Author Archives: Barry Sugarman

Ixabepilone to Treat Children and Young Adults with Solid Tumors

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Ixabepilone to Treat Children and Young
Adults with Solid Tumors

This study is currently
recruiting patients.
Verified by National Institutes of Health Clinical Center (CC) March
29, 2006

Sponsored by: National
Cancer Institute (NCI)
Information provided by: National Institutes of Health
Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00318526

Purpose

Background:
-Ixabepilone is a
member of a new class of anticancer drugs called epothilones, which
interfere with the ability of cancer cells to divide. Ixabepilone kills
cancer cells in the test tube and in animals.
-Epothilones are
similar to a class of drugs called taxanes, which include Taxol®
(Registered Trademark) (paclitaxel) and Taxotere® (Registered
Trademark) (docetaxel). Epothilones can kill cancer cells that are
resistant to Taxol® (Registered Trademark) in the laboratory.
-Ixabepilone has been
tested in a small number of adults and children with cancers resistant
to standard treatment.
Objectives:
-To measure the
response of solid tumors to treatment with ixabepilone.
-To determine for how
long ixabepilone can stop tumors from growing.
-To evaluate a new
method of measuring tumors in the chest with a method that measures
tumor volume.
-To further define the
side effects of ixabepilone.
Eligibility:
-Patients with
osteosarcoma, Ewing's sarcoma/peripheral neuroectodermal tumor,
rhabdomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath
tumor, neuroblastoma, or Wilms tumor.
-Patients must be 12
months or older when entering the study.
-Patients with sarcoma
must have been no more than 35 years old at the time of diagnosis.
-Patients with Wilms
tumor or neuroblastoma must have been no more than 21 years old at the
time of diagnosis.
Design:
-Up to 20 patients
with each type of tumor may be enrolled.
-Patients are given
ixabepilone as a 1-hour infusion through a vein on days 1-5 of every
21-day cycle.
-Patients have a
physical exam and urine test before each cycle, blood tests weekly,
pregnancy test (for women who can bear children) every other cycle, and
tests to evaluate the tumor (radiological, imaging, or others,
depending on the tumor type) after the first cycle and then after every
other cycle.
-Patients may continue
treatment as long as their tumor responds to therapy and the side
effects are not unacceptable.

Condition Intervention Phase
Refractory Solid Tumors  Drug: Ixabepilone Phase
II

MedlinePlus consumer
health information 

Study Type: Interventional
Study Design: Treatment, Safety/Efficacy

Official Title: Phase II Trial of Ixabepilone
(BMS-247550), an Epothilone B Analog, in Children and Young Adults with
Refractory Solid Tumors

Further study details as provided by National
Institutes of Health Clinical Center (CC):
Expected Total Enrollment:  120

Study start: April 20, 2006

Background:
Ixabepilone (BMS-247550) is a semi-synthetic analog of the natural
product epothilone B. The epothilones are a novel class of non-taxane
microtubule-stabilizing agents obtained from the fermentation of the
cellulose degrading myxobacteria, Sorangium cellulosum. Ixabepilone is
active against preclinical cancer models that are naturally insensitive
to paclitaxel or have developed resistance to paclitaxel, both in-vitro
and in-vivo. The National Cancer Institute (NCI) Pediatric Oncology
Branch is conducting a phase I trial of Ixabepilone on a daily x 5
consecutive day schedule. The drug has been well tolerated in children
at doses of up to 8 mg/m(2)/d.
Objectives: This Phase
II trial is designed to establish the objective response rate (CR+PR)
using RECIST criteria of Ixabepilone in solid tumors occurring in
pediatric and young adult patients. Time to disease progression is a
secondary trial endpoint. In addition, for patients with measurable
chest disease, comparison of automated volumetric tumor measurement
with standard RECIST and WHO methods is a secondary endpoint on this
trial.
Eligibility: Patients
will be accrued in one of six disease strata: osteosarcoma, Ewing's
sarcoma/Peripheral neuroectodermal tumor (PNETs), rhabdomyosarcoma,
synovial sarcoma and malignant peripheral nerve sheath tumor (MPNSTs),
neuroblastoma, or Wilms tumor. Patients are eligible if they have
measurable disease and have not previously received taxanes. Patients
must be greater than or equal to 12 months old at trial entry. Patients
with sarcoma must have been less than or equal to 35 years old at
original diagnosis; patients with Wilms tumor or neuroblastoma must
have been less than or equal to 21 years old at original diagnosis.
Design: Ixabepilone
will be administered as a one-hour infusion on Days 1 to 5 every 21
days at a dose of 8 mg/m(2)/dose. The trial will use a two-stage design
targeting a response rate of 30%. Up to 20 patients will be accrued to
each tumor stratum.

Eligibility

Genders Eligible for
Study:  Both
Criteria
INCLUSION CRITERIA:
Important note: The
eligibility criteria listed below are interpreted literally and cannot
be waived (per COG policy posted 5/11/01). All clinical and laboratory
data required for determining eligibility of a patient enrolled on this
trial must be available in the patient's medical/research record which
will serve as the source document for verification at the time of
audit.
Age
-Patients must be
greater than or equal to 12 months old at trial entry.
-Patients with
neuroblastoma or Wilms tumor must have been less than 22 years of age
when originally diagnosed with the malignancy to be treated on this
protocol.
-All other patients
must have been less than 36 years of age when originally diagnosed with
the malignancy to be treated on this protocol.
Histologic Diagnosis
The target tumors are:
-Embryonal or alveolar
rhabdomyosarcoma
-Osteosarcoma
-Ewing's
sarcoma/Peripheral neuroectodermal tumor (PNET)
-Synovial sarcoma or
malignant peripheral nerve sheath tumor (MPNST)
-Wilms tumor
-Neuroblastoma
Patients must have had
histologic verification of the malignancy at original diagnosis or at
recurrence.
All patients must have
refractory or recurrent tumors with no known curative treatment options.
For patients with
sarcoma and Wilms tumor:
Patients must have
measurable disease. Measurable disease is defined as lesions that can
be measured in at least one dimension by medical imaging techniques (CT
or MRI scan). Ascites, pleural effusions, bone marrow disease, and
lesions detectable only by bone scan will not be considered measurable
disease.
For patients with
neuroblastoma:
Patients with either
clinically or radiographically measurable disease or evaluable disease
by 123I-MIBG or bone scan are eligible.
-For evaluable tumor,
(123)I-MIBG or bone scan must be positive at a minimum of one site. If
the lesion was previously radiated, a biopsy must be done at least 6
weeks after radiation is complete and demonstrate viable neuroblastoma.
Performance Level
Patients must have an
ECOG performance status of 0, 1 or 2, or Karnofsky greater than or
equal to 50% (patients greater than 16 years of age) or Lansky greater
than or equal to 50% (patients less than or equal to 16 years).
Life Expectancy
Patients must have a
life expectancy of greater than or equal to 8 weeks.
Prior Therapy
Patients must have
fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study.
-Myelosuppressive
chemotherapy: Must not have received within 2 weeks of entry onto this
study (4 weeks if prior nitrosourea).
-Biologic
(anti-neoplastic agent): At least 7 days since the completion of
therapy with a biologic agent.
-XRT: greater than or
equal to 2 wks for local palliative XRT (small port); greater than or
equal to 6 months must have elapsed if prior craniospinal XRT or if
greater than or equal to 50% radiation of pelvis; greater than or equal
to 6 wks must have elapsed if other substantial BM radiation.
-Stem Cell Transplant
(SCT): No evidence of active graft vs. host disease. For allogeneic
SCT, greater than or equal to 4 months must have elapsed; for
autologous SCT greater than or equal to 2 months must have elapsed.
-Study specific
limitations on prior therapy: Patients may not have received prior
taxane (paclitaxel, docetaxel) therapy.
Concomitant
Medications Restrictions
No other cancer
chemotherapy or immunomodulating agents (including steroids) will be
used. However, steroids may be used for the treatment and prevention of
hypersensitivity reactions, if necessary.
Growth factor(s): Must
not have received within 1 week of entry onto this study, with the
exception of erythropoietin.
Study Specific:
Patients may not be currently receiving strong inhibitors of CYP3A4,
and may not have received these medications within 1 week of entry.
These include:
-Antibiotics:
clarithromycin, erythromycin, troleandomycin
-Antifungals:
itraconazole, ketoconazole, fluconazole (doses greater than 3
mg/kg/day), voriconazole
-Antidepressants:
nefazodone, fluovoxamine
-Calcium channel
blockers: verapamil, diltiazem
-Antiemetics: Do not
use aprepitant (Emend® (Registered Trademark)) as it is CYP3A4
substrate, moderate inhibitor and inducer.
-Miscellaneous:
amiodarone,
-In addition,
grapefruit juice should be avoided, as it inhibits CYP3A4.
-Patients must also
avoid St. John's Wort, an inducer of CYP3A4.
-Patients may not be
taking enzyme -inducing anticonvulsants, and may not have received
these medications within 1 week of entry, as these patients may
experience different drug disposition. These medications include:
-Carbamazepine
(Tegretol)
-Felbamate (Felbtol)
-Phenobarbital
-Phenytoin (Dilantin)
-Primidone (Mysoline)
-Oxcarbazepine
(Trileptal)
Organ Function
Requirements
All patients must have:
Adequate Bone Marrow
Function Defined As
-Peripheral absolute
neutrophil count (ANC) greater than or equal to 1500/uL (off growth
factors)
-Platelet count
greater than or equal to 75,000/uL (transfusion independent)
-Hemoglobin greater
than or equal to 10.0 gm/dL (may receive RBC transfusions)
Adequate Renal
Function Defined As
Creatinine clearance
or radioisotope GFR greater than or equal to 60mL/min/1.73m(2)
OR
A serum/plasma
creatinine calculation of GFR 60mL/min/1.73m(2) using the Schwartz
formula
(Schwartz et al. J.
Peds, 106:522, 1985)
Estimated Creatinine
Clearance (in mL/min/1.73 m(2))
(k)(L)/Pcr
Where L &eq;
child's length in cm
Pcr &eq; plasma
(or serum) creatinine (in mg/dL)
K Values &eq;
0.33 low birth weight
infant
0.45 term infant
0.55 child
0.55 adolescent female
0.70 adolescent male
**The conversion
formula for serum/plasma creatinine when reported in
uMol/L units:
(k ” ht)/(sCr in
uMol/L ” 88.4)
Adequate Liver
Function Defined As
-Total bilirubin less
than or equal to 1.5 x upper limit of normal (ULN) for age, and
-SGPT (ALT) less than
or equal to 2.5 x upper limit of normal (ULN) for age.
Nervous System
Function Defined As
-Patients with seizure
disorder may be enrolled if on anticonvulsants and well controlled.
Enzyme inducing anticonvulsant drugs are not allowed on this trial.
-CNS toxicity less
than or equal to Grade 2.
-Existing sensory or
motor neuropathy must be grade less than or equal to1.
EXCLUSION CRITERIA:
-Clinically
significant unrelated systemic illness, such as serious infections,
hepatic, renal or other organ dysfunction, which would, in the judgment
of the treating physician, compromise the patient's ability to tolerate
the investigational agent or is likely to interfere with the study
procedures or results.
-Pregnant or
breast-feeding females, because Ixabepilone may be harmful to the
developing fetus or nursing child. Patients of child-bearing potential
must use appropriate birth control measures.
-Patients with known
severe prior hypersensitivity reaction to agents containing Cremophor
EL.
-Patients with active
brain metastases.
For patients with
sarcoma and Wilms tumor:
Ascites, pleural
effusions, bone marrow disease, and lesions detectable only by bone
scan will not be considered measurable disease. Patients who have
disease in these locations without radiographically measurable (CT,
MRI) disease are excluded.
For patients with
neuroblastoma:
Patients with elevated
urinary catecholamines and/or bone marrow evidence of tumor, without
measurable or evaluable disease clinically or by imaging modalities
(CT, MRI, MIBG, or Bone Scan) are excluded.

Location and Contact Information

Please refer to this study by ClinicalTrials.gov
identifier  NCT00318526
Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda, 
Maryland,  20892,  United States; Recruiting

Patient Recruitment and Public Liaison Office
 1-800-411-1222    prpl@mail.cc.nih.gov 

TTY  1-866-411-1010 

More Information

Detailed
Web Page

Publications

Jordan
A, Hadfield JA, Lawrence NJ, McGown AT. Tubulin as a target for
anticancer drugs: agents which interact with the mitotic spindle. Med
Res Rev. 1998 Jul;18(4):259-96. Review.

Wilson
L, Jordan MA. Microtubule dynamics: taking aim at a moving target. Chem
Biol. 1995 Sep;2(9):569-73. Review.

Huizing
MT, Misser VH, Pieters RC, ten Bokkel Huinink WW, Veenhof CH, Vermorken
JB, Pinedo HM, Beijnen JH. Taxanes: a new class of antitumor agents.
Cancer Invest. 1995;13(4):381-404. Review.

Study ID Numbers:  060146; 06-C-0146
Last Updated:  June 3, 2006
Record first received:  April 25, 2006
ClinicalTrials.gov Identifier:  NCT00318526
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this
record on 2006-07-03

Pharming Recieves Orphan Drug Designations For rhC1INH From US FDA

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http://www.pharming.com/index.php?act=show&pg=278

Pharming Recieves Orphan Drug Designations For rhC1INH From US FDA

Leiden, The Netherlands, June 14, 2006. Biotech company Pharming Group
NV (“Pharming” or “the Company”) (Euronext: PHARM) announced today it
has received orphan drug designations for recombinant human C1
inhibitor (rhC1INH) from the Food and Drug Administration (FDA). The
Company has obtained designations on rhC1INH for two separate disease
indications – the prevention and/or the treatment of Delayed Graft
Function (DGF) after solid organ transplantation and the treatment of
Capillary Leakage Syndrome (CLS).

Over 25,000 solid organs were transplanted in the US in 2005, including
kidney, liver, lung and heart transplants. Delayed Graft Function is a
common complication affecting all solid organs in the post-transplant
period. DGF results in significant morbidity and mortality from early
graft dysfunction and from decreased long-term graft survival. The
condition also prolongs hospitalization and requires substitute
therapies for these patients, such as dialysis or ventilatory support.
DGF remains a critical unmet medical need despite improvements in
immunosuppression, organ preservation, and surgical technique. C1
inhibitor has been shown in numerous models of organ transplantation to
improve early graft function.

Over 100,000 patients in the US develop Capillary Leakage Syndrome
annually as a complication of various disease states, including bone
marrow/stem cell transplantation, IL-2 therapy, sepsis, and neonatal
cardiac surgery. CLS is a severe life-threatening condition
characterized by excessive fluid loss into the tissue space, which can
result in hemodynamic instability, pulmonary edema, ascites, and death.
Current therapies for patients with CLS are limited to supportive care
and treatment of the underlying condition. Previous clinical work has
demonstrated that C1 inhibitor may be an effective anti-inflammatory
that can control the mechanisms contributing to CLS.

“Pharming’s rhC1INH product could provide new treatments for immune
mediated diseases such as Delayed Graft Function in organ
transplantation and Capillary Leakage Syndrome, conditions with a high
burden and limited treatment options for patients,” said Dr. Francis
Pinto, CEO of Pharming. “The Orphan Drug designations from the FDA
further validate the potential of rhC1INH as an innovative therapy and
are a significant achievement as we advance development of rhC1INH for
these indications.”

The FDA Orphan Drug designation is reserved for promising new therapies
being developed to treat diseases that affect fewer than 200,000 people
in the United States. This designation provides an accelerated review
process, tax advantages and a seven-year period of market exclusivity
in the US upon product approval. Pharming also has an Orphan Drug
designation on rhC1INH for the treatment of Hereditary Angioedema.

Background on Pharming Group NV
Pharming Group NV is developing innovative protein products for unmet
needs. The Company’s products include potential treatments for genetic
disorders, specialty products for surgical indications, intermediates
for various applications and food products. Pharming has two products
in late stage development – recombinant human C1 inhibitor for
Hereditary Angioedema (Phase III) and recombinant human lactoferrin for
use in functional foods. The advanced technologies of the Company
include innovative platforms for the production of protein
therapeutics, as well as technology and processes for the purification
and formulation of these products. Additional information is available
on the Pharming website: http://www.pharming.com.

This press release contains forward looking statements that involve
known and unknown risks, uncertainties and other factors, which may
cause the actual results, performance or achievements of the Company to
be materially different from the results, performance or achievements
expressed or implied by these forward looking statements. The press
release also appears in Dutch. In the event of any inconsistency, the
English version will prevail over the Dutch version.

Contact:

Carina Hamaker, Investor Voice, T: +31 (0)6 537 49959
Sarah MacLeod, Financial Dynamics, T: +44 (0)20 7269 7148
Samir Singh, Pharming Group NV, T: +31 (0)71 524 7429

FDA Approves New Treatment for Myelodysplastic Syndromes (MDS), a Potential Secondary Disease to Treatment of Ewing's Sarcoma

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http://www.fda.gov/bbs/topics/NEWS/2006/NEW01366.html

FDA News

FOR IMMEDIATE RELEASE
P06-64
May 3, 2006
   

Media Inquiries:
Laura Alvey, 301-827-6242
Consumer Inquiries:
888-INFO-FDA

FDA Approves New Treatment for Myelodysplastic Syndromes (MDS)

The Food and Drug Administration (FDA) today approved Dacogen
(decitabine) injection for the treatment of myelodysplastic syndromes
(MDS). Dacogen is a new molecular entity that received orphan drug
status. Orphan products are developed to treat rare diseases or
conditions that affect fewer than 200,000 people in the U.S. The Orphan
Drug Act provides a seven-year period of exclusive marketing to the
first sponsor who obtains marketing approval for a designated orphan
drug.

Patients with MDS have bone marrow that does not produce enough mature
blood cells. This causes a lack of healthy blood cells that can
function properly in the body. Dacogen is thought to work by promoting
normal development of blood cells. Different types of MDS exist,
resulting in different manifestations of the disease. For example, some
patients with MDS require chronic blood transfusions.

“Today's approval of Dacogen offers patients with this rare disease an
additional treatment option that may help these patients avoid blood
transfusions,” said Steven Galson, MD, Director of FDA's Center for
Drug Evaluation and Research.

MDS can develop following treatment with drugs or radiation therapy for
other diseases or it can develop without any known cause. Some forms of
MDS can progress to acute myeloid leukemia (AML), a type of cancer in
which too many white blood cells are made.

An estimated 7,000 to 12,000 new cases of MDS are diagnosed yearly in
the United States. Although MDS occurs in all age groups, the highest
prevalence is in people over 60 years of age. Typical symptoms include
weakness, fatigue, infections, easy bruising, bleeding, and fever.

The safety and effectiveness of Dacogen were demonstrated in a
randomized, controlled trial where patients received either Dacogen or
the standard therapy and in two non-randomized studies where all of the
patients received Dacogen. The new drug was evaluated in a total of 268
patients. About 22% of patients in the three trials had complete or
partial responses to Dacogen. Responses consisted of complete or
partial normalization of blood counts and of fewer immature cells in
the bone marrow. In responders the need for transfusions was eliminated
during the period of response.

The most common side effects reported in clinical trials included
neutropenia (low white blood cell count), thrombocytopenia (low
platelets in blood), anemia, fatigue, fever, nausea, cough, bleeding in
the skin, constipation, diarrhea, and hyperglycemia (high blood sugar).

Dacogen is manufactured by Pharmachemie B.V. Haarlem, The Netherlands
for MGI PHARMA, INC., Bloomington, MN.

####

Risk of cancer in children with the diagnosis immaturity at birth

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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,

The Limb Preservation Foundation

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http://comment.colostate.edu/index.asp?page=display_article&article_id=396523010
The Limb Preservation Foundation
CBS News Program TONIGHT at 5:30 p.m.
The CBS Evening News will feature a story on today's broadcast (April 18
at 5:30 MST) about the collaborative efforts between Dr. Ross Wilkins of
the Denver Clinic for Extremities at Risk, and Dr. Stephen Withrow of
the Colorado State University Animal Cancer Center, and their efforts to
find the cause and the cure for bone cancer and other extremity diseases.
The April 18 news story will be entitled "A Tale of Two Doctors" and
will feature interviews with both doctors and information on their
research collaborations in regard to osteosarcoma. Drs. Wilkins and
Withrow have been working together for many years on collaborative
research pertaining to osteosarcoma treatments and protocols for
patients with limb cancer.
Thanks to their joint efforts, the survival rate of pediatric limb
cancer patients has increased from 60% in 1986 to 92% today. The Limb
Preservation Foundation is committed to the research being conducted by
these two doctors and is working to continue their efforts through the
development of a Limb Preservation University Chair in support of
research in Musculoskeletal Biology at the CSU Animal Cancer Center in
Fort Collins. The Foundation will be working with CSU to jointly fund
this research position with the goal of raising $3,000,000 together in
the next three years.
Dr. Ross Wilkins is Founder of The Limb Preservation Foundation and
Medical Director of the Denver Clinic for Extremities at Risk.
Dr. Stephen Withrow is the Director of the CSU Animal Cancer Center and
holds a seat on the Board of Directors of The Limb Preservation
Foundation. The Limb Preservation Foundation is a charitable
organization that was established in 1987. The mission of the Foundation
is to support the prevention and treatment of limb threatening
conditions due to trauma, tumor or infection.
The Foundation coordinates and funds patient treatment programs,
educational programs and research with the goal of addressing the needs
of individuals who are facing the potential loss of a limb.
Category: Events and Coming Attractions
Submitted: Tuesday, April 18, 2006
Subject: ACC
Contact: Lynda J Reed
E-mail: Lynda.Reed@colostate.edu
Phone: (970) 297-4175

Neurosurgical Use of Interstitial Laser Therapy (ILT)

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http://www.clinicaltrials.gov/ct/show/NCT00207350

Neurosurgical Use of Interstitial Laser
Therapy (ILT)

This study is currently
recruiting patients.
Verified by Brigham and Women's Hospital September 2005

Sponsored by: Brigham and Women's Hospital
Information provided by: Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT00207350

Purpose

Our specific aims are
to test the following hypotheses: Hypothesis 1: A tumor can be
completely ablated by ILT with MRI-guidance; Hypothesis 2: The
MRI-based 3D temperature map of tissue during ILT is predictive of
destruction; Hypothesis 3: The 3D “thermal dose” map that is based on
the tissue’s temperature over time is more predictive of tissue
destruction than the temperature map.

Condition Intervention
Brain Tumor  Device: Interstitial Laser Therapy

MedlinePlus related
topics:  Brain Cancer

Study Type: Interventional
Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled,
Single Group Assignment, Efficacy Study

Further study details as provided by Brigham and
Women's Hospital:
Primary Outcomes: A tumor can be completely
ablated by ILT with MRI-guidance
Secondary
Outcomes: Patients undergoing ILT will be assessed pre- and
post-operatively based on a neurological exam by a physician and
patient self-assessment using the Glioma Outcomes Questionnaire.
Expected Total Enrollment:  24

Study start: January 2002
Last follow-up: December 2004

The
goal is to evaluate the use of minimally invasive interstitial laser
therapy (ILT) in the brain. Our group is in a unique position to offer
image-guided ILT because of our expertise and resources here at Brigham
& Women's Hospital in the Departments of Neurosurgery and
Radiology. The therapy will be monitored and controlled by the use of
magnetic resonance imaging (MRI). ILT is a minimally invasive procedure
in which the targeted tissue is thermally destroyed in situ in a
controlled fashion. The intra-operative MRI provides a way to “see” the
treatment. It can be used to treat disease by guiding surgery by
providing images of tissue changes during therapy.

In spite of its appeal as a minimally
invasive technique, MRI-guided ILT is not commonly practiced in the
United States. One reason is that proper clinical implementation of ILT
requires an operating room (OR) setting and an MRI scanner – a very
rare combination. Our MRI-OR suite includes a sterile procedure room
with a 0.5 Tesla vertically “open” magnet. In the past, we have
performed MRI-guided ILT procedures in 9 patients. While few in number,
this is the most extensive U.S. experience in ILT in the brain.

We have recently created a new image
networking and display package for the visualization of 3D information
during laser therapy. This provides a view of multiple image planes
taken through the tissue volume around the fiber tip.

Each patient will undergo ILT. The
procedure will be performed under anesthesia as per standard
procedures. The surgical placement of the laser fiber is a procedure
identical to the well-developed and practiced technique of brain
biopsy. A hole approximately 1 cm in diameter will be drilled in the
skull through which the laser fiber will be placed under image guidance
to confirm the actual progress during the advance of the fiber. We will
deliver energy at a rate and distribution of 1-12 watts/cm for
exposures less than 20 minutes. After the laser has been turned off,
and the tissue cooled, MRI will show the region of ablation. As needed,
the laser fiber will be moved/re-located to assure that the total
target has been ablated. After the treatment is complete, the fiber is
withdrawn, final images are acquired and the surgical site is closed
and dressed. On the day after the procedure, the patient will undergo a
24 hr follow-up MRI exam. There will be post-operative care as with any
neurosurgical patient.

The following continuous variables will be measured in this study.

  • the pre-operative tumor volume (VO) in cc
  • the post-operative ablated volume (V1) in cc
  • the intra-operative critical temperature volume (VT) in cc
  • the intra-operative critical dose
    volume (VD) in cc.

The following statistical hypothesis tests will be conducted.

Statistical Hypothesis 1. A tumor can be completely ablated by ILT
with MRI-guidance.

We
propose that the difference between the mean the pre-op tumor volumes
and the post-op ablated volumes (VO and V1, respectively) is zero.
Residual tumor is defined as (V0-V1). This will be determined by
calculating the mean of the values of the proportion of residual tumor,
defined as (V0-V1)/ V0.Use of the proportion normalizes the data for
different sized tumors.

Statistical Hypothesis 2. The MRI-based
3-D temperature map of the tissue during ILT is predictive of
destruction. We propose that the difference between the mean post-op
ablated volumes and the intra-operative critical temperature volumes
(VT and V1, respectively) is zero. This will be determined by
calculating the mean of the values of the proportion of the difference
between them, defined as (VT-V1)/VT.

Statistical Hypothesis 3. The thermal dose map is predictive of
tissue destruction.

We
propose that the difference between the mean post-op ablated volumes
and the intra-operative critical dose volumes (VD and V1, respectively)
is zero. This will be determined by calculating the mean of the values
of the proportion of the difference between them, defined as (VD-V1
/VD).

Also, data will be collected through Neurological Examinations and
GOC Questionnaire.

Eligibility

Ages Eligible for
Study:  18 Years and above,  Genders Eligible for Study:  Both
Criteria

Inclusion Criteria:

Male or female Age 18+ Surgically difficult to access tumors
including intracerebral metastases and vascular malformations

–

Exclusion Criteria:

Patients
unwilling or unable to give written consent Patients at risk for
cardiac ischemia Patients who cannot physically fit in the MRI scanner
in the MRI OR Patients with contra-indications to MRI imaging such as
pacemakers, non-compatible aneurysm clips, shrapnel, and other internal
ferromagnetic objects Patients with coagulopathies, severe medical
problems, cardiac arrythmias or abnormal BUN –

Location and Contact Information

Please refer to this study by ClinicalTrials.gov
identifier  NCT00207350
Joanne E O'Hara, M.A.      617-732-6992    johara1@partners.org
Donna Dello Iacono, RN, MS      617-732-6826    ddelloiacono@partners.org
Massachusetts
      Brigham & Women's Hospital, Boston,  Massachusetts,  02115, 
United States; Recruiting

Peter M Black, MD, PhD,  Principal Investigator

Study chairs or principal investigators
Peter M Black, MD, PhD,  Principal Investigator,  Brigham and Women's
Hospital   

More Information

Website
for Image Guided Therapy Program at Brigham & Women's Hospital

Publications

Schulze
PC, Vitzthum HE, Goldammer A, Schneider JP, Schober R. Laser-induced
thermotherapy of neoplastic lesions in the brain–underlying tissue
alterations, MRI-monitoring and clinical applicability. Acta Neurochir
(Wien). 2004 Aug;146(8):803-12. Epub 2004 Jun 7. Review.

Peller
M, Muacevic A, Reinl H, Sroka R, Abdel-Rahman S, Issels R, Reiser MF.
[MRI-assisted thermometry for regional hyperthermia and interstitial
laser thermotherapy] Radiologe. 2004 Apr;44(4):310-9. German.

McNichols
RJ, Gowda A, Kangasniemi M, Bankson JA, Price RE, Hazle JD. MR
thermometry-based feedback control of laser interstitial thermal
therapy at 980 nm. Lasers Surg Med. 2004;34(1):48-55.

Leonardi
MA, Lumenta CB. Stereotactic guided laser-induced interstitial
thermotherapy (SLITT) in gliomas with intraoperative morphologic
monitoring in an open MR: clinical expierence. Minim Invasive
Neurosurg. 2002 Dec;45(4):201-7.

Straube
T, Kahn T. Thermal therapies in interventional MR imaging. Laser.
Neuroimaging Clin N Am. 2001 Nov;11(4):749-57. Review.

Muacevic
A, Peller M, Sroka R, Kalusche B, Pongratz T, Kreth FW, Steiger HJ,
Reiser M, Reulen HJ. [Brain protective interstitial laser
thermotherapy. Therapy of brain tumors without secondary damage] MMW
Fortschr Med. 2001 May 28;143 Suppl 2:87-8. German.

Study ID Numbers:  2001-P-001794
Last Updated:  December 8, 2005
Record first received:  September 12, 2005
ClinicalTrials.gov Identifier:  NCT00207350
Health Authority: United States: Institutional Review Board
ClinicalTrials.gov processed this
record on 2006-04-18

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

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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.

High histologic and overall response to dose intensification of ifosfamide, carboplatin, and etoposide with cyclophosphamide, doxorubicin, and vincristine in patients with high-risk ewing sarcoma family tumors

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http://www3.interscience.wiley.com/cgi-bin/abstract/112476870

High histologic and overall response to dose intensification of
ifosfamide, carboplatin, and etoposide with cyclophosphamide,
doxorubicin, and vincristine in patients with high-risk ewing sarcoma
family tumors

The Bambino Gesù Children's Hospital experience
Giuseppe Maria Milano, M.D. 1 *, Raffaele Cozza, M.D. 1, Ilaria Ilari,
M.D. 1, Luigi De Sio, M.D. 1, Renata Boldrini, M.D. 2, Alessandro
Jenkner, M.D. 1, Maretta De Ioris, M.D. 1, Alessandro Inserra, M.D. 3,
Carlo Dominici, M.D. 1 4, Alberto Donfrancesco, M.D. 1
1Division of Pediatric Oncology, Ospedale Pediatrico Bambino
Gesù-IRCCS, Rome, Italy
2Division of Pathology, Ospedale Pediatrico Bambino Gesù-IRCCS, Rome,
Italy
3Division of Pediatric Surgery, Ospedale Pediatrico Bambino Gesù-IRCCS,
Rome, Italy
4Department of Pediatrics, La Sapienza University, Rome, Italy
email: Giuseppe Maria Milano (milano_gm@hotmail.com)

*Correspondence to Giuseppe Maria Milano, Dipartimento di
Oncoematologia Pediatrica e Servizio Immunotrasfusionale, UO di
Oncologia, Ospedale Pediatrico Bambino Gesù-IRCCS, Piazza Sant'Onofrio
4, Rome, 00165, Italy
Fax: (011) 396 68592242

Keywords
Ewing sarcoma family tumors • chemotherapy • dose intensification •
histologic response • tumor necrosis • survival

Abstract

BACKGROUND
Ewing sarcoma (ES) and extraosseous ES/primitive neuroectodermal tumors
(PNET) share histopathologic features of the ES family of tumors
(ESFT). The authors report on their results from a regimen of
ifosfamide, carboplatin, and etoposide (ICE) with cyclophosphamide,
doxorubicin, and vincristine (CAV) dose intensification in patients
with high-risk ESFT.

METHODS
Since 1990, patients with ESFT and with 1 or more of the following risk
factors were reviewed: tumor volume > 200 mL, tumor site with a poor
prognosis, and pulmonary and/or bone marrow metastases.

RESULTS
Thirty-six patients with ESFT who were involved in the study were
divided into 2 arms of 18 patients each. One group received treatment
with various regimens, and the other group received treatment with ICE
plus CAV. The disease was brought under control more rapidly in the
latter patients, for whom surgery was more easily feasible, and up to
90% of patients achieved a major response, with an estimated 3-year
overall survival rate of 67% ± 12%.

CONCLUSIONS
The current results showed that ICE plus CAV was tolerated well and was
effective in the studied subset of tumors, indicating that dose
intensification correlates with better disease control, a high
percentage of necrosis, and conservative surgery in patients with
high-risk ESFT. Cancer 2006. © 2006 American Cancer Society.

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

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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]

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.

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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]