In Lab Study, Researchers Find Molecule That Disrupts Ewing’s Sarcoma Oncogene


CONTACT: Karen Mallet

In Lab Study,
Researchers Find Molecule That Disrupts
Ewing’s Sarcoma Oncogene

SAN DIEGO – Researchers at
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
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
, Baltimore, MD., and
, 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

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.


Risk of cancer in children with the diagnosis immaturity at birth

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

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

Publisher: Blackwell Publishing

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:

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,

Pediatric Cancers Are Infiltrated Predominantly by Macrophages and Contain a Paucity of Dendritic Cells: a Major Nosologic Difference with Adult Tumors

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

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:

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

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.

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

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.

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]

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.

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.

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]

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

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.

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]

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

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

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

Iezzoni JC, Mills SE.

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

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]

Long-term follow-up of 15 patients with non-metastatic Ewing's sarcoma and a skip lesion.

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

Department of Orthopaedic Surgery, Vrije Universiteit Medical Centre,

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]

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

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

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: .

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.

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

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


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.