http://explore.georgetown.edu/news/?ID=32887

 

FOR IMMEDIATE RELEASE: April 13, 2008
CONTACT:	Karen Mallet 414-312-7085 km463@georgetown.edu
In Lab Study, Researchers Find Molecule That Disrupts Ewing’s Sarcoma Oncogene
SAN DIEGO – Researchers at Georgetown University Medical Center have found a small molecule they say can block the action of the oncogene that causes Ewing’s sarcoma, a rare cancer found in children and young adults. If further studies continue to prove beneficial, they say the novel agent could be the first targeted therapy to treat the disease, which can produce tumors anywhere in the body. The findings, presented today at the annual meeting of the American Association for Cancer Research (AACR) in San Diego, suggest that the unique way in which this molecule works – through a so-called protein-protein interaction – could provide a model upon which to design other therapies, says the study’s lead investigator, Jeffrey Toretsky, M.D., a pediatric oncology physician and researcher at Georgetown University’s Lombardi Comprehensive Cancer Center. “I think this holds really wonderful promise as a unique way of targeting fusion proteins,” he says. “People thought it wasn’t possible to have a small molecule that can bind between flexible proteins, but we have shown that it can be done.” This study was conducted in laboratory cells, so additional research is necessary before the novel agent can be tested in patients, Toretsky says. In vivo studies are now underway, he says. Ewing’s sarcoma is caused by the exchange of DNA between two chromosomes, a process known as a translocation. The new gene, known as EWS-FLI1, is created when the EWS gene on chromosome 22 fuses to the FLI1 gene on chromosome 11, and its product is the fusion protein responsible for cancer formation. In the United States, about 500 patients annually are diagnosed with the cancer, and they are treated with a combination of five different chemotherapy drugs. Between 60-70 percent of patients survive over time, but many have effects that linger from the therapy. Toretsky has long led research into the causes of, and treatments for, Ewing’s sarcoma. He and his laboratory colleagues were the first to make a recombinant EWS-FLI1 fusion protein. “We did this in order to find out if EWS-FLI1 might be binding with other cellular proteins,” he says. They found that, indeed, the fusion protein stuck to another protein, RNA helicase A (RHA), a molecule that forms protein complexes in order to control gene transcription. “We believe that when RHA binds to EWS-FLI1, the combination becomes more powerful at turning genes on and off,” says the study’s first author, Hayriye Verda Erkizan, Ph.D., a postdoctoral researcher in Toretsky’s lab who is presenting the study results at AACR. The researchers used a laboratory technique to keep RHA apart from the fusion protein, and found that both were important to cancer formation. Knowing that, they worked to identify the specific region on RHA that stuck to EWS-FLI1, and then collaborated with investigators in Georgetown’s Drug Discovery Program to find a molecule that would keep the two proteins separated. In other words, such an agent would stick to EWS-FLI1 in the very place that RHA bound to the fusion molecule. Using a library of small molecules loaned to Georgetown from the National Cancer Institute, the team of investigators tested 3,000 compounds to see if any would bind to immobilized EWS-FLI1 proteins. They found one that did, and very tightly. This was a wonderful discovery, Erkizan says, because the notion long accepted among scientists is that it is not possible to block protein-protein interactions given that the surface of these proteins are slippery, and much too flexible for a drug to bind to. “These are wiggly proteins yet this study shows that inhibition of protein-protein interactions with a small molecule is possible,” Toretsky says. This possibility means that fusion proteins, such as those produced in other sarcomas as well as diverse disorders, might be inhibited, he says. This is a different process than other drugs that have been shown to work against fusion proteins, such as Gleevec, which blocks the enzyme produced by the chromosomal translocation responsible for chronic myelogenous leukemia (CML). “Gleevec inhibits a single protein, while we are trying to block the binding of two proteins, and we are very enthusiastic about the results so far,” Toretsky says. Toretsky recently received a $750,000 Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund (BWF), which he will use to accelerate these translational efforts to help treat Ewing’s sarcoma, utilizing GUMC’s drug discovery program. The study was funded by the Children’s Cancer Foundation, Baltimore, MD., and Dani’s Foundation, Denver, CO. About Lombardi Comprehensive Cancer Center The Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Lombardi is one of only 39 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington, DC, area. For more information, go to http://lombardi.georgetown.edu. About Georgetown University Medical Center Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through our partnership with MedStar Health). Our mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing and Health Studies, both nationally ranked, the world-renowned Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO), home to 60 percent of the university’s sponsored research funding. ###

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16629697

Risk of cancer in children with the diagnosis immaturity at birth

Authors: Mellemkjær, Lene; Hasle, Henrik1; Gridley, Gloria2; Johansen, Christoffer3; Kjær, Susanne K.3; Frederiksen, Kirsten3; Olsen, Jørgen H.3

Source: Paediatric & Perinatal Epidemiology, Volume 20, Number 3, May 2006, pp. 231-237(7)

Publisher: Blackwell Publishing

Abstract:
Summary Mellemkjær L, Hasle H, Gridley G, Johansen C, Kjær SK, Frederiksen K, Olsen JH. Risk of cancer in children with the diagnosis immaturity at birth. Paediatric and Perinatal Epidemiology 2006; 20: 231–237.

Cancer risk in children born before term has been assessed in a large number of case–control studies but very rarely in cohort studies. We carried out a cohort study of 35 178 children with the diagnosis immaturity at birth in the Hospital Discharge Register during 1977–89. The children were followed for cancer in the Danish Cancer Registry until 1994 and comparisons were made with incidence rates for all children in Denmark. The 64 observed cases of childhood cancer in the cohort corresponded closely to the expected number {standardised incidence ratio (SIR) = 1.03; [95% confidence interval (CI) 0.80, 1.32]}. The only cancer site with an observed number that deviated significantly from the expected number was central nervous system (CNS) tumours (26 cases observed; SIR = 1.57; [95% CI 1.02, 2.30]) in particular medulloblastoma (9 cases observed; SIR = 3.1; [95% CI 1.4, 5.9]). In a nested case–control study of the CNS tumours, we found that more cases than controls had been exposed to diagnostic X-rays, but the result was not significant. Surprisingly, for those born before term, the risk of CNS tumours increased with increasing gestational age in the nested case–control data. Our results are in line with previous evidence that children born before term are not at increased risk for childhood cancer in general. An explanation behind the excess of CNS tumours could not be identified, but the effect of diagnostic X-rays in newborns may deserve further attention.

Keywords:  childhood cancer; CNS tumours; preterm; newborn X-rays

Document Type: Research article

DOI: 10.1111/j.1365-3016.2006.00717.x

Affiliations: 1: Department of Paediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark, and 2: Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA 3: Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen,

Clinical Cancer Research Vol. 12, 2049-2054, April 2006
© 2006 American Association for Cancer Research
Human Cancer Biology

Pediatric Cancers Are Infiltrated Predominantly by Macrophages and Contain a Paucity of Dendritic Cells: a Major Nosologic Difference with Adult Tumors
Jukka Vakkila1,2, Ronald Jaffe3, Marilyn Michelow3 and Michael T. Lotze1

http://clincancerres.aacrjournals.org/cgi/content/abstract/12/7/2049

Authors' Affiliations: 1 Molecular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 2 Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland; and 3 Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Requests for reprints: Jukka Vakkila, Department of Bacteriology and Immunology, Haartman Institute, Haartmaninkatu 31, FIN-00014 University of Helsinki, Helsinki, Finland. Phone: 358-40-821-6939; Fax: 358-10-414-4619; E-mail: jukka.vakkila@mehilainen.fi.

Purpose: Adult cancer is frequently preceded by a period of prolonged chronic inflammation caused by infectious microbial agents or physical or chemical irritants. By contrast, an association between the classic pediatric neoplasias and inflammatory triggers is only rarely recognized. We hypothesized that the difference could be reflected in the inflammatory cell infiltrates of pediatric and adult cancer.

Experimental Design: Three investigators retrospectively studied 27 pediatric and 13 adult cancers at first diagnosis by immunohistochemistry. Inflammatory cells were identified and counted, and their location in relation to tumor tissue was analyzed.

Results: A majority of tumor-associated leukocytes (TAL) in adult tumors were located at the edges of tumor islands forming inflammatory foci between the supporting stroma and the malignant infiltrate. In contrast, TALs in pediatric tumors were scattered within the malignant tumor islands. In adult tumors, TALs were composed of diverse leukocyte types; but in pediatric tumors, the infiltrating cells were predominantly macrophages that accumulated in areas of necrosis within the tumors. The most striking feature in the pediatric tumors was the virtual absence of dendritic cells. The proportion of intratumoral dendritic cells in pediatric samples was 4.1%; whereas in adult tumors, they formed 36.9% of TALs within the tumor islands and 25.1% around the tumors.

Conclusions: We conclude that TALs in pediatric cancers are composed mainly of macrophages and largely devoid of dendritic cell. The findings may provide a major nosologic difference reclassifying pediatric and adult tumors based on nominal inflammatory and noninflammatory etiologies.

Am J Clin Pathol. 2006 Jan;125(1):57-63. Related Articles, Links 

ALK-positive anaplastic large cell lymphoma with primary bone involvement in children.

NA, Ross CW, Finn WG, Valdez R, Ruiz R, Koujok K, Schnitzer B.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16482992&dopt=Abstract

Department of Pathology, Oklahoma University Health Sciences Center, Oklahoma City, USA.

We describe the clinical, radiologic, and pathologic features of primary bone anaplastic large cell lymphoma (ALCL) in 3 boys. Radiologic imaging showed lytic lesions involving sacrum, femur, or rib. Bone was the only site of disease in 2 cases; an associated partial lymph node was involved in case 3. Differential diagnoses included osteomyelitis and small round cell tumors of childhood, particularly Ewing sarcoma. Preoperatively, ALCL was not a diagnostic consideration in any case. Two cases showed classic large pleomorphic cells; 1 showed a composite pattern with a distinct small cell component and the more typical large cell type. Neoplastic cells in all cases showed strong CD30 and anaplastic lymphoma kinase expression with relatively weak epithelial membrane antigen positivity. Cytotoxic granule protein was expressed in 2 cases. All cases showed unusually strong expression of neuron-specific enolase (NSE). Two patients were disease-free at last follow-up (15 months and 11 years); 1 patient died of disseminated disease within a year of diagnosis. ALCL should be considered a diagnostic possibility when evaluating neoplastic bone lesions in children. Although expression of NSE in ALCL has not been emphasized in the literature, it is worth noting because it may pose a diagnostic pitfall.

PMID: 16482992 [PubMed - in process]

Histopathology. 2006 Mar;48(4):363-76.
 
Ewing's sarcoma of bone: the detection of specific transcripts in a large, consecutive series of formalin-fixed, decalcified, paraffin-embedded tissue samples using the reverse transcriptase-polymerase chain reaction.

Mangham DC, Williams A, McMullan DJ, McClure J, Sumathi VP, Grimer RJ, Davies AM.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16487358&dopt=Abstract

Department of Musculoskeletal Pathology, Royal Orthopaedic Hospital, The Medical School, University of Birmingham, Birmingham, UK.

Aims : (i) To report on the routine use of the reverse transcriptase-polymerase chain reaction (RT-PCR) technique on decalcified or non-decalcified, formalin-fixed, paraffin-embedded tissue (FFPET) for translocation detection, with particular emphasis on improved RNA extraction methodology and the use of PCR primers designed to generate small amplicons. (ii) To report on the relative incidences of translocation types and transcript variants in a large, single institution series of Ewing's sarcoma of bone. Methods and results : Using RT-PCR to detect specific transcript variants, we analysed FFPET from 54 consecutive cases of Ewing's sarcoma of bone. We used 'gold standard' detection methods on corresponding fresh and fresh frozen tissue to validate the technique. We have demonstrated the effective use of RT-PCR on decalcified and non-decalcified FFPET samples for sarcoma-specific translocation detection (96% sensitivity, 100% specificity). Tissue decalcification did not affect the detection rate. The relative incidence of Ewing's sarcoma-specific translocation types and transcript variants was entirely consistent with previously published data. Conclusions : With equal effectiveness, RT-PCR can be applied to both acid decalcified and non-decalcified FFPET for (Ewing's sarcoma) translocation detection and the technique can be introduced into routine practice in histopathology departments.

PMID: 16487358 [PubMed - in process]

J Laparoendosc Adv Surg Tech A. 2006 Feb;16(1):74-6.

Laparoscopic Removal of Extraosseous Ewing's Sarcoma of the Kidney in a Pediatric Patient.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16494555&dopt=Abstract
 
Perer E, Shanberg AM, Matsunaga G, Finklestein JZ.

Miller Children's Hospital, Long Beach Memorial Medical Center, Long Beach, California., Antoci Center for Pediatric Urology and Nephrology, UC Irvine Medical Center, Orange, California.

In the pediatric population, to the best of our knowledge, only 2 cases of renal extraosseous Ewing's sarcoma/primitive neuroectodermal tumor (EES/PNET) have been published. We report the initial case of renal EES/PNET occurring in a 10-year-old girl treated by a laparoscopic radical nephrectomy. The regimen used is the first documented use of neoadjuvant chemotherapy prior to laparoscopic radical nephrectomy for PNET. This approach obviated the need for a large incision and a prolonged postsurgical recovery. The minimally invasive nature of the laparoscopic procedure allowed for a rapid convalescence and resumption of her chemotherapy regimen within 14 days of the surgery.

PMID: 16494555 [PubMed - in process]

Am J Clin Pathol. 2005 Dec;124 Suppl:S110-21.

"Undifferentiated" small round cell tumors of the sinonasal tract: differential diagnosis update.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16468421&dopt=Abstract

Iezzoni JC, Mills SE.

Robert E. Fechner Laboratory of Surgical Pathology, Department of Pathology, University of Virginia Health System, Charlottesville 22908, USA.

Sinonasal tract neoplasms composed of light microscopically seemingly "undifferentiated" small round cells often generate considerable diagnostic difficulty. Although the careful review of H&E-stained sections remains of critical and central importance in this evaluation, the recent improvements in the immunohistochemical diagnostic armamentarium and molecular diagnostic techniques applicable to paraffin-embedded tissue samples may add diagnostically valuable information. Accordingly, this review will discuss the differential diagnosis of undifferentiated small blue cell tumors of the sinonasal tract based on the light microscopic and clinical features and, as needed, the results of these ancillary studies. Tumors discussed include olfactory neuroblastoma, sinonasal undifferentiated carcinoma, small cell undifferentiated (neuroendocrine) carcinoma, undifferentiated (lymphoepithelioma-like) carcinoma, malignant melanoma, pituitary adenoma, Ewing sarcoma/peripheral neuroectodermal tumor, rhabdomyosarcoma, mesenchymal chondrosarcoma, small cell osteosarcoma, synovial sarcoma, extranodal natural killer/T-cell lymphoma, nasal type, and extramedullary plasmacytoma.

PMID: 16468421 [PubMed - in process]

Acta Orthop. 2005 Dec;76(6):899-903.
 
Long-term follow-up of 15 patients with non-metastatic Ewing's sarcoma and a skip lesion.

Jiya TU, Wuisman PI

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16470449&dopt=Abstract

Department of Orthopaedic Surgery, Vrije Universiteit Medical Centre, Amsterdam. tim.jiya@wanadoo.nl

BACKGROUND Skip lesions in Ewing's sarcoma of the bone seem to be rare; to our knowledge only 7 cases have been published in the English medical literature. METHODS: We retrospectively reviewed imaging and histological data relating to 235 patients with non-metastatic Ewing's sarcoma of the bone who participated in the cooperative Ewing's sarcoma study (CESS 86 and CESS 91), and we identified 15 patients with a skip lesion at diagnosis. RESULTS: The skip lesion was located in the same bone as the primary tumor in 13 patients, and in an adjacent juxtaarticular bone in 2 cases. The average follow-up was 11 years. Despite aggressive treatment including surgery in all cases, tumor relapse occurred in 9 patients, and 7 of these patients died due to metastatic disease. INTERPRETATION: Skip lesions in patients with otherwise non-metastatic skeletal Ewing's sarcoma may be of the same consequence as the molecular detection of marrow metastases and possibly confer a worse prognosis. Newer imaging modalities (for example PET) and careful staging work-up may indicate that skip metastases in Ewing's sarcoma are more common than previously suspected.

PMID: 16470449 [PubMed - indexed for MEDLINE]

Journal of Pediatric Psychology, Vol. 26, No. 4, 2001, pp. 225-235
© 2001 Society of Pediatric Psychology

http://jpepsy.oxfordjournals.org/cgi/content/abstract/26/4/225

Psychological Adaptation and Social Support of Parents of Pediatric Cancer Patients: A Prospective Longitudinal Study

Josette E. H. M. Hoekstra-Weebers, PhD, Jan P. C. Jaspers, PhD, Willem A. Kamps, PhD and Ed C. Klip, PhD
University Hospital Groningen, The Netherlands

All correspondence should be sent to Josette Hoekstra-Weebers, Department of Medical Psychology, University Hospital, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: j.hoekstra-weebers@medps.azg.nl .

Objective: To investigate levels of support and the concurrent and prospective effects of support on the psychological functioning of parents of children with cancer in a prospective longitudinal study.

Methods: Parents' (n = 128) self-perceived level of psychological distress, quantity of support, and dissatisfaction with support were assessed, at diagnosis, at 6, and at 12 months.

Results: Parents received most support at diagnosis. Self-perceived quantity decreased with time, but parents indicated they remained equally satisfied. Support significantly predicted concurrent and prospective distress of fathers, but not of mothers. Dissatisfaction with support and negative interactions were consistent risk factors for fathers. Mothers who adjusted well psychologically received more support and were less dissatisfied than mothers who remained clinically distressed. Nevertheless, no persisting effect of support was found.

Conclusions: Findings illustrate that social support varies with the stress situation and with gender. Identification of vulnerable parents at diagnosis on the basis of their perception of received quantity of and dissatisfaction with support seems difficult. Intervention efforts aimed at mobilization of needed support may be efficacious.

Journal of Pain and Symptom Management
Volume 30, Issue 6 , December 2005, Pages 570-577

http://www.mdlinx.com/readArticle.cfm?art_id=1447035
      
Copyright © 2005 U.S. Cancer Pain Relief Committee Published by Elsevier Inc.
Clinical Note

When Nothing Helps: Propofol as Sedative and Antiemetic in Palliative Cancer Care

Staffan Lundström MDCorresponding Author Contact Information, Ulla Zachrisson MD and Carl Johan Fürst MD, PhD

Palliative Care Services (S.L., U.Z., C.J.F.), Stockholms Sjukhem Foundation; and Department of Oncology-Pathology (S.L., C.J.F.), Karolinska Institutet, Stockholm, Sweden

Accepted 27 May 2005.  Available online 21 December 2005.


Abstract

Benzodiazepines, neuroleptics, and barbiturates are commonly used for sedation to achieve symptom control in end-of-life care. Propofol has several advantages over traditional sedating agents that would indicate its use in treatment-refractory situations. We report on the use of propofol in 35 patients. In 22 patients, propofol was used for palliative sedation when treatment with benzodiazepines had failed. The mean dose range during treatment was between 0.90 and 2.13 mg/kg/h. The effect was assessed as good or very good in 91% of the patients. Thirteen patients were treated with propofol due to intractable nausea and vomiting. The mean dose range during the infusion period was 0.67–1.01 mg/kg/h. The effect was judged as good or very good in 69% of the patients. Based on our experience, we propose clinical guidelines on the safe use of propofol in specialized palliative inpatient units.

Key Words: Propofol; sedative; sedation; antiemetic; nausea; vomiting; palliative care


Corresponding Author Contact InformationAddress reprint requests to: Staffan Lundström, MD, Stockholms Sjukhem Foundation, Mariebergsgatan 22, S-112 35 Stockholm, Sweden.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16455477&dopt=Abstract

Lancet Oncol. 2006 Feb;7(2):132-40.

Survival from rare cancer in adults: a population-based study.

Gatta G, Ciccolallo L, Kunkler I, Capocaccia R, Berrino F, Coleman MP, De Angelis R, Faivre J, Lutz JM, Martinez C, Moller T, Sankila R; EUROCARE Working Group.

Epidemiology Unit, National Cancer Institute, Milan, Italy. gemma.gatta@istitutotumori.mi.it

BACKGROUND: Rare cancers are a challenge to clinical practice, and treatment experience, even in major cancer centres to which rare cancers are usually referred, is often limited. We aimed to study the epidemiology of rare cancers in a large population of several countries. METHODS: We analysed survival by age, sex, subsite, and morphology in 57,144 adults with 14 selected rare cancers diagnosed 1983-94. Variations in survival over time and between European regions were also assessed for variations in quality of care. We also estimated the adjusted relative excess risk of death for every rare cancer. FINDINGS: Overall 5-year relative survival was good (ie, >65%) for placental choriocarcinoma (85.4% [95% CI 81.4-89.5]), thyroid medullary carcinoma (72.4% [69.2-75.5]), ovarian germ-cell cancer (73.0% [70.0-76.0]), lung carcinoid (70.1% [67.3-72.9]), and cervical adenocarcinoma (65.5% [64.3-66.6]); intermediate (ie, 35-65%) for testicular cancer at age 65 years or older (64.0% [59.3-68.7]), sarcoma of extremities (60.0% [58.9-61.2]), digestive-system endocrine cancers (55.6% [54.9-56.3]), anal squamous-cell carcinoma (53.1% [51.5-54.8]), and uterine sarcoma (43.5% [42.0-44.9]); low for carcinoma of adrenal-gland cortex (32.7% [28.3-37.2]) and bladder squamous-cell carcinoma (20.4% [18.8-22.0]); and poor for angiosarcoma of liver (6.4% [1.8-11.0]) and mesothelioma (4.7% [4.3-5.2]). Survival was usually better for women than men and poor in those aged 75 years or older. Survival significantly improved over time for ovarian germ-cell cancer, sarcomas of extremities, digestive-system endocrine tumours, anal squamous-cell carcinoma, and angiosarcoma of liver. Survival in northern Europe was higher than in the other geographic groupings for most cancers. INTERPRETATION: Because effective treatments are available for several of the rare cancers we assessed, further research is needed to ascertain why survival is lower in some European countries than in others, particularly in older patients. Audit of best practice for rare cancers with treatment protocols would be useful.

PMID: 16455477 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16400337&dopt=Abstract

Bone Marrow Transplant. 2006 Feb;37(4):345-51.

Population pharmacokinetics of intravenous busulfan in patients undergoing hematopoietic stem cell transplantation.

Takama H, Tanaka H, Nakashima D, Ueda R, Takaue Y.

1Product Development Department, Pharmaceutical Division, Kirin Brewery Company Ltd, Shibuya-ku, Tokyo, Japan.

A population pharmacokinetic analysis was performed in 30 patients who received an intravenous busulfan and cyclophosphamide regimen before hematopoietic stem cell transplantation. Each patient received 0.8 mg/kg as a 2 h infusion every 6 h for 16 doses. A total of 690 concentration measurements were analyzed using the nonlinear mixed effect model (NONMEM) program. A one-compartment model with an additive error model as an intraindividual variability including an interoccasion variability (IOV) in clearance (CL) was sufficient to describe the concentration-time profile of busulfan. Actual body weight (ABW) was found to be the determinant for CL and the volume of distribution (V) according to NONMEM analysis. In this limited study, the age (range 7-53 years old; median, 30 years old) had no significant effect on busulfan pharmacokinetics. For a patient weighting 60 kg, the typical CL and V were estimated to be 8.87 l/h and 33.8 l, respectively. The interindividual variability of CL and V were 13.6 and 6.3%, respectively. The IOV (6.6%) in CL was estimated to be less than the intraindividual variability. These results indicate high interpatient and intrapatient consistency of busulfan pharmacokinetics after intravenous administration, which may eliminate the requirement for pharmacokinetic monitoring.Bone Marrow Transplantation (2006) 37, 345-351. doi:10.1038/sj.bmt.1705252; published online 9 January 2006.

PMID: 16400337 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16450380&dopt=Abstract

Int J Cancer. 2006 Jan 31; [Epub ahead of print] 

Generation of tumoricidal PAX3 peptide antigen specific cytotoxic T lymphocytes.

Rodeberg DA, Nuss RA, Elsawa SF, Erskine CL, Celis E.

Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

The transcription factor PAX3 is expressed during early embryogenesis and in multiple cancer types, including embryonal rhabdomyosarcoma (ERMS), Ewing sarcoma (ES) and malignant melanoma (MEL), suggesting that it could function as a general tumor associated antigen. Major histocompatibility complex (MHC) peptide binding algorithms were used to predict potential epitopes in PAX3 capable of stimulating in vitro naive HLA-A0201 restricted cytotoxic T-lymphocytes (CTLs). Two peptides, PAX3-282 (QLMAFNHLI) and a modified version of this peptide PAX3-282.9V (QLMAFNHLV), were capable of inducing antigen-specific CTLs. Of these peptides, PAX3-282.9V was the most efficient inducer of primary CTL response. These CTLs were able to lyse HLA-A0201 expressing target cells that were pulsed with peptide, and more importantly, were effective in killing tumor cells that express PAX3, including ERMS, ES and MEL cell lines. These findings provide compelling evidence that peptide PAX3-282 is naturally processed by tumors and is presented in the context of HLA-A0201 in adequate amounts to allow CTL recognition. Also, PAX3-282.9V is an effective immunogenic peptide able to induce CTL recognition of PAX3-containing tumors and may be used as an antitumor peptide vaccine. (c) 2006 Wiley-Liss, Inc.

PMID: 16450380 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16446642&dopt=Abstract

Ann Dermatol Venereol. 2005 Dec;132(12 Pt 1):986-9.

Primary cutaneous extraskeletal Ewing's sarcoma

[Article in French]

Kourda M, Chatti S, Sfia M, Kraiem W, Ben Brahim E.

Service de Dermatologie, Hopital de Nabeul, Tunisie. kourda_mouna@yahoo.fr

BACKGROUND: Cutaneous extraskeletal Ewing's sarcoma is rare, being seen principally in children. We report a case of cutaneous sarcoma in the sole of the foot in a child. CASE REPORT: A 9-year-old child with no medical history of note was presenting a skin tumor for 3 months on the heel of the right foot. This tumor was burgeoning and painful and measured 3.5 cm in diameter; it was ulcerative at the surface and covered with a crust. Histological and immunohistochemical examinations confirmed the diagnosis of Ewing's sarcoma. Staging examinations proved negative and the patient underwent polychemotherapy, resulting in complete regression of the tumor. COMMENTS: Until 1998, 37 cases of cutaneous and subcutaneous Ewing's sarcoma were reported, being seen in 21 girls and 16 boys. Mean age at diagnosis was 15 years and mean tumor size was 3 cm (range: 1 to 12 cm). The tumors were observed throughout the body, being seen in the sole of the foot in 2 cases. Confirmation of the diagnosis was made by histological examination (malignant proliferation of small round cells in the dermis), immunohistochemical examination (CD99+) and cytogenetic analysis (translocation between chromosomes 22 and 11). The prognosis for cutaneous Ewing's sarcoma appears more favorable than that of Ewing's sarcoma in bone. Of the 37 patients treated, 7 had metastases and 2 presented relapse. Treatment for cutaneous Ewing's sarcoma, though not codified, consists of polychemotherapy associated with surgery and/or radiotherapy.

PMID: 16446642 [PubMed - in process]

http://www.pedresearch.org/cgi/content/abstract/59/2/259

CLINICAL INVESTIGATIONS

Patterns of Growth and Body Proportions After Total-Body Irradiation and Hematopoietic Stem Cell Transplantation During Childhood

BOUDEWIJN BAKKER, WILMA OOSTDIJK, RONALD B. GESKUS, W. HENRIËTTE STOKVIS-BRANTSMA, JAAK M. VOSSEN and JAN M. WIT

Department of Pediatrics [B.B., W.O., W.H.S.-B., J.M.V., J.M.W.], Department of Medical Statistics [R.B.G.], Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

Patterns of growth and body proportions were studied in 75 children receiving total-body irradiation (TBI) and hematopoietic stem cell transplantation (SCT) before onset of puberty. Of the 19 patients receiving GH, only data obtained before onset of GH were included. Thirty-two patients reached final height (FH). Median change in height SD score (SDS) between SCT and FH was –1.7 in boys and –1.1 in girls. Peak height velocity (PHV) was decreased in the majority of the patients (median PHV 5.7 cm/y in boys and 5.3 cm/y in girls), even though it occurred at appropriate ages. Changes in body proportions were analyzed by linear mixed-effects models. Decrease in sitting height SDS did not differ between boys and girls. In boys, decrease in leg length SDS was of comparable magnitude, whereas, in girls, decrease in leg length was less pronounced, leading to a significant decrease in SDS for sitting height/height ratio in girls only. The sex-specific effects of several variables on height SDS were analyzed by linear mixed-effects modeling, showing a slightly faster decrease in younger children and a more pronounced decrease during puberty in boys compared with girls. We conclude that 1) younger children are more susceptible to growth retardation after TBI and SCT, 2) pubertal growth is more compromised in boys, and 3) leg growth is relatively less affected in girls, possibly due to a high incidence of gonadal failure in girls.

Abbreviations:
FH, final height
PHV, peak height velocity
SCT, stem cell transplantation
SDS, standard deviation score
TBI, total-body irradiation

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16394892&dopt=Abstract

J Pediatr Hematol Oncol. 2006 Jan;28(1):40-2.
   
Long-term survival following a phase I/II trial with VETOPEC for solid tumors in childhood

Ziegler DS, McCowage G, Cohn RJ, White L.

Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Randwick, NSW, Australia.

The objective of this study was to evaluate long-term survival after treatment during a phase I/II trial with a specific regimen of vincristine, etoposide, and escalating cyclophosphamide (VETOPEC). Fifty-six children with poor-prognosis solid tumors were enrolled on study between May 1991 and May 1994. All had tumors that had relapsed on, or were refractory to, conventional treatment, or for whom existing treatment options were considered ineffective. The records of all surviving patients were reviewed to ascertain their disease and health status. Of the 56 patients, 10 patients (18%) remain alive with no further disease progression at a median follow-up of 11 years (range 7-13 years). Eight patients (14%) remain completely free of disease. None of the patients show long-term side effects directly attributable to the VETOPEC regimen, apart from one patient with ovarian failure. The VETOPEC regimen can offer not only good tumor responses but also the chance of cure for a surprisingly large number of children with very-poor-prognosis solid tumors. This regimen warrants continuing development and consideration for use in future trials.

PMID: 16394892 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16425266&dopt=Abstract

Pediatr Blood Cancer. 2006 Jan 19; [Epub ahead of print]
 
Analysis of biologic surrogate markers from a Children's Oncology Group Phase I trial of gefitinib in pediatric patients with solid tumors.


Jimeno A, Daw NC, Amador ML, Cusatis G, Kulesza P, Krailo M, Ingle AM, Blaney SM, Adamson P, Hidalgo M.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.

This trial evaluated the effect of gefitinib on the plasma circulating levels of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-2 and -9 of patients treated on a pediatric Phase I trial. Complete plasma correlative studies were obtained from 16 of the 25 enrolled patients. There was a trend for lower MMP-2 baseline levels in patients with partial response or stable disease. The Ewing sarcoma from the only patient with partial response lacked egfr mutations. Gefitinib did not induce any significant variation in the levels of the assessed parameters, and none of these determinations showed significant predictive or prognostic value. Pediatr Blood Cancer (c) 2006 Wiley-Liss, Inc.

PMID: 16425266 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16435380&dopt=Abstract

Pediatr Blood Cancer. 2006 Jan 24; [Epub ahead of print]   

Topotecan by 21-day continuous infusion in children with relapsed or refractory solid tumors: A Children's Oncology Group study.

Hawkins DS, Bradfield S, Whitlock JA, Krailo M, Franklin J, Blaney SM, Adamson PC, Reaman G.

Children's Hospital and Regional Medical Center, Seattle, Washington.

PURPOSE: The Children's Oncology Group conducted a phase II trial of 21-day continuous infusion topotecan to determine the response rate in pediatric patients with recurrent or refractory malignant solid tumors. PROCEDURE: Patients with Ewing sarcoma family of tumors (ESFT), osteosarcoma (OS), soft tissue sarcomas (STS), medulloblastoma (MB)/primitive neuroectodermal tumor (PNET), astrocytoma, or neuroblastoma (NB) recurrent or refractory to conventional therapy, measurable disease, and adequate organ function were treated with topotecan 0.3 mg/m(2)/day by continuous intravenous infusion for 21 consecutive days, followed by 7 days without therapy prior to response assessment. RESULTS: Fifty-five patients were enrolled; two were ineligible, two were removed from protocol therapy prior to evaluation for response, and one was inevaluable for response, leaving 53 and 50 patients evaluable for toxicity and response, respectively. Objective responses were seen in 2/20 patients with ESFT (both partial responses, 4 and 19 courses), 0/10 OS patients, and 0/12 STS patients. There were insufficient patients enrolled to determine the response rate for the MB/PNET, astrocytoma, and NB strata. The most common Grade 3 or 4 toxicities during the first course of therapy were thrombocytopenia (12/53), neutropenia (8/53), and fatigue (7/53). CONCLUSION: Intravenous topotecan by 21-day continuous infusion is tolerable in pediatric patients with recurrent or refractory solid tumors. Limited activity was seen in ESFT and further development of this topotecan schedule as a single agent is not warranted. Pediatr Blood Cancer (c) 2006 Wiley-Liss, Inc.

PMID: 16435380 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16421909&dopt=Abstract

Pediatr Blood Cancer. 2006 Jan 18; [Epub ahead of print]

An analysis of primary site control and late effects according to local control modality in non-metastatic Ewing sarcoma.

Paulino AC, Nguyen TX, Mai WY.

Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine and Methodist Hospital, Houston, Texas.

PURPOSE: To examine prognostic factors for primary site control and analyze late effects according to local treatment modality in non-metastatic Ewing sarcoma (ES). MATERIALS AND METHODS: From 1976 to 2001, 76 patients with localized ES and a median age of 14.5 years were seen and treated at one institution. Tumors were located in the extremity in 38, pelvis in 13, spine in 11, trunk in 8, and head and neck in 6. Tumor size was </=8 cm in 44 and >8 cm in 32. Local therapy included radiotherapy (RT) alone in 40, surgery (S) alone in 27, and surgery followed by postoperative radiotherapy (S + RT) in 9. Chemotherapy (CT) was delivered to 65 patients (86%). Median follow-up for surviving patients was 9.7 years. RESULTS: The 5- and 10-year overall survival rates were 57.5% and 52.1% while the 5- and 10-year local control rate was 79.2%. The 5- and 10-year local control rates were 78.2% for RT, 77.6% for surgery, and 88.9% for S + RT (P = 0.68). Multivariate analysis showed that only the use of CT was found to be a prognostic factor for local control (P = 0.014). The 5- and 10-year local control rates were 83.7% for those receiving CT and 51.1% for those not receiving CT. For patients followed at least 5 years from diagnosis, late effects were seen in 10 of 19 (52.6%) receiving RT, 2 of 5 (40%) receiving S + RT, and 4 of 16 (25%) receiving surgery alone. The most common late effects with RT were muscular atrophy, limb length growth delay, and development of second malignancy. Scoliosis and decrease range of motion of an extremity were seen regardless of local treatment modality. Three patients who had surgery alone had an amputation whereas two who had RT had an amputation secondary to relapse or development of osteosarcoma. CONCLUSION: In this single institution study, the use of CT was the only factor found to impact on local control. Late effects were common regardless of local control strategy. Pediatric Blood Cancer (c) 2006 Wiley-Liss, Inc.
PMID: 16421909 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16411221&dopt=Abstract


Pediatr Blood Cancer. 2006 Jan 12; [Epub ahead of print]

Second and third malignant solid tumor in a girl with ovarian Sertoli-Leydig tumor.

Panagiotou JP, Polychronopoulou S, Sofou K, Vanvliet-Constantinidou C, Papandreou E, Haidas S.

Department of Pediatric Hematology/Oncology, "Aghia Sophia" Children's Hospital, Athens, Greece.

We report a Sertoli-Leydig cell (SLC) tumor of the right ovary in a 10-year-old girl, which was dealt with surgical removal. Three months after resection, she presented with a new episode of acute abdomen because of an abdominal mass, which histologically was compatible with an undifferentiated embryonal rhabdomyosarcoma. Chemotherapy, according to SIOP-??? 89 protocol, was administered additionally to radiotherapy (3,960 cGy). Three years after completing treatment, the patient developed a painful swelling at her left upper arm. The diagnosis was Ewing sarcoma of the humerus, which was confirmed by identification of the typical 11; 22 translocation on cytogenetic and molecular analysis of the tumor tissue. The patient died 14 months from Ewing diagnosis due to progressive disease. Pediatr Blood Cancer (c) 2006 Wiley-Liss, Inc.

PMID: 16411221 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16418250&dopt=Abstract

Radiographics. 2006 Jan-Feb;26(1):157-71.

Causes of facial swelling in pediatric patients: correlation of clinical and radiologic findings.

Khanna G, Sato Y, Smith RJ, Bauman NM, Nerad J.

Department of Radiology, University of Iowa College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242, USA. geetika-khanna@uiowa.edu

Facial swelling is a common clinical problem in pediatric patients. The causes of swelling are diverse, and knowledge of the typical clinical and imaging manifestations and the most common sites of occurrence of these conditions is needed to formulate a differential diagnosis. The general clinical manifestations may be classified into the following four groups: (a) acute swelling with inflammation, (b) nonprogressive swelling, (c) slowly progressive swelling, and (d) rapidly progressive swelling. Conditions that may account for acute swelling accompanied by inflammation include lymphadenitis, sinusitis, odontogenic infection, and abscess. Contrast-enhanced computed tomography is the modality of choice for detection of abscesses requiring surgical drainage. Nonprogressive midfacial swelling is suggestive of a congenital anomaly (eg, a cephalocele, nasal glioma, or nasal dermoid or epidermoid cyst). Slowly progressive swelling may indicate the presence of a neurofibroma, hemangioma, lymphangioma, vascular malformation, or pseudocyst, or of fibrous dysplasia. The differential diagnosis for rapidly progressive facial swelling in association with cranial nerve deficits should include rhabdomyosarcoma, Langerhans cell histiocytosis, Ewing sarcoma, osteogenic sarcoma, and metastatic neuroblastoma. (c) RSNA, 2006.

PMID: 16418250 [PubMed - in process]

Volume 333:1594-1599           December 14, 1995           Number 24

Cancer in the Parents of Children with Cancer

http://content.nejm.org/cgi/content/abstract/333/24/1594

Jørgen H. Olsen, M.D., John D. Boice, Sc.D., Niels Seersholm, M.D., Andrea Bautz, and Joseph F. Fraumeni, M.D.

Background Certain types of cancer in children and young adults have been linked with an increased risk of cancer in close relatives. However, the relation between childhood cancer and familial risk remains to be fully assessed in population-based studies.

Methods We conducted a nationwide study in Denmark of 11,380 parents of children with cancer. The children were identified from records in the Danish Cancer Registry; their parents were identified from population registers. The occurrence and rate of cancer in the parents were determined with use of the Cancer Registry's files and compared with national incidence rates for various categories of tumor.

Results Overall, 1445 cancers were diagnosed in the parents, as compared with 1496 expected from national incidence rates, to yield standardized incidence ratios of 1.0 (95 percent confidence interval, 0.9 to 1.0) for all parents, 1.0 for mothers, and 0.9 for fathers. The lower rate of cancer among fathers reflected their lower standardized incidence ratio for lung cancer (0.8; 95 percent confidence interval, 0.6 to 0.9), as calculated from 114 observations.

Conclusions Genetic determinants are important in several types of childhood cancer, but the genetic susceptibility to tumors does not generally extend to the parents of children with cancer, nor do the patterns of incidence point to the influence of shared environmental factors. Thus, cancer in children should not be viewed as a general marker for an increased risk of cancer in the patients' parents.


Source Information

From the Division for Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark (J.H.O., N.S., A.B.); and the Epidemiology and Biostatistics Program, National Cancer Institute, Bethesda, Md. (J.D.B., J.F.F.).

Address reprint requests to Dr. Olsen at the Danish Cancer Society, Division for Cancer Epidemiology, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.