Clinical Evaluation of High Weekly Intravenous Doses of Methotrexate in Advanced Oropharyngeal Carcinoma

1970 ◽  
Vol 56 (5) ◽  
pp. 259-268 ◽  
Author(s):  
Giuseppe M. de Palo ◽  
Mario De Lena ◽  
Roberto Molinari ◽  
Antonio Cunsolo ◽  
Silvio Monfardini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Side Effects ◽  
Intravenous Administration ◽  
Renal Toxicity ◽  
Severe Depression ◽  
Response To Treatment ◽  
Oropharyngeal Carcinoma ◽  
Intraarterial Infusion ◽  
Intravenous Injections ◽  
Duration Of Response

Methotrexate (MTX) was given by weekly rapid intravenous injections to 27 patients with inoperable oropharyngeal carcinoma. 9 cases were untreated while 18 had received radiotherapy or chemotherapy before administration of MTX. In 20 cases the dose was 40 mg/m2/week (patients over 50 years) and in 7 cases 60 mg/m2/week (table 1). In responsive patients, maintenance treatment was given at the dose of 15 mg/m2 every 4 days either orally or intramuscularly. 23 cases were adequately evaluable, i.e. they received treatment for a minimum of 3 weeks. Response to treatment was evaluated according to Karnofsky's scale. Considering only category 1 regressions, 11/16 (75%) patients adequately treated with 40 mg/m2 showed objective improvement and respectively 4/7 (57%) given 60 mg/m*. 8 out of 15 cases (41%) with category 1 response showed a regression greater than 50%. The mean duration of response for category 1 patients was 3.5 months, while the longest regression lasted 9 months (table 2). 18 patients had one or more side effects: 9 had oral lesions or gastroenteritis, 12 bone marrow depression, 3 hepatic and 1 renal toxicity. One patient died from hepatic and renal toxicity; in the remaining cases the side effects were quickly reversible (table 3). The percent regression rate for category 1 response and its average duration obtained with intravenous MTX seems comparable to intraarterial infusion (table 4). Systemic toxicity seems also comparable (table 5). Furthermore, intravenous administration obviates the typical local complications occurring with intra-arterial treatment and therapy can be given also at outpatients. For this reason, intravenous administration of MTX is preferred to intra-arterial infusion in the control of primary inoperable oropharyngeal carcinomas, provided no severe depression of liver, kidney and bone marrow is present.

Results of Treatment of Severe Aplastic Anaemia in Children Using Rabbit Antithymocyte Globulin(r-ATG),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3435-3435
Author(s):  
Malgorzata Salamonowicz ◽  
Katarzyna Pawelec ◽  
Michal Matysiak ◽  
Jerzy Kowalczyk ◽  
Walentyna Balwierz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Side Effects ◽  
Aplastic Anemia ◽  
Cyclosporine A ◽  
Antithymocyte Globulin ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Event Free Survival ◽  
Relapse Free Survival ◽  
Free Survival

Abstract Abstract 3435 Objective: One of the main patophysiological mechanism of aplastic anemia (AA) is immune-mediated destruction of hematopoietic cells. In children with severe acquired aplastic anemia (SAA) allogenic bone marrow transplantation is the first choice. If there is no matched sibling donor the first line of treatment is immunosuppressive therapy (IST) which consists of ATG combined with cyclosporine A. Aim. The aim of this study was to analyze the results of IST containing rabbit anti-thymocyte globulin (r-ATG) performed on children with SAA and vSAA treated between 1996–2009 yr. We wanted to assess the influence of such factors as response to treatment, etiology, sex, age, type of AA, for: event free survival (EFS), and progression free survival (PFS) We analyzed deaths rate, relapses rate, clonality and side effects of IST. Materials and methods. We retrospectively analyzed group of 55 children with SAA and vSAA. The group consisted of 23 girls and 32 boys, the median age was 10 years (range 6mth-17,5 years). IST contained antithymocyte globulin,given intravenous at a dose of 3,75 mg/kg/day for 5 days, and cyclosporine A(CSA) at 5 mg/kg/day by mouth in divided doses started on day 1 and continued for at least 6 months(till 24 months). Response rate was assessed on 112, 180 and 360 day and defined as CR, PR, NR. Kaplan–Meier estimator, univariate analysis and multivariate Cox regression models were used to estimate the influence of such factors as response to treatment, etiology, sex, age for EFS, PFS, toxicity and other side effects. Results. The 2- year probability of event free survival (EFS) was 71,52%. The 5 and 10 –year EFS was 57,7%. Progression free survival (PFS) was 66,53%, at 2 years and 59,13% at 5- and 10 year Patients with CR and PR had significantly longer EFS than children with no response(NR) (p<0.0001 Wilcoxon). There was no significant correlation between EFS, PFS and such factors as etiology, sex, age, severity of AA (p > 0,05 Log rank). In all group we observed 15 deaths (27,27%), 5 early and 10 late deaths. Infections were the main causes of death. The relapse rate was 1,81%. The 2-year probability of not having relapse was 87,68%. Relapse free survival was 75,16% at 5 and 10 years. There was one transformation to paroxysmal nocturnal hemoglobinuria (PNH).Non responders (4 patients) received second IST and 11 children underwent MUD-BMT. Infections were the most often side effects of IST (FUO-26,92% of infectious side effects). There was significant association found between EFS and infectious side effects. (p=0,00093 log rank) The most common adverse effects after rabbit immunoglobulin were fever (30,30%) and dyspnoe (24,24%). After CSA treatment we observed mainly gingival hyperplasia (29,16% of side effects of CSA). Most common hemorrhagic side effects were skin petechie. There was significant correlation between hemorrhagic side effects and PFS (p= 0,0144 log rank) Conclusions. 1. Rabbit-ATG is an effective frontline therapy for children with SAA without familiar bone marrow donor.2.Remission achieved on day 112 seems to be constant. 3.5-year EFS seems to be stable within next 5 years.4.5-year relapse free survival seems to be constant during the next 5 years.5.Etiology, type of SAA, age and sex have no influence on the survival.)6.Infectious and hemorrhagic side effects are a very important factors affecting the survival rate in children with SAA. Disclosures: No relevant conflicts of interest to declare.

Role of the norepinephrine transporter polymorphisms in atomoxetine treatment: From response to side effects in children with ADHD

2021 ◽  
pp. 026988112110152
Author(s):  
Melike Kevser Gul ◽  
Elif Funda Sener ◽  
Muge Gulcihan Onal ◽  
Esra Demirci
Keyword(s):  
Side Effects ◽  
Treatment Response ◽  
Large Population ◽  
Norepinephrine Transporter ◽  
Response To Treatment ◽  
Nucleotide Polymorphisms ◽  
Children With Adhd ◽  
Real Time Quantitative Pcr ◽  
Treatment Side Effects ◽  
Adhd Treatment

Objective: Atomoxetine (ATX), one of the most commonly used drugs after stimulants in attention deficit hyperactivity disorder (ADHD) treatment, is an inhibitor of the norepinephrine transporter ( NET/SLC6A2), which is also associated with the etiology of ADHD. In this study, we aimed to investigate the effect of NET gene polymorphisms on response to ATX treatment and to find the answers to the questions about whether there is a relationship between the severity of the disorder and the observed side effects in children with ADHD. Method: About 100 children with ADHD and 80 healthy controls (HCs) were included in this study. The dose of ATX was started at 0.5 mg/kg/day and titrated at 1.2 mg/kg/day. Response to treatment of 78 patients was evaluated 2 months after the beginning of the treatment. After whole blood samples were obtained, DNAs were isolated, and samples were stored at −80°C. Two single-nucleotide polymorphisms (SNPs) (rs12708954 and rs3785143) were analyzed by real-time quantitative PCR (qRT-PCR). Results: The patients with both rs12708954 and rs3785143 heterozygous genotype had better treatment response and more side effects than patients with wild type. There was not found any association between any of the investigated NET polymorphisms and ADHD severity. Conclusion: It was, however, found that the NET rs12708954 and rs3785143 genotypes affect the treatment response to ATX in our study; thus, further studies with a large population are needed to understand the effects of NET polymorphisms on treatment, side effects, and also the severity of ADHD.

scholarly journals Response to treatment with intra-articular triamcinolone hexacetonide and triamcinolone acetonide in oligo articular juvenile idiopathic arthritis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Rana Harhay ◽  
Wajiha Jeelani ◽  
Barbine Tchamba Agbor Agbor ◽  
Teresa Hennon ◽  
Brian H. Wrotniak ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Side Effects ◽  
Triamcinolone Acetonide ◽  
The United States ◽  
Response To Treatment ◽  
Joint Injection ◽  
Triamcinolone Hexacetonide ◽  
Active Arthritis ◽  
General Response

Abstract Background Oligo-articular juvenile idiopathic arthritis (Oligo JIA) is the most common subtype of juvenile idiopathic arthritis. Intra-articular corticosteroid (IAC) injection is a mainstay treatment of oligo JIA providing pain relief, improving mobility and preventing further joint destruction in the majority of patients. In 2015, production of triamcinolone hexacetonide (TH) an intra-articular corticosteroid was discontinued in the United States leading to use of triamcinolone acetonide (TA) as an alternative. In this study, we compared response to treatment in children with oligo JIA who underwent therapy with intra-articular TA and TH injection. Methods Our study is a retrospective chart review of children with oligo JIA who were treated with IAC injections with TH between January 2012 and June 2015 and TA between J uly 2015 and December 2018. The two groups were followed at John R. Oishei Children’s Hospital of Buffalo and were evaluated for response to treatment, side effects and predictors of response including duration of disease before treatment, erythrocyte sedimentation rate (ESR), and c-reactive protein (CRP). Response to treatment was defined as at least 6 months follow up without evidence of active arthritis in injected joints. Patients were considered to be non-responders if they continued to show active arthritis during their first follow up after joint injection. The primary objective was to evaluate whether there was a significant difference in rate of response between TH and TA. Results Forty-nine patients, 38 female and 11 male with oligo JIA were included in the study. The average age was 6.7 years. A total of 111 joints were injected includin g 78 knees, 13 ankles, 9 wrists, 4 hips, 4 elbows, 2 TMJ and one subtalar joint. In the TA group, 49% (29/59) did not show response to injection compared to 27% (14/52) in the TH group. After 6 months, response rates were better for individuals injected with TH compared to TA (73% vs. 51%). In general, response to intra-articular TH was superior to TA with P = .016 using chi-square test of independence. This difference in outcome was not influenced by other variables such as duration of illness before treatment (P value 0.784) or elevated ESR and CRP. No difference in side effects between the two groups were noted. Conclusion Our results in conjunction with prior published data suggests that TH intra-articular joint injection in oligo JIA is superior to TA, although future controlled trials are necessary for confirmation. An effective, long lasting treatment can have a great impact on the outcome of these children.

scholarly journals Dysregulation of CCAAT/enhancer binding protein-alpha (CEBPA) expression in the bone marrow of acute myeloid leukemia patients

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Naglaa M. Hassan ◽  
Fadwa Said ◽  
Roxan E. Shafik ◽  
Mona S. Abdellateif
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Binding Protein ◽  
Response To Treatment ◽  
Pathological Features ◽  
Poor Prognostic Factor ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a heterogeneous malignant disease characterized by accumulation of different types of mutations commonly the CCAAT/enhancer binding protein-alpha (CEBPA). However, the dysregulations of CEBPA expression in AML is still a debatable issue. The aim of the current study was to assess CEBPA gene expression in bone marrow (BM) aspiration specimens of 91 AML patients, compared to 20 control donors of bone marrow transplantation (BMT), using RT-PCR. Data were correlated with patients’ clinico-pathological features, response to treatment, progression-free survival (PFS), and overall survival (OS) rates. Results There was overexpression of CEBPA gene in AML patients compared to normal control [1.7 (0.04–25.6) versus 0.17 (0–4.78), respectively, P < 0.001]. Upregulation of CEBPA expression associated significantly with increased BM hypercellularity, total leucocyte counts, peripheral blood blast cell count, and poor PFS (P < 0.001, 0.002, 0.001, and 0.013, respectively). There was no significant association between CEBPA expression and any other relevant clinico-pathological features or OS rates (P = 0.610) of the patients. ROC analysis for biological relevance of CEBPA expression with AML showed that sensitivity and specificity of CEBPA expression at a cut-off value of 0.28 are 92.3% and 78.6%, respectively (P < 0.001). All patients who had CEBPA overexpression and mutant FLT3 showed BM hypercellularity, adverse cytogenetic risk, increased TLC, and PB blast cells count (P = 0.007, P < 0.001, 0.016, and 0.002, respectively). Conclusion CEBPA overexpression could be used as a genetic biological marker for AML diagnosis, as well as a poor prognostic factor for disease progression. It has no impact on OS rates of the patients.

scholarly journals Intra-Bone Marrow Administration of Mesenchymal Stem/Stromal Cells Is a Promising Approach for Treating Osteoporosis

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Hideki Agata ◽  
Yoshinori Sumita ◽  
Tatsuro Hidaka ◽  
Mayumi Iwatake ◽  
Hideaki Kagami ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mineral Content ◽  
Bone Mineral ◽  
Intravenous Administration ◽  
Stromal Cells ◽  
Mineral Content ◽  
Bone Diseases ◽  
Research Progress ◽  
Bone Thickness ◽  
Mineral Density

Mesenchymal stem/stromal cells (MSCs) are known to be useful for treating local bone diseases. However, it is not known if MSCs are effective for treating systemic bone diseases, as the risk for mortality following intravenous MSC administration has hindered research progress. In this study, we compared the safety and efficacy of intra-bone marrow and intravenous administration of MSCs for the treatment of ovariectomy- (OVX-) induced osteoporosis. Cells capable of forming bone were isolated from the murine compact bones and expanded in culture. Relatively pure MSCs possessing increased potential for cell proliferation, osteogenic differentiation, and inhibition of osteoclastogenesis were obtained by magnetic-activated cell sorting with the anti-Sca-1 antibody. Sca-1-sorted MSCs were administered to OVX mice, which were sacrificed 1 month later. We observed that 22% of the mice died after intravenous administration, whereas none of the mice died after intra-bone marrow administration. With respect to efficacy, intravenous administration improved bone mineral density (BMD) by increasing bone mineral content without affecting bone thickness, whereas intra-bone marrow administration improved BMD by increasing both bone mineral content and bone thickness. These results indicate that intra-bone marrow administration of pure MSCs is a safer and more effective approach for treating osteoporosis.

scholarly journals The critical role of T cells in glucocorticoid-induced osteoporosis

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Song ◽  
Lijuan Cao ◽  
Rui Liu ◽  
Hui Ma ◽  
Yanan Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Steady State ◽  
Side Effects ◽  
Critical Role ◽  
Wild Type ◽  
Receptor Activator ◽  
Steady State Levels ◽  
Induced Apoptosis

AbstractGlucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.

1128 Total body irradiation (TBI) before bone marrow grafting (BMG): Analysis of late side effects

1995 ◽  
Vol 31 ◽  
pp. S236
Author(s):  
V. Fayrel ◽  
Th. Schmitt ◽  
J.L. Stephan ◽  
D. Guyotat ◽  
G. Puel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Side Effects ◽  
Total Body Irradiation ◽  
Late Side Effects ◽  
Total Body ◽  
Bone Marrow Grafting ◽  
Late Side

Dr. Shannon Replies

PEDIATRICS ◽  
1975 ◽  
Vol 56 (4) ◽  
pp. 619-619
Author(s):  
Daniel C. Shannon
Keyword(s):  
Gastrointestinal Tract ◽  
Side Effects ◽  
Intravenous Administration ◽  
Ductus Arteriosus ◽  
Oral Feeding ◽  
Blood Levels ◽  
Severe Toxicity ◽  
Potential Toxicity ◽  
Nasojejunal Tube ◽  
Rectal Route

Dr. Morens raises questions of potential toxicity of theophylline in the gastrointestinal tract, kidney and ductus arteriosus. Except for vomiting, which has occurred in some infants when blood levels have been excessive (mainly 2Oµg/ml), we have not observed any of these side effects in treating 93 infants. In all infants, treatment was given through a nasogastric or nasojejunal tube until oral feeding was possible. Because acute severe toxicity in children and adults has been related to intravenous administration, we have used this route only when necessary. Because of erratic absorption, we have avoided the rectal route.

scholarly journals Prooxidant and antioxidant activity of blood plasma and histology of internal organs of rats after intravenous administration of magnetite nanoparticles

2013 ◽  
Vol 59 (3) ◽  
pp. 330-338 ◽  
Author(s):  
I.V. Milto ◽  
T.K. Klimenteva ◽  
I.V. Suhodolo ◽  
N.A. Krivova
Keyword(s):  
Antioxidant Activity ◽  
Blood Plasma ◽  
Intravenous Administration ◽  
Magnetite Nanoparticles ◽  
The Body ◽  
Antioxidant Systems ◽  
Internal Organs ◽  
Intravenous Injections ◽  
Magnetite Particles ◽  
Dose Dependent

The effect of a single and multiple intravenous injections of a nanosized magnetite suspension on total prooxidant and antioxidant activity of blood plasma has been investigated by the method of luminol-dependent chemoluminescence. Magnetite nanoparticles possess dose-dependent prooxidant properties due to their iron atoms and at the same time their trigger compensatory activation of antioxidant systems in the rat blood plasma. After a single intravenous administration of magnetite the studied parameters of blood plasma returned to the normal level by the end of the experiment as due to removal of nanoparticles from the body. In the case of multiple administration of the magnetite suspension dose-dependent changes in the pro- and antioxidant plasma activity persist during the whole experiment. Accumulation of magnetite particles in the cells of the mononuclear phagocytic system in the rats’ liver, lungs and kidneys is associated with hemodynamic damages, local dystrophic and necrotic changes of parenchyma in these organs. After a single intravenous injection magnetite nanoparticles are identified in the rat organs for 40 days, but their number decreases by the end of the experiment.

scholarly journals Transplantation for Congenital Sideroblastic Anaemia Is Feasible and Offers Outcomes Comparable to Other Transfusion Dependent Anaemias. a Joint Retrospective Study of the Paediatric Diseases and Severe Aplastic Anaemia Working Parties (PDWP/SAAWP) of EBMT

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-47
Author(s):  
Josu de la Fuente ◽  
Dirk-Jan Eikema ◽  
Paul Bosman ◽  
Robert F Wynn ◽  
Miguel Díaz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Response To Treatment ◽  
Variable Response ◽  
Advisory Committees ◽  
Grade Ii

Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment &gt;20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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