Embase

20160199642

Moroncini G.; Albani L.; Nobili L.; Gabrielli A.;

(Moroncini, Albani, Nobili, Gabrielli) Dipartimento di Scienze Cliniche e Molecolari, Universita Politecnica delle Marche and Clinica Medica, Ospedali Riuniti Ancona, Ancona 60126, Italy

Netherlands

Biologic therapy in inflammatory immunomediated systemic diseases: Safety profile.

Current Drug Safety. 11 (1) (pp 44-46), 2016. Date of Publication: 01 Mar 2016.

Bentham Science Publishers B.V. (P.O. Box 294, Bussum 1400 AG, Netherlands)

Curr. Drug Saf.

The discovery of some key molecular mechanisms underlying the dysregulation of the immune system responsible for inflammatory systemic diseases as severe as Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), and Systemic Vasculitides, led to the development and subsequent introduction into clinical practice of biological drugs which are significantly improving the management of such complex disorders. This novel molecular targeted therapeutics represents in fact a valid alternative or complementary treatment to conventional immunosuppressive strategies, characterized by broad, unspecific actions and severe adverse effects. Main advantages of the use of biologic drugs reside in their steroid-sparing effect and in the ability of inducing remission of refractory disease states or curing specific organ involvements. Aim of this article is to review and briefly discuss the scientific evidence supporting the use of biologics in these diseases, with a particular emphasis on their efficacy and safety profile compared to the canonical drugs.

1574-8863

Journal: Review

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

20160211641

Punzo D.; Errico F.; Cristino L.; Sacchi S.; Keller S.; Belardo C.; Luongo L.; Nuzzo T.; Imperatore R.; Florio E.; De Novellis V.; Affinito O.; Migliarini S.; Maddaloni G.; Sisalli M.J.; Pasqualetti M.; Pollegioni L.; Maione S.; Chiariotti L.; Usiello A.;

(Punzo, Keller, Florio, Affinito, Sisalli, Chiariotti) Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (CNR), Naples 80131, Italy
(Punzo, Nuzzo, Usiello) Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Caserta 81100, Italy
(Errico, Nuzzo, Usiello) Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, Naples 80145, Italy
(Errico, Keller, Florio, Affinito, Chiariotti) Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy
(Cristino, Imperatore) Institute of Biomolecular Chemistry, CNR, Pozzuoli 80078, Italy
(Sacchi, Pollegioni) Department of Biotechnology and Life Sciences, University of Insubria, Varese 21100, Italy
(Sacchi, Pollegioni) Protein Factory Research Center, Politecnico di Milano and University of Insubria, Milan 20133, Italy
(Belardo, Luongo, De Novellis, Maione) Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples 80138, Italy
(Migliarini, Maddaloni, Pasqualetti) Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa 56126, Italy
(Pasqualetti) Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, Rovereto 38068, Italy

United States

Age-related changes in D-aspartate oxidase promoter methylation control extracellular D-aspartate levels and prevent precocious cell death during brain aging.

Journal of Neuroscience. 36 (10) (pp 3064-3078), 2016. Date of Publication: 09 Mar 2016.

Society for Neuroscience

J. Neurosci.

The endogenous NMD Areceptor (NMDAR) agonist D-aspartate occurs transiently in the mammalian brain because it is abundant during embryonic and perinatal phases before drastically decreasing during adulthood. It is well established that postnatal reduction of cerebral D-aspartate levels is due to the concomitant onset of D-aspartate oxidase (DDO) activity, a flavoenzyme that selectively degrades bicarboxylic D-amino acids. In the present work, we show that D-aspartate content in the mouse brain drastically decreases after birth, whereas DdomRNAlevels concomitantly increase. Interestingly, postnatal Ddo gene expression is paralleled by progressive demethylation within its putative promoter region. Consistent with an epigenetic control on Ddo expression, treatment with the DNA-demethylating agent, azacitidine, causes increased mRNA levels in embryonic cortical neurons. To indirectly evaluate the effect of a putative persistent Ddo gene hypermethylation in the brain, we used Ddo knock-out mice (Ddo^-/-), which show constitutively suppressed Ddo expression. In these mice, we found for the first time substantially increased extracellular content of D-aspartate in the brain. In line with detrimental effects produced by NMDAR overstimulation, persistent elevation of D-aspartate levels in Ddo^-/- brains is associated with appearance of dystrophic microglia, precocious caspase-3 activation, and cell death in cortical pyramidal neurons and dopaminergic neurons of the substantia nigra pars compacta. This evidence, along with the early accumulation of lipufuscin granules in Ddo^-/- brains, highlights an unexpected importance of Ddo demethylation in preventing neurodegenerative processes produced by nonphysiological extracellular levels of free D-aspartate.

0270-6474

Journal: Article

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

20160211096

Ju F.-H.; Gong X.-B.; Jiang L.-B.; Hong H.-H.; Yang J.-C.; Xu T.-Z.; Chen Y.; Wang Z.;

(Ju, Jiang, Hong, Yang, Xu, Chen, Wang) Department of Respiratory Medicine, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310006, China
(Gong) Department of Clinical Laboratory, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China

Greece

Chronic myeloid leukaemia following repeated exposure to chest radiography and computed tomography in a patient with pneumothorax: A case report and literature review.

Oncology Letters. 11 (4) (pp 2398-2402), 2016. Date of Publication: April 2016.

Spandidos Publications (10 Vriaxidos Street, Athens 116 10, Greece)

Oncol. Lett.

It is well known that radioactive rays may cause damage to the human body. Progress in modern medicine has led to an increased risk of therapeutic and diagnostic radiation exposure of patients. Although clear evidence of a radiation dose-dependent risk of chronic myeloid leukaemia, particularly for patients exposed to radiation at a young age, has been established, it is not known whether radiation exposure during diagnostic imaging also increases the risk of cancer. The present study reports the case of a patient who underwent several diagnostic imaging tests (including repeated chest radiography and computed tomography) for recurrent pneumothorax. At around one year subsequent to these tests, the patient was diagnosed with chronic myeloid leukaemia. The patient exhibited an increase in white blood cell count over time, and a bone marrow smear test showed a myeloid/erythroid ratio of 13.9:1. In addition, the qualitative breakpoint cluster region (BCR)/Abelson (ABL) gene test revealed positive results for BCR/ABL fusion (p210). Based on the data reported in the current case, research aimed at elucidating the potential risks associated with diagnostic radiation is urgently required. It is crucial that medical professionals consider the potential harmful side effects of diagnostic radiation when ordering radiation-based diagnostic imaging examinations.

1792-1074

Journal: Review

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

20160119079

Imai Y.; Dobrian A.D.; Morris M.A.; Taylor-Fishwick D.A.; Nadler J.L.;

(Imai, Morris, Nadler) Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA 23507, United States
(Dobrian) Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, United States
(Morris, Taylor-Fishwick) Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States

Germany

Lipids and immunoinflammatory pathways of beta cell destruction.

Diabetologia. 59 (4) (pp 673-678), 2016. Date of Publication: 01 Apr 2016.

Springer Verlag

Diabetologia

Islet inflammation contributes to beta cell demise in both type 1 and type 2 diabetes. 12-Lipoxygenase (12-LO, gene expressed as ALOX12 in humans and 12-Lo in rodents in this manuscript) produces proinflammatory metabolites such as 12(S)-hydroxyeicosatetraenoic acids through dioxygenation of polyunsaturated fatty acids. 12-LO was first implicated in diabetes when the increase in 12-Lo expression and 12(S)-hydroxyeicosatetraenoic acid was noted in rodent models of diabetes. Subsequently, germline 12-Lo^-/- was shown to prevent the development of hyperglycemia in mouse models of type 1 diabetes and in high-fat fed mice. More recently, beta cell-specific 12-Lo^-/- was shown to protect mice against hyperglycaemia after streptozotocin and a high-fat diet. In humans, 12-LO expression is increased in pancreatic islets of autoantibody-positive, type 1 diabetic and type 2 diabetic organ donors. Interestingly, the high expression of ALOX12 is associated with the alteration in first-phase glucose-stimulated insulin secretion in human type 2 diabetic islets. To further clarify the role of islet 12-LO in diabetes and to validate 12-LO as a therapeutic target of diabetes, we have studied selective pharmacological inhibitors for 12-LO. The compounds we have identified show promise: they protect beta cell lines and human islets from apoptosis and preserve insulin secretion when challenged by proinflammatory cytokine mixture. Currently studies are underway to test the compounds in mouse models of diabetes. This review summarises a presentation given at the 'Islet inflammation in type 2 diabetes' symposium at the 2015 annual meeting of the EASD. It is accompanied two other mini-reviews on topics from this symposium (by Simone Baltrusch, DOI: 10.1007/s00125-016-3891-x and Marc Donath, DOI: 10.1007/s00125-016-3873-z) and a commentary by the Session Chair, Piero Marchetti (DOI: 10.1007/s00125-016-3875-x).

0012-186X

Journal: Review

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

20160194226

Helenius I.J.; Keskinen H.; Syvanen J.; Lukkarinen H.; Mattila M.; Valipakka J.; Pajulo O.;

(Helenius, Keskinen, Syvanen, Lukkarinen, Mattila, Valipakka, Pajulo) Turku University Hospital, Turku, Finland
(Helenius, Keskinen, Syvanen, Lukkarinen, Pajulo) Department of Paediatric Orthopaedic Surgery, University of Turku, Turku University Hospital, Kiinamyllynkatu 4-8, Turku FI-20900, Finland
(Mattila) Helsinki University Central Hospital, Stenbackinkatu 11, Helsinki FI-00029, Finland
(Valipakka) Department of Paediatric Surgery, Tampere University Hospital, Teiskontie 35, Tampere FI-33521, Finland

United Kingdom

Gelatine matrix with human thrombin decreases blood loss in adolescents undergoing posterior spinal fusion for idiopathic scoliosis.

Bone and Joint Journal. 98B (3) (pp 395-401), 2016. Date of Publication: March 2016.

British Editorial Society of Bone and Joint Surgery

Bone Jt. J.

Aims: In a multicentre, randomised study of adolescents undergoing posterior spinal fusion for idiopathic scoliosis, we investigated the effect of adding gelatine matrix with human thrombin to the standard surgical methods of controlling blood loss. Patients and Methods: Patients in the intervention group (n = 30) were randomised to receive a minimum of two and a maximum of four units of gelatine matrix with thrombin in addition to conventional surgical methods of achieving haemostasis. Only conventional surgical methods were used in the control group (n = 30). We measured the intra-operative and total blood loss (intra-operative blood loss plus post-operative drain output). Results: Each additional hour of operating time increased the intra-operative blood loss by 356.9 ml (p < 0.001) and the total blood loss by 430.5 ml (p < 0.001). Multiple linear regression analysis showed that the intervention significantly decreased the intra-operative (-171 ml, p = 0.025) and total blood loss (-177 ml, p = 0.027). The decrease in haemoglobin concentration from the day before the operation to the second post-operative day was significantly smaller in the intervention group (-6 g/l, p = 0.013) than in the control group. Conclusion: The addition of gelatine matrix with human thrombin to conventional methods of achieving haemostasis reduces both the intra-operative blood loss and the decrease in haemoglobin concentration post-operatively in adolescents undergoing posterior spinal fusion for idiopathic scoliosis. Take home message: A randomised clinical trial showed that gelatine matrix with human thrombin decreases intra-operative blood loss by 30% when added to traditional surgical haemostatic methods in adolescents undergoing posterior spinal fusion for idiopathic scoliosis.

2049-4394

Journal: Article

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

20160193249

Costerus J.M.; Brouwer M.C.; Van Der Ende A.; Van De Beek D.;

(Costerus, Brouwer, Van De Beek) Departments of Neurology, Academic Medical Center, Center of Infection and Immunity Amsterdam, Amsterdam, Netherlands
(Van Der Ende) Departments of Medical Microbiology, Academic Medical Center, Center of Infection and Immunity Amsterdam, Amsterdam, Netherlands
(Van Der Ende) Netherlands Reference Laboratory for Bacterial Meningitis, Academic Medical Center, Center of Infection and Immunity Amsterdam, Amsterdam, Netherlands

United States

Community-acquired bacterial meningitis in adults with cancer or a history of cancer.

Neurology. 86 (9) (pp 860-866), 2016. Date of Publication: 01 Mar 2016.

Lippincott Williams and Wilkins

Neurology

Objectives: To study the incidence, clinical presentation, causative bacteria, and outcome of community-acquired bacterial meningitis in adults with cancer. Methods: We evaluated incidence and characteristics of patients with cancer included in a nationwide prospective cohort study of adults with community-acquired meningitis performed in the Netherlands from March 1, 2006, to September 31, 2014. All patients underwent a neurologic examination at hospital discharge, and outcome was graded using the Glasgow Outcome Scale. Results: Active cancer was identified in 68 of 1,351 episodes (5%) and a history of cancer in 87 (6%). The annual incidence of community-acquired bacterial meningitis was 2.71-fold (95% confidence interval [CI] 1.68-4.36, p < 0.001) increased for patients with cancer compared to patients without cancer in 2010, and 3.52-fold (95% CI 2.16-5.73, p < 0.001) in 2013. The clinical presentation of bacterial meningitis in patients with cancer compared to patients without cancer was similar. Patients with active cancer presented with lower leukocyte count in blood (12.1 x 10 9 cells/L vs 17.3 x 10 9 cells/L, p < 0.001) and CSF (670 cells/mm 3 vs 2,567 cells/mm 3, p < 0.001) and were more likely to be infected with Listeria monocytogenes (21% vs 5%, p < 0.001) than patients without cancer. Active cancer was identified as an independent risk factor for unfavorable outcome in bacterial meningitis (odds ratio 1.85, 95% CI 1.09-3.13). Conclusions: One of 8 patients with community-bacterial meningitis was identified to have a history of cancer and cancer was considered active in half of these patients. Patients with active cancer present with lower CSF leukocyte counts, are more likely to be infected with L monocytogenes, and are at high risk of unfavorable outcome.

0028-3878

Journal: Article

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

72222054

Singh M.; Dhakal B.; Shrestha A.; Atallah E.; Carlson K.; Pasquini M.C.; Rein L.; Banerjee A.; Esselmann J.; Ramirez S.; Zellner K.; Essenmacher A.; Hari P.N.; Michaelis L.C.;

(Singh) General Internal Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
(Dhakal) Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, United States
(Shrestha) Hematology and Oncology, University of Kansas Medical Center, Kansas, KS, United States
(Atallah, Carlson) Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, United States
(Pasquini) CIBMTR, Milwaukee, WI, United States
(Rein, Banerjee, Esselmann, Ramirez, Zellner, Essenmacher) Medical College of Wisconsin, Milwaukee, WI, United States
(Hari) Department of Medicine, CIBMTR (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI, United States
(Michaelis) Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, United States

Salvage therapy with hypomethylating agents (HMA) and/or lenalidomide (len) for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) relapse following allogeneic stem cell transplantation (allo-SCT).

Biology of Blood and Marrow Transplantation. Conference: 2016 BMT Tandem Meetings Honolulu, HI United States. Conference Start: 20160218 Conference End: 20160222. Conference Publication: (var.pagings). 22 (3 SUPPL. 1) (pp S357), 2016. Date of Publication: March 2016.

Elsevier Inc.

Biol. Blood Marrow Transplant.

Introduction: Relapse after allo-SCT is a major cause of treatment failure in patients with AML or MDS and is associated with dismal prognosis. In this patient population HMA and len are attractive treatment options for their immunomodulatory effects, direct cytotoxicity and acceptable toxicity profile. Here we present the outcomes of HMA/len combination in patients relapsing after allo-SCT for MDS/AML at our center. Methods: We conducted a retrospective chart review of 11 pts. who relapsed after allo-SCT and were treated with HMA (5-azacitidine or decitabine) and/or len as a first salvage therapy. Patients with hematological relapse were defined as bone marrow blasts >5%, or circulating blasts in peripheral blood, or extra medullary disease. The primary objective was to assess the complete response (CR) after treatment and overall survival (OS). Results: Nine (81.8%) of 11 pts. relapsed with AML, remaining two pts. had MDS. Median age was 57.8 years (range 35.2- 70.7). Five (45.5%) of 11 pts. received HMA prior to allo-SCT. Nine (81.8%) pts. received matched related and two (18.2%) received matched unrelated grafts. Five pts. had known residual disease at the time of transplant. Of 11 pts., reduced intensity conditioning regimens were used in six patients, and myeloablative conditioning in remaining patients. Median time to relapse was 175 days (range 84-619). Ten pts. received combined therapy with HMA and len, one received len only. Patients received an average of four cycles of HMA and three cycles of len. The median follow up of survivors was of 3.1 years (range 0.9 - 4.8). Four (36.4%) pts achieved CR, OS at 1 year and 2 years was 70% and 58% respectively Conclusions: Our data suggests that HMA/len combination as a salvage treatment in relapsed pts. with AML/MDS post allo-SCT has promising outcomes. A prospective study to validate these findings is planned.

1083-8791

Journal: Conference Abstract

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

72222671

Aman J.; Van Bezu J.; Valent E.; Eringa E.C.; Van Hinsbergh V.W.; Van Nieuw Amerongen G.P.;

(Aman, Van Bezu, Valent, Eringa, Van Hinsbergh, Van Nieuw Amerongen) VU University Medical Center, Amsterdam, Netherlands

ABl2 mediates endothelial barrier disruption by modulating integrin ?5?1 distribution.

Journal of Vascular Research. Conference: Joint Meeting of the European Society for Microcirculation, ESM, European Vascular Biology Organisation, EVBO 2015 Pisa Italy. Conference Start: 20150603 Conference End: 20150606. Conference Publication: (var.pagings). 52 (pp 84), 2015. Date of Publication: June 2015.

S. Karger AG

J. Vasc. Res.

Aim: Abl2 belongs to the Abl kinase family of non-receptor kinases, involved in cell-matrix interaction. Imatinib protects the endothelial barrier via inhibition of Abl2, but little is known about the role of Abl2 in endothelial barrier regulation. Abl2 may mediate endothelial barrier disruption by disturbing cell-matrix interaction. Methods: Abl2 was depleted in human endothelial cells (ECs) using siRNA. Endothelial barrier function was evaluated with Electrical Cell Substrate Impedance Sensing. Cell-matrix interaction was evaluated by traction force measurements and integrin studies. In vivo, vascular leak was evaluated with Miles'assay and intratracheal instillation of LPS in Abl2-/- mice. Results: EC inflammatory stimulation led to Abl2 activation. In Abl2-depleted ECs thrombin-induced endothelial barrier disruption was attenuated by 43%. Abl2-/- mice showed reduced vascular leak in the skin and the lungs. Mechanistically, Abl2 depletion led to enhanced expression of alpha5beta1 integrin, enhanced presence of alpha5beta1 at the cell membrane, and redistribution of alpha5beta1 to cell-cell contacts. These integrin changes were associated with less traction forces and better cell-matrix adhesion. Conclusions: Abl2 is activated during inflammation, and mediates endothelial barrier disruption in vitro and in vivo by regulating integrin alpha5beta1 dynamics. Selective Abl2 inhibition may help treating vascular leak. JA is funded by Dutch Heart Foundation.

1018-1172

Journal: Conference Abstract

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

72217132

Bruhn O.; Drerup K.; Kaehler M.; Haenisch S.; Roder C.; Cascorbi I.;

(Bruhn, Drerup, Kaehler, Haenisch, Cascorbi) Institute of Experimental and Clinical Pharmacology, University of Kiel, Kiel, Germany
(Roder) Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany

Differential mirna interaction of abcb1 (p-glycoprotein) through 3'-UTR length variants.

Clinical Pharmacology and Therapeutics. Conference: 2016 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, ASCPT 2016 San Diego, CA United States. Conference Start: 20160309 Conference End: 20160312. Conference Publication: (var.pagings). 99 (pp S97), 2016. Date of Publication: February 2016.

Nature Publishing Group

Clin. Pharmacol. Ther.

BACKGROUND: Overexpression of ABCB1 contributes to pharmacotherapy resistance in various medical indications. MicroRNAs contribute to posttranscriptional regulation through binding to the mRNA 3'-UTR. In silico analysis revealed conflicting data of the ABCB1 3-'UTR length in data bases compared to reported microRNA binding sites. The aim of this study was to identify the length and possible variations of the ABCB1 3'-UTR as an important regulatory motif of this drug transporter. METHODS: RNA was isolated from different human cell lines and liver tissue and the 3'-UTR was amplified from cDNA by 3'-rapid amplification of cDNA ends (3'-RACE). ABCB1 3'-UTRs were sequenced, aligned and compared to recent database entries and reported ABCB1-regulating microRNA binding sites. The abundance of various 3'-UTR fragments was analyzed using qRT-PCR. RESULTS: We identified five different ABCB1 3'-UTR length variants. Only one of these was in agreement with recent database entries. So far, described ABCB1 microRNA binding sites were found to be located only on the three longer fragments, but were absent on the two shorter 3'-UTRs. Interestingly, leukemia cells resistant to the tyrosine-kinase inhibitor imatinib expressed predominantly shorter 3'-UTRs than imatinib-sensitive cells. These short 3'-UTRs lackmicroRNA binding sites. CONCLUSION: The experimentally validated differential expression of five different ABCB1 3'-UTR length variants indicates that alternative polyadenylation is a mechanism for controlling ABCB1 synthesis. Shortening of the ABCB1 3'-UTR contributes to the loss of microRNA dependent translational control contributing to the phenomenon of elevated resistance against ABCB1 substrates such as imatinib.

0009-9236

Journal: Conference Abstract

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

72220816

Elebrashi M.

(Elebrashi) Mansoura University, Clinical Oncology, Dakahlia, Egypt

Phase II study of single agent oral vinorelbine as a first line treatment for postmenopausal patients with locally recurrent or metastatic breast cancer previously treated with anthracycline or taxanes.

European Journal of Cancer. Conference: 10th European Breast Cancer Conference, EBCC-10 Amsterdam Netherlands. Conference Start: 20160309 Conference End: 20160311. Conference Publication: (var.pagings). 57 (pp S113), 2016. Date of Publication: April 2016.

Elsevier Ltd

Eur. J. Cancer

Background: Breast cancer arises in about 48% of patients older than 65 years and more than 30% occurs in those over 70 years. Elderly patients tolerate chemotherapy poorly compared to their younger counterpart. Chemotherapy is indicated in elderly patients with advanced breast cancer resistant to hormonal treatment or with visceral disease. Oral chemotherapy may offer the specific advantage of fewer and shorter hospital visits, delayed use of central venous access and maintained social activities. Oral vinorelbine has demonstrated similar activity as IV formulation with better patient convenience in metastatic breast cancer. This study examined the efficacy and safety of oral vinorelbine as 1st line treatment in elderly metastatic breast cancer patients. Patients and Methods: 50 postmenopausal patients with histologically proven metastatic breast cancer were enrolled in the study between June 2012 and June 2015. All patients presented with anthracyclines +/- taxanes WHOP <2, with adequate bone marrow, renal and liver functions, all patients had measurable disease and were treated with oral vinorelbine 60 mg/m²/week until disease progression, death or unacceptable toxicity. Oral serotonin antagonist was given 30-60 minutes prior to each administration of oral vinorelbine. The use of prophylactic or curative GCSF is allowed. The primary end points was toxicity, the secondary end points were PR, PFS & OS. Assessment of response was done every 8 weeks. Results: All patients were evaluated for response, toxicity & survival. The median age was 75 years (range 68-80 years), median number of weekly oral vinorelbine was 32 (range 20-88). The overall response rate was 48% (CR 14%, PR 34%), stable disease was observed in 20 patients (40%) and 6 patients (12%) experienced disease progression. Response rate observed by disease site, sites were found in 30% of patients with liver metastases, 40% of patients with lung metastases, 60% of patients with skin metastases, 60% of patients with lymph node metastases. No WHO grade 4 toxicities were noted, 2 patients (4%) had G3 anemia and 4 patients (8%) G2 neutropenia. The most frequent adverse events were G2 nausea & vomiting (4%), fatigue (4%), alopecia (4%) and neuropathy (2%). The median DFS and survival were 14 and 20 months respectively. Conclusion: Oral vinorelbine is an active, safe, feasible and effective chemotherapy in recurrent or metastatic breast cancer elderly patients resistant to hormonal therapy or with visceral metastases.

0959-8049

Journal: Conference Abstract

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

72220809

Brems-Eskildsen A.S.; Linnet S.; Luczak A.; Nielsen H.; Vestlev P.; Jacobsen E.H.; Neimann J.; Jensen C.B.; Dongsgaard T.; Langkjer S.T.;

(Brems-Eskildsen, Neimann, Jensen, Langkjer) University Hospital of Aarhus, Department of Oncology, Aarhus, Denmark
(Linnet, Dongsgaard) Hospital of Herning, Department of Oncology, Herning, Denmark
(Luczak) University hospital of Aalborg, Department of Oncology, Aalborg, Denmark
(Nielsen) Hospital of Hillerod, Department of Oncology, Hillerod, Denmark
(Vestlev) Hospital of Roskilde, Department of Oncology, Roskilde, Denmark
(Jacobsen) Hospital of Esbjerg, Department of Oncology, Esbjerg, Denmark

Metronomic chemotherapy is well tolerated, less toxic and as effective as standard chemotherapy. Results from the Xe Na trial; a randomized phase 2 trial combining vinorelbine and capecitabine in the treatment of advanced HER2 negative breast cancer.

European Journal of Cancer. Conference: 10th European Breast Cancer Conference, EBCC-10 Amsterdam Netherlands. Conference Start: 20160309 Conference End: 20160311. Conference Publication: (var.pagings). 57 (pp S110), 2016. Date of Publication: April 2016.

Elsevier Ltd

Eur. J. Cancer

Background: Metronomic treatment is hypothesized to be less toxic and more effective compared to standard treatment. The continuously low dose administered theoretically affects the angiogenesis in tumors. Vinorelbine is effective especially in the combination with other treatments and the toxicity profile of capecitabine and vinorelbine is not overlapping. Long term disease control is beneficial to the patients with disseminated breast cancer. Material and Methods: We have tested the metronomic treatment principle in a randomized phase 2 setting combined with standard Xeloda treatment in the XeNa trial with Clinical Trials.gov identifier number: NCT0141771. 120 patients with disseminated or locally advanced HER2 negative breast cancer are included by June 2015. Randomization are between Arm A: "vinorelbine (Navelbine Oral)" 60 mg/m² day 1 + day 8 in the first cycle followed by 80 mg/m² day 1 + day 8 in the following cycles or Arm B: continually "vinorelbine (Navelbine Oral)" 50 mg three times a week. "Capecitabine (Xeloda)" 1000 mg/m² twice a day for day 1-14 is administered in both arms. Dose reduction is allowed if toxicity is unacceptable. Results: The study population is well balanced in the two study arms. The number of patients presenting with visceral metastasis was 80% and the number of patients with "no visceral" metastasis was 16%. The reported adverse events in the standard versus metronomic arm are presented in Table 1. The grade 3 and 4 toxicity profile of the metronomic arm seems beneficial as the number of febrile neutropenia (3 versus 2), alopecia (6 versus 0) and thromboembolic events (6 versus 2) were lower in arm B. The response rate is 21.4% (arm A) versus 20.8% (arm B). The clinical benefit rate is 61.9% (arm A) versus 60.4% (arm B). (Table Presented) Preliminary calculation of progression free survival and overall survival shows equal effect as mean time to progression is 228 days (confidence interval 175-281) in arm A and 199 days (confidence interval 147-250) in arm B, and overall survival is 285 days (confidence interval 229-341) in arm A and 247 days (confidence interval 193-301) in arm B. Conclusion: The study meets its primary endpoint by determining an equal overall response rate of 21% in both treatment arms. The secondary endpoints determining the toxicity and safety of the treatment reveal a lower frequency of adverse events in the metronomic treatment arm and the combined treatment is considered safe. Preliminary efficacy data shows equal time to progression and overall survival. Survival data will be updated upon time for the congress.

0959-8049

Journal: Conference Abstract

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

72220801

Cazzaniga M.E.; Porcu L.; Cortesi L.; Ferzi A.; Giovanardi F.; Ciccarese M.; Pugliese P.; Della Torre S.; Nicolini M.; Verusio C.; Piazza E.; Zanlorenzi L.; Comande M.; Clivio L.; Torri V.;

(Cazzaniga) AO San Gerardo, Medical Oncology, Monza, Italy
(Porcu, Clivio, Torri) Istituto Mario Negri, Oncology Unit, Milano, Italy
(Cortesi) University of Modena and Reggio Emilia, Hematology and Respiratory Diseases, Modena, Italy
(Ferzi) AO Legnano, Medical Oncology, Legnano, Italy
(Giovanardi) Ospedale Di Guastalla, Medical Oncology, Guastalla, Italy
(Ciccarese) AO Vito Fazio, Medical Oncology, Lecce, Italy
(Pugliese) AO Sant'Anna, Medical Oncology, Como, Italy
(Della Torre) AO Garbagnate, Medical Oncology, Garbagnate, Italy
(Nicolini) AUSL Romagna, Medical Oncology, Rimini, Italy
(Verusio) AO Busto Arsizio, Medical Oncology, Saronno, Italy
(Piazza) AO Sacco, Medical Oncology, Milano, Italy
(Zanlorenzi) AO Busto Arsizio, Medical Oncology, Busto Arsizio, Italy
(Comande) AO Serbelloni, Medical Oncology, Gorgonzola, Italy

Metronomic combination of vinorelbine (VNR) and capecitabine (CAPE) in HER2-negative advanced breast cancer (ABC) patients (pts): Preliminary results of efficacy and safety of the VICTOR-2 study.

European Journal of Cancer. Conference: 10th European Breast Cancer Conference, EBCC-10 Amsterdam Netherlands. Conference Start: 20160309 Conference End: 20160311. Conference Publication: (var.pagings). 57 (pp S107), 2016. Date of Publication: April 2016.

Elsevier Ltd

Eur. J. Cancer

Background: One of the main objectives in the treatment of ABC pts is the preservation of QoL, also by limiting chemotherapy (CHT)-related toxicities. Metronomic CHT (mCHT) is a novel way of administering cancer drugs at doses higher than the MTD with lower side effects. Grade 3-4 neutropenia, neuropathy and gastro-intestinal toxicity are frequently observed when VNR and CAPE are used at standard doses. We recently published the results of the VICTOR-1 study, demonstrating that the mVRL-CAPE leads to a very low incidence of Grade 3-4 toxicities. The VICTOR-2 study was designed aiming to confirm the efficacy and safety data of the previous trial. Here we present for the first time data of efficacy and safety. Materials and Methods: The treatment consisted of VNR 40 mg thrice a week + CAPE 500 mg thrice-a-day, continuously, as 1st or further lines of treatment. One cycle was conventionally defined as 3 weeks of treatment. Main inclusion criteria were: measurable or evaluable HER2- negative disease, HR known status. mCHT-related toxicity was collected by using NCI-CTCAE Version 4.02 Criteria. Results: From September 2011 to May 2015, 85 pts entered the study, of whom 74 (87.1%) are evaluable for toxicity at the time of the present analysis. Median age was 66 years (38-86). A total of 669 cycles were administered; median number of cycles per patient was 6.5 (1-55). Thirty eight (79.2%) out of 84 patients have discontinued the treatment mainly for progressive disease (76.3%). Only 3 pts (7.9%) have discontinued due to CHT toxicity. Table 1 summarizes the toxicity observed. Conclusion: These preliminary results of a large Phase II study confirm that the metronomic combination of VNR and CAPE in ABC pts is active and well tolerated, with a very low incidence of side effects, thus being a valid option of treatment both as 1st or further lines of treatment for HER2- negative BC patients.

0959-8049

Journal: Conference Abstract

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

72219656

Mourmoura E.; Vial G.; Chate V.; Rigaudiere J.P.; Demaison L.;

(Mourmoura, Chate, Demaison) LBFA,INSERM U1055, Universite Joseph Fourier, Grenoble, France
(Vial) Laboratoire CarMeN, INSERM U 1060, Universite Lyon 1, Lyon, France
(Demaison) UNH,INRA,UMR 1019, Universite d'Auvergne, Clermont-Ferrand, France

Is diabetic cardiomyopathy a problem of coronary perfusion?.

Journal of Molecular and Cellular Cardiology. Conference: 33rd Meeting of the ES-ISHR Bordeax France. Conference Start: 20150701 Conference End: 20150704. Conference Publication: (var.pagings). 86 (pp S31-S32), 2015. Date of Publication: September 2015.

Academic Press

J. Mol. Cell. Cardiol.

Diabetic cardiomyopathy is generally attributed to the harmful actions of toxic molecules such as reactive oxygen species or glycated proteins. Our objective is to known if development of diabetic cardiomyopathy is associated with troubles of coronary perfusion. We used several models of pre-diabetic and diabetic animals including Wistar rats fed a high fat (HF) diet for 3- and 7-months, ZDF fa/fa rats and streptozotocin (65 mg/kg)-treated Wistar rats. In rats fed the HF diet for 3 months, the cardiac functioning was evaluated in vivo. In all the animals, the coronary reactivity was estimated ex vivo. These measurements were completed with determinations of glycaemia and/or insulinemia. In rats fed for 3 and 7 months, glycaemia was only slightly increased. In vivo cardiac function was significantly augmented, which was sustained by an increased coronary reactivity due to accumulation of arachidonic acid in cardiac phospholipids. In 11-week old ZDF fa/fa rats, hyperglycemia and hyper-insulinemia occurred. The coronary reactivity was maintained at the same level as in their lean littermates. Finally, in streptozotocin-injected rats, the high glycaemia and low insulinemia were associated with a large decrease in the function of coronary endothelial and smooth muscle cells. We conclude that the function of coronary vessels progressively decreases with the development of hyperglycemia and hypo-insulinemia. This shift leads to disequilibrium between energy production and utilization which induces ischemia and development of diabetic cardiomyopathy.

0022-2828

Journal: Conference Abstract

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

72221348

Jones J.; Wang H.; Theodore S.; Karanam B.; Welch D.R.; Grizzle W.; Yates C.;

(Jones, Wang, Theodore, Karanam, Yates) Department of Biology, Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, United States
(Welch) Department of Cancer Biology, University of Kansas Medical Center, University of Kansas Cancer Center, Kansas City 66045, United States
(Grizzle) Department of Pathology, University of Alabama at Birmingham, School of Medicine, Birmingham, AL 35205, United States

Nuclear localization of Kaiso is a prognostic biomarker in African American Women and promoter of EMT in infiltrating ductal breast carcinomas.

Clinical and Experimental Metastasis. Conference: 15th International Biennial Congress of the Metastasis Research Society Heidelberg Germany. Conference Start: 20140628 Conference End: 20140701. Conference Publication: (var.pagings). 32 (3) (pp 248), 2015. Date of Publication: March 2015.

Springer Netherlands

Clin. Exp. Metastasis

Background: The expression and biological consequences of Kaiso, a novel BTB-POZ bi-modal transcription factor, in infiltrating ductal carcinomas (IDCs) have not been widely investigated. Methods: Kaiso expression and subcellular localization was determined in 146 normal tissues, 376 IDCs, and 85 lymph node metastases by immunohistochemistry. Semi-quantitative analysis of staining was evaluated with clinicopathological features of IDCs using Chi square analysis and Kaplan-Meier Curves. MCF-7 cells were induced to overexpression Kaiso, whereas MDA-MB-468 and MDAMB- 231 cells were treated with si-Kaiso or si-Scr and assayed for cell migration, invasion, RNA and protein expression. Chromatin Immunoprecipitation assay was performed in MDA-MB-231 cells to determine the direct interaction of Kaiso with methylated sequences within E-cadherin promoter. Results: Kaiso expression in both the cytoplasmic and nuclear compartments correlated with age<48 (cytoplasmic p<0.0093; nuclear p<0.0001) and moderate differentiation (cytoplasmic p<0.0042; nuclear p<0.0001), However, only nuclear Kaiso correlated with poor prognostic factors, i.e., race (African Americans) (p<0.0001), poor differentiation (p<0.0001), and metastases (p<0.0001). Nuclear Kaiso was also associated with worse overall survival (p<0.0019), with African American patients displaying worse survival rates relative to Caucasian patients (p<0.029). Overexpression of Kaiso in MCF-7 cells increased cell migration and invasion, but treatment of MDA-MB-468 and MDA-MB-231 cells with si-Kaiso decreased cell migration and invasion. Treatment also induced the expression of E-cadherin and a reversal of mesenchymal associated cadherins, N-cadherin and cadherin 11, as well as decreased vitmenin expression. Further, Kaiso directly bound to methylated sequences in the E-cadherin promoter, an effect prevented by 5-aza-2-deoxycytidine. Lastly, immunofluorescence co-staining of poorly differentiated IDCs demonstrated that nuclear Kaiso is associated with a loss of E-cadherin expression. Conclusions: Collectively, these findings support an oncogenic role for Kaiso in promoting aggressive breast tumors.

0262-0898

Journal: Conference Abstract

Copyright 2016 Elsevier B.V., All rights reserved.

Embase

72220273

Osborne W.L.; O'Brien S.G.; Hedgley C.; Foroni L.; Apperley J.; Terril P.; Rowe P.; McCullough J.; Holyoake T.; Pocock C.; Byrne J.; Bescoby R.; Copland M.; Clark R.;

(Osborne, O'Brien, Hedgley, Terril, Rowe, McCullough, Bescoby) Northern Institute for Cancer Research, Newcastle University, Medical School, United Kingdom
(Foroni, Apperley) Centre for Haematology, Imperial College, London, United Kingdom
(Holyoake, Copland) Paul O'Gorman Research Centre, University of Glasgow, United Kingdom
(Pocock) Kent and Canterbury Hospital, United Kingdom
(Byrne) Faculty of Medicine and Health Sciences, Nottingham University, United Kingdom
(Clark) Department of Molecular and Cancer Medicine, University of Liverpool, United Kingdom

SPIRIT 2: An NCRI randomised study comparing dasatinib with imatinib in patients with newly diagnosed chronic myeloid leukaemia-2 year follow up.

British Journal of Haematology. Conference: 55th Annual Scientific Meeting of the British Society for Haematology Edinburgh United Kingdom. Conference Start: 20150420 Conference End: 20150422. Conference Publication: (var.pagings). 169 (pp 15), 2015. Date of Publication: April 2015.

Blackwell Publishing Ltd

Br. J. Haematol.

SPIRIT 2 is the largest trial comparing imatinib 400 mg with dasatinib 100 mg daily. 814 newly diagnosed patients were recruited from 144 hospitals in the UK between August 2008 and March 2013. 812 patients were randomised, 406 in each arm. The primary end point of the study is event-free survival at 5 years. A key secondary endpoint is rate of a major molecular response (MMR, MR3, BCRABL1/ ABL ratio <0.1% international scale). With a median follow up of 37.4 months, 236 imatinib and 276 dasatinib patients were still receiving their designated treatment. 133 patients discontinued due to non-haematological toxicity, 53/406 (13.1%) on the imatinib arm (predominantly gastrointestinal toxicity) and 80/406 (19.7%) on the dasatinib arm (predominantly thrombocytopenia). 45/814 patients discontinued due to sub-optimal response as assessed by the treating physician (not defined by the protocol). These were predominantly patients on imatinib (42/406 (10.3%), compared to only 3/406 (0.7%) on dasatinib. Pleural effusions occurred in 90/406 (22.2%) patients on dasatinib and 13 of these effusions required drainage. There was no significant difference in arterial cardiovascular events: imatinib 3/406 (0.7%); dasatinib 9/406 (2.2%). The MR3 rate at 12 months was significantly (p < 0.001) higher in dasatinib 237/406 (58.4%) than in imatinib 175/406 (43.1%) patients; Pleural effusion did not affect rate of the MR3. Accelerated phase (imatinib 1/406; dasatinib 2/406) and blast crisis (imatinib 7/406; dasatinib 4/406) were observed in 14 patients. 38 patients died with no difference between arms of the study. In conclusion, dasatinib treated patients have a higher rate of molecular response at 1 year but so far there is no significant difference in rates of disease progression or overall survival. More patients abandoned imatinib than dasatinib due to investigators' and/or patient's concern about sub-optimal responses. Further follow up will evaluate differences in the primary endpoint: event free survival at 5 years.

0007-1048

Journal: Conference Abstract

Copyright 2016 Elsevier B.V., All rights reserved.

Ovid MEDLINE(R)

26161025

MEDLINE

Lee NR; Jang JW; Kim HS; Yhim HY; .

Lee,Na-Ri. Division of Hematology and Oncology, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea. ; Research Institute of Clinical Medicine, Chonbuk National University Hospital, Jeonju, Korea.
Jang,Ji Won. Division of Hematology and Oncology, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea.
Kim,Hee Sun. Department of Nursing, Wonkwang University School of Medicine, Iksan, Korea.
Yhim,Ho-Young. Division of Hematology and Oncology, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea. ; Research Institute of Clinical Medicine, Chonbuk National University Hospital, Jeonju, Korea.

Imatinib mesylate-induced interstitial lung disease in a patient with prior history of Mycobacterium tuberculosis infection.

Korean Journal of Internal Medicine. 30(4):550-3, 2015 Jul.

Korea (South)

2005-6648

Case Reports. Letter. .

20150711

Ovid MEDLINE(R)

25996455

MEDLINE

Tse A; Verkhivker GM; .

Tse,A. Graduate Program in Computational and Data Sciences, Department of Computational Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA.

Small-world networks of residue interactions in the Abl kinase complexes with cancer drugs: topology of allosteric communication pathways can determine drug resistance effects.

Molecular Biosystems. 11(7):2082-95, 2015 Jul.

England

The human protein kinases play a fundamental regulatory role in orchestrating functional processes in complex cellular networks. Understanding how conformational equilibrium between functional kinase states can be modulated by ligand binding or mutations is critical for quantifying molecular basis of allosteric regulation and drug resistance. In this work, molecular dynamics simulations of the Abl kinase complexes with cancer drugs (Imatinib and Dasatinib) were combined with structure-based network modeling to characterize dynamics of the residue interaction networks in these systems. The results have demonstrated that structural architecture of kinase complexes can produce a small-world topology of the interaction networks. Our data have indicated that specific Imatinib binding to a small number of highly connected residues could lead to network-bridging effects and allow for efficient allosteric communication, which is mediated by a dominant pathway sensitive to the unphosphorylated Abl state. In contrast, Dasatinib binding to the active kinase form may activate a broader ensemble of allosteric pathways that are less dependent on the phosphorylation status of Abl and provide a better balance between the efficiency and resilience of signaling routes. Our results have unveiled how differences in the residue interaction networks and allosteric communications of the Abl kinase complexes can be directly related to drug resistance effects. This study offers a plausible perspective on how efficiency and robustness of the residue interaction networks and allosteric pathways in kinase structures may be associated with protein responses to drug binding.

1742-2051

Journal Article. Research Support, Non-U.S. Gov't. .

Ovid MEDLINE(R)

25744099

MEDLINE

Negintaji K; Zarifkar A; Ghasemi R; Moosavi M; .

Negintaji,Kourosh. Department of Physiology, Shiraz University of Medical Sciences, Shiraz, Iran.

Humanin Does Not Protect Against STZ-Induced Spatial Memory Impairment.

Journal of Molecular Neuroscience. 56(2):290-8, 2015 Jun.

United States

[Gly14]-Humanin (HNG) is a 24-amino acid peptide which was first identified in the brains of patients diagnosed with Alzheimer's disease (AD). In this region, some neurons were protected against cell damage occurring in this disease. Further studies suggested a neuroprotective role for humanin against Abeta and some other insults. Intraventricularly administered streptozotocin (STZ) disrupts insulin signaling pathway which leads to behavioral and biochemical changes resemble to early signs of AD; therefore, STZ model has been proposed as a model for sporadic Alzheimer's disease (sAD). Regarding the reported beneficial effects of humanin in AD, this study was aimed to investigate if this peptide prevents spatial memory and hippocampal PI3/Akt signaling impairment induced by centrally injected STZ. Adult male Sprague-Dawely rats weighting 250-300 g were used, and cannuls were implanted bilaterally into lateral ventricles. STZ was administered on days 1 and 3 (3 mg/kg), and humanin (0.01, 0.05, 0.1, and 1 nmol) or saline were injected from day 4 and continued till day 14. The animal's learning and memory capability was assessed on days 15-18 using Morris water maze. After complement of behavioral studies, the hippocampi were isolated, and the level of phosphorylated Akt (pAkt) was assessed through Western blot analysis. The results showed that STZ significantly impaired spatial memory, and humanin in a wide range of doses (0.01, 0.05, 0.1, and 1 nmol) failed to restore STZ-induced deficit. It was also revealed that humanin was not efficient in restoring pAkt disruption. It seems that humanin is not capable in restoring memory deterioration that resulted from insulin signaling disruption.

1559-1166

Journal Article. Research Support, Non-U.S. Gov't. .

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations

26026053

In-Process

Liao Z; Gu L; Vergalli J; Mariani SA; De Dominici M; Lokareddy RK; Dagvadorj A; Purushottamachar P; McCue PA; Trabulsi E; Lallas CD; Gupta S; Ellsworth E; Blackmon S; Ertel A; Fortina P; Leiby B; Xia G; Rui H; Hoang DT; Gomella LG; Cingolani G; Njar V; Pattabiraman N; Calabretta B; Nevalainen MT; .

Liao,Zhiyong. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Gu,Lei. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Vergalli,Jenny. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Mariani,Samanta A. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
De Dominici,Marco. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Lokareddy,Ravi K. Department of Biochemistry, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Dagvadorj,Ayush. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Purushottamachar,Puranik. School of Pharmacy, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
McCue,Peter A. Department of Pathology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Trabulsi,Edouard. Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Lallas,Costas D. Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Gupta,Shilpa. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Ellsworth,Elyse. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Blackmon,Shauna. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Ertel,Adam. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Fortina,Paolo. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Leiby,Benjamin. Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Xia,Guanjun. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Rui,Hallgeir. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Pathology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Hoang,David T. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Gomella,Leonard G. Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Cingolani,Gino. Department of Biochemistry, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Njar,Vincent. School of Pharmacy, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Pattabiraman,Nagarajan. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
Calabretta,Bruno. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Nevalainen,Marja T. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. mnevalainen@mcw.edu.

Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia.

Molecular Cancer Therapeutics. 14(8):1777-93, 2015 Aug.

United States

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic myeloid leukemia (CML). The lead compound inhibitor of Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl-mediated phosphorylation and dimerization of Stat5a/b, and selectively inhibited transcriptional activity of Stat5a (IC50 = 1.5mumol/L) and Stat5b (IC50 = 3.5 mumol/L). IST5-002 suppressed nuclear translocation of Stat5a/b, binding to DNA and Stat5a/b target gene expression. IST5-002 induced extensive apoptosis of prostate cancer cells, impaired growth of prostate cancer xenograft tumors, and induced cell death in patient-derived prostate cancers when tested ex vivo in explant organ cultures. Importantly, IST5-002 induced robust apoptotic death not only of imatinib-sensitive but also of imatinib-resistant CML cell lines and primary CML cells from patients. IST5-002 provides a lead structure for further chemical modifications for clinical development for Stat5a/b-driven solid tumors and hematologic malignancies.Copyright ©2015 American Association for Cancer Research.

1538-8514

Journal Article. Research Support, N.I.H., Extramural. .

20160322

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations

25503648

PubMed-not-MEDLINE

Vogelhuber M; Feyerabend S; Stenzl A; Suedhoff T; Schulze M; Huebner J; Oberneder R; Wieland W; Mueller S; Eichhorn F; Heinzer H; Schmidt K; Baier M; Ruebel A; Birkholz K; Bakhshandeh-Bath A; Andreesen R; Herr W; Reichle A; .

Vogelhuber,M. Department of Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Straus-Allee 11, 93053, Regensburg, Germany.

Biomodulatory Treatment of Patients with Castration-Resistant Prostate Cancer: A Phase II Study of Imatinib with Pioglitazone, Etoricoxib, Dexamethasone and Low-Dose Treosulfan.

Cancer Microenvironment. 8(1):33-41, 2015 Apr.

Netherlands

Therapeutic options for patients with castration-resistant prostate cancer (CRPC) remain limited. In a multicenter, Phase II study, 65 patients with histologically confirmed CRPC received a biomodulatory regimen during the six-month core study. Treatment comprised daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan and dexamethasone. The primary endpoint was prostate-specific antigen (PSA) response. Responders could enter an extension phase until disease progression or intolerable toxicity occurred. Mean PSA was 45.3 ng/mL at baseline, and 77 % of patients had a PSA doubling time <3 months. Of the 61 evaluable patients, 37 patients (60.6 %) responded or had stable disease and 23 of them (37.7 % of 61 patients) were PSA responders. Among the 23 responders mean PSA decreased from 278.9+/-784.1 ng/mL at baseline to 8.8+/-11.6 ng/mL at the final visit (week 24). The progression-free survival (PFS) was 467 days in the ITT population. Of the 947 adverse events, 57.6 % were suspected to be drug-related, 13.8 % led to dose adjustment or permanent discontinuation and 40.2 % required concomitant medication. This novel combination approach led to an impressive PSA response rate of 37.7 % in CRPC patients. The good PSA response and PFS rate combined with the manageable toxicity profile suggest an alternative treatment option.

1875-2292

Journal Article.

20160322

Embase Daily Alerts

20160229028

Rose T.L. Milowsky M.I.

(Rose) Division of Hematology/Oncology, Department of Medicine, University of North Carolina Lineberger Comprehensive Cancer Center, 170 Manning Drive, CB #7305, Chapel Hill, NC 27599, United States
(Milowsky) Division of Hematology/Oncology, Department of Medicine, University of North Carolina Lineberger Comprehensive Cancer Center, 170 Manning Drive, CB #7295, Chapel Hill, NC 27599, United States

United States

Improving Systemic Chemotherapy for Bladder Cancer.

Current Oncology Reports. 18 (5) 2016. Article Number: 27. Date of Publication: 01 May 2016.

Current Medicine Group LLC 1

Curr. Oncol. Rep.

Systemic chemotherapy is integral to the management of muscle-invasive and metastatic bladder cancer (BCa). Neoadjuvant chemotherapy has been increasingly utilized for muscle-invasive BCa over the past several years, and several options for cisplatin-based regimens have emerged. Adjuvant chemotherapy may be considered for select patients who did not receive neoadjuvant therapy. Systemic chemotherapy added to radiotherapy is a critical component of a bladder-preserving approach and superior to radiotherapy alone. Cisplatin-based chemotherapy has been the mainstay for metastatic BCa for more than three decades. Novel targeted agents are in development fueled by the recent molecular characterization of BCa. Recent trials of immunotherapy have demonstrated the possibility of a less toxic and potentially more effective treatment for metastatic disease. It is an extremely exciting time for BCa research, and much needed improvements in systemic treatment are most certainly on the horizon.

1523-3790

Journal: Review

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

20160226489

Rubio M.T. Savani B.N. Labopin M. Piemontese S. Polge E. Ciceri F. Bacigalupo A. Arcese W. Koc Y. Beelen D. Gulbas Z. Wu D. Santarone S. Tischer J. Afanasyev B. Schmid C. Giebel S. Mohty M. Nagler A.

(Rubio, Labopin, Polge, Mohty) Service d'Hematologie et de Therapie Cellulaire, Saint Antoine Hospital, Paris, France
(Rubio, Labopin, Polge, Mohty) INSERM, UMR 938, Paris, France
(Rubio, Labopin, Polge, Mohty, Nagler) Universite Pierre et Marie Curie, Paris, France
(Rubio, Savani, Labopin, Piemontese, Polge, Mohty) Acute Leukemia Working Party of EBMT, Paris, France
(Savani) Vanderbilt University Medical Center, Nashville, TN, United States
(Labopin, Polge, Mohty) EBMT Paris Study Office, CEREST-TC, Paris, France
(Piemontese, Ciceri) Ospedale San Raffaele S.r.l., Ematologia, Milan, Italy
(Bacigalupo) Department of Haematology II, Ospedale San Martino, Genoa, Italy
(Arcese) Rome Transplant Network, Stem Cell Transplant Unit, Tor Vergata University, Rome, Italy
(Koc) Stem Cell Transplant Unit, Medical Park Hospitals, Antalya, Turkey
(Beelen) Department of Bone Marrow Transplantation, University Hospital, Essen, Germany
(Gulbas) Bone Marrow Transplantation Department, Anadolu Medical Center Hospital, Kocaeli, Turkey
(Wu) Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China
(Santarone) Ospedale Civile BMT Center, Pescara, Italy
(Tischer) Department of Internal Medicine III, Ludwig-Maximilians-University Hospital of Munich-Grosshadern, Munich, Germany
(Afanasyev) SPb State I. Pavlov Medical University, St. Petersburg, Russian Federation
(Schmid) Klinikum Augsburg, University of Munich, Munich, Germany
(Giebel) Department of Bone Marrow Transplantation and Hemato-Oncology, Cancer Center, Gliwice, Poland
(Nagler) Hematology Division, Chaim Sheba Medical Center, Tel Hashomer, Israel

United Kingdom

Impact of conditioning intensity in T-replete haplo-identical stem cell transplantation for acute leukemia: A report from the acute leukemia working party of the EBMT.

Journal of Hematology and Oncology. 9 (1) 2016. Article Number: 248. Date of Publication: 15 Mar 2016.

BioMed Central Ltd.

J. Hematol. Oncol.

Background: Increasing numbers of patients are receiving haplo-identical stem cell transplantation (haplo-SCT) for treatment of acute leukemia with reduced intensity (RIC) or myeloablative (MAC) conditioning regimens. The impact of conditioning intensity in haplo-SCT is unknown. Methods: We performed a retrospective registry-based study comparing outcomes after T-replete haplo-SCT for patients with acute myeloid (AML) or lymphoid leukemia (ALL) after RIC (n = 271) and MAC (n = 425). Regimens were classified as MAC or RIC based on published criteria. Results: A combination of post-transplant cyclophosphamide (PT-Cy) with one calcineurin inhibitor and mycophenolate mofetil (PT-Cy-based regimen) for graft-versus-host disease (GVHD) prophylaxis was used in 66 (25 %) patients in RIC and 125 (32 %) in MAC groups. Patients of RIC group were older and had been transplanted more recently and more frequently for AML with active disease at transplant. Percentage of engraftment (90 vs. 92 %; p = 0.58) and day 100 grade II to IV acute GVHD (24 vs. 29 %, p = 0.23) were not different between RIC and MAC groups. Multivariable analyses, run separately in AML and ALL, showed a trend toward higher relapse incidence with RIC in comparison to MAC in AML (hazard ratio (HR) 1.34, p = 0.09), and no difference in both AML and ALL in terms of non-relapse mortality (NRM) chronic GVHD and leukemia-free survival. There was no impact of conditioning regimen intensity in overall survival (OS) in AML (HR = 0.97, p = 0.79) but a trend for worse OS with RIC in ALL (HR = 1.44, p = 0.10). The main factor impacting outcomes was disease status at transplantation (HR > 1.4, p < 0.01). GVHD prophylaxis with PT-Cy-based regimen was independently associated with reduced NRM (HR 0.63, p = 0.02) without impact on relapse incidence (HR 0.99, p = 0.94). Conclusions: These data suggest that T-replete haplo-SCT with both RIC and MAC, in particular associated with PT-Cy, are valid options in first line treatment of high risk AML or ALL.

Journal: Article

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

609137954

Desar I.M.E. van Herpen C.M.L. van Erp N.P. Kaal S.E.J. van de Kerkhof P.C.M. van der Graaf W.T.A.

(Desar) Departments of aMedical Oncology bPharmacy cDermatology, Radboud University Medical Centre, Nijmegen, The Netherlands

United Kingdom

A successful approach to overcome imatinib-induced skin toxicity in a GIST patient.

Anti-Cancer Drugs. 2016. Date of Publication: 15 Mar 2016.

Lippincott Williams and Wilkins

Anti-Cancer Drugs

Since the introduction of tyrosine kinase inhibitors in gastrointestinal stromal tumor patients, the median survival of patients has increased from less than 1 to more than 5 years. The chronic use of a tyrosine kinase inhibitor has an impact on quality of life because of its toxicity. Adequate supportive therapy is therefore important. We describe a female patient with a metastatic gastrointestinal stromal tumor. During treatment with the c-KIT inhibitor imatinib, she developed severe therapy-limiting skin toxicity. After several different supportive attempts, the combination of doxycycline and clemastine proved to be the solution, enabling successful chronic treatment with imatinib. Chronic use of doxycycline and clemastine is useful in the management of skin toxicity caused by c-KIT inhibitors, enabling the needed long-term use of these kind of anticancer drugs without hampering the quality of life.

0959-4973

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

609136816

Satoi S. Fujii T. Yanagimoto H. Motoi F. Kurata M. Takahara N. Yamada S. Yamamoto T. Mizuma M. Honda G. Isayama H. Unno M. Kodera Y. Ishigami H. Kon M.

(Satoi) *Department of Surgery, Kansai Medical University +Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine ++Department of Surgery, Tohoku University Graduate School of Medicine Department of Surgery, University of Tsukuba PDepartment of Gastroenterology, Graduate School of Medicine, the University of Tokyo

Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital **Department of Chemotherapy, the University of Tokyo.

United States

Multicenter Phase II Study of Intravenous and Intraperitoneal Paclitaxel With S-1 for Pancreatic Ductal Adenocarcinoma Patients With Peritoneal Metastasis.

Annals of Surgery. 2016. Date of Publication: 11 Mar 2016.

Lippincott Williams and Wilkins

Ann. Surg.

OBJECTIVE:: To evaluate the clinical efficacy and tolerability of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel combined with S-1, "an oral fluoropyrimidine derivative containing tegafur, gimestat, and otastat potassium" in chemotherapy-naive pancreatic ductal adenocarcinoma (PDAC) patients with peritoneal metastasis. BACKGROUND:: PDAC patients with peritoneal metastasis (peritoneal deposits and/or positive peritoneal cytology) have an extremely poor prognosis. An effective treatment strategy remains elusive. METHODS:: Paclitaxel was administered i.v. at 50?mg/m and i.p. at 20?mg/m on days 1 and 8. S-1 was administered at 80?mg/m/d for 14 consecutive days, followed by 7 days of rest. The primary endpoint was 1-year overall survival (OS) rate. The secondary endpoints were antitumor effect and safety (UMIN000009446). RESULTS:: Thirty-three patients who were pathologically diagnosed with the presence of peritoneal dissemination (n = 22) and/or positive peritoneal cytology (n = 11) without other organ metastasis were enrolled. The tumor was located at the pancreatic head in 7 patients and the body/tail in 26 patients. The median survival time was 16.3 (11.47-22.57) months, and the 1-year survival rate was 62%. The response rate and disease control rate in assessable patients were 36% and 82%, respectively. OS in 8 patients who underwent conversion surgery was significantly higher than that of nonsurgical patients (n = 25, P = 0.0062). Grade 3/4 hematologic toxicities occurred in 42% of the patients and nonhematologic adverse events in 18%. One patient died of thrombosis in the superior mesenteric artery. CONCLUSIONS:: This regimen has shown promising clinical efficacy with acceptable tolerability in chemotherapy-naive PDAC patients with peritoneal metastasis.

0003-4932

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609136488

Park E. Goldberg N.R. Adams S.

(Park) aDepartment of Internal Medicine, New York University School of Medicine bDepartment of Ophthalmology, Mount Sinai School of Medicine, New York, New York, USA

United Kingdom

Nab-paclitaxel-induced cystoid macular edema in a patient with pre-existing optic neuropathy.

Anti-Cancer Drugs. 2016. Date of Publication: 15 Mar 2016.

Lippincott Williams and Wilkins

Anti-Cancer Drugs

Paclitaxel is a widely used chemotherapy agent that has rarely been associated with ophthalmic toxicities. Cystoid macular edema is one such rare side effect of paclitaxel therapy. Its pathophysiology remains poorly understood. Here, we report on a 69-year-old woman who developed cystoid macular edema associated with the albumin-bound formulation of paclitaxel after several months of therapy for breast cancer. After 2 months of drug withdrawal, her vision improved and there was a significant improvement in the macular edema by imaging with spectral-domain optical coherence tomography. Oncologists using taxane agents should be aware of this rare adverse outcome for timely patient referral to an ophthalmologist and appropriate treatment to preserve a patient's visual acuity.

0959-4973

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609135947

Huang Z.-Z. Li D. Ou-Yang H.-D. Liu C.-C. Liu X.-G. Ma C. Wei J.-Y. Liu Y. Xin W.-J.

(Huang) From the Pain Research Center and Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China (Z.-Z.H., D.L., X.-G.L., J.-Y.W., Y.L., W.-J.X.); Department of Anesthesiology, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China (H.-D.O.-Y.); and Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China (C.-C.L., C.M.).

United States

Cerebrospinal Fluid Oxaliplatin Contributes to the Acute Pain Induced by Systemic Administration of Oxaliplatin.

Anesthesiology. 2016. Date of Publication: 15 Mar 2016.

Lippincott Williams and Wilkins

Anesthesiology

BACKGROUND:: Systemic administration of oxaliplatin has no effect on the tumors in the central nervous system (CNS) due to the limited concentration of oxaliplatin in the cerebrospinal fluid (CSF), while it was clinically reported that oxaliplatin can induce acute encephalopathy. Currently, the impairment of neuronal functions in the CNS after systemic administration of oxaliplatin remains uninvestigated. METHODS:: The von Frey test and the plantar test were performed to evaluate neuropathic pain behavior after a single intraperitoneal administration of oxaliplatin (4 mg/kg) in rats. Inductively coupled plasma-mass spectrometry, electrophysiologic recording, real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, Western blot, immunohistochemistry, and small interfering RNA were applied to understand the mechanisms. RESULTS:: Concentration of oxaliplatin in CSF showed a time-dependent increase after a single administration of oxaliplatin. Spinal application of oxaliplatin at the detected concentration (6.6 nM) significantly increased the field potentials in the dorsal horn, induced acute mechanical allodynia (n = 12 each) and thermal hyperalgesia (n = 12 each), and enhanced the evoked excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in the projection neurokinin 1 receptor-expressing lamina I to II neurons. The authors further found that oxaliplatin significantly increased the nuclear factor-kappaB p65 binding and histone H4 acetylation in cx3cl1 promoter region. Thus, the upregulated spinal CX3CL1 markedly mediated the induction of central sensitization and acute pain behavior after oxaliplatin administration. CONCLUSIONS:: The findings of this study suggested that oxaliplatin in CSF may directly impair the normal function of central neurons and contribute to the rapid development of CNS-related side effects during chemotherapy. This provides novel targets to prevent oxaliplatin-induced acute painful neuropathy and encephalopathy.

0003-3022

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609135819

Zhou J. Ahmad F. Parikh S. Hoffman N.E. Rajan S. Verma V.K. Song J. Yuan A. Shanmughapriya S. Guo Y. Gao E. Koch W. Woodgett J.R. Muniswamy M. Kishore R. Lal H. Force T.

(Zhou) 1Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN; 2Department of Pharmacology, Vanderbilt University Medical Center, Nashville; 3Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA, and; 4Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.

United States

Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy.

Circulation Research. 2016. Date of Publication: 15 Mar 2016.

Lippincott Williams and Wilkins

Circ. Res.

RATIONALE:: Cardiac myocyte-specific deletion of either Glycogen Synthase Kinase (GSK)3A or GSK3B leads to cardiac protection following myocardial infarction, suggesting that deletion of both isoforms may provide synergistic protection. This is an important consideration due to the fact that all GSK-3-targeted drugs including the drugs already in clinical trial target both isoforms of GSK-3 and none are isoform specific. OBJECTIVE:: To identify the consequences of combined deletion of cardiac myocyte GSK3A and GSK3B in heart function. METHODS AND RESULTS:: We generated tamoxifen-inducible cardiac myocyte-specific mice lacking both GSK-3 isoforms (double knockout, DKO). We unexpectedly found that cardiac myocyte GSK-3 is essential for cardiac homeostasis and overall survival. Serial echocardiographic analysis reveals that within 2 weeks of tamoxifen treatment, DKO hearts leads to excessive dilatative remodeling and ventricular dysfunction. Further experimentation with isolated adult cardiac myocytes and fibroblasts from DKO implicated cardiac myocytes intrinsic factors responsible for observed phenotype. Mechanistically, loss of GSK-3 in adult cardiac myocytes resulted in induction of mitotic catastrophe, a previously unreported event in cardiac myocytes. DKO cardiac myocytes showed cell cycle progression resulting in increased DNA content and multi-nucleation. However, increased cell cycle activity was rivaled by marked activation of DNA damage, cell cycle checkpoint activation, and mitotic catastrophe induced apoptotic cell death. Importantly, mitotic catastrophe was also confirmed in isolated adult cardiac myocytes. CONCLUSION:: Together, our findings suggest that cardiac myocyte GSK-3 is required to maintain normal cardiac homeostasis and its loss is incompatible with life due to cell cycle dysregulation that ultimately results in a severe fatal dilated cardiomyopathy.

0009-7330

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609131423

Aminsharifi A. Hekmati P. Noorafshan A. Karbalay-Doost S. Nadimi E. Aryafar A. Hosseinabadi O.K. Naseri M.M. ZarePoor M.

(Aminsharifi, Hekmati, Aryafar) Department of Urology, Shiraz University of Medical Sciences, Shiraz, Iran
(Aminsharifi, Hosseinabadi) Stem Cell and Transgenic Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
(Noorafshan, Karbalay-Doost, Nadimi) Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
(Noorafshan, Karbalay-Doost) Department of Anatomy, Shiraz University of Medical Sciences, Shiraz, Iran
(Naseri, ZarePoor) Department of Power and Electricity, Shiraz University, Shiraz, Iran

United States

Scrotal Cooling to Protect Against Cisplatin-induced Spermatogenesis Toxicity: Preliminary Outcome of an Experimental Controlled Trial.

Urology. 2016. Date of Publication: June 22, 2015.

Elsevier Inc.

Urology

Objective: To investigate the protective effects of scrotal cooling on cisplatin-induced gonadal toxicity in an animal model. Methods: Twenty-one male BALB/c mice were divided into 3 groups. The cisplatin group received 2 cycles of cisplatin (2.5 mg/kg/day for 5 days with 16 days of recovery) intraperitoneally, and the cisplatin + cooling group received the same regimen of cisplatin with a cooling protocol: cooling induction for 30 minutes before injection and cooling for 60 minutes after injection. Mice in control group were given an injection of 2 mL normal saline intraperitoneally. After 35 days of recovery (1 cycle of spermatogenesis), the volume of the testes (Cavalieri method), volume density of the tubules and epithelium (point-counting method), and number of cells (optical dissector method) were estimated. Results: The volume of the testes, tubules, and epithelium was reduced between 61% and 66%, and the number of the spermatogonia, spermatocytes, round spermatids, and long spermatids was reduced between 70% and 93% in cisplatin group compared with that of control mice. Cisplatin affected spermatids to a greater extent, and Sertoli cells to a lesser extent than the other cells. The volume and number of the cells were reduced in the cisplatin + cooling group but to a lesser extent compared with those of mice in the cisplatin group. Sertoli cells were more intact in the cisplatin + cooling group compared with those of the control group. Conclusion: Scrotal cooling during cisplatin administration seems to have beneficial effects on spermatogenesis. Scrotal cooling may hold promise as a way to protect fertility.

0090-4295

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609111749

Dad T. Tighiouart H. Joseph A. Bostom A. Carpenter M. Hunsicker L. Kusek J.W. Pfeffer M. Levey A.S. Weiner D.E.

(Dad, Tighiouart, Joseph, Levey, Weiner) Tufts Medical Center and Tufts University School of Medicine, Boston, MA
(Tighiouart) The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA
(Tighiouart) Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA
(Bostom) Rhode Island Hospital, Providence, RI
(Carpenter) University of North Carolina, Chapel Hill, NC
(Hunsicker) University of Iowa, Iowa City, IA
(Kusek) National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
(Pfeffer) Brigham and Women's Hospital, Boston, MA

United States

Aspirin Use and Incident Cardiovascular Disease, Kidney Failure, and Death in Stable Kidney Transplant Recipients: A Post Hoc Analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial.

American Journal of Kidney Diseases. 2016. Date of Publication: July 12, 2015.

W.B. Saunders

Am. J. Kidney Dis.

Background: Cardiovascular disease (CVD) is the leading cause of death in kidney transplant recipients. Whether aspirin may reduce the risk for CVD, death, and kidney failure outcomes is uncertain. Study Design: Post hoc cohort analysis of FAVORIT, a randomized trial examining the effect of homocysteine-lowering vitamins on CVD in kidney transplant recipients. Setting & Participants: Prevalent adult kidney transplant recipients with hyperhomocysteinemia and stable kidney function from the United States, Canada, and Brazil participating in FAVORIT, with no known history of CVD. Predictor: Aspirin use, with aspirin users matched to nonusers using a propensity score. Outcomes: Incident CVD events, kidney failure, all-cause mortality, a composite of CVD events or mortality, and a composite of kidney failure or mortality. Cox proportional hazards models with a robust variance to account for the correlation in outcomes within matched pairs were sequentially adjusted for demographic, clinical, and laboratory characteristics to assess the association between aspirin use and events. Results: 981 aspirin users were matched to 981 nonusers. During a 4-year mean follow up, there were 225 CVD events, 200 deaths, 126 kidney failure events, 301 composite kidney failure or mortality events, and 324 composite CVD or mortality events. Adjusted models showed no significant difference associated with aspirin use in risk for CVD events, all-cause mortality, kidney failure, composite of kidney failure or mortality, or composite of primary CVD events or mortality (HRs of 1.20 [95% CI, 0.92-1.58], 0.92 [95% CI, 0.69-1.23], 1.19 [95% CI, 0.81-1.74], 1.03 [0.82-1.31], and 1.11 [95% CI, 0.88-1.38], respectively). Limitations: We did not examine dose or continued use of aspirin after randomization. CVD history is dependent on participant report at baseline. Aspirin use was non-randomly assigned. Conclusions: Aspirin use is not associated with reduced risk for incident CVD, all-cause mortality, or kidney failure in stable kidney transplant recipients with no history of CVD.

0272-6386

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609111699

Ferfar Y. Mirault T. Desbois A.C. Comarmond C. Messas E. Savey L. Domont F. Cacoub P. Saadoun D.

(Ferfar, Desbois, Comarmond, Savey, Domont, Cacoub, Saadoun) Assistance Publique-Hopitaux de Paris (AP-HP), Groupe Hospitalier Pitie-Salpetriere, Service de Medecine Interne et d'Immunologie clinique, Centre de reference des maladies autoimmunes et systemiques rares, DHU I2B, Immunopathology, Inflammation and Biotherapy, Universite Pierre et Marie Curie (UPMC)-Paris VI, Paris, France
(Mirault, Messas) Assistance Publique-Hopitaux de Paris (AP-HP), Groupe Hospitalier HEGP, Service de Medecine Vasculaire, Centre national de reference des maladies vasculaires rares, France

Netherlands

Biotherapies in large vessel vasculitis.

Autoimmunity Reviews. 2016. Date of Publication: February 02, 2016.

Elsevier

Autoimmun. Rev.

Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are large vessel vasculitis (LVV) and aortic involvement is not uncommon in Behcet's disease (BD) and relapsing polychondritis (RP). Glucocorticosteroids are the mainstay of therapy in LVV. However, a significant proportion of patients have glucocorticoid dependance, serious side effects or refractory disease to steroids and other immunosuppressive treatments such as cyclophosphamide, azathioprine, mycophenolate mofetil and methotrexate. Recent advances in the understanding of the pathogenesis have resulted in the use of biological agents in patients with LVV. Anti-tumor necrosis factor-alpha drugs seem effective in patients with refractory Takayasu arteritis and vascular BD but have failed to do so in giant cell arteritis. Preliminary reports on the use of the anti-IL6-receptor antibody (tocilizumab), in LVV have been encouraging. The development of new biologic targeted therapies will probably open a promising future for patients with LVV.

1568-9972

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609111633

Takigawa H. Kitadai Y. Shinagawa K. Yuge R. Higashi Y. Tanaka S. Yasui W. Chayama K.

(Takigawa, Kitadai, Yuge, Chayama) Department of Gastroenterology and Metabolism Hiroshima University Hiroshima Japan
(Shinagawa) Department of Endoscopy Hiroshima Prefectural Hospital Hiroshima Japan
(Higashi) Department of Cardiovascular Physiology and Medicine Hiroshima University Hiroshima Japan
(Tanaka) Department of Endoscopy Hiroshima University Hospital Hiroshima Japan
(Yasui) Department of Molecular Pathology Hiroshima University Hiroshima Japan

United Kingdom

Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma.

Cancer Science. 2016. Date of Publication: 2016.

Blackwell Publishing Ltd

Cancer Sci.

Interaction between tumor cells and stromal cells plays an important role in the growth and metastasis of colon cancer. We previously found that carcinoma-associated fibroblasts (CAFs) expressed platelet-derived growth factor receptor-beta (PDGFR-beta) and that PDGFR targeted therapy using imatinib or nilotinib inhibited stromal reaction. Bone marrow-derived mesenchymal stem cells (MSCs) migrate to tumor stroma and differentiate into CAFs. A novel oral multikinase inhibitor regorafenib inhibits receptor tyrosine kinases expressed on stromal cells (vascular endothelial growth factor receptor 1-3, TIE2, PDGFR-beta, and fibroblast growth factors) and tumor cells (c-KIT, RET, and BRAF). These molecules are involved in tumor growth, angiogenesis, lymphangiogenesis, and stromal activation. Therefore, we examined whether regorafenib impaired the tumor-promoting effect of CAFs/MSCs. KM12SM human colon cancer cells alone or KM12SM cells with MSCs were transplanted into the cecal wall of nude mice. Co-implantation of KM12SM cells with MSCs into the cecal wall of nude mice produced tumors with abundant stromal component and promoted tumor growth and lymph node metastasis. Single treatment with regorafenib inhibited tumor growth and metastasis by inhibiting both tumor cells and stromal reaction. This tumor-inhibitory effect of regorafenib was more obvious in tumors developed by co-implanting KM12SM cells with MSCs. Our data suggested that targeting of the tumor microenvironment with regorafenib affected tumor cell-MSC interaction, which in turn inhibited the growth and metastasis of colon cancer.

1347-9032

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609111587

Niegisch G. Retz M. Siener R. Albers P.

(Niegisch, Albers) Department of Urology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany
(Retz) Department of Urology, Klinikum rechts der Isar der Technischen Universitat Munchen, Munich, Germany
(Siener) Department of Urology, Bonn University, Bonn, Germany

United States

Quality of life in patients with cisplatin-resistant urothelial cancer: Typical ailments and effect of paclitaxel-based salvage therapy.

Urologic Oncology: Seminars and Original Investigations. 2016. Date of Publication: July 17, 2015.

Elsevier Inc.

Urol. Oncol. Semin. Orig. Invest.

Introduction: Efficacy of palliative second-line treatment in patients suffering from advanced urothelial cancer (aUC) is limited. Accordingly, careful observation of patient-reported and treatment-related changes of quality of life (QoL) is mandatory. Therefore, we evaluated "typical" ailments and treatment related QoL changes in these patients. Patients and methods: Results of the EORTC QLQ-C30 questionnaire were reviewed in 129 patients included in 2 prospective trials on paclitaxel-based treatment of cisplatin-resistant aUC (gemcitabine/paclitaxel: 102 patients [AB 20/99]; paclitaxel/everolimus: 27 patients [AB 35/09]). Eligible patients had completed EORTC QLQ-C30 questionnaire questionnaire before treatment start and available data on response. Global health status (QL), functional scales (FuSc) and symptom scales (SySc) were compared with published normative data for patients suffering from metastatic/recurrent cancers. Treatment related changes of QoL were evaluated. For statistical evaluation 2-way analysis of variance was used. Results: A total of 87 patients were eligible (63 men and 24 women, median age = 65 [interquartile range: 60-71]. y, AB 20/99: 63 patients [72%], AB 35/09: 24 patients [28%]). Compared with metastatic/recurrent cancers normative data, impaired emotional FuSc (-11.6 [95% CI:-21.0 to-2.1] points, P<0.01) and higher pain SySc (+12.9 [CI: 3.7-22.1] points, P<0.001) were the most relevant differences. QL and further FuSc/SySc were comparable. Pain SySc was significantly lower after 3 (-15.8 [CI:-31.4 to-0.7] points, P<0.01] and 4 cycles (-13.6 [CI:-29.2-2.1] points, P<0.05). Further changes of QL, FuSc or SySc during treatment were not observed. QL, FuSc, and SySc at baseline and during treatment did not differ between responders and nonresponders. Conclusions: Patients with aUC who received additional treatment demonstrated QoL changes similar to persons with other recurrent/metastatic cancers. Special emphasis should be attributed to pain and emotional problems. Despite treatment related side effects, patients did not report impairment of QoL.

1078-1439

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609108603

Phillips O.A. Al-Soraj M.

Switzerland

Proceedings of the 5th Kuwait International Pharmacy Conference (5th KIPC), Faculty of Pharmacy, Health Sciences Center, Kuwait University, Kuwait, February 1-3, 2015.

Medical Principles and Practice. 2016. Date of Publication: 17 Mar 2016.

S. Karger AG

Med. Princ. Pract.

Objective:<br><br>Kuwait International Pharmacy Conference (KIPC) is a biennial interdisciplinary conference of the Faculty of Pharmacy, Health Sciences Centre, Kuwait University, Kuwait. The theme of the 5th KIPC was "Advances in cancer therapeutics: From bench to bedside". Its main aim was to provide a medium for the exchange of up-to-date knowledge among healthcare professionals (pharmacists, physicians, medical and pharmaceutical scientists, academics and students) in the following major areas:- 1.drug delivery in cancer 2.drug resistance in cancer3.novel approaches to cancer therapeutics4.pharmaceutical care of cancer patients5.public awareness in cancerCancer continues to be one of the major non-communicable diseases posing a significant threat to world health and Kuwait is not exempted in this regard. According to WHO, approximately 14 million new cases and 8.2 million cancer related deaths occurred in 2012. On the first day of the conference, the Keynote address, titled "How are we doing in the war against cancer?" presented an overview of the progress on novel therapeutic options in cancer treatment. This was followed by a series of plenary lectures which focused on specific themes, including novel approaches to cancer therapeutics and pharmaceutical care of cancer patients. The second day of the conference focused on drug resistance in cancer, drug delivery in cancer and novel developments in the pharmaceutical care of cancer patients. This was followed by three professional workshops on pharmaceutical care of cancer patients with regards to automation of chemotherapeutic agents, patient counseling and immune-oncology as a new paradigm in cancer management. The third day of the conference was devoted to sessions on drug resistance in breast cancer, novel approaches to cancer therapeutics and pharmaceutical care of cancer patients. This last day was crowned by a public awareness in cancer session, which attracted the general public and people from all works of life. This supplement to Medical Principles and Practice, features seven review articles to showcase some of the topics discussed at the conference. Professor Sakar discussed the role of highly complex signaling networks (resistome) in therapy-resistance and heterogeneous gastrointestinal (GI) cancers with emphasis on design of novel holistic therapeutic approaches. He reviewed various challenges in understanding GI resistome in pancreatic and colon cancers and the utilization of computational biology in designing potentially effective therapy in overcoming resistance. Professor Sakar also discussed the scientific basis for the usefulness of a combination of enzalutamide with BioResponse 3,3'-diindoylmethane (BR-DIM) in treating castrate-resistant prostate cancer (CRPC). Endocrine resistance and metastasis in breast cancer continue to play major roles in morbidity and mortality worldwide, placing breast cancer among the fifth most common causes of cancer death. Dr. Khajah discussed the effect of extracellular alkaline pH in resistant breast cancer blebbing and the significance of this phenomenon in enhancing invasive capacity and metastasis. He further disclosed that the inhibition of cellular blebs could serve as potential therapeutic target in controlling tumor metastasis. The use of aromatase inhibitors and selective estrogen receptor modulator (SERMS) as therapeutic strategies in breast cancer patients is about 50% success rate in women with advanced metastatic disease despite adequate levels of estrogen receptor (ER). Professor Luqmani, discussed the implications of multiple mechanisms that could lead to therapeutic failure, including, loss or modification in ER expression, antagonistic action of SERMS and small non-coding microRNAs as critical gene regulators exhibiting differential expression in tamoxifen sensitive versus resistant cell lines, among others. He further suggests that targeting these could serve as effective therapeutic options in managing resistant breast cancer. Dr. Zujewski critically evaluated the changing paradigms in breast cancer therapeutics over a 15 years period (2000-2015). She highlighted that in general, breast cancer has increased in incidence over the past several decades, but decreased mortality has been noted in regions of the world with access to effective cancer health care provisions. She further discussed the significance of genetic profiles on health and disease. The development of new drugs against HER-2 positive breast cancer is also disclosed. She concluded that the challenge of 2015 and beyond is precision medicine, prevention and early treatment strategies, tailored to the individual variability, tumor characteristics and patient preferences.Natural products continue to serve as rich sources for the discovery of novel cancer chemotherapeutic agents. Professor Pezzuto discussed several structurally diverse and unique agents with novel mechanisms of action as potential cancer chemotherapeutic and chemoprotective agents. He concludes that natural product research is a powerful approach for discovery of biologically active compounds, which could serve as chemical leads that may interact with most pharmacotherapy targets. Finally, Dr. Abdelbary discussed issues surrounding the utilization of liposomal formulations as means of pulmonary drug delivery by inhalation and their anticancer applications. The three day event provided a forum for the exchange and dissemination of scientific information that stimulated and challenged members of the health care in their future practices and research activities. The successful organization of the 5th KIPC 2015 conference could not have been achieved without the valuable financial support from our Sponsors, namely Kuwait University and Kuwait Foundation for the Advancement of Sciences (KAFAS), Advanced Technology Company K. S. C., Kuwait Saudi Pharmaceutical Industries Company, Kuwait Pharmacists Association, Bristol-Myers Squibb, Roche and Hamad Saleh Al-Homaizi Gransons Pharma Company. Finally, the support of Professor Pierre Moreau, Dean of the Faculty of Pharmacy, Kuwait University and the relentless efforts and contributions of the Organizing and Scientific Committee members are highly appreciated. Disclosure StatementThe authors, disclosed no conflicts of interestGuest EditorsProf. Oludotun Adebayo Phillips, (5th KIPC 2015, Chair, Scientific Committee) Dr. Monerah Al-Soraj, (5th KIPC 2015, Chair, Organizing Committee)<br><br>Materials (Subjects) and Methods<br><br><br><br>Results: <br><br><br><br>Conclusion:<br><br>

1011-7571

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609108487

Oshima Y. Yuji K. Tojo A.

(Oshima, Yuji, Tojo) The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

Japan

"Imatinib-induced gastric antral vascular ectasia" in a reporting system of the Japanese Adverse Drug Event Report database.

International Journal of Hematology. (pp 1-3), 2016. Date of Publication: 15 Mar 2016.

Springer-Verlag Tokyo

Int. J. Hematol.

0925-5710

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

609105302

Marmor M.F. Kellner U. Lai T.Y.Y. Melles R.B. Mieler W.F.

(Marmor) Department of Ophthalmology and Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California
(Kellner) Zentrum fur Seltene Netzhauterkrankungen, AugenZentrum Siegburg, Siegburg, Germany
(Lai) Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong
(Melles) Department of Ophthalmology, Kaiser Permanente, Redwood City Medical Center, Redwood City, California
(Mieler) Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois, Chicago, Illinois

United States

Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision).

Ophthalmology. 2016. Date of Publication: January 28, 2016.

Elsevier Inc.

Ophthalmology

Background: The American Academy of Ophthalmology recommendations on screening for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are revised in light of new information about the prevalence of toxicity, risk factors, fundus distribution, and effectiveness of screening tools. Pattern of Retinopathy: Although the locus of toxic damage is parafoveal in many eyes, Asian patients often show an extramacular pattern of damage. Dose: We recommend a maximum daily HCQ use of <5.0 mg/kg real weight, which correlates better with risk than ideal weight. There are no similar demographic data for CQ, but dose comparisons in older literature suggest using <2.3 mg/kg real weight. Risk of Toxicity: The risk of toxicity is dependent on daily dose and duration of use. At recommended doses, the risk of toxicity up to 5 years is under 1% and up to 10 years is under 2%, but it rises to almost 20% after 20 years. However, even after 20 years, a patient without toxicity has only a 4% risk of converting in the subsequent year. Major Risk Factors: High dose and long duration of use are the most significant risks. Other major factors are concomitant renal disease, or use of tamoxifen. Screening Schedule: A baseline fundus examination should be performed to rule out preexisting maculopathy. Begin annual screening after 5 years for patients on acceptable doses and without major risk factors. Screening Tests: The primary screening tests are automated visual fields plus spectral-domain optical coherence tomography (SD OCT). These should look beyond the central macula in Asian patients. The multifocal electroretinogram (mfERG) can provide objective corroboration for visual fields, and fundus autofluorescence (FAF) can show damage topographically. Modern screening should detect retinopathy before it is visible in the fundus. Toxicity: Retinopathy is not reversible, and there is no present therapy. Recognition at an early stage (before any RPE loss) is important to prevent central visual loss. However, questionable test results should be repeated or validated with additional procedures to avoid unnecessary cessation of valuable medication. Counseling: Patients (and prescribing physicians) should be informed about risk of toxicity, proper dose levels, and the importance of regular annual screening.

0161-6420

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609104367

Rakoczi E. Perge B. Vegh E. Csomor P. Pusztai A. Szamosi S. Bodnar N. Szanto S. Szucs G. Szekanecz Z.

(Rakoczi) Institute of Clinical Pharmacology, Infectious Diseases and Allergology, Kenezy Gyula Hospital, 2-6, Bartok B street, 4034 Debrecen, Hungary
(Perge, Vegh, Csomor, Pusztai, Szamosi, Bodnar, Szanto, Szucs, Szekanecz) Department of Rheumatology, Medical and Health Sciences Center, Faculty of Medicine, University of Debrecen, 98, Nagyerdei street, 4032 Debrecen, Hungary

France

Evaluation of the immunogenicity of the 13-valent conjugated pneumococcal vaccine in rheumatoid arthritis patients treated with etanercept.

Joint Bone Spine. 2016. Date of Publication: 2016.

Elsevier Masson SAS (62 rue Camille Desmoulins, Issy les Moulineaux Cedex 92442, France)

Jt. Bone Spine

Objectives: To prospectively evaluate the immunogenicity of a 13-valent conjugated pneumococcal vaccine (PCV13) in rheumatoid arthritis (RA) patients undergoing etanercept therapy. Methods: Twenty-two RA patients treated with etanercept (ETA) in combination with methotrexate (MTX) (n = 15) or monotherapy (n = 7) for at least one year were included. Altogether 24 osteoarthritis patients not receiving biological or MTX therapy, treating only NSAIDs or analgesics served as controls. All subjects were vaccinated with a single dose (0.5. ml) of the PCV13. Pneumococcal antibody levels at baseline, 4 and 8. weeks were assessed by a VaccZymeTM Anti-PCP IgG Enzyme Immunoassay Kit. Based on recommendations of the American Academy of Allergy, Asthma & Immunology, an at least two-fold increase in antibody level, as the protective antibody response (pAR) was an indicator of responsiveness (i.e., ratio of postvaccination and prevaccination antibody levels). The antibody levels and their ratios were analysed in a variety of different ways, vaccine safety parameters (fever, infections, changes in regular antirheumatic treatments) were assessed at baseline, 4 and 8. weeks after vaccination. Results: Four weeks after vaccination, the anti-pneumococcal antibody levels significantly increased in both groups. At week 8, antibody levels somewhat decreased in both groups, however, still remained significantly higher compared to baseline. Compared with postvaccination levels at 4 and 8. weeks between two groups, the mean protective antibody levels were higher in control group (1st month P = 0.016; 2nd month: P = 0.039). Possible predictors of pAR were analysed by logistic regression model. In RA, increases of antibody levels at week 8 compared to baseline exerted a negative correlation with age, (Spearman's R = -0,431; P = 0.045). There were no clinically significant side effects or reaction after administration of vaccine observed in any of these patients after the 2-month follow-up period, all patients medical condition were stable. Conclusions: In RA patients treated with ETA, vaccination with PCV13 is effective and safe, resulting in pAR one and two months after vaccination. Higher age at vaccination was identified as predictors of impaired pAR. The efficacy of vaccination may be more pronounced in younger RA patients. The vaccine is safe in RA patients on ETA.

1297-319X

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

609104040

Fall S. Ndiaye F.S.D. Dior O.D. Sall A.F. Sloma I. Toure-Fall A. Keita Y.

(Fall, Ndiaye, Dior) Unite hematologie clinique de l'hopital Aristide Le Dantec, 30, avenue Pasteur, Dakar, Senegal
(Sall, Toure-Fall) Service de biologie de l'hopital Aristide Le Dantec, 30, avenue Pasteur, Dakar, Senegal
(Sloma) Inserm UMRS 935, service d'hematologie biologique/pole BPPSP, plateforme de genetique des cancers, hopitaux universitaires Paris-Sud, 94804 Villejuif cedex, France
(Keita) Service de pediatrie de l'hopital Aristide Le Dantec, 30, avenue Pasteur, Dakar, Senegal

France

Chronic myeloid leukemia in young patients: Experience in a clinical hematology unit in Senegal.

Revue d'Oncologie Hematologie Pediatrique. 2015. Date of Publication: May 31, 2015.

Elsevier Masson SAS (62 rue Camille Desmoulins, Issy les Moulineaux Cedex 92442, France)

Rev. Oncol. Hematol. Pediatr.

Purpose: As far as we know, there is not yet any study available about chronic myeloid leukemia in children and adolescents in sub-Saharan Africa. In order to describe its clinical, cytogenetic, prognostic, and evolving characteristics, we conducted a retrospective descriptive study during 6. years (February 2008-July 2014). Method: This study was conducted in the Hematology Clinical Unit of the Aristide Le Dantec Hospital (Senegal) involving patients aged 17. years or more, suffering from chronic myeloid leukemia, treated using Imatinib Mesylate. Results: Nine of the 87 patients (10.4%) were included in the study. These were 7 boys and 2 girls, whose median age was 14. years [9-17. years]. They were received in either the chronic phase (7 cases) or the accelerated phase (2 cases). The median diagnostic delay was 19. months [2-54. months]. The Sokal score was low (4 cases), intermediate (3 cases) and high (2 cases). One patient had also a trisomy 8. The overall trend was marked by a complete cytogenetic remission in 6 cases, a partial remission in 2 cases and a minor remission in the remaining case. Two patients lost the response to the treatment, with a mutation of BCR-Abelson objectified in 1 case. Toxic effects were vomiting (1 case), diffuse depigmentation (1 case) and thrombocytopenia (2 cases). Conclusion: In our study, chronic myeloid leukemia in children and adolescents is uncommon and is diagnosed late. Imatinib Mesylate is effective, but the loss of response related to mutations, required the use of other tyrosine kinase inhibitors and/or bone marrow transplantation, which are not available in our regions.

2213-4670

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

20160225304

Krop I.E. Modi S. LoRusso P.M. Pegram M. Guardino E. Althaus B. Lu D. Strasak A. Elias A.

(Krop) Dana-Farber Cancer Institute, Breast Oncology, 450 Brookline Avenue, Boston, MA 02215, United States
(Modi) Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States
(Modi) Weill Cornell Medical College, 445 E 69th St, New York, NY 10021, United States
(LoRusso) Yale University, 800 Howard Ave, New Haven, CT 06519, United States
(Pegram) Stanford University School of Medicine, Stanford Cancer Institute, 900 Blake Wilbur, Stanford, CA 94305, United States
(Guardino, Althaus, Lu) Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States
(Strasak) F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, Basel ch-4070, Switzerland
(Elias) University of Colorado Cancer Center, 1665 Aurora Ct, Aurora, CO 80045, United States

United Kingdom

Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer.

Breast Cancer Research. 18 (1) 2016. Article Number: 34. Date of Publication: March 15, 2016.

BioMed Central Ltd.

Breast Cancer Res.

Background: In pre-clinical studies, the anti-tumor activity of T-DM1 was enhanced when combined with taxanes or pertuzumab. This phase 1b/2a study evaluated the safety/tolerability of T-DM1 + paclitaxel +/- pertuzumab in HER2-positive advanced breast cancer. Methods: In phase 1b (n = 60), a 3 + 3 dose-escalation approach was used to determine the maximum tolerated dose (MTD) of T-DM1 + paclitaxel +/- pertuzumab. The primary objective of phase 2a was feasibility, with 44 patients randomized to T-DM1 + paclitaxel +/- pertuzumab at the MTD identified in phase 1b. Results: The MTD was T-DM1 3.6 mg/kg every three weeks (q3w) or 2.4 mg/kg weekly + paclitaxel 80 mg/m² weekly +/- pertuzumab 840 mg loading dose followed by 420 mg q3w. Phase 2a patients had received a median of 5.0 (range: 0-10) prior therapies for advanced cancer. In phase 2a, 51.2 % received >12 paclitaxel doses within 15 weeks, and 14.0 % received 12 paclitaxel doses by week 12. Common all-grade adverse events (AEs) were peripheral neuropathy (90.9 %) and fatigue (79.5 %). A total of 77.3 % experienced grade >3 AEs, most commonly neutropenia (25.0 %) and peripheral neuropathy (18.2 %). Among the 42 phase 2a patients with measurable disease, the objective response rate (ORR) was 50.0 % (95 % confidence interval (CI) 34.6-65.4); the clinical benefit rate (CBR) was 56.8 % (95 % CI 41.6-71.0). No pharmacokinetic interactions were observed between T-DM1 and paclitaxel. Conclusions: This regimen showed clinical activity. Although there is potential for paclitaxel to be added to T-DM1 +/- pertuzumab, peripheral neuropathy was common in this heavily pretreated population. Trial registration: ClinicalTrials.gov NCT00951665. Registered August 3, 2009.

1465-5411

Journal: Article

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

20160223461

Apice G. Pizzolorusso A. Di Maio M. Grignani G. Gebbia V. Buonadonna A. De Chiara A. Fazioli F. De Palma G. Galizia D. Arcara C. Mozzillo N. Perrone F.

(Apice, Pizzolorusso, Di Maio, De Chiara, Fazioli, De Palma, Mozzillo, Perrone) Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Via Mariano Semmola, Napoli 80131, Italy
(Grignani, Galizia) Institute for Cancer Research and Treatment, Strada Provinciale, km 3.95, Candiolo, Turin 10060, Italy
(Gebbia, Arcara) Medical Oncology Unit, La Maddalena Hospital, Via San Lorenzo Colli 312/d, Palermo 90146, Italy
(Buonadonna) Departments of Radiation Oncology and Medical Oncology, CRO, National Cancer Institute, Via Franco Gallini 2, Aviano 33081, Italy

United States

Confirmed Activity and Tolerability of Weekly Paclitaxel in the Treatment of Advanced Angiosarcoma.

Sarcoma. 2016 2016. Article Number: 6862090. Date of Publication: 2016.

Hindawi Publishing Corporation (410 Park Avenue, 15th Floor, 287 pmb, New York NY 10022, United States)

Sarcoma

Background. In several prospective and retrospective studies, weekly paclitaxel showed promising activity in patients with angiosarcoma. Patients and Methods. Our study was originally designed as a prospective, phase II multicenter trial for patients younger than 75, with ECOG performance status 0-2, affected by locally advanced or metastatic angiosarcoma. Patients received paclitaxel 80 mg/m² intravenously, at days 1, 8, and 15 every 4 weeks, until disease progression or unacceptable toxicity. Primary endpoint was objective response. Results. Eight patients were enrolled but, due to very slow accrual, the trial was prematurely stopped and further 10 patients were retrospectively included in the analysis. Out of 17 evaluable patients, 6 patients obtained an objective response (5 partial, 1 complete), with an objective response rate of 35% (95% confidence interval 17%-59%). Of note, five responses were obtained in pretreated patients. In the paper, details of overall survival, progression-free survival, and tolerability are reported. Conclusions. In this small series of patients with locally advanced or metastatic angiosarcoma, weekly paclitaxel was confirmed to be well tolerated and active even in pretreated patients.

1357-714X

Journal: Article

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

20160221750

Sato K. Watanabe S. Ohtsubo A. Shoji S. Ishikawa D. Tanaka T. Nozaki K. Kondo R. Okajima M. Miura S. Tanaka J. Sakagami T. Koya T. Kagamu H. Yoshizawa H. Narita I.

(Sato, Ohtsubo, Shoji, Ishikawa, Tanaka, Nozaki, Kondo, Okajima, Miura, Sakagami, Koya, Kagamu, Narita) Niigata University Medical and Dental Hospital, Department of Medicine (II), Niigata City, Niigata, Japan
(Watanabe, Yoshizawa) Niigata University Medical and Dental Hospital, Bioscience Medical Research Center, Niigata City, Niigata, Japan
(Tanaka) Niigata University Medical and Dental Hospital, Department of Health Promotion Medicine, Niigata City, Niigata, Japan

United Kingdom

Nephrotoxicity of cisplatin combination chemotherapy in thoracic malignancy patients with CKD risk factors.

BMC Cancer. 16 (1) 2016. Article Number: 222. Date of Publication: March 15, 2016.

BioMed Central Ltd.

BMC Cancer

Background: Nephrotoxicity is the major side effect that limits the dose of cisplatin that can be safely administered, and it is a clinical problem in cancer patients who received cisplatin combination chemotherapy. Recent evidence has demonstrated that patients with chronic kidney disease (CKD) have an increased risk of developing acute kidney injury (AKI). The present study was conducted to evaluate the prevalence of CKD risk factors in patients who received cisplatin and to assess the correlation between CKD risk factors and cisplatin-induced AKI. Methods: We retrospectively analyzed 84 patients treated with cisplatin combination chemotherapy for thoracic malignancies. AKI was defined as a decrease in the estimated glomerular filtration rate (eGFR) > 25 % from base line, an increase in the serum creatinine (sCre) level of > 0.3 mg/dl or > 1.5 times the baseline level. Results: Eighty of the 84 patients (95.2 %) had at least one risk factor for CKD. All enrolled patients received cisplatin with hydration, magnesium supplementation and mannitol. Cisplatin-induced AKI was observed in 18 patients (21.4 %). Univariate analysis revealed that cardiac disease and use of non-steroidal anti-inflammatory drugs (NSAIDs) were associated with cisplatin-induced nephrotoxicity (odds ratios [OR] 6 and 3.56, 95 % confidence intervals [CI] 1.21-29.87 and 1.11-11.39, p = 0.04 and p = 0.04, respectively). Multivariate analysis revealed that cisplatin nephrotoxicity occurred significantly more often in patients with both risk factors (OR 13.64, 95 % CI 1.11-326.83, p = 0.04). Patients with more risk factors for CKD tended to have a greater risk of developing cisplatin-induced AKI. Conclusions: We should consider avoiding administration of cisplatin to patients with CKD risk factors, particularly cardiac disease and NSAID use.

Journal: Article

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

20160221673

Hijaz M. Das S. Mert I. Gupta A. Al-Wahab Z. Tebbe C. Dar S. Chhina J. Giri S. Munkarah A. Seal S. Rattan R.

(Hijaz, Mert, Al-Wahab, Tebbe, Dar, Chhina, Munkarah, Rattan) Henry Ford Hospital, Division of Gynecology Oncology, Department of Women's Health, Detroit, MI, United States
(Das, Gupta, Seal) University of Central Florida, Advanced Materials Processing and Analysis Center, Nanoscience and Technology Center, Materials Science and Engineering, Orlando, FL, United States
(Mert) Wayne State University, Detroit, MI, United States
(Giri) Henry Ford Hospital, Department of Neurology, Detroit, MI, United States
(Giri, Munkarah, Rattan) Henry Ford Hospital, Josephine Ford Cancer Institute, Detroit, MI, United States
(Seal) University of Central Florida, College of Medicine, Orlando, FL, United States

United Kingdom

Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer.

BMC Cancer. 16 (1) 2016. Article Number: 220. Date of Publication: March 15, 2016.

BioMed Central Ltd.

BMC Cancer

Background: Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-alpha, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin. Methods: Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects. Results: We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model. Conclusion: Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy.

Journal: Article

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

609104176

Landrum L.M. Brady W.E. Armstrong D.K. Moore K.N. DiSilvestro P.A. O'Malley D.M. Tenney M.E. Rose P.G. Fracasso P.M.

(Landrum, Moore) Department of OB/GYN, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
(Brady) NRG Oncology/Gynecologic Oncology Group Statistics and Data Center, Roswell Park Cancer Institute, Buffalo, NY, United States
(Armstrong) Department of Gynecology and Obstetrics, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, United States
(DiSilvestro) Department of Gynecologic Oncology, Women and Infant's Hospital, Providence, RI, United States
(O'Malley) Department of Gynecologic Oncology, The Ohio State University, Columbus, OH, United States
(Tenney) Department of Gynecologic Oncology, University of Chicago, Chicago, IL, United States
(Rose) Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Cleveland Clinic, Cleveland, OH, United States
(Fracasso) Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, United States
(Fracasso) Bristol-Myers Squibb Company, Princeton, NJ, United States

United States

A phase I trial of pegylated liposomal doxorubicin (PLD), carboplatin, bevacizumab and veliparib in recurrent, platinum-sensitive ovarian, primary peritoneal, and fallopian tube cancer: An NRG Oncology/Gynecologic Oncology Group study.

Gynecologic Oncology. 2016. Date of Publication: September 29, 2015.

Academic Press Inc.

Gynecol. Oncol.

Objective: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of veliparib combined with PLD and carboplatin (CD) in patients with recurrent, platinum-sensitive epithelial ovarian cancer. To determine the tolerability at the MTD combined with bevacizumab. Methods: Patients received PLD (30mg/m², IV) and carboplatin (AUC 5, IV) on day 1 with veliparib on days 1-7 (intermittent) or days 1-28 (continuous). Standard 3+3 design was used in the dose escalation phase with DLTs based on the first cycle. Once the MTDs were determined, cohorts of 6 patients were enrolled to each regimen with bevacizumab (10mg/kg on days 1 and 15) to assess feasibility. DLTs were based on the first 4cycles of treatment in the bevacizumab cohorts. Results: In the dose-escalation phase, 27 patients were treated at 3 dose levels with DLTs noted in 6 patients including grade 4 thrombocytopenia (n = 4), and prolonged neutropenia >. 7. days (n = 3). At the MTD of veliparib (80. mg p.o. b.i.d. for both dosing arms), myelosuppression was the DLT. At MTD, 12 additional patients were treated with bevacizumab with 9 patients experiencing DLTs including grade 4 thrombocytopenia (n = 4), prolonged neutropenia >. 7. days (n = 1), grade 3 hypertension (n = 5), and grade 5 sepsis (n = 1). Conclusions: The MTD of veliparib combined with CD is 80. mg p.o. b.i.d. in women with recurrent, platinum-sensitive ovarian cancer. With bevacizumab, DLTs were noted in 9 out of 12 patients. Lower doses of veliparib will need to be considered when given in combination with platinum-based therapies.

0090-8258

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609102718

Li C. Ge Y. Dworkin L. Peng A. Gong R.

(Li, Peng) Department of Nephrology, Shanghai Tenth People's Hospital Tongji University School of Medicine Shanghai China
(Li, Ge, Dworkin, Gong) Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital Brown University School of Medicine Providence, Rhode Island USA

United Kingdom

The beta isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy.

Journal of Pathology. 2016. Date of Publication: 2016.

John Wiley and Sons Ltd (Southern Gate, Chichester, West Sussex PO19 8SQ, United Kingdom)

J. Pathol.

Converging evidence points to glycogen synthase kinase (GSK) 3 as a key player in the pathogenesis of podocytopathy and proteinuria. However, it remains unclear if GSK3 is involved in podocyte autonomous injury in glomerular disease. In normal kidneys, the beta isoform of GSK3 was found to be the major GSK3 expressed in glomeruli and intensely stained in podocytes. GSK3beta expression in podocytes was markedly elevated in experimental or human proteinuric glomerulopathy. Podocyte-specific somatic ablation of GSK3beta in adult mice attenuated proteinuria and ameliorated podocyte injury and glomerular damage in experimental adriamycin (ADR) nephropathy. Mechanistically, actin cytoskeleton integrity in podocytes was largely preserved in GSK3beta knockout mice following ADR insult, concomitant with a correction of podocyte hypermotility and lessened phosphorylation and activation of paxillin, a focal adhesion-associated adaptor protein. In addition, GSK3beta knockout diminished ADR-induced NFkappaB RelA/p65 phosphorylation selectively at serine 467; suppressed de novo expression by podocytes of NFkappaB-dependent podocytopathic mediators, including B7-1, cathepsin L, and MCP-1; but barely affected the induction of NFkappaB target pro-survival factors, such as Bcl-xL. Moreover, the ADR-elicited podocytopenia and podocyte death were significantly attenuated in GSK3beta knockout mice, associated with protection against podocyte mitochondrial damage and reduced phosphorylation and activation of cyclophilin F, a structural component of mitochondria permeability transition pores. Overall, our findings suggest that the beta isoform of GSK3 mediates autonomous podocyte injury in glomerulopathy by integrating multiple podocytopathic signalling pathways.

0022-3417

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609102215

Yao M. Woods C. Lavertu P. Fu P. Gibson M. Rezaee R. Zender C. Wasman J. Sharma N. Machtay M. Savvides P.

(Yao, Woods, Machtay) Department of Radiation OncologyUniversity Hospitals Case Medical Center, Seidman Cancer HospitalCleveland, Ohio
(Lavertu, Rezaee, Zender) Department of Otolaryngology - Head and Neck SurgeryUniversity Hospitals Case Medical Center, Seidman Cancer HospitalCleveland, Ohio
(Gibson, Sharma, Savvides) Department of Internal Medicine (Medical Oncology)University Hospitals Case Medical Center, Seidman Cancer HospitalCleveland, Ohio
(Wasman) Department of PathologyUniversity Hospitals Case Medical Center, Seidman Cancer HospitalCleveland, Ohio
(Fu) Department of Epidemiology and BiostatisticsCase Western Reserve University School of MedicineCleveland, Ohio
(Savvides) The University of Arizona Cancer Center500 W Thomas RoadPhoenix 85013AZ

United States

Phase II study of erlotinib and docetaxel with concurrent intensity-modulated radiotherapy in locally advanced head and neck squamous cell carcinoma.

Head and Neck. 2016. Date of Publication: 2016.

John Wiley and Sons Inc. (P.O.Box 18667, Newark NJ 07191-8667, United States)

Head Neck

Background: The purpose of this study was to establish the efficacy and toxicities of concurrent erlotinib and docetaxel with intensity-modulated radiotherapy (IMRT) for locally advanced head and neck squamous cell carcinoma (HNSCC). Methods: Patients received daily erlotinib for 2 weeks, followed by daily IMRT with concurrent weekly docetaxel and daily erlotinib, followed by daily erlotinib for up to 2 years. The primary objective was disease-free survival (DFS). Secondary objectives included overall survival (OS), patterns of failure, and toxicities. Forty-three patients were recruited for this study. Results: With a median follow-up of 48.7 months, the 3-year DFS, OS, locoregional failure-free survival, and distant metastasis-free survival was 69.5%, 81%, 82.4%, and 83.7%, respectively. The most common grade III/IV local toxicities were dysphagia, dermatitis, and mucositis. Patients with p16-positive tumors had significantly better outcomes. Conclusion: The regimen is tolerable and effective. It is worthy of further investigation in selected patients and may be useful in patients who cannot tolerate cisplatin.

1043-3074

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

609100710

Calderon B. Guerder C. Resbeut M. Fakhry N. Dupuis C. Cowen D.

(Calderon, Cowen) Service de radiotherapie, centre hospitalier universitaire de la Timone, 264, rue Saint-Pierre, 13005 Marseille, France
(Guerder) Centre de radiotherapie Saint-Louis, Croix-Rouge francaise, quartier Sainte-Musse, rue Andre-Blondel, 83100 Toulon, France
(Resbeut) Service de radiotherapie, institut Paoli-Calmettes, 232, boulevard Sainte-Marguerite, 13273 Marseille cedex 9, France
(Fakhry) Service de chirurgie ORL, centre hospitalier universitaire de la Timone, 264, rue Saint-Pierre, 13005 Marseille, France
(Dupuis) Service d'oncologie medicale, centre hospitalier universitaire de la Timone, 264, rue Saint-Pierre, 13005 Marseille, France
(Cowen) Faculte de medecine de Marseille, 27, boulevard Jean-Moulin, 13005 Marseille, France

France

Observance and results of concurrent chemoradiotherapy after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil for locally advanced head and neck cancers.

Cancer/Radiotherapie. 2016. Date of Publication: May 22, 2015.

Elsevier Masson SAS (62 rue Camille Desmoulins, Issy les Moulineaux Cedex 92442, France)

Cancer Radiother.

Purpose: Retrospectively evaluate the safety, feasibility and efficacy of concomitant chemoradiotherapy after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil for locally advanced head and neck cancers. Patients and methods: Patients' data from three radiotherapy centres in South of France, with locally advanced head and neck cancers, and treated between December 2007 and July 2013 by concomitant chemoradiotherapy, after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil, were analysed. Adverse effects were graduated according to CTCAE v3.0 criteria. Overall survival and disease-free survival were calculated according to Kaplan-Meier method. Results: One hundred and sixty-eight patients, mostly oropharynx (38 %) T4 (46 %) N2 (54 %) tumors, received, after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil, a concomitant chemoradiotherapy with platin or cetuximab, which delivered 66 to 70Gy. Grade 3-4 adverse effects were less frequent in the group of patients who received cisplatin (with or withour 5-fluoro-uracil) at 100mg/m² each 21 days compared to cetuximab (radiomucositis: 32.5 % vs 61 %, P =0.018; radioepithelitis: 13 % vs 61 %, P <0.0001). Chemopotentiation was incomplete for 21 % of patients without impacting survival. Two years overall survival and disease-free survival were respectively of 81 % and 64 %. Lymph nodes status and WHO status significantly influenced these survivals (overall survival 84 % if N<3 vs 56 % if N3, P =0.017 and 85 % if WHO status<1 vs 50 % if WHO status>1, P =0.006; disease-free survival 66 % if N<3 vs 47 % if N3, P =0.046). Conclusion: The association of induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil and concomitant chemoradiotherapy shows satisfying results with an acceptable toxicity. The terms of the chemopotentiation and its superiority to a single concomitant chemoradiotherapy treatment still remain to be clarified.

1278-3218

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

609100391

Flatmark K. Saelen M.G. Hole K.H. Abrahamsen T.W. Fleten K.G. Hektoen H.H. Redalen K.R. Seierstad T. Dueland S. Ree A.H.

(Flatmark, Saelen, Abrahamsen, Fleten, Hektoen) Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Norway
(Flatmark) Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Norway
(Hole, Seierstad) Department of Radiology, Norwegian Radium Hospital, Oslo University Hospital, Norway
(Redalen, Seierstad) Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Norway
(Dueland) Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Norway
(Hektoen, Redalen, Ree) Department of Oncology, Akershus University Hospital, Norway
(Flatmark, Saelen, Hole, Fleten, Ree) Institute of Clinical Medicine, University of Oslo, Norway

Ireland

Individual tumor volume responses to short-course oxaliplatin-containing induction chemotherapy in locally advanced rectal cancer - Targeting the tumor for radiation sensitivity?.

Radiotherapy and Oncology. 2016. Date of Publication: December 21, 2015.

Elsevier Ireland Ltd

Radiother. Oncol.

Background: Neoadjuvant treatment of locally advanced rectal cancer (LARC) involves chemoradiotherapy (CRT), which may cause significant toxicity, and the potential role and sequential placement of neoadjuvant chemotherapy (NACT) relative to CRT is under debate. Patients and methods: In a non-randomized study of 72 LARC patients, short-course oxaliplatin-containing NACT was administered prior to CRT. Tumor volumes were calculated from magnetic resonance images before and after NACT, and four weeks after CRT, and associations between tumor volume responses and outcome were analyzed. Additionally, the impact of oxaliplatin exposure on radiosensitivity was examined in colorectal carcinoma cell lines. Results: All tumors except one responded to NACT, with better responses in T3 than T4 cases, and 69/72 patients obtained additional tumor volume reduction after subsequent CRT. However, no associations were found between tumor volume reduction and long-term outcome. Of note, oxaliplatin-resistant cells were significantly more radiosensitive than the oxaliplatin-sensitive counterparts. Conclusions: Oxaliplatin-containing NACT led to substantial tumor volume reduction with particularly good responses in T3 cases. NACT did not impede subsequent CRT response, and experimental results rather suggested enhanced radiosensitivity in oxaliplatin-exposed cells, encouraging studies to explore the administration of NACT prior to CRT. Data are still lacking to support omitting radiation in LARC management.

0167-8140

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

Embase Daily Alerts

609099838

Phillip V. Zahel T. Bartl K. Rasch S. Ebert O. Schmid R.M. Rummeny E. Algul H.

(Phillip, Rasch, Ebert, Schmid, Algul) II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universitat Munchen, Ismaninger Strase 22, 81675 Munchen, Germany
(Zahel, Rummeny) Institut fur diagnostische und interventionelle Radiologie, Klinikum rechts der Isar der Technischen Universitat Munchen, Ismaninger Strase 22, 81675 Munchen, Germany
(Bartl) Chirurgische Abteilung, Kreisklinik Wolfratshausen, Moosbauerweg 5, 82515 Wolfratshausen, Germany

Netherlands

Influence of Sorafenib and Bevacizumab on pancreatic volume - A monocentric CT based analysis.

Pancreatology. 2016. Date of Publication: 2016.

Elsevier

Pancreatology

Background/Objectives: Angiogenesis plays a central role in tumor growth and metastasis and tyrosine kinases are crucial in the modulation of growth factor signaling. Several side effects of tyrosine kinase inhibitors have been reported, including diarrhea due to pancreatic insufficiency. The suspected mechanism is the anti-angiogenetic effect of the inhibited vascular endothelial growth factor (VEGF) causing a disturbance of the microvasculation. The aim of the present study was to determine the volume of the pancreas before and after a therapy both with the multi-tyrosine kinase inhibitor Sorafenib and Bevacizumab, which is a humanized monoclonal immunoglobulin G1 antibody against VEGF. Methods: Retrospective monocentric study including 42 patients who received either Sorafenib, Bevacizumab combined with Flourouracil and/or Irinotecan, or singly Flourouracil and Irinotecan for different non-pancreatic malignancies. The volume of the pancreas was measured before and after therapy by CT-scan based volumetry. Results: The pancreatic volume was statistically significantly lower after treatment with Sorafenib (75.4 mL vs. 71.0 mL; p = 0.006) or Bevacizumab and Fluorouracil +/- Irinotecan (71.8 mL vs. 62.6 mL; p = 0.020). The pancreatic volume did not change statistically significantly after treatment with Fluorouracil +/- Irinotecan only (51.1 mL vs. 49.9 mL; p = 0.142). Conclusions: Pancreatic volume decreases statistically significantly under treatment with both the multi-tyrosine kinase inhibitor Sorafenib and the angiogenesis inhibitor Bevacizumab. This volume reduction is most likely due to a reduced microvasculation by inhibition of VEGF.

1424-3903

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609097119

Alim Z. Beydemir S.

(Alim) Biochemistry Division Department of Chemistry Faculty of Science and Arts Ahi Evran University Kirsehir 40000 Turkey
(Beydemir) Biochemistry Division Department of Chemistry Faculty of Sciences Ataturk University Erzurum 25240 Turkey
(Beydemir) Department of Food Sciences Faculty of Engineering Igdir University Igdir Turkey

United Kingdom

Some Anticancer Agents Act on Human Serum Paraoxonase-1 to Reduce Its Activity.

Chemical Biology and Drug Design. 2016. Date of Publication: 2016.

Blackwell Publishing Ltd

Chem. Biol. Drug Des.

Human serum paraoxonase (hPON1) is an important antioxidant enzyme. It protects low-density lipoproteins against oxidative stress and prevents atherosclerosis development. Anticancer agents have cardiotoxic effects, and this situation can lead to significant complications. Our aim was to evaluate the in vitro effects of some of the anticancer agents such as cetuximab, paclitaxel, etoposide, docetaxel, and ifosfamide on the activity of hPON1 in this study. For this reason, PON1 was purified from human serum with a specific activity of 3654.2 EU/mg and 16.84% yield using simple chromatographic methods. The five chemotherapeutic agents dose dependently decreased in vitro hPON1 activity. IC₅₀ values for cetuximab, paclitaxel, etoposide, docetaxel, and ifosfamide were 0.0111, 0.042, 0.226, 0.665, and 23.3 mm, respectively. K_i constants were 0.0194, 0.0165, 0.131, 0.291, and 8.973 mm, respectively. The inhibition mechanisms of cetuximab, etoposide, docetaxel, and ifosfamide were non-competitive, and for paclitaxel was competitive. Consequently, inhibition of hPON1 by these anticancer agents may explain some of the cardiotoxic actions of these drugs.

1747-0277

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609079602

Yang Z. Chen D. Zhang J. Yao D. Gao K. Wang H. Liu C. Yu J. Li L.

(Yang, Chen, Zhang, Yao, Gao, Wang, Li) Department of Gynecologic Oncology, Affiliated Tumor Hospital of Guangxi Medical University, 71, Hedi Road, Nanning, Guangxi 530021, China
(Yang, Chen, Zhang, Yao, Gao, Wang, Li) Key Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, China
(Liu) Department of Gynecology, The Red Cross Hospital of Yulin, China
(Yu) Department of Gynecology, 181st Hospital of Chinese People's Liberation Army, China

United States

The efficacy and safety of neoadjuvant chemotherapy in the treatment of locally advanced cervical cancer: A randomized multicenter study.

Gynecologic Oncology. 2016. Date of Publication: March 06, 2015.

Academic Press Inc.

Gynecol. Oncol.

Objective: This study sought to evaluate the toxicity and curative effect of irinotecan plus cisplatin neoadjuvant chemotherapy (NACT) for stage Ib2, IIa2, and IIb cervical cancer patients. Methods: A total of 219 patients were randomly assigned to two groups: 109 patients were treated with 1-2 cycles of chemotherapy (NACT group), and 110 patients in the control group were treated directly with surgery (DS group). Patients in the NACT group were randomly assigned to two groups: 50 patients were treated with irinotecan plus cisplatin followed by surgery (IP group), and 59 patients were treated with paclitaxel plus cisplatin followed by surgery (TP group). Patients with pathological recurrence risk factors received post-operative radiotherapy. Results: Survival analysis revealed no significant difference in disease-free survival (DFS) or overall survival (OS) between the NACT and DS groups. Analysis of clinicopathologic factors showed that the lymphovascular space invasion (LVSI) and deep stromal invasion rates were significantly lower in the NACT group. Grade 3/4 neutropenia and grade 3/4 diarrhea were both higher in the IP group than in the TP group. DFS and OS were similar in the IP and TP groups. Univariate analysis showed that LVSI was the only factor associated with DFS. Conclusion: NACT did not improve overall survival but did reduce the number of patients who received post-operative radiotherapy. NACT consisting of irinotecan plus cisplatin for cervical cancer showed similar efficacy and higher toxicity compared with the use of paclitaxel plus cisplatin, although the toxicity was tolerable.

0090-8258

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609079386

Shinozuka K. Tang H. Jones R.B. Li D. Nieto Y.

(Shinozuka, Tang, Li) Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
(Jones, Nieto) Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas

United States

Impact of Polymorphic Variations of Gemcitabine Metabolism, DNA Damage Repair, and Drug-Resistance Genes on the Effect of High-Dose Chemotherapy for Relapsed or Refractory Lymphoid Malignancies.

Biology of Blood and Marrow Transplantation. 2016. Date of Publication: February 18, 2015.

Elsevier Inc.

Biol. Blood Marrow Transplant.

The goal of this study was to determine whether single nucleotide polymorphisms (SNPs) in genes involved in gemcitabine metabolism, DNA damage repair, multidrug resistance, and alkylator detoxification influence the clinical outcome of patients with refractory/relapsed lymphoid malignancies receiving high-dose gemcitabine/busulfan/melphalan (Gem/Bu/Mel) with autologous stem cell support. We evaluated 21 germline SNPs of the gemcitabine metabolism genes CDA, deoxycytidine kinase, and hCNT3; DNA damage repair genes RECQL, X-ray repair complementing 1, RAD54L, ATM, ATR, MLH1, MSH2, MSH3, TREX1, EXO1, and TP73; and multidrug-resistance genes MRP2 and MRP5; as well as glutathione-S-transferase GSTP1 in 153 patients with relapsed or refractory lymphoma or myeloma receiving Gem/Bu/Mel. We studied the association of genotypes with overall survival (OS), progression-free survival (PFS), and nonhematological grade 3 or 4 toxicity. CDA C111T and TREX1 Ex14-460C>T genotypes had a significant effect on OS (P = .007 and P = .005, respectively), and CDA C111T, ATR C340T, and EXO1 P757L genotypes were significant predictors for severe toxicity (P = .037, P = .024, and P = .025, respectively) in multivariable models that adjusted for clinical variables. The multi-SNP risk score analysis identified the combined genotypes of TREX1 Ex14-460 TT and hCNT3 Ex5 +25A>G AA as significant predictors for OS and the combination of MRP2 Ex10 + 40GG/GA and MLH1 IVS12-169 TT as significant predictor for PFS. Polymorphic variants of certain genes involved in gemcitabine metabolism and DNA damage repair pathways may be potential biomarkers for clinical outcome in patients with refractory/relapsed lymphoid tumors receiving Gem/Bu/Mel.

1083-8791

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609079289

Rasmussen J.H. Hakansson K. Vogelius I.R. Aznar M.C. Fischer B.M. Friborg J. Loft A. Kristensen C.A. Bentzen S.M. Specht L.

(Rasmussen, Hakansson, Vogelius, Aznar, Friborg, Kristensen, Specht) Rigshospitalet, Department of Oncology, Section of Radiotherapy, University of Copenhagen, Denmark
(Fischer, Loft) Rigshospitalet, Department of Clinical Physiology, Nuclear Medicine and PET, University of Copenhagen, Denmark
(Bentzen) Division of Biostatistics and Bioinformatics, University of Maryland Greenebaum Cancer Center and Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, USA

Ireland

Phase I trial of 18F-Fludeoxyglucose based radiation dose painting with concomitant cisplatin in head and neck cancer.

Radiotherapy and Oncology. 2016. Date of Publication: August 31, 2015.

Elsevier Ireland Ltd

Radiother. Oncol.

Purpose: The CONTRAST (CONventional vs.Tumor Recurrence Adapted Specification of Target dose) phase I trial tested the safety of FDG PET guided dose redistribution in patients receiving accelerated chemo-radiotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC). Methods and materials: CONTRAST was designed with two pre-defined dose-escalation steps to the FDG PET-avid volume (GTV_PET). The primary end point was any early grade 4+ toxicity according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE). The dose to GTV_PET was escalated to a uniform prescription of 82Gy EQD2 in the first step. All patients received accelerated radiotherapy (6 fractions a week) delivering 34 fractions of 2.34Gy to the GTV_PET as well as concomitant weekly cisplatin. Inclusion criteria were (1) primary SCC of oral cavity, oro- or hypo-pharynx, or laynx, (2) candidates for concomitant chemo-radiotherapy and (3) p16 negative tumors or p16 positive tumors in patients with smoking history of >10 pack years. GTV_PET was defined by a specialist in nuclear medicine and a radiologist, while the anatomic GTV was defined in collaboration between an oncologist and a radiologist. Results: Median follow up time from the end of treatment was 18. months (range 7-21. months). All 15 patients completed treatment without interruptions and no incidents of early grade 4+ toxicity were observed. Four patients had ulceration at the evaluation two months after treatment, two have subsequently healed, but two remain, raising concerns regarding late effects. Conclusions: With all 15 cases having completed four month follow up and no incidence of early grade 4+ toxicity FDG PET based dose escalation to 82. Gy passed the protocol-defined criterion for dose escalation. However, two cases of concern regarding late outcome led us to refrain from further dose escalation and proceed with the current dose level in a larger comparative effectiveness trial.

0167-8140

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.

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609078790

Acher C. Acher C.W. Marks E. Wynn M.

(Acher, Acher) Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisc
(Marks, Wynn) Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisc

United States

Intraoperative neuroprotective interventions prevent spinal cord ischemia and injury in thoracic endovascular aortic repair.

Journal of Vascular Surgery. 2016. Date of Publication: September 11, 2015.

Mosby Inc.

J. Vasc. Surg.

Objective: Transient and permanent paraparesis and paraplegia (spinal cord injury [SCI]) are reported in up to 13% of patients undergoing thoracic endovascular aortic repair (TEVAR) for descending thoracic aortic aneurysm, thoracoabdominal aortic aneurysm, and thoracic aortic dissection. We hypothesize that aggressive intraoperative and postoperative neuroprotective interventions prevent or significantly reduce all SCI in TEVAR. Methods: Using a prospectively maintained, Institutional Review Board-approved database, we retrospectively reviewed all TEVARs performed in a university tertiary referral center from 2005 to 2014 to study the incidence of all transient and permanent lower extremity SCI. Only TEVARs for traumatic aortic tear were excluded. Arch debranching and carotid subclavian bypass were performed before TEVAR in patients with arch involvement. All patients had moderate systemic hypothermia (34degreeC), mean arterial pressure >90 mm Hg, and hemoglobin >10 g/dL. Patients received mannitol (12.5 g), methylprednisolone (30 mg/kg), and naloxone (1 mug/kg/h). Patients in whom >12 cm of aortic coverage was planned had spinal fluid drained to a pressure of <8 mm Hg intraoperatively and postoperatively until normal leg strength was confirmed. The main outcome measure was transient or permanent SCI. Results: One hundred fifty-five patients had TEVAR between 2005 and 2014. Mean age was 74 years, and 56.1% were male. Descending thoracic aortic aneurysm was present in 91.6%, thoracoabdominal aortic aneurysm in 8.4%, and dissection in 28.8%. Presentation was acute in 42.5%. The procedure included carotid-subclavian bypass in 18.7% of patients. Seventy-two percent of patients had spinal fluid drainage. Mean aortic coverage was 25 cm. Eighty-one percent of patients had >12 cm aortic coverage, and 49% had complete coverage of the thoracic aorta (coverage from subclavian to celiac artery). In-hospital mortality was 1.94%. Stroke occurred in 1.32% of patients. No patient had renal failure. SCI occurred in 0.65% (1 of 154) of patients. Conclusions: SCI in TEVAR can be significantly reduced by using proactive intraoperative and postoperative neuroprotective interventions that prolong spinal cord ischemic tolerance and increase spinal cord perfusion and oxygen delivery.

0741-5214

Journal: Article In Press

Copyright 2016 Elsevier B.V., All rights reserved.