manuel , Barcelo Jose Ramon , Tarrazona Vicente , Varela Andres , Aguilo Rafael , Astudillo Julio , Muguruza Ignacio , Artal Angel , Hernando-Trancho Florentino , Massuti Bartomeu , Sanchez-Ronco Maria , Rosell Rafael
Published: October 2007

Purpose

To assess the activity of induction chemotherapy followed by surgery in stage IIIA and selected stage IIIB non–small-cell lung cancer patients.

Patients and Methods

Mediastinoscopy proof of either positive N2 (IIIA) or T4N0-1 (IIIB) disease was required. Induction therapy was three cycles of cisplatin/gemcitabine/docetaxel, followed by surgery.

Results

From December 1999 to March 2003, 136 patients were entered onto the study; the clinical response rate in 129 assessable patients was 56%. The overall complete resection rate was 68.9% of patients eligible for surgery (72% of stage IIIA patients and 66% of stage IIIB patients) and 48% of all assessable patients. Eight (12.9%) of 62 completely resected patients had a pathologic complete response. Seven patients (7.8%) died during the postoperative period. The median overall survival time was 15.9 months, 3-year survival rate was 36.8%, and 5-year survival rate was 21.1%, with no significant differences in survival between stage IIIA and stage IIIB patients. Median survival time was 48.5 months for 62 completely resected patients, 12.9 months for 13 incompletely resected patients, and 16.8 months for 15 nonresected patients (P = .005). Three- and 5-year survival rates were 60.1% and 41.4% for completely resected patients, 23.1% and 11.5% for incompletely resected patients, and 31.1% and 0% for nonresected patients, respectively. In the multivariate analysis, complete resection (hazard ratio [HR] = 0.35; P < .0001), clinical response (HR = 0.32; P < .0001), and age younger than 60 years (HR = 0.64; P = .027) were the most powerful prognostic factors.

Conclusion

Induction chemotherapy followed by surgery is effective in stage IIIA and in selected stage IIIB patients attaining complete resection.
Bevacizumab Plus Irinotecan in Recurrent Glioblastoma Multiforme
Authors: Vredenburgh James J. , Desjardins Annick , Herndon James E. , Marcello Jennifer , Reardon David A. , Quinn Jennifer A. , Rich Jeremy N. , Sathornsumetee Sith , Gururangan Sridharan , Sampson John , Wagner Melissa , Bailey Leighann , Bigner Darell D. , Friedman Allan H. , Friedman Henry S.
Published: October 2007

Purpose

The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan.

Patients and Methods

This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging.

Results

The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli).

Conclusion

Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.
Combined Immunochemotherapy With Reduced Whole-Brain Radiotherapy for Newly Diagnosed Primary CNS Lymphoma
Authors: Shah Gaurav D. , Yahalom Joachim , Correa Denise D. , Lai Rose K. , Raizer Jeffrey J. , Schiff David , LaRocca Renato , Grant Barbara , DeAngelis Lisa M. , Abrey Lauren E.
Published: October 2007

Purpose

Our goals were to evaluate the safety of adding rituximab to methotrexate (MTX)-based chemotherapy for primary CNS lymphoma, determine whether additional cycles of induction chemotherapy improve the complete response (CR) rate, and examine effectiveness and toxicity of reduced-dose whole-brain radiotherapy (WBRT) after CR.

Patients and Methods

Thirty patients (17 women; median age, 57 years; median Karnofsky performance score, 70) were treated with five to seven cycles of induction chemotherapy (rituximab, MTX, procarbazine, and vincristine [R-MPV]) as follows: day 1, rituximab 500 mg/m2; day 2, MTX 3.5 gm/m2 and vincristine 1.4 mg/m2. Procarbazine 100 mg/m2/d was administered for 7 days with odd-numbered cycles. Patients achieving CR received dose-reduced WBRT (23.4 Gy), and all others received standard WBRT (45 Gy). Two cycles of high-dose cytarabine were administered after WBRT. CSF levels of rituximab were assessed in selected patients, and prospective neurocognitive evaluations were performed.

Results

With a median follow-up of 37 months, 2-year overall and progression-free survival was 67% and 57%, respectively. Forty-four percent of patients achieved a CR after five or fewer cycles, and 78% after seven cycles. The overall response rate was 93%. Nineteen of 21 CR patients received the planned 23.4 Gy WBRT. The most commonly observed grade 3 to 4 toxicities included neutropenia (43%), thrombocytopenia (36%), and leukopenia (23%). No treatment-related neurotoxicity has been observed.

Conclusion

The addition of rituximab to MPV increased the risk of significant neutropenia requiring routine growth factor support. Additional cycles of R-MPV nearly doubled the CR rate. Reduced-dose WBRT was not associated with neurocognitive decline, and disease control to date is excellent.
Phase II Study of Vinflunine in Malignant Pleural Mesothelioma
Authors: Talbot Denis C. , Margery Jacques , Dabouis Gérard , Dark Graham , Taylor Henry , Boussemart Hélène , Cadic Véronique , Pinel Marie-Claire , Rivière Alain , Ollivier Liliane , Ruffié Pierre
Published: October 2007

Purpose

Malignant pleural mesothelioma (MPM) is a disease of increasing incidence for which treatment options are limited. This study reports the clinical efficacy data for vinflunine, a novel microtubule inhibitor, in MPM.

Patients and Methods

Patients with a histologically confirmed diagnosis of MPM were eligible for enrollment onto this multicenter phase II trial if they had not received prior chemotherapy or radiotherapy and had measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Vinflunine 320 mg/m2by 10-minute intravenous infusion was administered on day 1 of 21-day cycles. Modifications of dose and schedule were made according to National Cancer Institute Common Toxicity Criteria version 2.0. Efficacy was assessed by an external, independent radiologist. The one-sample multiple testing procedure of Fleming was applied at the predetermined recruitment stages of 20 and 40 assessable patients.

Results

Sixty-seven patients were enrolled. Five patients were not assessable for tumor response. The response rate was 13.8% (95% CI, 6.5% to 24.7%). The median survival was 10.8 months (95% CI, 7.8 to 12.0 months). The most common adverse events were anemia, neutropenia, fatigue, constipation, and nausea. Of grade 3 and 4 toxicities, neutropenia and constipation were the most common (45% and 9% of patients, respectively).

Conclusion

Vinflunine can be delivered with high-dose intensity in patients with MPM. The response rate and median survival are encouraging for a single agent. These data suggest that vinflunine should be further evaluated in the management of MPM.