Curr Opin Mol Ther 2003 Feb;5(1):44-51

     Recombinant toxins for the treatment of cancer.

     Kreitman RJ.

     Division of Cancer Biology, National Institutes of Health, 9000
Rockville, Bethesda, MD 20892, USA. kreitmar@...

     Recombinant toxins are proteins made by genetic engineering
consisting of a toxin fused to a ligand which binds selectively to a
target cell.

Recombinant toxins used for cancer treatment generally contain either
a growth factor or a recombinant fragment of a monoclonal antibody
fused to a truncated bacterial toxin, derived either from Pseudomonas
exotoxin or from diphtheria toxin.

One recombinant toxin containing human interleukin (IL)-2 and
truncated diphtheria toxin (DAB389-IL-2, denileukin diftitox or Ontak;
Seragen Inc) is approved for clinical use in advanced stage cutaneous
T-cell lymphoma. Recombinant toxins containing truncated Pseudomonas
exotoxin and fragments of anti-CD22 and anti-CD25 monoclonal
antibodies have induced remissions in chemotherapy-resistant
hematological malignancies, particularly hairy cell leukemia, and are
currently undergoing experimental testing.

The number of approved recombinant toxins for the treatment of cancer
is expected to increase in the coming years.

PMID: 12669470 [PubMed - in process]

Curr Opin Mol Ther 2003 Feb;5(1):39-43

     Proteomics for monitoring immune responses to cancer vaccines.

     Mosca PJ, Lyerly HK, Ching CD, Hobeika AC, Clay TM, Morse MA.

     Department of Surgery, Duke University Medical Center, Box 2606
DUMC, Durtham, NC 27710, USA. mosca001@...

     Standardized biomarkers for the detection of clinically
significant immunological responses would be extremely valuable in
immunotherapy trials. Most available assays measure either the
frequency or function of antigen-specific T-cells, or the titers of
antibodies or immune complexes. These assays have generally exhibited
either inadequate sensitivity or too high a signal-to-noise ratio to
reliably detect the low-frequency T-cell responses induced by cancer
vaccines. In addition, such assays reflect only one aspect of the
immune response rather than the complete picture.

Proteomics, the study of proteins within a cell or biological sample,
may offer a novel approach to immunological monitoring that
complements existing immunological assays. By studying the protein
content of T-cells responding to a vaccine or in the serum of
vaccinated individuals, it may be possible to develop a metric for
quantitating the magnitude of immunological responses. Proteomics
could also provide a tool for establishing the quality of the immune
response and for obtaining valuable information regarding the
underlying regulatory mechanisms and pathways.

Advances in miniaturization and automation may also permit
characterization of the immune response more rapidly and from smaller
amounts of biological material than is possible with existing assay
systems.

PMID: 12669469 [PubMed - in process]

Medical experts agree SARS will continue to spread

Copyright © 2003 AP Online Print Story    Email Story    Save to your
PDA with AvantGo


By DANIEL Q. HANEY, AP Medical Editor

(April 5, 2003 1:53 p.m. EST) - Can severe acute respiratory syndrome
be stopped? As hard as public health officials work to stamp out the
virus, many experts reluctantly conclude it is likely if not
inevitable that it eventually will spread everywhere.

The highly contagious disease has already sickened more than 2,000
people, and new cases appear daily in Hong Kong, despite an all-out
effort to isolate victims and quarantine those at risk.

Experts acknowledge that the eventual course of any new disease is
almost impossible to predict. Some frightening new infections have
burned themselves out, while others, like AIDS, have become global
disasters.

However, several features of SARS make epidemiologists, virologists
and infectious disease experts fear total victory is unlikely.

"Will it explode into a major epidemic that will propagate over the
years? Or will it fizzle out or be contained at a low rate? That's
unknown," said Dr. Lee Harrison of the University of Pittsburgh. "I
suspect we will see this disease for at least the next several years.
It's hard to imagine it will be over soon."

Perhaps the most ominous sign is the steep climb in new cases,
especially in Hong Kong, which has had a nearly fourfold increase in
just two weeks. Each person who gets it may spread the infection to
several others before they even know they have it.

While many are infected through face-to-face contact, evidence is
mounting that the virus may also spread through the air or be picked
up from contaminated surfaces.

On Friday, President Bush gave federal health officials the power to
quarantine Americans sick with SARS, although there is no plan to use
that power now. There are more than 100 suspected cases in the United
States, but no one has died.

"Most people are hesitant to say it will just go away," said Dr. Ruth
Berkelman, head of Emory University's Center for Public Health
Preparedness and Research. "Too many people are infected to think we
won't see it for a long time to come."

Besides quarantining the sick, health officials have tried to minimize
SARS' spread by urging people with suspicious symptoms not to fly on
airlines.

However, some experts worry that those who are clearly sick may not be
the biggest concern.

People catch bad colds from friends who have mild ones. And the same
may be true for SARS. Those who have slight symptoms or even seem
perfectly well could still spread the disease. In such a scenario,
isolating the sick and quarantining their contacts will not work.

"We may be able to slow transmission, but we won't be able to stop it
if there are many other cases of milder disease out there," said Dr.
Arnold Monto, a University of Michigan epidemiologist.

Although the cause of the outbreak has not been proven beyond doubt,
investigators say most evidence points to a previously unknown version
of the coronavirus, the bug that causes about a third of all colds.
Some who study this family of viruses say that because it spreads
through coughs and sneezes, they cannot imagine totally wiping it out
now that it has infected so many people.

Some suggest that even if this outbreak dies down, the virus could pop
up again with no warning or it might follow a seasonal pattern, like
colds and flu.

Just how it acts in the long run will depend on its genetic makeup and
origins. Birds and other animals have their own versions of
coronavirus, and some of them cause much worse disease than the human
type. Researchers say SARS may be caused by a coronavirus that moved
from animals to people. Or perhaps it is a standard human coronavirus
that picked up menacing genes from an animal version of the virus.

Such leaps have happened in the recent past. The hendra virus spread
from horses to people in Australia, while the nipah virus went from
pigs to humans in Malaysia. However, neither bug then spread from
person to person.

But SARS has found a home in humans. Experts say it could grow less
virulent as it reproduces inside the human body and then passes on, or
it might grow worse.

Whatever happens, the virus is likely to change over time, says Dr.
Michael Lai of the University of Southern California, a coronavirus
expert. This variety of viruses mutates and swaps genes frequently.

"The severe problems we are seeing right now might represent a very
small minority of the coronavirus infections," Lai said.

The World Health Organization is still officially optimistic. "We
think it's possible that this disease can be beaten back, that with
more effort this doesn't have to get out of hand," said Dick Thompson,
a WHO spokesman.

Such an outcome is far from definite, cautioned Dr. James Hughes,
infectious disease chief at the U.S. Centers for Disease Control and
Prevention. He called SARS "an urgent global public health threat" and
added: "I think we had better all keep an open mind here. We've seen
it spread very dramatically and very rapidly."

Eur J Clin Nutr 2003 Mar;57(3):439-46

     Mediterranean diet, but not red wine, is associated with
beneficial changes in primary haemostasis.

     Mezzano D, Leighton F, Strobel P, Martinez C, Marshall G, Cuevas
A, Castillo O, Panes O, Munoz B, Rozowski J, Pereira J.

     Department of Haematology-Oncology, Faculty of Biological
Sciences, Pontificia Universidad Catolica de Chile, Santiago, Chile.

     OBJECTIVE:: (1) To compare the effect of an alcohol-free
Mediterranean-type diet (MD) and a high-fat diet (HFD) on variables of
primary haemostasis (bleeding time, plasma von Willebrand factor and
platelet aggregation/secretion). (2) To test whether red wine
supplementation modified these variables, independently of the diet.
DESIGN, SUBJECTS AND INTERVENTION:: Controlled prospective
intervention study. Two groups, each consisting of 21 healthy male
university students (22+/-3.4 y), received either MD or HFD during 90
days. Between days 30 and 60, both diets were supplemented with 240
ml/day of red wine. Baseline (T0) and T30, T60 and T90-day samples
were drawn. Bleeding time was measured before (day 30) and after (day
60) wine supplementation. No drop out from the study was experienced.
SETTING:: University campus and outpatient nutrition clinic. RESULTS::
All baseline (day 0) variables did not differ significantly between
study groups. On day 30, individuals on MD had significantly higher
levels of plasma beta-carotene, folate, ascorbate, and
eicosapentaenoic acid in plasma lipid fractions, than those on HFD.
Total plasma cholesterol, HDL and LDL did not change significantly in
either study group at any time point. After 30 days on each diet,
individuals on MD had longer bleeding time (BT) than those on HFD
(7.6+/-2.8 vs 5.8+/-1.7 min; P=0.017). BT did not change significantly
after I month of wine supplementation (7.1+/-2.0 vs 5.5+/-2.0 min,
respectively). Plasma von Willebrand factor (vWF : Ag) on day 0 was
89+/-40 and 111+/-70% in MD and HFD groups, respectively (P=0.21).
These values did not change significantly at 30, 60 or 90 days. MD
intake was associated with an increase in platelet serotonin secretion
(P=0.02) and a marginal increase in platelet aggregation after
stimulation with epinephrine (P=0.07). Wine intake resulted in a
marginal decrease in platelet (14)C-5-HT secretion with 4 micro M ADP
(P=0.07). However, both platelet aggregation and secretion were
consistently increased when using collagen as agonist (1 and 2 micro
g/ml, P=0.01).

CONCLUSION:: The longer BT in individuals on MD, obtained
independently of red wine, denotes less interaction of platelets with
the vascular wall, which could be beneficial from the point of view of
cardiovascular (CV) risk. This effect is not explained by changes in
the measured haemostatic determinants of BT (plasma vWF, ex vivo
platelet function), and might be attributed to other as yet unknown
vascular factors. Moderate consumption of red wine results in a
significant increase in ex vivo platelet aggregation and secretion
after stimulation with collagen. This observation contradicts previous
reports, although further studies are required to elucidate the
influence of this finding on CV risk.

SPONSORSHIP:: P. Catholic University of Chile.European Journal of
Clinical Nutrition (2003) 57, 439-446. doi:10.1038/sj.ejcn.16001558

PMID: 12627181 [PubMed - in process]

Cancer 2003 Apr 15;97(8):1914-9

     Clinical relevance of the expression of the CD31 ligand for CD38
in patients with B-cell chronic lymphocytic leukemia.

     Ibrahim S, Jilani I, O'Brien S, Rogers A, Manshouri T, Giles F,
Faderl S, Thomas D, Kantarjian H, Keating M, Albitar M.

     Section of Molecular Hematopathology, New York University, New
York, New York.

     BACKGROUND: CD31 (platelet endothelial cell adhesion molecule-1
[PECAM-1]) is the ligand for CD38, a transmembrane glycoprotein that
is expressed on the surface of leukemic cells in many patients with
B-cell chronic lymphocytic leukemia (B-CLL). In a previous study, the
authors showed that CD38 expression was correlated with a poor
prognosis in patients with B-CLL. In the current study, blood samples
from patients with B-CLL were examined to identify CD31 surface marker
expression, and CD31 expression was correlated with several other
known prognostic variables, including CD38.

METHODS: Using flow cytometry, peripheral blood samples from 120
patients with B-CLL were analyzed for CD31 and CD38 expression on CD19
positive leukemic B cells.

RESULTS: Thirteen of 120 patients (11%) had CD31 expression on < 20%
of their B cells, and the remaining patients had various levels of
CD31 expression. The median expression of CD31 was 76% of leukemic,
CD19 positive cells. Levels of CD31 expression were not correlated
with survival outcomes or with any of the known prognostic parameters
when all patients were considered. Patients who had high CD38
expression (>/= 20%), as expected, had significantly shorter survival
(P = 0.001) compared with patients who had low CD38 expression (< 20%).

However, in patients with low CD38 expression, a subgroup with low
CD31 expression (< 76%) had significantly longer survival compared
with the survival for the entire group (P = 0.0001). Moreover, the
survival pattern of patients with low CD38 expression and high CD31
expression was not significantly different from the survival pattern
seen in patients with high CD38 expression.

CONCLUSIONS: CD31 expression further defined a subgroup of patients
with B-CLL who had a different survival outcome. Defining the
interaction between CD31 expression and CD38 expression in patients
with CLL will require further exploration.

Cancer 2003;97:1914-9.

Copyright 2003 American Cancer Society

PMID: 12673718 [PubMed - in process]

Blood First Edition Paper
prepublished online April 3, 2003

Submitted April 23, 2002
Accepted March 19, 2003

G-CSF as immune regulator in T cells expressing the G-CSF receptor:
implications for transplantation and autoimmune diseases

Anke Franzke*, Wenji Piao, Joerg Lauber, Patricia Gatzlaff, Christian
Koenecke, Wiebke Hansen, Angela Schmitt-Thomsen, Bernd Hertenstein,
Jan Buer, and Arnold Ganser

Department of Hematology and Oncology, Hannover Medical School,
Hannover, Germany
Mucosal Immunity Group, GBF-German Research Centre for Biotechnology,
Braunschweig, Germany
Department of Transfusion Medicine, Hannover Medical School, Hannover,
Germany
Institute of Medical Microbiology, Hannover Medical School, Hannover,
Germany


Results from experimental models, in vitro studies, and clinical data
indicate that G-CSF (Granulocyte colony-stimulating factor (AKA
filgrastim))* stimulation alters T-cell function and induces Th2
immune responses. The immune modulatory effect of G-CSF on T-cells
results in an unexpected low incidence of acute graft-versus-host
disease in peripheral stem cell transplantation. However, the
underlying mechanism for the reduced (allo-) reactivity of T-cells
upon G-CSF treatment is still unknown.

In contrast to the general belief that G-CSF  acts exclusively on
T-cells via monocytes and dendritic cells, our results clearly show
the expression of the G-CSF receptor in class I- and II-restricted
T-cells at the single cell level both in vivo and in vitro. Kinetic
studies demonstrate the induction and functional activity of the G-CSF
receptor in T-cells upon G-CSF exposure.

Expression profiling of T-cells from G-CSF treated stem cell donors
allowed identification of several immune modulatory genes, which are
regulated upon G-CSF administration in vivo (e.g., LFA1-{alpha},
ISGF3-{gamma}), and which are likely responsible for the reduced
(allo-) reactivity. Most importantly, the induction of GATA-3, the
master transcription factor for a Th2 immune response, could be
demonstrated in T-cells upon G-CSF treatment in vivo accompanied by an
increase of spontaneous interleukin-4 secretion.

Hence, G-CSF is a strong immune regulator of T-cells and a promising
therapeutic tool in acute graft-versus-host disease as well as in
conditions associated with Th1/Th2 imbalance, such as bone marrow
failure syndromes and autoimmune diseases.


*G-CSF stimulates the production of (particularly) neutrophiles.

Blood First Edition Paper
prepublished online April 3, 2003

Submitted May 20, 2002
Accepted March 27, 2003

Inhibition of megakaryocytopoiesis in vitro by immune thrombocytopenic
purpura (ITP) plasma and purified ITP monoclonal autoantibodies
Mei Chang*, Peggy A Nakagawa, Shirley A Williams, Michael R Schwartz,
Karen L Imfeld, Jeffrey S Buzby, and Diane J Nugent

Children's Hospital of Orange County, Orange, CA, USA

* Corresponding author; email: mchang@....

To determine if megakaryocytes (the large marrow cells which give rise
to platelets) are targeted by ITP autoantibodies, as are platelets, we
have studied the effects of ITP plasma on in vitro megakaryocytopoiesis.

Umbilical cord blood mononuclear cells were incubated in the presence
of thrombopoietin and 10% plasma from either ITP patients (n=53) or
healthy donors. The yield of megakaryocytic cells, as determined by
flow cytometry, was significantly reduced in the presence of ITP
plasma containing anti-platelet glycoprotein (GP) Ib autoantibodies
(p<0.001) as compared to both the control and patient plasma with no
detectable anti-GP-IIb/IIIa or -Ib autoantibodies. Platelet absorbtion
of anti-GP-Ib autoantibodies in ITP plasmas resulted in double the
megakaryocyte production of the same plasmas without absorption,
whereas platelet absorption of normal control plasma had no effect on
megakaryocyte yield.

Furthermore, two human monoclonal autoantibodies isolated from ITP
patients, 2E7, specific for human platelet glycoprotein IIb heavy
chain and 5E5, specific for a neoantigen on glycoprotein IIIa
expressed on activated platelets, had significant inhibitory effects
on in vitro megakaryocytopoiesis (p<0.001).

Taken together, these data indicate that autoantibodies against either
platelet GP-Ib or GP-IIb/IIIa in ITP plasma are not only involved in
platelet destruction, but may also contribute to the inhibition of
platelet production.

Blood First Edition Paper
prepublished online April 3, 2003

Submitted December 3, 2002
Accepted March 26, 2003

Chronic lymphocytic leukemia patients with highly stable and indolent
disease show distinctive phenotypic and genotypic features

Anna Guarini, Gianluca Gaidano, Francesca Romana Mauro, Daniela
Capello, Francesca Mancini, Maria Stefania De Propris, Marco Mancini,
Enrica Orsini, Massimo Gentile, Massimo Breccia, Antonio Cuneo,
Gianluigi Castoldi, and Robert Foa*

Dipartimento di Biotecnologie Cellulari ed Ematologia, Universita 'La
Sapienza', Rome, Italy
Dipartimento di Scienze Mediche & IRCAD, Universita del Piemonte
Orientale, Novara, Italy
Dipartimento di Scienze Biomediche e Terapie Avanzate, Universita
degli Studi, Ferrara, Italy

* Corresponding author; email: rfoa@....

Different biologic features have been associated with a more or less
aggressive clinical course in chronic lymphocytic leukemia (CLL).

In the present study, 20 patients with highly stable CLL observed at a
single institution over a period of 10-23 years and who never required
treatment have been extensively characterized. The aim was to identify
a distinct and reproducible biologic profile associated with disease
stability that may be utilized to recognize at presentation CLL
patients who are likely to have a very benign clinical course and for
whom treatment is not indicated.

The results obtained indicate that numerous parameters are closely
associated with disease stability: a typical CLL morphology and
immunophenotype, the lack of expression of the CD38 antigen, the
mutated IgVH pattern, the absence of p53 mutations, a CD4/CD8 ratio
>1, the lack of 17p and 11q deletions, as well as of complex
karyotypic aberrations, and the occurrence of the 13q14 deletion.

No case displayed the VH3-21 gene that has been linked in mutated CLL
with a poor outcome. In addition, the VH1-69 gene associated with
unmutated CLL cases was never detected.

These biologic features were coupled with an indolent clinical course
characterized by an unmodified clinical stage from diagnosis to the
time of this study, lack of autoimmune phenomena and of major
infections requiring parental antibiotics.

At a time when aggressive therapeutic strategies are always more
frequently being utilized in the management of CLL, the distinctive
features of patients with long- lived stable disease should be
prospectically identified at presentation.

uncertainty@...
Some Doctors Use Patient E-mail in Their Practices, but Most Aren't
Ready to Log On

     Doctors say e-mail is easier than tracking a patient down by
phone, and patients say e-mail is easier than an office visit.


By Francesca Lunzer Kritz
Special to the Washington Post
Tuesday, April 1, 2003; Page HE01


Ellen Ranzman of Bethesda has tried a wide range of medications and
procedures for her chronic heartburn condition. But ask her the most
effective treatment for the problem, and she'll answer: e-mail.

"It's amazing, I absolutely love it," says Ranzman, 56, about her
ability to fire off questions on symptoms and medication issues to
her Washington gastroenterologist, David Shocket.

Early one recent morning, rather than leave her name and phone number
with the doctor's answering service, she e-mailed Shocket to say she
was gulping down antacid to no avail. A few hours later, Schocket's
office contacted her by phone to schedule a procedure to dilate her
esophagus. The procedure, she says, has brought her considerable
relief.

"[E-mail] gives me the opportunity to communicate with him when it's
convenient for me, at night or first thing in the morning, and I get
very quick responses," Ranzman says. It hasn't eliminated phone
contact: If she sends an e-mail that concerns him, Shocket may still
phone her. And she sometimes still dials in, too. But, she says, e-
mailing with Shocket, and with her internist, Jody Robinson, "has
made my ability to get things done medically much more efficient."

The two doctors say responding to e-mail relieves them of the hassle
of tracking a patient down by phone -- it may surprise some patients
to learn their doctors complain about phone tag almost as much as
they do. E-mail lets them leave a direct response to a patient's
message instead.

"I don't like to leave a detailed medical message on an answering
machine, because I don't know who's [listening to] it," says
Robinson. "Unless a patient tells me otherwise, I assume they're the
only ones reading their e-mail and I leave detailed messages." The
exception -- "If I need to be talking about sensitive issues" -- say,
lab tests that indicate a serious medical concern -- he says, "I
won't do that by e-mail." Most physicans asked about their e-mail
habits say they follow similar etiquette.

Doctor-patient e-mail communiques are still more the exception than
the rule -- according to the American Medical Association, about 25
percent of physicians contact at least some of their patients by e-
mail. Among the reasons doctors have been slow to embrace the
concept: worries about liability, patient privacy and reimbursement.

Lately, however, there have been signs resistance is beginning to
crumble.

Several business startups such as RelayHealth, based in Emeryville,
Calif., and HealthyEmail, based in Dallas, are aggressively
marketing "secure" -- or hacker-resistant -- messaging services to
Washington area doctors. RelayHealth hopes to sign with a local
insurer later this year for a pilot program in which the carrier
would reimburse physicians for some comprehensive e-mail consults

MedStar Health, which owns hospitals in the District and Maryland, is
offering a secure e-mail option to doctors affiliated with the
hospitals. The pilot project is free for the first year. After that,
doctors may have to pay an annual fee or $2.50 per e-mail they send.
Other hospital corporations are considering similar moves.

To Mark Bard, president of Manhattan Research, a marketing
information and services firm, the question is not if but when
physician e-mail use will catch up to patient demand.

"A number of market-based drivers will fuel the continued growth of
online communication between patients and their physicians over the
next one to two years," Bard says, increasing the percentage of
doctors who e-mail patients to 30 to 40 percent. Growth, he says,
won't likely stop there. In other words, it could be just a matter of
time before e-mailing your doctor becomes almost as routine as
ordering a book online.

What use could an e-mail consult be to you? According to data
compiled by Manhattan Research, the most frequent topics in
patient/doctor e-mails are symptoms and treatment options, and
determining whether an office visit is necessary.

A disproportionate number of such requests are reportedly directed at
gynecologists -- the likeliest doctors to e-mail their patients,
according to Ed Fotsch, CEO of Medem, a physician e-mail service to
which some Washington area doctors subscribe.

Case in point, says Fotsch: When the government last year halted a
study that linked hormone replacement therapy (HRT) to a heightened
risk for heart attack, stroke and breast cancer, dozens of area
gynecologists fielded e-mail questions from anxious patients taking
the drugs.

The situation, says Peter Basch, head of e-health initiatives for
MedStar, was tailor-made for e-mail response.

"That's a case where a doctor could thoughtfully develop a response
to a common concern and then send out it out to all patients who e-
mail their questions, with an offer to handle individual concerns as
well."

Concerns over another drug also flooded Basch's electronic in-box in
his other role of staff internist. "Last year with the release of
conflicting data on the use of statin [drugs] for high cholesterol --
one week a story would marvel at the wonders of statins, the next
week, question their safety -- I received many e-mail queries from my
patients as to whether they should start or stop their medications,
depending on the news story."

Staff use e-mail to communicate with patients about billing issues,
notification of test results (bad news is unlikely to be communicated
by e-mail, says Basch) scheduling appointments and routine
prescription refills. Many doctors who interact by e-mail frequently
remind patients that in an emergency, they should call.

"How can a patient be sure that I'm sitting by my computer when they
are trying to reach me?" worries David Eisenman, an ear, nose and
throat specialist with a group practice in Washington. That's
especially a worry for pediatricians, who will often take
prescription refill requests or appointments by e-mail but are often
reluctant to communicate by e-mail [about other matters] lest a
message about an emergency go unnoticed.

"If a parent phones in, we can assess the situation right away," says
Jeffrey Bernstein, head of a four-doctor practice in Silver
Spring, "but it's not possible to continuously monitor a computer
screen to make sure we're not missing an emergency."

Meeting Doctors' Concerns

There are no easy answers to doctors' fears that e-mail consults may
expose them to greater liability. Could a doctor make a misdiagnosis
on the basis of an e-mail, subjecting a patient to danger? What if a
patient misunderstands e-mailed instructions from a doctor and, as a
result, incurs harm?

While liability worries about 64 percent of doctors, says Bard, so
far, the fears have a theoretical basis only. "It's not a situation
where they have heard or have experienced horror stories," he
says. "It's really more about doctors practicing in a litigious
society where malpractice [is a] primary concern when doing
[anything] outside the ordinary."

Daniel Sands, an assistant professor of medicine at Harvard Medical
School and clinical director of electronic patient records and
communication for Beth Israel Deaconess Medical Center in Boston,
advises doctors to be sure that both they and patients understand
that e-mail is not for emergencies. Patients in need of an immediate
reply, he says, should call the office or 911.

Doctors' other e-mail concerns may be easier to address. Can a doctor
be sure a confidential reply to a patient won't be read by an
unauthorized party? (Such concerns dovetail with medical privacy
regulations to take effect later this month under the Health
Insurance Portability and Accountability Act.) Many of the systems
being marketed encrypt messages in case information about, say, a
Viagra prescription or an antidepressant refill goes astray.

And what's to keep e-mails from becoming a major drain on doctors'
time and pay? That fear, says Bard, is really the big one. Solve
this, he says, and the other obstacles will fall away.

Some companies are trying.

MedStar's Basch says the best option would be to have insurers
reimburse doctors for their e-mail time. Some insurers -- though so
far, none in the Washington area -- have set up pilot projects that
follow that recommendation. The most recent, announced in early March
by RelayHealth and Blue Cross of Massachusettts, will test an e-mail
system for non-urgent matters, such as self-treatment for back
spasms. Blue Cross won't bear physician e-mail costs alone; it will
charge some patients $5 to $20 every time they exercise the e-mail
option. Last year a California pilot study of close to 6,000 patients
found that medical-office-based claims were lower by $1.92 per member
per month, and that total health care claims were reduced by more
than $3 per member per month for those who had been given access to
the RelayHealth service. Multiply such per-member savings by the
carrier's millions of members and the dollars add up. Such savings
could lead more insurers to reimburse physicians for e-mailing
patients, and would quickly speed up its use, says Bard.

Other companies have put forth other solutions. Medem, which is
affiliated with several medical associations including the American
Medical Association, lets doctors charge patients up to $200 for each
online consultation about symptoms or treatment; the average charge
is $25, according to Medem. (Other, quicker communiqués -- refills,
referrals, appointment scheduling -- are free.) To send an e-mail
message to participating doctors on most secure sites, patients log
on to a password-protected Medem Web site and select a doctor's name.
Once the doctor has replied, patients get an e-mail message to their
personal accounts asking them to return to the company Web site to
access the reply.

Joseph Zebley, a Baltimore family practitioner, is one doctor who has
begun offering Medem online consultations for which he charges $30.
Zebley offers a disclaimer on his Web site that such
interactions "may not be for everyone" and may be best suited
for "those busy professionals for whom time truly is money."

E-mail Pros and Cons

Even if your doctor isn't promoting e-mail, you may want to ask
whether you can reach him or her that way for quick questions,
refills and other non-urgent matters. Some doctors who don't make e-
mail a standard part of their practice permit it with select
patients, especially those who can't easily call or come in.

Charles Faselis, an internist with the Medical Faculty Associates at
George Washington University Medical Center, cites one patient as an
example. The patient, a lawyer who travels frequently, was diagnosed
with high cholesterol two years ago. Now, the patient e-mails Faselis
each time he needs a refill for his statin drug or a slip for the lab
test to check his liver function -- a requirement for patients on
statin therapy.

"Making it easy to contact me about the test and refills has made the
patient fully compliant and kept his cholesterol at normal levels.
That's an excellent use of my time and the patient's time via e-
mail," says Faselis.

At least one local practice, the Washington ENT Group, is using e-
mail features, including initial patient registration, appointment
requests and requests for non-narcotic prescription refills, to
improve efficiency. Some caveats are in place, though. Only refills
for established patients can be handled by e-mail, and only after
those patients are reached by phone to verify the request. And for
now, the e-mail goes one way only: Doctors respond by phone or fax.
But that should change later this month when the practice puts a
secure system in place, says Barth Doroshuk, the practice's chief
operating officer.

Consumer advocates like Arthur Levin, head of the Center for Medical
Consumers in New York, say patients may be surprised by how efficient
e-mail may be for at least some of their medical needs. "Who hasn't
been frustrated by not getting a return phone call from a physician?"
asks Levin. "But with e-mail, you contact the doctor -- say, to ask
whether you should stick with a drug regimen -- when it's convenient
for you, and you don't have to worry about sticking close by the
phone in order to get an answer."

The system's not foolproof, of course, as I discovered recently.
Since my father had a small stroke last summer, I have used e-mail to
communicate with many of his doctors, with his and their permission.
Several weeks ago a call to one netted instructions from the
secretary to e-mail her instead. My response was answered three weeks
later, with instructions to contact her by phone.

Experts like Sands suggest patients learn their doctors' e-mail
habits so they know when to expect a reply -- and when it's time to
try the office by phone.

Bard says most doctors tend to do their e-mail replying from home at
night and on weekends, often because they don't have easy access to
computers by day. Doctors with daytime access, however, like
MedStar's Basch and Harvard's Sands, say they try to keep up with e-
mail flow during the day.

Ultimately, as patient records become fully electronic, patients
should find that physicians can access all their data -- history,
previous visits, test results -- while replying to an e-mail from a
patient. Bard says about 15 percent of physicians who e-mail patients
also use electronic medical records and 40 percent use a personal
digital assistant, though almost no doctors use a PDA for e-mail
access.

Waiting for an Answer


You may be an electronic pioneer now, but look for changes as more
folks catch on and some regulatory bodies weigh in.

In October, a group of malpractice insurers, physicians and specialty
medical groups called the eRisk Working Group for Health Care drew up
voluntary guidelines for doctors who communicate by e-mail. Two of
their recommendations:

• E-mail communication should take place only in preexisting
doctor/patient relationships. (This recommendation pretty much
disqualifies Web sites such as ciberclinic.com, mydoc.com and
medicalweb.com, which invite health queries -- for a price -- from
most comers.)

• Each e-mail should contain language outlining the terms of service.

The American Medical Association has also issued e-mail ethics
guidelines. Among other things, the guidelines advise doctors to
remind patients that e-mail answers may not be as complete as those
they would likely receive at a scheduled doctor visit and recommend
they secure patients' authorization before sending them e-mail.
Doctors are more likely to ask for that authorization under
provisions of HIPAA, says Stephen Bernstein, a Boston HIPAA lawyer.

But even if you tell your doctor you'd rather he e-mailed than phoned
you, you may still find yourself waiting longer than you'd like for a
reply. In a survey last year by Harris Interactive, doctors said they
respond to patients e-mail questions within 18 hours of receipt. But
patients said they received replies about 30 hours after their
messages were sent.•

Francesca Lunzer Kritz often writes about drug and patient care
issues for the Health section.



© 2003 The Washington Post Company

Food combining 'fights cancer'

Eating certain foods together, such as chicken and broccoli or salmon
and watercress could help to fight cancer, say researchers.
Combining two food components called sulforaphane and selenium make
them up to 13 times more powerful in attacking cancer together than
they are alone, they suggested.

The discovery could mean it could be possible to design special
cancer-fighting foods or diets.


It opens up new possibilities for functional foods, food supplements
or simply new guidelines for healthy eating
Dr Yongping Bao, IFR
Sulforaphane, a plant chemical which could be used to prevent and
treat cancer, is found at high concentrations in broccoli, sprouts,
cabbage, watercress and salad rocket.
Foods rich in the essential mineral selenium include nuts, poultry,
fish, eggs, sunflower seeds and mushrooms.

Selenium deficiency has been linked to the incidence of many types of
cancers, including prostate. But UK diets include half the levels of
the mineral as they did 20 years ago.

Scientists from the Institute of Food Research (IFR) in Norwich were
looking at genes that play an important role in the formation and
development of tumours and the spread of tumour cells.

When combined, sulforaphane and selenium had a bigger impact on the
genes than they did alone.

The IFR research has concentrated on cell cultures. Human trials
could begin next year.

Concentrations

Researchers say it may be possible to develop special foods or issue
new guidelines for healthy eating.

Top chefs may even be asked to develop cancer-fighting recipes such
as a chicken dish with sprouts, red cabbage and nuts sprinkled on
top.

Dr Yongping Bao, senior researcher at the IFR, said: "As a result of
this research, we hope to begin a human cancer prevention trial next
year.

"It opens up new possibilities for functional foods, food supplements
or simply new guidelines for healthy eating."

He added: "High concentrations in the diet are normally required to
protect against cancer, but when these compounds act synergistically,
lower doses are needed to prevent cancer formation.

"This is particularly good news as selenium and sulforaphane can be
toxic at high levels."

The research is published in the journal Carcinogenesis.

Story from BBC NEWS:
http://news.bbc.co.uk/go/pr/fr/-/2/hi/health/2903739.stm

Published: 2003/03/31 23:04:15

© BBC MMIII

Science News
Week of March 29, 2003; Vol. 163, No. 13


Cranberry Juice—A Cocktail for the Heart

Janet Raloff

Chemist Joe Vinson has a passion for foods and the potentially
beneficial antioxidants they bring to the dinner table.

Three years ago, for instance, he reported data showing that molecule
for molecule, the antioxidants in chocolate exceed the potency of
vitamin C. Now he finds another powerful stash of these protective
compounds in cranberries and their juice. Moreover, the University of
Scranton scientist reports this week at the American Chemical
Society's spring meeting in New Orleans, regular consumption of that
juice yields cholesterol benefits in middle-age men and women.

Many plant-based foods, especially the colorful ones, contain large
quantities of polyphenols. As antioxidants, these compounds quash the
damage that natural oxidants can do in the body. Indeed, a large
number of disorders associated with aging—including cancer, heart
disease, diabetes, and several types of dementia—have been linked to
damage caused by a slow and unremitting onslaught of oxidants.

In his latest study, Vinson and his colleagues provided 20 men and
women 8-ounce servings of cranberry juice cocktail, which contains 27
percent juice. He offered his recruits the type available in stores,
which is heavily sweetened with high-fructose corn syrup and
supplemented with extra vitamin C, or a low-calorie alternative that
the Scranton scientists concocted daily from pure juice. Twelve chose
the low-cal juice, which was sweetened solely with a sugar-free
compound.

Drinking cranberry juice three times a day over the course of a month
increased all the volunteers' blood concentration of high-density
lipoprotein (HDL) cholesterol—the so-called good cholesterol—by 10
percent. The juice didn't affect low-density lipoprotein (LDL) or
triglycerides, which are other fatty substances in the blood.
However, epidemiological studies by others have correlated HDL-
cholesterol increases of this magnitude with about a 40 percent drop
in heart-disease risk, Vinson notes.

Cranberries lead the antioxidant pack

In earlier studies, the Scranton team surveyed the antioxidant
potential of several fruits and vegetables. Overall, fruits surpassed
the veggies, "and cranberries had more antioxidants than any other
fruit," Vinson observes. Several of cranberry's polyphenol
antioxidants are procyanidins, the same family of pigments that make
cherries red.

When the chemists investigated pure cranberry juice, they found its
antioxidant punch exceeded by 50 percent the potency of its next
closest juice competitor, grape juice. However, because cranberries
are so tart, their juice has to be diluted and sweetened to be
palatable. Yet even in this cocktail form, Vinson found, 27 percent
cranberry juice still ranked second only to pure grape juice in its
ability to defuse oxidants.

With funding and cranberries supplied by the Cranberry Institute, he
then investigated antioxidants delivered to the blood by juice.

To evaluate whether it was the cranberry juice or the sugar and
vitamin C in the cocktail that provided any benefit in the new study,
the Scranton chemists offered just an 8-ounce glass of the sugar
water and the vitamin to 10 men and women as a breakfast drink. Each
had fasted the night before.

Over the next 4 hours, the researchers periodically sampled the
volunteers' blood and tested its ability to quash oxidants. To
Vinson's surprise, the blood actually fostered oxidation. After a
bagel and soft drink at lunchtime, the assays continued and showed
that the potentially unhealthy pro-oxidant effect lasted a total of 7
hours, Vinson told Science News Online.

On another day, he repeated the tests, this time giving each
volunteer an 8-ounce glass of the sugar-sweetened cranberry juice
cocktail. This time, he notes, "we had a good antioxidant effect for
the whole 7 hours, even after that blast of high-fructose corn syrup
[in the soft drink] and bagel at lunch."

More juice, better protection

In a follow-up trial, Vinson's team put 20 adults, mostly middle age
and all with moderately elevated, unhealthy total-blood-cholesterol
concentrations, on a cranberry-juice regimen. For the first month,
each person drank a daily 8-ounce glass of either the sugared or
surgarfree cranberry-juice cocktail. During the second month, each
recruit drank two glasses daily. During the last month of the
experiment, daily juice intake increased to three glasses.

Before the trial and at the end of each month, the scientists ran a
series of tests on the blood of each participant. Those data
confirmed that the antioxidant defense of the blood increased
steadily with the increasing juice intake. Compared with the before-
juice measurements, concentrations of oxidation products in the
volunteers' blood was 15 percent lower after the first month of the
trial and about 40 percent lower by the close of the third month.

Assays of the participants' blood showed no change in their
triglycerides or total cholesterol concentrations. However, HDL
cholesterol increased—but only in the three-glass-per-day phase of
the trial. Just that's worth a lot, says Vinson. Doctors lament the
fact that although low-HDL cholesterol is a major risk factor for
heart disease, there are few prescriptions they can offer patients
that raise this lipid—other than to give up smoking, drink a little
alcohol, or exercise regularly.

For people who would prefer a pocket version of the potential
cranberry therapy for cholesterol, Vinson notes that dried berries
are available in stores. His assays, by the way, indicate that dried
cranberries pack 10 percent more antioxidants than prunes and 50
percent more than raisins do.


References and Sources

References:

2003. Study provides new evidence that cranberry juice may help fight
heart disease. American Chemical Society press release. March 24.
Available at http://www.newswise.com/articles/2003/3/BERRY.ACS.html.

Vinson, J.A., et al. 2003. Single-dose and supplementation studies
with cranberry juice relevant to its role in heart disease as an
antioxidant. American Chemical Society spring national meeting. March
24. New Orleans. Available at
http://www.newswise.com/articles/2003/3/BERRY.ACS.html.

Further Readings:

Raloff, J. 2002. Berry colorful nutrition news (with recipes).
Science News Online (April 20). Available at
http://www.sciencenews.org/20020420/food.asp.

______. 2001. Berry promising anticancer prospects. Science News
Online (March 17). Available at
http://www.sciencenews.org/20010317/food.asp.

______. 2001. Path to heart health is one with a peel. Science News
Online (Feb. 24). Available at
http://www.sciencenews.org/20010224/food.asp.

______. 1999. Well-done research. Science News 155(April 24):264-266.
Available at http://www.sciencenews.org/sn_arc99/4_24_99/bob1.htm.

______. 1996. Unnaturally red cherries—naturally. Science News Online
(Oct. 19). Available at
http://www.sciencenews.org/sn_arch/10_19_96/food.htm.

______. 1989. Do you know your HDL? Science News 136(Sept. 9):171-173.

Sources:

The Cranberry Institute
3203-B Cranberry Highway
East Wareham, MA 02538
Web site: http://www.cranberryinstitute.org/


http://www.sciencenews.org/20030329/food.asp

From Science News, Vol. 163, No. 13, March 29, 2003, p. .

Copyright (c) 2003 Science Service. All rights reserved.

Study: Flu Shot Cuts Risk of Dying of Any Cause
Wed April 2, 2003 05:56 PM ET

NEW YORK (Reuters Health) - Men and women over the age of 65 stand to
gain a host of health benefits from getting a flu shot, including a
decreased risk of dying of any cause during flu season, scientists
reported Wednesday.
"Our findings highlight the benefits to be realized with vaccination
and lend urgency to efforts to improve the rate of vaccination among
the elderly," according to Dr. Kristin L. Nichol of the Veterans
Affairs Medical Center in Minnesota, Minneapolis, and colleagues.

Past studies have suggested that upper respiratory tract infections,
such as influenza, can boost a person's risk for heart attack and
stroke, especially among the elderly. To see if a flu shot might cut
the risk, Nichol's team looked at more than 140,000 men and women 65
years and older during the 1998-1999 flu season and again during the
1999-2000 flu season.

In 1999, 56 percent of the group had a flu shot; that proportion rose
to nearly 60 percent in 2000.

Vaccination against flu reduced the risk of being hospitalized for
heart disease by 19 percent, according to the report in Thursday's
issue of The New England Journal of Medicine.

Additionally, those who got the flu shot reduced the chances of being
hospitalized for cerebrovascular disease by 16 to 23 percent and the
risk of being hospitalized for pneumonia or influenza by 29 to 32
percent.

Overall, a flu shot cut the risk of dying of any cause by 48 to 50
percent, according to the report.

"These findings highlight the benefits of vaccination and support
efforts to increase the rates of vaccination among the elderly,"
Nichol and her colleagues conclude.

Each year, 114,000 people are hospitalized and 20,000 die from the
flu, experts estimate.

The vaccine usually protects 70 to 90 percent of healthy adults and
is 50 to 60 percent effective in preventing pneumonia in the elderly
and the immunocompromised. People can't get the flu from the vaccine.

SOURCE: The New England Journal of Medicine 2003;348:1322-1332.

Drugs 2003;63(8):803-843


Rituximab : A Review of its Use in Non-Hodgkin's Lymphoma and Chronic
Lymphocytic Leukaemia.

Plosker G, Figgitt D.

Adis International Limited, Auckland, New Zealand.

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated
efficacy in patients with various lymphoid malignancies, including
indolent and aggressive forms of B-cell non-Hodgkin's lymphoma (NHL)
and B-cell chronic lymphocytic leukaemia (CLL).

While the optimal use of the drug in many clinical settings has yet
to be clarified, two pivotal trials have established rituximab as a
viable treatment option in patients with relapsed or refractory
indolent NHL, and as a standard first-line treatment option when
combined with cyclophosphamide, doxorubicin, vincristine and
prednisone (CHOP) chemotherapy in elderly patients with diffuse large
B-cell lymphoma (the most common type of aggressive NHL).

The former was a noncomparative trial in relapsed indolent NHL
(follicular and small lymphocytic subtypes) with clinical responses
achieved in about half of patients treated with rituximab 375 mg/m(2)
intravenously once weekly for 4 weeks, which was similar to some of
the most encouraging results reported with traditional
chemotherapeutic agents. The latter was a randomised comparison of
eight cycles of CHOP plus rituximab 375 mg/m(2) intravenously (one
dose per cycle) versus CHOP alone in previously untreated elderly
patients (60 to 80 years of age) with diffuse large B-cell lymphoma.

In this pivotal trial, 2-year event-free and overall survival were
significantly higher with rituximab plus CHOP, and there was no
increase in clinically significant adverse effects compared with CHOP
alone. Treatment with rituximab is generally well tolerated,
particularly in terms of adverse hematological effects and serious or
opportunistic infections relative to standard chemotherapy. Infusion-
related reactions occur in the majority of patients treated with
rituximab; these are usually mild to moderate flu-like symptoms that
decrease in frequency with subsequent infusions.

In approximately 10% of patients, however, severe infusion-related
reactions develop (e.g. bronchospasm, hypotension). These reactions
are usually reversible with appropriate interventions and supportive
care but there have been rare reports of fatalities.

Conclusion: Clinical trials with rituximab indicate that the drug has
broad application to B-cell malignancies, although further
clarification is needed to determine its optimal use in many of these
clinical settings. Importantly, rituximab in combination with CHOP
chemotherapy has emerged as a new treatment standard for previously
untreated diffuse large B-cell lymphoma, at least in elderly
patients.

Compared with conventional chemotherapy, rituximab is associated with
markedly reduced haematological events such as severe neutropenia, as
well as associated infections. Rituximab may be particularly suitable
for elderly patients or those with poor performance status, and its
tolerability profile facilitates its use in combination with
cytotoxic drugs.

Pharmacodynamic Properties: Rituximab is a mouse/human chimaeric IgG
(1)-kappa monoclonal antibody that targets the CD20 antigen found on
the surface of malignant and normal B lymphocytes. Although treatment
with rituximab induces lymphopenia in most patients, typically
lasting about 6 months, a full recovery of B lymphocytes in the
peripheral blood is usually seen 9-12 months after therapy, as CD20
is not expressed on haematopoietic stem cells. CD20 is, however,
expressed on >90% of B-cell non-Hodgkin's lymphomas (NHL) and to a
lesser degree on B-cell chronic lymphocytic leukaemia (CLL) cells.

Although not fully elucidated, the cytotoxic effects of rituximab on
CD20-positive malignant B cells appears to involve complement-
dependent cytotoxicity, complement-dependent cellular cytotoxicity,
antibody-dependent cellular cytotoxicity and induction of apoptosis.
In addition, in vitro data indicate that rituximab sensitizes tumor
cells to the effects of conventional chemotherapeutic drugs.

Pharmacokinetic Properties: Serum rituximab concentrations increased
in proportion to dose across a wide range of single- and multiple-
dose intravenous regimens in patients with B-cell NHL. When
administer NHL. When administered at a dose of 375 mg/m(2) once
weekly for 4 weeks in a pivotal trial in patients with relapsed or
refractory indolent B-cell NHL (follicular or small lymphocytic
subtypes), peak serum concentrations essentially doubled from the
first (239.1 mg/L) to the fourth (460.7 mg/L) infusion, while
elimination half-life (t(½)) increased from 76.3 to 205.8 hours
(3.2 to 8.6 days).

The concomitant increase in serum rituximab concentrations and t
(½) with each successive infusion may be due, at least in part,
to the elimination of circulating CD20-positive B cells and reduction
or saturation of CD20-binding sites after the initial infusions of
rituximab. The pharmacokinetic properties of rituximab are also
characterised by wide inter-individual variability, and serum drug
concentrations that are correlated with clinical response. Although
pharmacokinetic data are limited in patients with aggressive forms of
NHL, such as diffuse large B-cell lymphoma, rituximab appears to have
a similar pharmacokinetic profile in these patients to that in
patients with indolent B-cell NHL.

The pharmacokinetics of rituximab are also reported to be similar
whether the drug is administered with or without cyclophosphamide,
doxorubicin, vincristine and prednisone (CHOP) chemotherapy.

Therapeutic Use: A number of studies have demonstrated efficacy of
intravenous rituximab in patients with various lymphoid malignancies
of B-cell origin, including indolent (e.g. follicular lymphoma) and
aggressive (e.g. diffuse large B-cell lymphoma) forms of NHL, and
CLL, but the drug has not yet been approved for use in CLL, and
approved indications in NHL vary between countries.

In the US, for example, rituximab is available for the treatment of
patients with low-grade or follicular, relapsed or refractory, CD20-
positive B-cell NHL. In Europe, the drug has similar approval for
relapsed or refractory follicular NHL as in the US, but has also been
approved for use in combination with CHOP chemotherapy for the most
common aggressive form of NHL (CD20-positive, diffuse large B-cell
lymphoma). Rituximab was approved for these indications primarily on
the basis of results from two pivotal trials.

In Japan, rituximab has been approved for indolent B-cell NHL and
mantle cell lymphoma (an aggressive form of B-cell NHL), primarily on
the basis of results of a Japanese phase II trial.

Indolent NHL: Results of several studies evaluating rituximab 375 mg/m
(2) once weekly for 4 weeks in patients with indolent forms of B-cell
NHL (primarily follicular and small lymphocytic lymphomas) showed
objective response (OR) rates ranging from approximately 40-60% in
those receiving the drug for relapsed or refractory indolent B-cell
NHL, and slightly higher (50-70%) for those receiving rituximab as
first-line therapy.

In a pivotal trial in 166 patients with relapsed or refractory low-
grade or follicular B-cell NHL, intent-to-treat (ITT) analysis showed
an OR rate of 48%, and a projected median time to progression of 13
months.

Encouraging data are also emerging on the use of rituximab in
combination with chemotherapeutic agents (e.g. CHOP, fludarabine-
containing regimens) or other drugs (e.g. interferon-alpha-2a) in
previously untreated patients with indolent forms of B-cell NHL
(primarily follicular and small lymphocytic subtypes). Rates for OR
were consistently around 95%, with the majority being complete
responses (CRs). Follow-up data from a study in 40 patients with low-
grade or follicular B-cell NHL treated with rituximab plus CHOP as
first-line therapy showed that responses were durable with a
progression-free survival and median duration of response of 5 years.

Bcl-2 gene rearrangement (t14;18) occurs in malignant cells in up to
85% of patients with follicular lymphoma, and minimal residual
disease in peripheral blood and bone marrow can be monitored using
polymerase chain reaction (PCR). In several studies assessing blood
and/or bone marrow, rituximab has achieved molecular response
(conversion from PCR-positive to PCR-negative bcl-2 status) in at
least half of the patients.

Aggressive NHL: Studies with rituximab as monotherapy in aggressive B-
cell NHL, a potentially curable disorder, have generally been
restricted to patients with relapsed or recurrent disease, since CHOP
has traditionally been the standard first-line treatment regimen.

However, promising results from phase II monotherapy studies prompted
further clinical investigation of rituximab in conjunction with
chemotherapy. Thus, most studies with rituximab in patients with
aggressive forms of B-cell NHL have involved combination therapy,
including a pivotal randomised trial comparing eight cycles of
standard CHOP therapy plus rituximab 375 mg/m(2) (one dose per cycle)
versus CHOP alone in 399 previously untreated elderly patients (60-80
years of age) with diffuse large B-cell lymphoma.

Results of the pivotal trial showed a clear advantage for rituximab
plus CHOP versus CHOP in terms of event-free survival (primary
endpoint) at 2 years (57% vs 38%, p < 0.001). Overall survival at
2 years (70% vs 57%, p < 0.01) and CR rate (76% vs 63%, p <
0.01) were also higher with the rituximab-CHOP combination.

Other, smaller trials with rituximab in combination with CHOP or
other chemotherapeutic regimens, either as first-line therapy or for
patients with relapsed or refractory aggressive B-cell NHL, have also
shown promising results in terms of clinical response rates.

CLL: In relatively small trials (n =40) conducted primarily in
patients with relapsed or refractory B-cell CLL, rituximab
monotherapy (various regimens) achieved OR rates of 23-45%, with
median duration of response ranging from approximately 3-10 months.

In a larger, randomised trial in 104 previously untreated patients
with B-cell CLL, concurrent treatment with six cycles of fludarabine
plus rituximab 375 mg/m(2) (seven doses in total) followed 2 months
later by four weekly doses of rituximab achieved an OR rate of 90%
compared with 77% for those who received sequential treatment using
fludarabine induction followed 2 months later by rituximab 375 mg/m
(2) once weekly for 4 weeks.

Although this difference was not statistically significant, there was
a significant advantage for concurrent versus sequential treatment in
terms of CR rates (47% vs 28%, p < 0.05). Several other studies
using rituximab in combination with fludarabine-containing regimens,
most of which are available only as abstracts, have shown good
clinical response rates in previously untreated patients with CLL, as
well as those with relapsed or refractory disease.

Tolerability: The majority of patients treated with rituximab will
experience one or more adverse events, the most common being infusion-
related reactions. Mild to moderate flu-like symptoms such as fever,
chills and rigours occur in most patients during their first infusion
of rituximab, although the incidence of infusion-related adverse
events decreases with subsequent rituximab infusions. Severe (grade 3
or 4) infusion-related reactions occur in approximately 10% of
patients, and may be accompanied by bronchospasm, hypotension,
angioedema and/or hypoxia.

In the vast majority of cases these adverse effects are reversible
with interruption or discontinuation of rituximab along with
supportive care. However, severe consequences of infusion-related
reactions have been reported, including pulmonary infiltrates, acute
respiratory distress syndrome and cardiovascular events. In patients
who develop cytokine release syndrome associated with tumor lysis
syndrome, renal, respiratory or multi-organ failure can occur.

Infusion-related fatalities with rituximab have been rare
(approximately 0.04-0.07% of patients). Grade 3 or 4 hematological
adverse effects generally occur infrequently with rituximab
monotherapy, aside from severe lymphopenia which occurs in about 40%
of patients, is related to the action of rituximab and does not
appear to be associated with adverse consequences. Moreover, the risk
of serious or opportunistic infections appears to be considerably
less than that reported with conventional chemotherapy. Various other
adverse events have been reported with rituximab, including rare
reports of fatal mucocutaneous reactions.

Pharmacoeconomic Considerations:  Several pharmacoeconomic analyses
of rituximab in B-cell NHL have been conducted and most have been
published only as abstracts. Cost analyses from the UK, France, the
US and Spain indicate that rituximab is associated with total direct
medical costs similar to or lower than those for fludarabine in
patients with relapsed or refractory indolent B-cell NHL (usually
follicular or small lymphocytic subtypes when histology was
specified). The higher acquisition costs of rituximab compared with
fludarabine were at least offset by reduced costs associated with
adverse haematological effects (e.g. neutropenia) and drug
administration. Although results were equivocal in cost comparisons
between rituximab and CHOP chemotherapy in patients with relapsed or
refractory indolent B-cell NHL, total direct medical costs appear to
be broadly similar for rituximab and CHOP.

In cost-effectiveness analyses of rituximab in patients with
aggressive B-cell NHL, investigators from France and the UK used
medical resource consumption and survival data from the pivotal trial
in patients with diffuse large B-cell lymphoma to determine the cost-
effectiveness ratio for rituximab plus CHOP versus CHOP alone. When
survival data from a protocol-scheduled interim analysis, or from 2-
year follow-up data, of the pivotal trial were projected over 10
years using published long-term survival data, favorable cost-
effectiveness ratios of approximately euro22-150-euro28-410 per life-
year gained were calculated (year of costing not reported). Results
were sensitive to the durability of the survival benefit and assumed
that the survival benefit shown during the study period persists to
10 years.

Dosage and Administration: The standard dose of rituximab is 375 mg/m
(2) administered as an intravenous infusion to adult patients.
However, the recommended dosage interval and duration of therapy
varies between countries and for different indications (see
Therapeutic Use summary section for approved indications in the US
and Europe).

For patients with relapsed or refractory follicular B-cell lymphoma
(the most common histology of indolent NHL), rituximab is
administered once weekly for 4 weeks (European recommendation) or for
4 or 8 weeks (US recommendation). For patients with diffuse large B-
cell lymphoma (the most common aggressive form of NHL), rituximab is
used in combination with CHOP chemotherapy for 6-8 cycles and is
administered on day 1 of each cycle (European recommendation).

For the first dose of rituximab, the initial infusion rate should be
50 mg/h for the first 30 minutes, which is increased in 50 mg/h
increments every 30 minutes, to a maximum of 400 mg/h. For subsequent
doses, the initial infusion rate is 100 mg/h, which is increased by
100 mg/h increments at 30-minute intervals, to a maximum of 400 mg/h.

For patients who do not tolerate the first dose of rituximab well,
subsequent rituximab doses should be administered according to
recommendations for the first infusion (US recommendation). For
patients who experience severe infusion-related reactions with
rituximab, therapy should be interrupted and supportive care measures
implemented.

After complete resolution of symptoms, rituximab infusion can
continue at half the previous rate in most patients.

PMID: 12662126 [PubMed - as supplied by publisher]

Bone Marrow Transplantation


March (1) 2003, Volume 31, Number 5, Pages 371-378

Stem Cell Mobilisation

Successful mobilization of peripheral blood stem cells after addition
of ancestim (stem cell factor) in patients who had failed a prior
mobilization with filgrastim (granulocyte colony-stimulating factor)
alone or with chemotherapy plus filgrastim
Space
L B To1, J Bashford2, S Durrant3, J MacMillan4, A P Schwarer5, H M
Prince6, J Gibson7, I Lewis1, B Swart1, J Marty4, T Rawling1, L
Ashman1, S Charles4 and B Cohen4
Space

1Division of Haematology, Hanson Centre for Cancer Research, IMVS,
Adelaide, Australia

2Wesley Medical Centre, Auchenflower, Queensland, Australia

3Royal Brisbane Hospital, Herston, Queensland, Australia

4Amgen Australia P/L, North Ryde, New South Wales, Australia

5BMT Program, Alfred Hospital, Prahan, Victoria, Australia

6Department of Haematology, Peter MacCallum Cancer Institute,
Melbourne, Victoria, Australia

7Institute of Haematology, Royal Prince Alfred Hospital, Camperdown,
New South Wales, Australia


This study assessed the ability of recombinant human stem cell factor
(rHuSCF) to mobilize stem cells in 44 patients who had failed a prior
mobilization (CD34+ yield 0.5-1.9 ´ 106/kg BW) with filgrastim-alone
or chemotherapy-plus-filgrastim. The same mobilization regimen was
used with the addition of rHuSCF.

In the filgrastim-alone group (n=13), rHuSCF 20 mug/kg was started 3
days before filgrastim and continued for the duration of filgrastim.
In the chemotherapy-plus-filgrastim group (n=31), rHuSCF 20 mug/kg/day
plus filgrastim 5-10 mug/kg/day were administered concurrently.
Leukaphereses were continued to a maximum of four procedures or a
target of 3 ´ 106 CD34+ cells/kg. In both groups, CD34+ yield (´
106/kg BW) of the study mobilization was higher than that of the prior
mobilization (median: 2.42 vs 0.84 P=0.002 and 1.64 vs 0.99 P=<0.001,
respectively).

In all 54 and 45% of patients in the filgrastim-alone group and
chemotherapy-plus-filgrastim group, respectively, reached the
threshold yield of 2 ´ 106/kg. The probability of a successful
mobilization was the same in those with a CD34+ yield of 0.5-0.75 ´
106/kg BW in the prior mobilization as in those with 0.76-1.99 ´
106/kg BW.

Downmodulation of c-kit expression and a lower percentage of Thy-1
positivity in the mobilized CD34+ cells were noted in the successful
mobilizers compared with those in the poor mobilizers.

This study shows that rhuSCF is effective in approximately half the
patients who had failed a prior mobilization and allows them to
proceed to transplant. It also points to the likely role of the
SCF/c-kit ligand pair in mobilization.

Bone Marrow Transplantation (2003) 31, 371-378. doi:10.1038/sj.bmt.1703860

(I'm assuming these studies are on acute leukemias, but their
application may include CLL and other chronic malignancies.

Leukemia

March 2003, Volume 17, Number 3, Pages 604-611

Original Manuscript

Inhibition of human leukemia in an animal model with human antibodies
directed against vascular endothelial growth factor receptor 2.
Correlation between antibody affinity and biological activity
Space

Z Zhu1, K Hattori2, H Zhang1, X Jimenez3, D L Ludwig3, S Dias2, P
Kussie4, H Koo3, H J Kim4, D Lu1, M Liu1, R Tejada2, M Friedrich2, P
Bohlen5, L Witte3 and S Rafii2
Space

1Department of Antibody Technology, ImClone Systems Incorporated, New
York, NY, USA

2Division of Hematology-Oncology, Cornell University Weill Medical
College, New York, NY, USA

3Department of Molecular and Cell Biology, ImClone Systems
Incorporated, New York, NY, USA

4Department of Protein Chemistry, ImClone Systems Incorporated, New
York, NY, USA

5Department of Research, ImClone Systems Incorporated, New York, NY, USA


Vascular endothelial growth factor (VEGF) and its receptors (VEGFR)
have been implicated in promoting solid tumor growth and metastasis
via stimulating tumor-associated angiogenesis. We recently showed that
certain 'liquid' tumors such as leukemia not only produce VEGF, but
also express functional VEGFR, resulting in an autocrine loop for
tumor growth and propagation.

A chimeric anti-VEGFR2 (or kinase insert domain-containing receptor,
KDR) antibody, IMC-1C11, was shown to be able to inhibit VEGF-induced
proliferation of human leukemia cells in vitro, and to prolong
survival of nonobese diabetic-severe combined immune deficient
(NOD-SCID) mice inoculated with human leukemia cells.

Here we produced two fully human anti-KDR antibodies (IgG1), IMC-2C6
and IMC-1121, from Fab fragments originally isolated from a large
antibody phage display library. These antibodies bind specifically to
KDR with high affinities: 50 and 200 pM for IMC-1121 and IMC-2C6,
respectively, as compared to 270 pM for IMC-1C11. Like IMC-1C11, both
human antibodies block VEGF/KDR interaction with an IC50 of
approximately 1 nM, but IMC-1121 is a more potent inhibitor to
VEGF-stimulated proliferation of human endothelial cells.

These anti-KDR antibodies strongly inhibited VEGF-induced migration of
human leukemia cells in vitro, and when administered in vivo,
significantly prolonged survival of NOD-SCID mice inoculated with
human leukemia cells. It is noteworthy that the mice treated with
antibody of the highest affinity, IMC-1121, survived the longest
period of time, followed by mice treated with IMC-2C6 and IMC-1C11.

Taken together, our data suggest that anti-KDR antibodies may have
broad applications in the treatment of both solid tumors and leukemia.
It further underscores the efforts to identify antibodies of high
affinity for enhanced antiangiogenic and antitumor activities.

Leukemia (2003) 17, 604-611.

Cancer Gene Therapy

March 2003, Volume 10, Number 3, Pages 201-208

Original Article

Downregulation of bcl-2 expression in lymphoma cells by bcl-2
ARE-targeted modified, synthetic ribozyme
Space
Ettore Luzi1,a, Laura Papucci1, Nicola Schiavone1, Martino Donnini1,
Andrea Lapucci1, Alessio Tempestini1, Ewa Witort1, Angelo Nicolin2 and
Sergio Capaccioli1
Space

1Department of Experimental Pathology and Oncology, University of
Florence, Viale Morgagni 50, 50134, Firenze, Italy

2Department of Pharmacology, University of Milan, 20129 Milan, Italy

Correspondence to: Dr E Luzi, Biosensor Laboratory, Department of
Chemistry, Polo Scientifico, Via della Lastruccia 3, Sesto
Fiorentino-Firenze 50019, Italy. E-mail: et.car@...
Space

aCurrent address: Biosensor Laboratory, Department of Chemistry, Polo
Scientifico, Via della Lastruccia 3, Sesto Fiorentino-Firenze 50019,
Italy.


Synthetic ribozymes are catalytic RNA molecules designed to inhibit
gene expression by cleaving specific mRNA sequences.

We investigated the potential of synthetic ribozymes to inhibit bcl-2
expression in apoptosis defective bcl-2 overexpressing tumors. A
chemically stabilized hammerhead ribozyme has been targeted to the
A+U-rich regulative element of bcl-2 mRNA that is involved in bcl-2
gene switch-off during apoptosis. The design of the ribozyme was based
on the results of probing accessibility of the RNA target in cellular
extracts with antisense DNA.

The ribozyme was lipotransfected to a bcl-2 overexpressing human
lymphoma cell line (Raji). The cellular uptake of this ribozyme
resulted in a marked reduction of both bcl-2 mRNA and BCL-2 protein
levels and dramatically increased cellular death by apoptosis.

Our results suggest a potential therapeutic application of such
ribozyme for the treatment of bcl-2 overexpressing tumors.


Received 10 October 2002
Space
March 2003, Volume 10, Number 3, Pages 201-208

Abstract
British Journal of Haematology
Volume 121 Issue 1 Page 143  - April 2003

SHORT REPORT
Treatment with short-term, high-dose cyclosporin A in children with
refractory chronic idiopathic thrombocytopenic purpura
Silverio Perrotta1, Giovanni Amendola2, Franco Locatelli3, Maria Luisa
Conte1, Francesca Rossi1, Giovanna d'Urzo1 and Bruno Nobili1

Summary. We report on 14 children (seven boys, seven girls) with
chronic idiopathic thrombocytopenic purpura (ITP) refractory to
multiple treatments, who were given a short-term therapy (range
between 6 and 10 weeks) with high doses of cyclosporin A (CyA)
(median, 10 mg/kg/d). Six patients experienced adverse events and one
developed severe systemic mycosis during therapy.

A complete response (CR) was observed in four patients and a partial
response (PR) in three patients. Only the four CR patients, who were
all girls, had a sustained response.

These data suggest that CyA may be effective in some children with
chronic symptomatic ITP.

Abstract
British Journal of Haematology
Volume 121 Issue 1 Page 109  - April 2003

T-cell depletion with Campath-1H 'in the bag' for matched related
allogeneic peripheral blood stem cell transplantation is associated
with reduced graft-versus-host disease, rapid immune constitution and
improved survival

Suparno Chakrabarti1,2, Dorothy MacDonald3, Geoff Hale4, Kathleen
Holder1, Virginia Turner3, Halina Czarnecka3, Jacqui Thompson3,
Christopher Fegan1, Herman Waldmann4 and Donald W. Milligan1

Summary. We studied the outcome of 24 peripheral blood stem cell
(PBSC) graft recipients, who were T-cell depleted (TCD) with either 20
mg (n = 14) or 10 mg (n = 10) Campath-1H in vitro, in comparison with
a retrospective cohort of 23 unmanipulated (UM) PBSC recipients.

While the neutrophil engraftment was similar, the platelet engraftment
occurred earlier in the TCD group (d 11 vs 14). The incidence of acute
and chronic graft-versus-host-disease (GVHD) was 8·7% and 4·4% in the
TCD group, respectively, compared with 47·7% and 56·3% in UM group (P
< 0·001).

In the TCD group, 5/6 chronic myeloid leukemia (CML) and 4/18 non-CML
patients relapsed (vs 0/6 and 3/17 in UM group, P = 0·06). All four
molecular or cytogenetic relapses of CML were disease-free survivors
following donor lymphocyte infusion.

There was no difference in the incidence of serious infection between
the TCD and UM groups and the lymphocyte recovery at 100 d was
comparable. In the TCD cohort, the lymphocyte recovery was quicker in
the 10 mg Campath-1H group. The non-relapse mortality (19·1%vs 66·3%)
and 3 year survival (73·1 vs 19·2) were improved in the TCD group (P =
0·05).

Thus elimination of late mortalities related to chronic GVHD and a
rapid immune reconstitution, limiting either infection or relapse
related deaths, contributed to an improved outcome following T-cell
depletion with Campath-1H 'in the bag'.

Abstract
British Journal of Haematology
Volume 121 Issue 1 Page 97  - April 2003

SHORT REPORT
Disparate expression of the PTEN gene: a novel finding in B-cell
chronic lymphocytic leukaemia (B-CLL)
Nicolas Leupin, Bruno Cenni, Urban Novak, Barbary Hügli, Hans U.
Graber, Andreas Tobler and Martin F. Fey

Summary. One fifth of B-cell chronic lymphocytic leukaemia (B-CLL)
patients exhibit loss of heterozygosity (LOH) at 10q23.3, the site of
the tumor suppressor PTEN. Microsatellite markers mapped complete LOH
to 10q23.3 in 2/41 B-CLL (5%) and allelic imbalances in 6/41 (15%). No
PTEN gene mutations were found.

PTEN protein expression was not detected in 11 B-CLL (28%), and was
reduced in eight patients (20%). LOH or allelic imbalances at 10q23.3
were fairly frequent in B-CLL, but did not encompass the PTEN gene.

Nevertheless, PTEN protein may be absent in B-CLL with a normal PTEN
genotype, suggesting a role of this phosphatase in the molecular
pathology of B-CLL.

Journal of the National Cancer Institute, Vol. 95, No. 7, 548-555,
April 2, 2003
© 2003 Oxford University Press

Antitumor Immunity After Vaccination With B Lymphoma Cells
Overexpressing a Triad of Costimulatory Molecules

Javier Briones, John M. Timmerman, Dennis L. Panicalli, Ronald Levy

Affiliations of authors: J. Briones, J. M. Timmerman, R. Levy,
Division of Oncology, Stanford University School of Medicine,
Stanford, CA; D. L. Panicalli, Therion Biologics Corporation,
Cambridge, MA.

Background: The costimulatory molecules B7-1, intercellular adhesion
molecule-1 (ICAM-1), and leukocyte function-associated antigen-3
(LFA-3) play pivotal roles in the activation of T cells. We
investigated whether in vivo vaccination with lymphoma cells infected
with a recombinant, nonreplicating fowlpox (FP) virus encoding this
triad of costimulatory molecules (TRICOM) could stimulate
lymphoma-specific immunity.

Methods: TRICOM-infected A20 B lymphoma cells were analyzed for
expression of B7-1, ICAM-1, and LFA-3. Mice (10 per group) were
vaccinated with irradiated A20 cells infected with either the TRICOM
vector or the wild-type FP virus (WT-FP), challenged with live A20
tumor cells, and followed for survival. Mice with established A20
tumors were also treated with irradiated TRICOM-infected A20 cells.
Survival curves were compared with the log-rank statistic.

The mechanism of the antitumor effect was studied by in vivo depletion
of CD4+ and CD8+ T cells and in vitro cytotoxicity assays. All
statistical tests were two-sided.

Results: A20 tumor cells infected with TRICOM expressed high levels of
B7-1, ICAM-1, and LFA-3. Mice vaccinated with irradiated
TRICOM-infected A20 cells had prolonged survival relative to mice
vaccinated with WT-FP-infected cells (80% versus 20% survival at 110
days; P<.001).

In mice with established tumors, tumor growth was slower in those
treated with TRICOM-infected tumor cells than in those treated with
WT-FP-infected cells, and this treatment provided a survival advantage
(P<.001). Depletion of CD4+ or CD8+ T cells reduced the antitumor
immunity provided by the tumor cell–TRICOM vaccine, and lymphocytes
from vaccinated mice displayed in vitro cytotoxic activity toward A20
cells.

Conclusions: Increasing expression of costimulatory molecules on B
lymphoma cells by infection with a recombinant FP virus encoding B7-1,
ICAM-1, and LFA-3 stimulates antitumor immune responses in vivo and
may provide a novel strategy for treating patients with B-cell
malignancies.

(This study did not look at the tissue of cancer patients themselves,
just hypothesized that looking at two distinct populations which were
either of an age when exposure to polio vaccine may have contained the
SV40 virus, or of an age when they were likely vaccinated with polio
virus that did not contain the SV40 virus.  The study seemingly
ignored all other variables, such as exposure to new chemicals in the
environment, an altered backgroud pollution level etc.  I wonder if
this paper wil be criticized on this basis.  However, I have not seen
the full paper where these factors may have been addressed.)

Journal of the National Cancer Institute, Vol. 95, No. 7, 532-539,
April 2, 2003
© 2003 Oxford University Press

ARTICLE

Cancer Incidence in Denmark Following Exposure to Poliovirus Vaccine
Contaminated With Simian Virus 40

Eric A. Engels, Hormuzd A. Katki, Nete M. Nielsen, Jeanette F.
Winther, Henrik Hjalgrim, Flemming Gjerris, Philip S. Rosenberg,
Morten Frisch

Affiliations of authors: E. A. Engels, H. A. Katki, P. S. Rosenberg,
Division of Cancer Epidemiology and Genetics, National Cancer
Institute, Department of Health and Human Services, Rockville, MD; N.
M. Nielsen, H. Hjalgrim, M. Frisch, Department of Epidemiology
Research, Danish Epidemiology Science Center, Statens Serum Institut,
Copenhagen, Denmark; J. F. Winther, Institute of Cancer Epidemiology,
Danish Cancer Society, Copenhagen; F. Gjerris, University Clinic of
Neurosurgery, Neuroscience Center, H.S., Rigshospitalet, Copenhagen.

Correspondence to: Eric A. Engels, M.D., M.P.H., Viral Epidemiology
Branch, Division of Cancer Epidemiology and Genetics, National Cancer
Institute, 6120 Executive Blvd., EPS 8010, Rockville, MD 20892
(e-mail: engelse@ exchange.nih.gov).

Background: Early poliovirus vaccines were accidentally contaminated
with simian virus 40 (SV40). In Denmark, poliovirus vaccine was
administered to most children from 1955 through 1961. SV40 DNA
sequences have been detected in several human malignancies, including
mesothelioma, ependymoma, choroid plexus tumors, and non-Hodgkin's
lymphoma.

To clarify whether SV40 infection increases risk of these cancers or
of cancers arising in children, we examined cancer incidence in three
Danish birth cohorts.

Methods: Population-based cancer incidence data from 1943 through 1997
were obtained from the Danish Cancer Registry. The relationship
between exposure to SV40-contaminated vaccine and cancer incidence was
evaluated by examining incidence in birth cohorts that differed in
exposure to SV40-contaminated vaccine. In addition, cancer incidence
was examined in children who were 0–4 years of age before, during, and
after the period of vaccine contamination. Incidence was compared
using Poisson regression, adjusting for age differences. All
statistical tests were two-sided.

Results: After 69.5 million person-years of follow-up, individuals
exposed to SV40-contaminated poliovirus vaccine as infants (i.e., born
1955–1961) or children (i.e., born 1946–1952) had lower overall cancer
risk (age-adjusted relative risk [RR] = 0.86, 95% confidence interval
[CI] = 0.81 to 0.91 and RR = 0.79, 95% CI = 0.75 to 0.84,
respectively; P<.001 for both) than unexposed individuals (i.e., born
1964–1970, after the vaccine was cleared of SV40 contamination).

Specifically, SV40 exposure was not associated with increased
incidence of mesothelioma, ependymoma, choroid plexus tumor, or
non-Hodgkin's lymphoma.

After 19.5 million person-years of follow-up, incidence of all cancers
combined, of intracranial tumors, and of leukemia among children aged
0–4 years was also not associated with SV40 exposure. Ependymoma
incidence was higher during the exposed period than during the
unexposed period (RR = 2.59, 95%CI = 1.36 to 4.92; P = .004 versus the
period before contamination); however, incidence peaked in 1969, after
the vaccine was cleared of SV40.

Conclusion: Exposure to SV40-contaminated poliovirus vaccine in
Denmark was not associated with increased cancer incidence.

Antibody therapy can increase the effectiveness of cancer vaccine,
early studys

BOSTON –– The benefit of some cancer vaccines may be boosted by
treating patients with an antibody that blocks a key protein on immune
system T cells, according to a small, preliminary study led by
researchers at Dana-Farber Cancer Institute and Brigham and Women's
Hospital.

The study, to be published online on April 1 in the Early Edition of
the Proceedings of the National Academy of Sciences (www.pnas.org),
tested the effect of a single injection of the antibody MDX-CTLA4 in
nine patients who had previously been treated with cancer vaccines for
either metastatic melanoma or metastatic ovarian cancer. The result,
in every patient who had received a particular kind of vaccine, was
widespread death of cancer cells and an increase in the number of
immune system cells within the tumors – evidence of a potent immune
system attack.

"This study makes a strong case that combined immunotherapy –
consisting of a vaccine and antibodies – can elicit a potent immune
response to some types of tumors in patients," says the study's senior
author, Glenn Dranoff, MD, of Dana-Farber.

The technique was inspired by the laboratory work of study co-author
James Allison, PhD, a Howard Hughes Medical Institute investigator at
the University of California, Berkeley. He and his colleagues
discovered that a protein, or antigen, called CTLA-4 on T cells
restrains the immune system from attacking cancer cells. In a series
of laboratory and animal experiments, Allison's team showed that
combining a cancer vaccine with an antibody able to block CTLA-4
resulted in an especially potent immune attack on tumors.

On the basis of those findings, Dranoff and his colleagues launched a
Phase I clinical trial of the technique in a small group of patients.
Because animal experiments had indicated that giving MDX-CTLA4 in
combination with a vaccine might prompt the immune system to attack
some normal cells, researchers decided to give the antibody to
patients who had already been vaccinated.

Seven of the study participants had metastatic melanoma, a potentially
fatal cancer that originates in skin cells, and two had metastatic
ovarian cancer. In all three melanoma patients who had been treated
with one form of vaccine, tumors showed extensive signs of cell death
and were saturated with large numbers of tumor-fighting immune cells.
The same results were seen in the two ovarian cancer patients who had
been treated with the same type of vaccine. (The vaccine is created by
loading tumor cells with a gene called GM-CSF that alerts the immune
system to the tumors' presence, prompting an anti-tumor attack.)

Of the four melanoma patients who had received a different type of
vaccine based on melanoma antigens, none experienced a similar
benefit, researchers found.

While none of the study participants had serious reactions to the
antibody itself, some of the melanoma patients developed a mild immune
reaction against normal skin cells called melanocytes, but it was not
a dangerous side effect.

Previous clinical trials have shown that vaccines can be at least
temporarily effective in treating metastatic melanoma and ovarian
cancer, but most patients eventually succumb to their disease. One of
the reasons for this may be that the CTLA-4 molecule gradually weakens
the immune system's ability to recognize and respond to tumor cells.

"By blockading CTLA-4 with antibodies, we had hoped to strengthen the
immune response produced by cancer vaccines," remarks Dranoff, who is
also an associate professor of medicine at Harvard Medical School and
a Leukemia and Lymphoma Society clinical scholar. "Work in the
laboratory and in animal models suggested that this approach could be
effective. The new study offers the first evidence that the technique
has promise in human patients, although much more study will be needed
to demonstrate that this is the case."

The study's lead author is Stephen Hodi, MD, of Dana-Farber. Other
co-authors were from Massachusetts General Hospital, Massachusetts Eye
and Ear Infirmary, Harvard Medical School, and Mederex, Inc.

###

Funding for the research was provided in part by the Berlex Oncology
Foundation, National Institutes of Health, the Leukemia and Lymphoma
Society, the Cancer Research Institute, and Mederex, Inc.

Dana-Farber Cancer Institute is a principal teaching affiliate of the
Harvard Medical School and is among the leading cancer research and
care centers in the United States. It is a founding member of the
Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive
cancer center by the National Cancer Institute.

Damage lingers from low-dose X-rays -German study

Last Updated: 2003-04-01 10:00:15 -0400 (Reuters Health)

WASHINGTON (Reuters) - Low doses of X-rays such as those patients
receive in the dentist's chair may do more long-lasting damage than
higher doses, German scientists reported on Monday in a study that
turns common wisdom on its head.

Their findings, based on experiments with cell cultures, will have to
be duplicated by other labs and then repeated in living animals before
doctors can offer guidance on the effects of low-dose X-rays on humans.

The team, led by Markus Lobrich at the Universitat des Saarlandes,
said its research suggests that doses of X-rays generally considered
harmless may in fact do long-lasting damage.

But they said they had developed a test that would help doctors look
for genetic damage in people exposed to low doses of X-rays, such as
cancer patients undergoing radiotherapy, patients getting X-rays and
professionals working with X-ray equipment.

Writing in the Proceedings of the National Academy of Sciences,
Lobrich's team said they exposed human cell cultures to varying X-ray
doses in the laboratory.

To their surprise, they found that damage from low radiation levels
lingered days to weeks longer than damage caused by more powerful levels.

"Usually, DNA double-strand breaks are repaired within a few hours
after radiation insult and after about one day all DNA double-strand
breaks were believed repaired," Lobrich told Reuters.

"In our study we observed that DNA double-strand breaks induced by
very low doses remain unrepaired for many days, and even two weeks
after the radiation insult most of the induced DNA double-strand
breaks were still present," he added.

Ionizing radiation like the kind produced by X-rays and some nuclear
breakdown products can cause leukemia and other cancers. The radiation
can cause breaks in DNA that go across both strands of its double
helix structure.

Scientists had assumed that the body moves to repair these breaks at
the same rate, no matter what the dose of radiation.

But Lobrich's team found this may not be true. It could be, they
propose, that the body simply does not recognize lower levels of
damage and does not move to repair it.

When these damaged cells divide and multiply, the unrepaired damage
multiplies along with them, they suggested.

"I would advise people to restrict their X-ray exams to cases that
give a clear medical benefit," said Lobrich.

Lobrich explained that if a woman has a hereditary indication for an
elevated breast cancer risk -- because the mother and/or the
grandmother had breast cancer -- they should have mammography exams
done and not worry too much about the radiation risk.

"I believe most of the dental exams are unnecessary but would not
worry too much about it as radiation is not very likely to cause
cancer in that part of the body," Lobrich said.

SOURCE: Proceedings of the National Academy of Sciences 2003;
10.1073/pnas0830918100

Copyright © 2003 Reuters Limited. All rights reserved.

Study: Not Enough Seniors in Cancer Drug Trials
Fri Mar 28,11:08 AM ET


LOS ANGELES (Reuters) - People over 65 are not represented in
sufficient numbers in studies on promising cancer treatments, thus
raising questions about how useful the research is for the age group
with the most cancer patients, a new study said on Thursday.

A report by the private, nonprofit RAND institute found that seniors
accounted for 61 percent of people diagnosed with cancer from 1997
through 2000, but made up just 32 percent of enrollees in
U.S.-sponsored cancer trials for the same period.

The RAND study found that the elderly were even less likely to be
enrolled in clinical trials for early-stage cancers than in trials for
late-stage cancers.

"As a physician, you can't know for sure that a drug would work for
your patient unless it was tested on similar people in a clinical
trial," said Dr. Joy Lewis, a RAND researcher who headed the study.

The study, published in the latest issue of the Journal of Clinical
Oncology, suggests that the major roadblock to seniors' participation
are rules that exclude patients from the studies if they have other
health problems, such as high blood pressure or lung ailments.

In addition, more than 80 percent of the trials required participants
to be either mobile or capable of living independently. Studies that
did not have such exclusions enrolled higher proportions of the
elderly, RAND said.

"Some protocol exclusions are clearly necessary because of toxicity
concerns, but each one needs to be carefully evaluated," Lewis said.
Alternatively, researchers could design more trials that focus
exclusively on older subjects or that address the treatment of cancer
patients with additional ailments, she said.

Federal laws now require that cancer trials enroll representative
samples of women and members of minority groups, but no similar
requirement exists for elderly patients.

The RAND researchers conducted their study by examining documentation
for 60,000 patients enrolled in 495 clinical trials sponsored by the
National Cancer Institute.

Med Oncol 2003 Feb;20(1):53-58


Phase I Trial of Fludarabine and Paclitaxel in Non-Hodgkin s Lymphoma


Department of Medicine, Jacobi Medical Center, Bronx, NY

Fludarabine is an active agent in low-grade non-Hodgkin's lymphoma
and chronic lymphocytic leukemia. Paclitaxel is also active in
patients with refractory lymphoma, and preclinical data suggest an
additive effect with fludarabine in vitro.

We performed a phase I trial of fludarabine (25 mg/m(2) d 1 3) plus a
3-h infusion of paclitaxel (125, 150, or 175 mg/m(2)) on d 3 every 28
d in 13 patients with non-Hodgkin s lymphoma. The paclitaxel dose was
escalated in cohorts of 3 4 patients using standard phase I design
schema.

Dose-limiting toxicity was defined as febrile neutropenia, platelet
nadir less than 50,000/&mgr;L, or grade 3 4 nonhematologic toxicity.
Thirteen patients were accrued to the study, 8 of these 13 patients
(62%) had received prior chemotherapy.

At the 125-, 150-, and 175-mg/m(2) dose levels of paclitaxel, dose-
limiting toxicity occurred in 1/4, 0/4, and 0/4 patients,
respectively. The single patient with dose-limiting toxicity had
febrile neutropenia.

Partial response occurred in two of eight patients with low-grade
lymphoma and none of five patients with other types of lymphoma. A
paclitaxel dose of 175 mg/m(2) given as a 3-h infusion on d 3 in
conjunction with fludarabine (25 mg/m(2) d 1 3 every 4 wk) is a well-
tolerated regimen for non-Hodgkin s lymphoma.

Further study will be required in order to determine whether the
fludarabine paclitaxel is more active than fludarabine alone in
patients with low-grade lymphoma and chronic lymphocytic leukemia.

PMID: 12665685 [PubMed - as supplied by publisher]

1: Eur Radiol 2003 Apr;13(4):771-9


Extranodal lymphoplasmacytoid lymphoma: spectrum of disease.

Guermazi A, Meignin V, Brice P.

Department of Radiology, University of California at San Francisco,
350 Parnassus Avenue, Suite 150, San Francisco, CA 94117, USA,
ali.guermazi@...

Lymphoplasmacytoid lymphomas (LPL) are non-Hodgkin's lymphomas
characterized by a proliferation of lymphoplasmacytoid cells or
plasma cells with intracytoplasmic monoclonal Ig.

The LPL are low-grade B-cell neoplasms close to B chronic lymphocytic
leukemia with plasmacytoid differentiation. T

hey show an indolent course, typically affect older men, and present
as a disseminated disease with predominantly nodal involvement.
Nevertheless, localized forms, some of them extranodal, have been
described.

The cases that best represent the range of radiographic findings on X-
ray, CT, and MR imaging are presented.

PMID: 12664116 [PubMed - in process]

J Huazhong Univ Sci Technolog Med Sci 2002;22(3):177-9, 182

Mutation analysis of IgVH gene in B-cell chronic lymphocytic leukemia.

Wang F, Zhu H, Zhu L, Yin B, Shen G.

Institute of Immunology, School of Basic Medical Sciences, Tongji
Medical College, Huazhong University of Science and Technology, Wuhan
430030.

The variable heavy chain region (VH) genes of 3 untreated patients
with B-cell chronic lymphocytic leukemia (B-CLL) were cloned and
analyzed. The VH family used was VH3-11, VH3-72 and VH3-33. More than
2% difference from the corresponding germline gene was detected in
all the 3 obtained potential functional genes (average 16.7).
Mutation pattern analysis indicated evidence of antigen selective
pressure observed in 1 of 3 cases.

Our findings suggested that the tumor cells originate from post-GC
cells.

PMID: 12658796 [PubMed - in process]

Smallpox vaccine to fight cancer
By Lauran Neegaard
01apr03
THE smallpox vaccine may be reborn - as a cancer treatment.

Scientists are rigging up the vaccine to carry an extra load, genes
that signal the immune system to start fighting advanced tumors.

Why use such a risky vaccine to do that job? The same super-reactive
characteristics that make smallpox inoculation prone to some bad,
occasionally deadly, side effects are, as the altered shots' creator
puts it, "an immunologist's dream:" They may rev up an immune system
that too often misses cancer.

Although still in very early stages of research, the smallpox-turned-
cancer shots look promising. They're the latest in a long quest to
create immune-harnessing vaccines to attack cancer.

"We're not there yet," cautions Jeffrey Schlom of the National Cancer
Institute, a specialist on cancer-treating vaccines who created the
smallpox vaccine-based approach. "But we're getting there."

Despite the name, most so-called cancer vaccines don't aim to prevent
tumours. These are not classic inoculations like the flu shot or even
regular smallpox vaccine, which teach the body to recognise and
subdue an invading virus or germ, preventing illness.

The immune system doesn't always recognise cancer as something to
attack, because tumors are made up of your own cells gone bad, not
foreign germs. The hope with therapeutic cancer vaccines is to train
powerful immune-system T cells to more easily spot and attack
malignant cells.

More than a dozen phase III studies - the most advanced testing - of
first-generation vaccines are under way.

Most involve making patients custom shots using their own tumor cells
mixed with immunity-boosting chemicals. Researchers frequently see a
handful of people whose cancer dramatically shrinks, even disappears,
at least for a while.

But those amazing responses are rare, because cancer adapts, says
NCI's Dr Steven Rosenberg. So scientists are trying to develop more
elaborate, hopefully better, vaccines.

Enter smallpox vaccine. Schlom thought it could prove a good cancer-
fighting platform because it's made with live vaccinia virus, a
smallpox relative that's so large that adding different genes into it
is fairly easy. Also, it's highly reactive, quickly causing a
distinctive, infectious pustule that clearly signals a stimulated
immune system.

Schlom took a vaccinia version engineered to be milder than today's
smallpox vaccine, which can occasionally cause deadly side effects.
He added to it a gene that makes an antigen, or marker, called CEA
that's found on many colon, pancreatic, lung and breast cancer cells.
Because people become immune to vaccinia quickly, he created booster
shots made with a less reactive vaccinia relative called fowlpox. And
he added three immune-boosting molecules to the mix, calling it
Tricom.

Injecting the altered smallpox vaccine plus boosters every few months
significantly increased survival of half the patients in the first,
small experiment at Georgetown University.

One patient saw her lung cancer disappear, and others who were
expected to die within the year instead lived two years and counting.

Jeannette DuBose Williams of Alexandra, Virginia, is one of them.
After three surgeries, radiation and chemotherapy, she had run out of
options to battle advanced colon cancer that had spread into her
pelvis. Today, after two-and-a-half years of Tricom shots, her cancer
is still there - but it hasn't grown, and she feels healthy, spending
her days golfing and visiting grandchildren.

"Cancer may be one thing you're not going to cure, but maybe you can
keep it in check," says Williams, 72. "I don't know what this live
virus is doing inside of me but ... I'm very grateful."

Small experiments at the Dana-Farber Cancer Institute and Columbia
University also proved promising. Now Schlom hopes to begin phase III
studies in another year.

So far, none of the 400 cancer patients who have received some
version of a smallpox-based shot have suffered serious side effects.
That's possibly due to the milder vaccinia, and possibly because too
few people have been vaccinated to count rare problems - but studies
are moving slowly as researchers carefully watch for side effects.

It's way too early to know if pox-based cancer vaccines will prove
truly helpful. Specialists won't even speculate on how soon more
advanced testing of older, first-generation cancer vaccines might
prove which ones are really useful - the field is littered with
setbacks.

But "we see the hope," says American Cancer Society vaccine
specialist TJ Koerner.

GM blood kills human cancer cells


18:29 01 April 03

NewScientist.com news service

Genetically modifying a patient's white blood cells turns them into
potent cancer killers, UK researchers have revealed.

The team modified T-cells - the immune system's first line of
defence - enabling them hunt out and destroy cancer cells in test
tube experiments. Both the cell types were taken from patients with
advanced bowel cancer.

The technique had destroyed the cancer cells in every experiment so
far, says team member Robert Hawkins, a medical oncologist at Cancer
Research UK's Paterson Institute in Manchester Hawkins.

The effectiveness of the new treatment will next be assessed in about
30 advanced bowel cancer patients, starting next year. White blood
cells will be taken from the patients, genetically modified, and then
transfused back into the patients.

Bowel cancer is estimated to affect 300,000 people in Europe and the
US each year. It is the second biggest cancer killer in the UK with
over 16,000 deaths a year.


Rogue version


The body's immune system effectively fights off many diseases because
it recognises the bacteria or viruses that cause them as foreign.
However, because cancerous cells are rogue versions of a patient's
own cells, the body fails to recognise them as dangerous.

"What we've done is give our immune cells the equipment they need to
recognise, home in on and destroy cells from tumours, allowing us to
harness the power of the immune system," says Hawkins.

Robert Souhami, Cancer Research UK's director of clinical research,
adds: "There's still a long way to go in the development of this new
technique, but it does seem to hold promise for the treatment of
cases which are out of reach of conventional medicine."


Punching holes


Hawkins and colleagues took blood samples from 10 patients with
advanced bowel cancer and isolated their T-lymphocyte cells. They
then genetically modified these cells to carry a gene that produces
an antibody that recognises a specific molecule on the surface of
bowel cancer cells.

This antibody allows the T-cell to bind onto the cancer cell and
trigger a chain of events that turns the T-cells into "killer cells".
The killer cells destroy the cancer cells by releasing a molecule
called perforin that punches holes in the cancer cells' walls. They
also release chemical messengers called cytokines, which call in
other immune cells to attack the cancer cells.

Hawkins said the technique also helped fight the cancer by
multiplying the patients' white blood cells. "We would take maybe 10
million cells, expand them to 10 billion cells, and then return them
to the patient," he told New Scientist.

Journal reference: British Journal of Cancer (DOI:
10.1038/sj.bjc.6600857-02th)


Shaoni Bhattacharya

Antiangiogenesis Activity of Interferon-Alpha Linked to VEGF
Inhibition



NEW YORK (Reuters Health) Mar 28 - Scientists believe they have
uncovered the heretofore unknown mechanism of action of interferon-
alpha's (IFN-alpha) antiangiogenic activity.

IFN-alpha inhibits vascular endothelial growth factor (VEGF) gene
transcription, Dr. Stefan Rosewicz of Humboldt-University in Berlin
and colleagues report in the March 19th issue of the Journal of the
National Cancer Institute.

"This is the first study to show in cell culture, mice, and human
cancer patients, that treatment with IFN-alpha is capable of
inhibiting the tumor cell expression of VEGF, which is the most
potent stimulus of tumor-associated angiogenesis," Dr. Rosewicz told
Reuters Health. "As a consequence of this phenomenon, blood supply to
the tumor is decreased and tumor growth is inhibited."

In mice with human neuroendocrine and pancreatic cancer xenografts,
IFN-alpha treatment statistically significantly inhibited tumor
growth by 36% and reduced microvessel density (p = 0.015), a measure
of angiogenesis, compared with control vehicle-treated mice.

In eight patients with neuroendocrine tumors, IFN-alpha treatment
significantly decreased VEGF plasma and VEGF mRNA levels as well as
microvessel density in biopsy specimens obtained from liver
metastases.

Results in cultured neuroendocrine tumor cells suggest that IFN-alpha
inhibits VEGF promotor activity by binding to the transcription
factors Sp1 and Sp3. This has not been previously observed, the
authors say.

"For the future, these observations might change our views on how to
use IFN-alpha in tumor therapy--as a long-term, chronic treatment
targeting the tumors essential need for adequate blood supply," Dr.
Rosewicz told Reuters Health. "It might therefore develop as one
cornerstone of more efficient anticancer combination therapy."

In an editorial, Dr. Giovanna Tosato of the National Cancer Institute
in Bethesda, Maryland says the current study adds to earlier results
suggesting that "IFN-alpha could be considered a broad-spectrum
indirect angiogenesis inhibitor."

"As our understanding of the regulation of angiogenesis continues to
improve, perhaps we will learn how best to use IFN-alpha as an
anticancer agent that targets tumor angiogenesis," Dr. Tosato writes.

J Natl Cancer Inst 2003;95:420-421,437-448.