Researchers unleash natural killer cells against disease

Montreal team found manipulating cells eliminated cancer quicker in mice

A group of Montreal scientists has found a promising new way to boost the immune system to fight cancer and infectious diseases such as hepatitis.

Coursing through the bloodstream of every human are infection-fighting white blood cells. There are about a dozen different types of white blood cells, including one called the natural killer.

Natural killer cells squeeze their way through the walls of blood vessels into human tissue to search and destroy other cells that are either abnormal, cancerous or infected with viruses. Without those cells, people would suffer many more infections.

Scientists at the Institut de recherches cliniques de Montreal have discovered a key protein in the natural killer cell that could be manipulated for the purposes of cancer therapy. The protein, called EAT-2, acts as a kind of brake, reigning in the killing ability of natural killer cells.

Without EAT-2, natural killer cells would "overdo" their job, explained Andre Veillette, director of molecular oncology research at the institute.

This would be a bad thing in a healthy person. But what about someone who has metastatic cancer or is infected with the hepatitis C virus? If their natural killer cells could be manipulated in such a way as to release the EAT-2 break, it's possible their cancer or infection could be cured, say the researchers.

To test their hypothesis, the scientists injected rat tumour cells in the bellies of a dozen lab mice. The scientists had already "knocked out" the EAT-2 protein in the natural killer cells of half the mice through genetic engineering.

In the control group, the natural killer cells were left untouched. The researchers found a striking difference.

In those mice whose natural killer cells were modified, the tumour cells were killed very quickly -- in well under two hours. In the control group, half of the tumour cells were destroyed after two hours.

Thus, in the control group the normal natural killer cells did their job, but not nearly as efficiently as in the mice with the "super" natural killer cells, Veillette said.

"The idea would be if you could remove the EAT-2 protein with (drug) inhibitors or blockers, or destroy this molecule somehow in humans, perhaps you could enhance the function of the natural killer cells to fight cancer cells," he said.

The research findings were released Monday in the journal Nature Immunology.

Veillette suggested a cancer patient's natural killer cells could be extracted from the blood and manipulated in the lab to boost their search-and-destroy capability. The modified, "super" natural killer cells would then be injected back into the patient.

The problem with most cancers is that there are micro-metastases -- undetected malignant cells that have spread to other parts of the body. Super natural killer cells might have the power to track them down and kill them before they can do more harm.

Veillette cautioned, however, that such a treatment would probably have to be undertaken in combination with chemotherapy. What's more, it would probably take years for a drug company to develop a treatment.

It is also conceivable this form of immunotherapy could be used to fight infections like hepatitis, Veillette said.

Montreal Gazette

The Proteasome and Proteasome Inhibitors in Cancer Therapy

The proteasome, a multicatalytic proteinase complex, is responsible for the majority of intracellular protein degradation. Pharmacologic inhibitors of the proteasome possess in vitro and in vivo antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL). Preclinical studies demonstrate that proteasome inhibition potentiates the activity of other cancer therapeutics, in part by down regulating chemoresistance pathways. Early clinical studies of bortezomib-based combinations, showing encouraging activity, support this observation. Molecular characterization of resistance to proteasome inhibitors has revealed novel therapeutic targets for sensitizing malignancies to these agents, such as the heat shock pathway. Below, we review the pharmacologic, preclinical, and clinical data that have paved the way for the use of proteasome inhibitors for cancer therapy; outline strategies aimed at enhancing the efficacy of proteasome inhibitors; and review other potential targets in the ubiquitin proteasome pathway for the treatment of cancer. Expected online publication date for the Annual Review of Pharmacology and Toxicology Volume 46 is January 6, 2006. Please see http://www.annualreviews.org/catalog/pub_dates.asp for revised estimates.

Voorhees PM, Orlowski RZ.

Department of Medicine, Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC 27599 Peter_Voorhees@med.unc.edu.

Red meat, cooking oil and high heat pose risks

Red meat, cooking oil and high heat pose risks

Disease culprits include heat-created compounds

MONTREAL - The wienerschnitzel was so large it hung off the plate. Topped with a sprinkling of chopped parsley and lemon juice, it was an absolute treat.

To this day, my mouth waters whenever I recall my first schnitzel experience. My aunt, who had arranged for us to come to Montreal after we'd fled Hungary during the 1956 uprising, owned the Riviera, a European style restaurant. It was there that I was introduced to the delights of a serving of veal, pounded almost paper thin, battered in flour, eggs and breadcrumbs, and quickly fried to a golden brown.

I just loved it. The Riviera is long gone, but I have learned to make a pretty acceptable schnitzel myself. But science has entered the picture and my enjoyment is now tainted by nutritional concerns. Some pretty dark clouds hang over the frequent consumption of red meat, and fried foods in particular.

The words "red meat" and "cancer" now appear in the same sentence in the scientific literature with alarming frequency and articles commonly conclude that many cancer cases can be prevented by dietary modification.

The suggested changes usually involve increasing fruit and vegetable consumption while curbing the intake of red meat and foods cooked at a high temperature. A huge European study, which enrolled almost half a million healthy men and women in the 1990s followed their health status. After about five years, about 1,300 cases of colorectal cancer had been detected and the lifestyles of these patients were then compared with those free of the disease.

The major finding was that bowel cancer was associated with an intake of red meats and processed meats. People who ate more than 160 grams of red or processed meat a day were 35-per-cent more likely to develop bowel cancer than those who ate less than 20 grams a day.

And 160 grams is not a lot. Eat a "quarter pounder" and you've got it. Chicken was not implicated and fish was associated with a lower risk of bowel cancer.

Exactly what the problem is with red and processed meats is hard to say, but it's a good bet that heterocyclic amines (HCAs) are involved.

Heating food unleashes a host of chemical changes. High temperatures allow compounds such as creatinine in meat to combine with aldehydes (glucose for example) to form heterocyclic amines, recognized carcinogens.

The higher the temperature, the longer the cooking time, the more HCAs form. Red meat consumption is also associated with prostate, stomach and pancreatic cancer, and researchers have found that women who routinely eat very well done meat face a five-fold increase in breast cancer risk when compared with women who eat meat rare or medium.

I don't know what the cooks in the Riviera used to fry my schnitzel, but it was probably some sort of animal fat. As scientists learned more about the cholesterol-raising properties of saturated fats, they pushed to replace them with polyunsaturated fats found in vegetable oils. These degraded more easily when heated and couldn't be reused as often. A remedy was found in the form of "partially hydrogenated" vegetable oils which had better keeping qualities.

But hydrogenation converted some unsaturated fats into the now notorious "trans fats," which were as bad for the heart as the animal fats.

Frying in unsaturated vegetable oils eliminates the trans fat problem but there is the emerging issue of trans-4-hydroxy-2-nonenal, or HNE.

HNE forms when polyunsaturated fats react with oxygen. Such fats are present in cell membranes and can give rise to HNE, which then can travel through the bloodstream. The bad news is that HNE has been linked with cardiovascular disease, Parkinson's, Alzheimer's, liver and kidney ailments, and even cancer.

HNE forms when polyunsaturated oils, including corn, soy and canola, are heated, especially if heated repeatedly. Those restaurant fries may be laden with HNE!

Monounsaturated fats like peanut oil or olive oil are less prone to such contamination.These aren't commonly used in restaurants so limiting fried foods when eating out is really important.

Montreal Gazette

Baylor, Stottlemyre share struggle with Myeloma

They faced one another in 1972, veteran right-hander versus rookie slugger. Batting behind Brooks Robinson in the Baltimore Orioles lineup, Don Baylor hit two doubles, despite New York Yankees starter Mel Stottlemyre's best efforts to back those elbows off the plate.

"He was tough," Stottlemyre recalled Monday. "He was fearless. He was a terrific player."

He is also a "terrific person," Stottlemyre said, which helps explain why, some three decades after their on-field encounters, the men are friends. Now, though, their relationship is rooted in something more emotional and complex than the game that has been their livelihood.

They each suffer from multiple myeloma, an incurable but treatable cancer of the plasma cells. Both were diagnosed after spring training physicals: Stottlemyre in 1999, Baylor four years later.

Shared experiences -- pills and biopsies taken, cell counts, doctor visits -- have built a bond between the men that stretches across the continent. Baylor is in his first season as the Mariners' hitting coach, while Stottlemyre, an Issaquah resident, rides through a tumultuous tenth -- and quite possibly final -- summer as the Yankees' pitching coach.

Both have undergone stem-cell transplants, and their cancers are in remission. Stottlemyre, 63, said he is "fine" but acknowledged the disease has made his days a "constant battle." Baylor, 56, does not even take prescription drugs for the condition, since his cell counts have returned to normal.

"My bones are as hard as a rock," Baylor said. "Every time I have a biopsy, the doctors are doing hand exercises a week, ten days out."

Work leaves Baylor and Stottlemyre breathlessly busy for most months every year, often too tied up to keep in touch. Although they were in the same building Monday evening, they were unable to find time to talk.

There was a time, though, when Baylor deeply needed Stottlemyre's counsel. Two years ago, shortly after he arrived at spring training for his first season as the New York Mets' bench coach, team doctors sent Baylor back to New York for tests. Baylor spent two long, awful days "in that tube," as MRIs were administered.

Doctors discovered a lesion on his hip, which was their basis for the diagnosis. As he came to grips with the news, Baylor needed answers -- not all of which doctors could provide. He sought out Stottlemyre.

"He helped me deal with the uncertainty," Baylor said. "The doctors can tell you one thing, but you don't really know until you speak with someone who's experienced it.

"Mel gave us a step-by-step. It was good to know."

Baylor also asked Stottlemyre about the decision to go public with his diagnosis. Stottlemyre waited one year before speaking publicly about it during an April 9, 2000, news conference at Safeco Field. Baylor discussed his condition with Mets personnel and reporters soon after the diagnosis in March 2003.

One consequence of disclosing his condition, Baylor said, was the potential impact it could have on his future employment. As a former American League MVP who has won 627 games as a big-league manager, he is qualified for most any job in baseball, provided he remains healthy.

For his own reassurance, Baylor could point to his friend's example.

"I looked at Mel," Baylor said. "He was healthy. I was banking on that."

Since then, Baylor and Stottlemyre have joined their efforts in aiding the Multiple Myeloma Research Foundation. They appeared with Kathy Giusti, the organization's CEO and founder, and their respective doctors as part of a first-pitch fundraiser before a Mets-Yankees game at Shea Stadium last season.

"The truth is, to run a good research foundation, you need people like Mel and Don to be public, and it's not always fun to be public," said Giusti, whose organization has raised $50 million since 1998. "I have great respect for them."

Former foes, now friends fighting a disease, they continue inspiring in ways they never could with a ball and bat.

© 1998-2005 Seattle Post-Intelligencer

Peripheral Neuropathy Dana Farber Therapies

Here is the Dana Farber list of possible pn therapies. Note the message at
the beginning!

DFCI NEUROPATHY REGIMEN

This is the DFCI Neuropathy regimen, posted with permission. Show this list
to your doctor, and work out your neuropathy treatment with him/her. Do not
treat yourself from this list without your doctor's help!

Neuropathy Treatments

Vitamins - Always take with food

MULTI-B COMPLEX VITAMIN
with B1, B6, B12 (at least 400mcg), folic acid and other

FOLIC ACID 1 to 2 mg
Folate

B6 VITAMINS
50mg in AM, 100mg in PM

MAGNESIUM
250MG twice a day -- may cause diarrhea in large doses

POTASSIUM
2 teaspoons Apple Cider Vinegar
Bananas, Oranges

VITAMIN E
400 IU daily

Amino Acids -- can be obtained at Health Food Stores . Take with food.

L- CARNITINE
500mg twice a day with food.
Can take up to 2000mg a day. Acetyl-Carnitine is best if available.

ALPHA-LIPOIC ACID
400mg to 600mg a day with food

L-GLUTAMINE
Start with 10gms a day for 1 week, then 1 gram 3 times a day with food.
Dissolve in 8oz. Liquid.

Medications - Prescription needed 

NEURONTIN (gabapentin)
Start with 100mg three times a day. Gradually work up to 600mg three times
a day.  Can dose as high as 2700mg total dose with Physician permission.
Neurontin comes in 100mg and 300mg pills.

ELAVIL (Amitriptyline)
25-50mg at bedtime.

ZOLOFT(Sertraline)
50-100mg at bedtime.

LIDODERM PATCH 5%
1 ½ patches to each area of pain. Remove after 12 hours each day.
Miscellaneous
TONIC WATER (Quinine or Seltzer water)
Drink one glass in evening and any other time cramping occurs.

CAPSAICIN CREAM (Zostrix)
Over-the-counter in pharmacy.  Apply to fingers or toes and feet once a day.
COCOA BUTTER (rich in Vitamin E and other emollients)
Apply to affected area twice a day with gentle massage.

Steroid Symptoms
SEROQUEL
25mg at bedtime.

RITALIN
5 to 10mg twice a day.

ATIVAN
.5 - 1mg before bedtime and every 4 hours if needed for anxiety. 

Nike Women's Marathon raises funds for Myeloma research

Nike announced the 2nd annual Nike Women's Marathon is sold out! 15,000 women across the globe have registered for this highly anticipated event which will take place on October 23, 2005 in San Francisco. This year marks the second year for the event -- which is quickly becoming the premier women's running event on the calendar.

Last year's inaugural race sold out a few weeks before race day, attracted more than 9,000 participants and raised more than $10 million for the Leukemia and Lymphoma Society (LLS). With an additional sixty percent of accepted race registrants (8,000 more runners), the 2005 Nike Women's Marathon sold out approximately seven weeks earlier and attracted over 15,000 participants from 17 different countries and 50 different states.

Race participants can train for the marathon through the Leukemia and Lymphoma Society's Team In Training(R), the world's largest sports endurance training program, or local participants can join Nike Club Run SF, Nike's free innovative and comprehensive training series. The Nike Women's Marathon will be an all-weekend celebration. Activities will include a race expo at Union Square featuring health and fitness consultations and demonstrations, as well as complimentary spa services. After the race, finishers will be able to enjoy a post-race concert.

To register with Team in Training, log onto http://www.teamintraining.org/nikewm or call 1-800-482-TEAM. Runners and walkers are also invited to register to run the race on their own at http://www.nikemarathon.com

About Team In Training
Team In Training is the world's largest endurance sports training program. The program provides training to run or walk a whole or half marathon or participate in a triathlon or century (100-mile) bike ride. Participants raise funds for leukemia, lymphoma and myeloma research and patient services inexchange for training, support, and lodging and airfare to the event of their choice. Since TNT's inception, more than 200,000 participants have raised more than $470 million.

About The Leukemia & Lymphoma Society
The Leukemia & Lymphoma Society(R), headquartered in White Plains, NY, is the world's largest voluntary health organization dedicated to funding blood cancer research and providing education and patient services. The Society's mission is to cure leukemia, lymphoma, Hodgkin's disease and myeloma, and to improve the quality of life of patients and their families. Since its founding in 1949, the Society has provided more than $360 million for research specifically targeting leukemia, lymphoma and myeloma.

Mayo Clinic research shows promise for myeloma patients

ROCHESTER, Minn. -- Mayo Clinic Cancer Center investigators report that
combination therapy with lenalidomide (RevlimidTM) and dexamethasone
(combination is called Rev/Dex) looks like a breakthrough treatment for
multiple myeloma. Results of a Phase II clinical trial were published online Aug. 23 in Blood.

"Previous studies have shown Rev/Dex to be effective for recurrent or highly resistant forms of myeloma," says S. Vincent Rajkumar, M.D., Mayo Clinic hematological oncologist and lead investigator of the study, "In this study, the first one to use the combination as initial therapy in newly diagnosed patients, we find that the Rev/Dex combination reduced the myeloma cancer protein levels by more than half in 91 percent of patients – much higher than response rates obtained with current approved therapies."

The goal of this clinical trial was to determine the response rate and toxicity (type and severity of side effects) of Rev/Dex in patients with previously untreated, newly diagnosed multiple myeloma. Over the course of the trial, 34 patients underwent the combination treatment, with 31 (91 percent) showing positive response to the treatment, and all within a rapid period – average response time was one month. In addition to the quick and positive responses, side effects were manageable, and common ones associated with thalidomide treatment, such as constipation, blood clots and neuropathy, were uncommon. Rev/Dex is administered orally – making it a more attractive option to many patients compared to traditional intravenous treatments.

"We see this as potentially the way of the future for many myeloma
patients," says Morie Gertz, M.D., Mayo hematological oncologist and
co-investigator, "We are happy that two large Phase III trials are currently ongoing, moving forward the testing of Rev/Dex as initial therapy for myeloma."

Standard therapy of melphalan and prednisone results in about 50 percent of patients having a positive response – i.e. the cancer
cells lessen by more than half. Vincristine, doxorubicin and dexamethasone (VAD) is another chemotherapy regimen used to treat myeloma, typically for patients who are candidates for stem cell transplantation because it allows adequate and safe stem cell harvest during treatment for a future transplantation. However, the use of VAD chemotherapy has decreased greatly because of the need for intravenous therapy and the need for a catheter – bringing other potential health risks.

Recent studies have looked at the oral combination of thalidomide and
dexamethasone (Thal/Dex) as an alternative to VAD. Although response rates are excellent (approximately 70 percent), the combination causes significant side effects. Lenalidomide is a compound similar to thalidomide, but one which previous studies have shown to work better both for recurrent and highly resistant myelomas, both alone and in conjunction with dexamethasone. It has fewer side effects than thalidomide and has even caused improvement in patients who are nonresponsive to thalidomide.

Lenalidomide is not commercially available; approval by the Food and Drug Administration is pending.

Contact: Elizabeth Zimmermann
newsbureau@mayo.edu
507-284-5005
Mayo Clinic

Combination therapy with lenalidomide plus dexamethasone (REV/DEX) for newly diagnosed myeloma

We report the results of a phase II trial using lenalidomide plus dexamethasone (Rev/Dex) as initial therapy for myeloma. 34 patients were enrolled. Lenalidomide was given orally 25 mg daily on days 1-21 of a 28-day cycle. Dexamethasone was given orally 40 mg daily on days 1-4, 9-12, 17-20 of each cycle. Objective response was defined as a decrease in serum monoclonal protein by 50% or greater and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours, confirmed by two consecutive determinations at least 4 weeks apart. Thirty-one of 34 patients achieved an objective response, including 2 (6%) achieving complete response (CR), and 11 (32%) meeting criteria for both very good partial response and near complete response, resulting in an overall objective response rate of 91%. Of the 3 remaining patients not achieving an objective response, two had minor response (MR) and one stable disease. Forty-seven percent of patients experienced grade 3 or higher non-hematologic toxicity, most commonly fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%) and rash (6%). Rev/Dex is a highly active regimen with manageable side-effects in the treatment of newly diagnosed myeloma.

S V Rajkumar^*, Suzanne R Hayman, Martha Q Lacy, Angela Dispenzieri, Susan M Geyer, Brian Kabat, Steven R Zeldenrust, Shaji Kumar, Philip R Greipp, Rafael Fonseca, John A Lust, Stephen J Russell, Robert A Kyle, Thomas E Witzig, and Morie A Gertz

Division of Hematology, Mayo Clinic, Rochester, MN, USA
Division of Biostatistics, Mayo Clinic, Rochester, MN, USA
Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA

Blood First Edition Paper, prepublished online August 23, 2005; DOI 10.1182/blood-2005-07-2817.

Stem cells' clock turned back

U.S. researchers reprogram adult cells to behave like embryonic stem cells

Researchers at Harvard University have reprogrammed adult skin and bone cells, teaching them how to revert to embryonic stem cells with all the potential for therapeutic regeneration those progenitor cells hold.

Though the process is far from ready for prime time, experts suggested Monday it points to a day when cells from an individual could be used to grow new tissues that would be an identical genetic match to the donor, avoiding the rejection problems associated with transplantation.

It also would provide researchers with an easy and accessible source of embryonic stem cells, a source untainted by the controversy that surrounds stem cell generation.

Embryonic stem cells can "differentiate" or mature into any type of tissue, and the reprogrammed cells appeared to have that skill. The researchers enticed them to mature into nerve cells, hair follicles, muscle cells and cells from the gut.

However, the fused cells carried a full set of genes from both the adult and the embryonic stem cells.

Only Cancer-Related Charity to Achieve Top Designation in AIP’s New Charity Rating Guide

The Multiple Myeloma Research Foundation (MMRF) announced today that it received an "A+" rating from the American Institute of Philanthropy (AIP), a nonprofit, independent information service that researches and evaluates efficiency, accountability and governance of non-profit organizations. The AIP issues the Charity Rating Guide three times a year to inform the public about how 500 national charities spend their money.

"We are proud to have received this grade from the AIP, as it is a reflection of our culture of fiscal responsibility that is carried throughout our organization -- from our board of directors to staff and volunteers," said Kathy Giusti, founder and chief executive officer of the MMRF. "We also pride ourselves on the fact that we rapidly put our fundraising dollars to work through funding ongoing myeloma research."

"The main reason why we received AIP's highest designation is because we only spend $3 to raise $100 and more than 94 percent of the money we raise goes towards research and related programming," said Scott T. Santarella, executive director of the MMRF. "Like our founder, the MMRF is all about efficiency, which is the driving force in our efforts to expedite the development of new and effective treatment options for multiple myeloma."

Oral melphalan, prednisone, and thalidomide for newly diagnosed patients with myeloma

Thalidomide is an immunomodulatory drug with strong antimyeloma activity. It is an effective treatment for multiple myeloma at disease recurrence and at diagnosis, both as a single agent and in combination with steroids or chemotherapy. No data are available on the association of thalidomide with oral melphalan and prednisone, still considered the standard treatment for elderly patients. METHODS: The feasibility and efficacy of the combination of melphalan, prednisone, and thalidomide (MPT) have been valuated in 49 newly diagnosed patients with multiple myeloma. RESULTS: According to European Bone Marrow Transplantation/ International Bone Marrow Transplantation Registry (EBMT/IBMTR) criteria, 18% of patients achieved immunofixation-negative complete disease remission (CR), 6% achieved immunofixation-positive near CR, 4% achieved a very good partial response, and 45% achieved a partial response, with a 50-89% reduction in monoclonal paraprotein. Six percent did not respond and 10% showed progressive disease. The median time to maximum response was 4 months. The Kaplan-Meier estimates of event-free survival and overall survival at 2 years were 64% and 91%, respectively. The major acute adverse events (National Cancer Institute Common Toxicity Criteria Grade III-IV) included thrombosis (20%), infections (12%), constipation (6%), and hematologic (22%) and neurologic (8%) toxicities. One patient died of pulmonary thromboembolism. CONCLUSIONS: These data suggested that MPT induced rapid and durable tumor responses with CR rates similar to those observed after autologous transplantation. Administration of prophylactic anticoagulant was required to prevent thromboembolism. MPT merits further investigation in randomized clinical trials. Cancer 2005. (c) 2005 American Cancer Society.

Palumbo A, Bertola A, Musto P, Caravita T, Callea V, Nunzi M, Grasso M, Falco P, Cangialosi C, Boccadoro M.

Divisione di Ematologia dell'Universita di Torino, Azienda Ospedaliera S. Giovanni Battista, Turin, Italy.

IMiDs: A Novel Class of Immunomodulators

IMiDs are structural and functional analogues of thalidomide that represent a promising new class of immunomodulators for treatment of a variety of inflammatory, autoimmune, and neoplastic diseases. The discovery of the antiangiogenic and T-cell co-stimulatory functions of IMiD compounds has led to the investigation of these agents for treatment of hematologic neoplasms such as multiple myeloma and myelodysplastic syndromes, as well as certain solid tumors. The second-generation IMiDs, such as lenalidomide and CC-4047, exhibited a greatly enhanced potency for immunomodulation and antiangiogenesis in non-clinical studies when compared with the parent compound, thalidomide. In clinical studies, the IMiDs appear to have reduced sedative and neurotoxicity effects, which are often associated with long-term thalidomide dosing. The precise mechanism of action of IMiDs in the treatment of specific diseases is not entirely clear and may differ for various diseases. Although IMiDs have similar effects on inflammatory cytokine secretion, T-cell modulation, angiogenesis, and expression of adhesion molecules, each IMiD has a unique potency profile for these activities, which may ultimately indicate selective applicability of specific IMiDs for distinct diseases and conditions. Clinical trials of lenalidomide, the primary second-generation IMiD, have shown clinical benefits in multiple myeloma and a better safety profile than that of thalidomide, with no evidence of teratogenicity. It is anticipated that lenalidomide and other IMiD compounds will become important alternatives to thalidomide because of their more potent anti-inflammatory and anticancer properties, as well as their improved side-effect profiles.

Clinical Research and Development - Oncology, Celgene Corporation, Summit, NJ.

Curcumin blocks Melanoma and Myeloma

Curcumin, the pungent yellow spice found in turmeric and curry powder, blocks a key biological pathway needed for development of melanoma and other cancers, M. D. Anderson researchers say.

The study, to be published in the Aug. 15 issue of the journal Cancer, and now available online, demonstrates how curcumin stops laboratory strains of melanoma from proliferating and pushes the cancer cells to commit suicide.

It does this, researchers say, by shutting down nuclear factor-kappa B (NF-kB) activation, a powerful master switch known to regulate an abnormal inflammatory response leading to a variety of disorders, including arthritis and cancer.

Results lead to studies of other cancers

Researchers treated three different melanoma strains with curcumin and assessed the activity of NF-kB. They also studied IKK, a protein kinase (enzyme/catalyst that turns other proteins on) that switches “on” NF-kB. The spice kept both proteins from being activated, so it worked to stop the growth of melanoma, and it also induced apoptosis (cell death).

“The antioxidant, anti-inflammatory and anti-carcinogenic properties of curcumin derived from turmeric are undergoing intense research here and at other places worldwide,” says one of the study’s authors, Bharat Aggarwal, Ph.D., professor of cancer medicine in the Department of Experimental Therapeutics.

At M. D. Anderson, for example, dramatic results from laboratory studies have led to two ongoing Phase I human clinical trials, testing the ability of daily capsules of curcumin to slow growth of pancreatic cancer and multiple myeloma. Given that curcumin is non-toxic, future trials are expected to begin in both animals and humans for other cancers, Aggarwal says.

Roots of spice’s healing powers run deep

Ground from the root of the Curcuma longa plant, curcumin is a member of the ginger family.

It has long been used in India and other Asian nations as a:

• Food preservative
• Coloring agent for food and textiles
• Spice (2% to 5% of turmeric is curcumin)
• Folk medicine to:
• Cleanse the body
• Heal wounds
• Prevent wrinkles
• Suppress inflammation

Knowledge of curcumin’s anti-inflammatory properties and the growing realization that cancer can result from inflammation has spurred mounting interest in the spice, Aggarwal says. Another fact that has generated further excitement: “The incidence of the top four cancers in the United States – colon, breast, prostate and lung – is as much as ten times lower in India,” he says.

Next step involves studies in animals, humans

M. D. Anderson and other institutions previously found that curcumin inhibits tumor cell proliferation and angiogenesis, the process by which new blood vessels form from existing vessels.

In the recent study, researchers found that besides inhibiting NF-kB, curcumin suppresses the STAT3 pathway that is also involved in tumor development. Both pathways play a central role in cell survival and proliferation.

An ability to suppress numerous biological routes to cancer development is important if an agent is to be effective, Aggarwal says. “Cells look at everything in a global way, and inhibiting just one pathway will not be effective.”

The study results are encouraging, Aggarwal says, yet he cautions that they are lab findings and much study needs to be done before any recommendations might be made regarding use of curcumin by the general public.

Green tea effects on myeloma cells

Green tea component, catechin, induces apoptosis of human malignant B cells via production of reactive oxygen species.

PURPOSE: Green tea polyphenol, (-)-epigallocatechin-3-gallate, has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The aim of this study was to investigate the possibility of (-)-epigallocatechin-3-gallate as a novel therapeutic agent for the patients with B-cell malignancies including multiple myeloma.

EXPERIMENTAL DESIGN: We investigated the effects of (-)-epigallocatechin-3-gallate on the induction of apoptosis in HS-sultan as well as myeloma cells in vitro and further examined the molecular mechanisms of (-)-epigallocatechin-3-gallate-induced apoptosis.

RESULTS: (-)-Epigallocatechin-3-gallate rapidly induced apoptotic cell death in various malignant B-cell lines in a dose- and time-dependent manner. (-)-Epigallocatechin-3-gallate-induced apoptosis was in association with the loss of mitochondrial transmembrane potentials (Deltapsim); the release of cytochrome c, Smac/DIABLO, and AIF from mitochondria into the cytosol; and the activation of caspase-3 and caspase-9. Elevation of intracellular reactive oxygen species (ROS) production was also shown during (-)-epigallocatechin-3-gallate-induced apoptosis of HS-sultan and RPMI8226 cells as well as fresh myeloma cells. Antioxidant, catalase, and Mn superoxide dismutase significantly reduced ROS production and (-)-epigallocatechin-3-gallate-induced apoptosis, suggesting that ROS plays a key role in (-)-epigallocatechin-3-gallate-induced apoptosis in B cells. Furthermore, a combination with arsenic trioxide (As2O3) and (-)-epigallocatechin-3-gallate significantly enhanced induction of apoptosis compared with As2O3 alone via decreased intracellular reduced glutathione levels and increased production of ROS.

CONCLUSIONS: (-)-Epigallocatechin-3-gallate has potential as a novel therapeutic agent for patients with B-cell malignancies including multiple myeloma via induction of apoptosis mediated by modification of the redox system. In addition, (-)-epigallocatechin-3-gallate enhanced As2O3-induced apoptosis in human multiple myeloma cells.

Nakazato T, Ito K, Ikeda Y, Kizaki M.Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

PMID: 16115949 [PubMed - in process]

Sustained molecular remission by non-myeloablative stem cell transplantation after autologous hematopoietic stem cell transplantation

Multiple myeloma (MM) is refractory to conventional chemotherapy. To achieve a sustained complete remission, we performed planned non-myeloablative allogeneic stem cell transplantation (NST) after autologous hematopoietic stem cell transplantation (HSCT) in a patient with stage III MM. Autologous HSCT was performed using high-dose melphalan after conventional chemotherapy, followed by NST from an HLA-identical sibling using low-dose total body irradiation (200 cGy) for conditioning. Cyclosporine and mycophenolate mofetil were used for graft-vs-host disease (GVHD) prophylaxis. Acute GVHD was transiently seen in the skin and intestine, while, in addition, mild chronic GVHD was seen in the oral mucosa and skin. Complete donor chimerism was achieved and the disappearance of tumor-derived monoclonal B cells was confirmed based on an analysis of immunoglobulin light chain messenger signals on day 156 when chronic GVHD occurred. The clinical course in this case strongly suggested the existence of a graft-vs-myeloma effect.

Nakashima Y, Shiratsuchi M, Abe Y, Muta K, Tani K, Shiokawa S, Nishimura J.

Division of Clinical Immunology, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan

Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma

Bortezomib, a proteasome inhibitor with efficacy in multiple myeloma, is associated with thrombocytopenia, the cause and kinetics of which are different from those of standard cytotoxic agents. We assessed the frequency, kinetics, and mechanism of thrombocytopenia following treatment with bortezomib 1.3 mg/m(2) in 228 patients with relapsed and/or refractory myeloma in two phase II trials. The mean platelet count decreased by approximately 60% during treatment but recovered rapidly between treatments in a cyclical fashion. Among responders, the pretreatment platelet count increased significantly during subsequent cycles of therapy. The mean percent reduction in platelets was independent of baseline platelet count, M-protein concentration, and marrow plasmacytosis. Serum thrombopoietin levels inversely correlated with platelet count. Murine studies demonstrated a reduction in peripheral platelet count following a single bortezomib dose without negative effects on megakaryocytic cellularity, ploidy, or morphology. These data suggest that bortezomib-induced thrombocytopenia is due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors. The exact mechanism underlying bortezomib-induced thrombocytopenia remains unknown, but it is unlikely to be related to marrow injury or decreased thrombopoietin production.

Lonial S, Waller EK, Richardson PG, Jagannath S, Orlowski RZ, Giver CR, Jaye DL, Francis D, Giusti S, Torre C, Barlogie B, Berenson JR, Singhal S, Schenkein DP, Esseltine DL, Anderson J, Xiao H, Heffner LT, Anderson KC

Winship Cancer Institute, Emory University, Atlanta, GA, USA

Strict diet may stop prostate cancer

A new study reveals that men with early-stage prostate cancer may be able to halt the progression of their disease by making substantial lifestyle changes such as adopting a very low-fat, vegan diet, exercising and meditating.

The authors of the study, published Thursday, August 11, in the Journal of Urology, say it is the first clinical trial showing that lifestyle changes can halt the progression of prostate cancer. The study could have implications for the more than 230,000 men who are diagnosed with prostate cancer each year.

Lead author Dean Ornish, a longtime crusader of ultra low-fat diets, said the study shows that adopting various lifestyle changes can be beneficial to men with prostate cancer in addition to whatever other conventional measures they take. Other study authors included researchers from UCSF and the Memorial Sloan-Kettering Cancer Center in New York.

Earlier epidemiological studies have linked various lifestyle measures such as a high-fat diet, especially animal fat, obesity and a lack of physical activity with an increased risk of developing prostate cancer.

There is hope that various dietary measures, such as eating fruits and vegetables or taking supplements such as lycopene, selenium and vitamin E, can lower risk, but that evidence still is insufficient, according to the National Cancer Institute.

There is some evidence that diets high in fat increase the risk of prostate cancer, and that certain foods -- such as broccoli, or the nutrient lycopene from cooked tomato products -- are protective.

The study involved 93 men with an average age of about 66 who were diagnosed by biopsies with low-grade prostate cancer. All of the men had decided to undergo so-called watchful waiting, which meant their cancer would be monitored but they would not immediately undergo conventional treatment such as surgery or radiation.

Forty-four of the men were put into an intensive intervention program. The other 49 men did not undergo intensive lifestyle changes. Researchers used the prostate-specific antigen, or PSA, test as a way to monitor the disease progression in the men. After one year, the men in the intervention program had an average 4 percent decline in their PSA test scores, compared with a 6 percent increase in the scores of the control group.

In another measure, six of the men in the control group went on to have surgery or some other treatment due to a progression of their disease, compared with none of the men in the intervention group.

In addition, blood samples were taken from the men to see if the serum could inhibit prostate cancer tumor growth in a laboratory dish. There was a 70 percent inhibition of tumor cell growth from the blood from the men in the intervention group, compared with 9 percent from the control group.

Howard Parnes, a physician with the National Cancer Institute, said the study's results appear to support the hypothesis that dietary and lifestyle measures can affect prostate cancer progression, "but there are a lot of caveats." One problem, he said, is that the PSA score, the primary measure in the study, is only a surrogate for disease progression. It is not a clinical outcome, such as mortality. The PSA score could have been affected by the soy, which has a weak hormonal affect, he said. In addition, there were so many variables in the study that it was impossible to sort out which ones may have caused the beneficial effects, he said.

In addition to lower PSA scores, the men in the intervention group lost an average of about 10 pounds and had significant improvements in their cholesterol levels.

In previous research, Ornish has showed that intensive intervention programs can reverse heart disease.

Here is the regimen researchers used on the men whose prostate cancer appeared to improve:

A low-fat, vegan diet, and daily tofu and soy supplements400 international units of vitamin E
Three grams of fish oil
200 micrograms of selenium
Two grams of vitamin C
30 minutes of moderate exercise six days a week
An hour a day of stress management with techniques such as meditation and yoga

FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies

Reccurent chromosomal translocation t(4;14) (p16.3;q32.3) occurs in patients with multiple myeloma (MM) and is associated with ectopic overexpression of fibroblast growth factor receptor 3 (FGFR3) that sometimes may contain the activation mutations such as K650E thanatophoric dysplasia type II (TDII). One potential therapeutic strategy is to inhibit FGFR3 in those myeloma patients that overexpress the receptor tyrosine kinase due to chromosomal translocation. Here we evaluated PKC412, a small molecule tyrosine kinase inhibitor, for treatment of FGFR3-induced hematopoietic malignancies. PKC412 inhibited kinase activation and proliferation of hematopoietic Ba/F3 cells transformed by FGFR3 TDII or a TEL-FGFR3 fusion. Similar results were obtained in PKC412 inhibition of several different t(4;14)-positive human MM cell lines. Furthermore, treatment with PKC412 resulted in a statistically significant prolongation of survival in murine bone marrow transplant models of FGFR3 TDII-induced pre-B cell lymphoma, or a peripheral T-cell lymphoma associated TEL-FGFR3 fusion-induced myeloproliferative disease. These data indicate that PKC412 may be a useful molecularly targeted therapy for MM associated with overexpression of FGFR3, and perhaps other diseases associated with dysregulation of FGFR3 or related mutants.Oncogene advance online publication, 8 August 2005; doi:10.1038/sj.onc.1208989.

Chen J, Lee BH, Williams IR, Kutok JL, Mitsiades CS, Duclos N, Cohen S, Adelsperger J, Okabe R, Coburn A, Moore S, Huntly BJ, Fabbro D, Anderson KC, Griffin JD, Gilliland DG.

Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA

Multicenter Phase II Trial of Thalidomide and Celecoxib for Patients with Relapsed and Refractory Multiple Myeloma

Preclinical data indicates that cyclooxygenase-2 (COX-2) inhibition impairs plasma cell growth and potentially synergizes with thalidomide. We performed a trial in previously treated patients with myeloma using thalidomide up to a maximum dose of 800 mg/d with celecoxib (400 mg bid). Outcomes were compared with a prior trial of thalidomide. Sixty-six patients with median age of 67 (range, 43-85) received a median dose of thalidomide and celecoxib of 400 and 800 mg/d, respectively, with median durations of treatment of 27 and 13 weeks, respectively. The most common toxicities associated with premature discontinuation of celecoxib (n = 30 of 53, 57%) were fluid retention and deterioration of renal function. Overall response rate (RR) was 42% and with 20 months median follow-up; the actuarial median progression-free survival and overall survival were 6.8 and 21.4 months, respectively. Unlike our prior study, age >65 years was not predictive of inferior RR due to improvement in RR in older patients with the combination (37% versus 15%, P = 0.08). The RR was superior in patients who received a total dose of celecoxib exceeding 40 g in the first 8 weeks of therapy (62% versus 30%, P = 0.021). Progression-free survival and overall survival were also improved. Other predictors for inferior progression-free survival were age >65 years (P = 0.016) and elevated beta(2)-microglobulin (P = 0.017). This study provides evidence that the addition of high-dose celecoxib adds to the antimyeloma activity of thalidomide but this comes with unacceptable toxicity. Future studies should use newer COX-2 inhibitors with thalidomide, or their respective derivatives.

GlycoGenesys updated on GCS-100

In collaboration with Dr. Kenneth Anderson and Dr. Paul Richardson of the Dana- Farber Cancer Institute, the Company designed a Phase I/II trial to study GCS-100 in patients with relapsed or refractory multiple myeloma both alone and in combination with dexamethasone, a standard chemotherapy in multiple myeloma. This is the first clinical trial combining GCS-100 with another therapy. Dexamethasone was chosen because in vitro tests have shown GCS-100 in combination with dexamethasone to have an additive effect allowing for lower dose levels of both GCS-100 and dexamethasone to be used.

The trial was initiated at the Dana-Farber in April 2005 and is enrolling patients. The Company recently initiated a second clinical site, the Lucy Curci Cancer Center in Rancho Mirage, California. It anticipates adding three more sites to expedite patient enrollment of the trial. The Company's clinical trial timeline calls for this trial to be completed in the third quarter of 2006.

Assuming favorable data in the Phase I/II trial, a Phase II study is planned to begin in the third quarter of 2006 and be completed in the first quarter of 2008. This study will be designed to enable the Company to expand to a pivotal trial if supported by an interim review of the data. If needed to demonstrate clinical significance, a Phase III trial is planned for initiation in the third quarter of 2008.

Prognostic significance of magnetic resonance imaging of bone marrow in previously untreated patients with multiple myeloma

Magnetic resonance imaging (MRI) has been a useful technique for the assessment of patients with multiple myeloma (MM). We evaluated the prognostic significance of different MRI patterns in symptomatic patients with MM. A total of 142 symptomatic MM patients underwent MRI before treatment. MRI patterns of involvement were correlated with known prognostic variables, including the International Staging System (ISS), response to treatment and survival. RESULTS: Focal marrow lesions were identified in 50% of patients, diffuse marrow replacement in 28%, a variegated pattern in 14% and normal pattern in 8%. When patients with the diffuse pattern were compared with patients with the other MRI patterns, they had features of more advanced disease such as higher ISS, anemia, hypercalcemia, elevated lactate dehydrogenase and extensive marrow plasmacytosis. Response rate was similar among patients with different MRI patterns. Median survival was 24 months for patients with the diffuse pattern, 51 months for those with the focal pattern, 52 months for those with the variegated pattern and 56 months for patients with the normal pattern (P = 0.001). The presence or absence of a diffuse MRI pattern separated patients with ISS stages I and II into two subgroups with significantly different survival times of 28 months and 61 months, respectively (P = 0.01). Furthermore, a diffuse MRI pattern predicted inferior outcome regardless of whether or not patients had received high-dose therapy with autologous stem cell transplantation. CONCLUSION: Diffuse marrow replacement on MRI adds to the evaluation of patients with multiple myeloma and their management.

Moulopoulos LA, Gika D, Anagnostopoulos A, Delasalle K, Weber D, Alexanian R, Dimopoulos MA

Department of Radiology, University of Athens School of Medicine, Athens, Greece

Immunotherapy in multiple myeloma--possibility or probability?

In a small number of patients with multiple myeloma (MM), long-term disease-free survival has been achieved by harnessing the immune phenomenon, 'graft-versus-tumour' effect, induced by allogeneic haemopoietic stem cell transplantation. This has prompted many investigators to examine ways in which a patient's own immune system can be more effectively directed against their disease, with the ultimate aim of tumour eradication. In this review we assess the current understanding of immunobiology in MM, and how the different components of the immune system, such as dendritic cells, T cells and natural killer cells, may be harnessed using in-vitro and in-vivo priming techniques. We look at the clinical immunotherapy trials reported to date and whether, in light of the current information, immunotherapy for MM is an achievable goal.

Harrison SJ, Cook G.

ATMU and Cancer Division, Section of Experimental Haematology, University of Glasgow, Glasgow, UK.

Combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed MM

The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta(2)-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.Leukemia advance online publication, 4 August 2005; doi:10.1038/sj.leu.2403890

Terpos E, Mihou D, Szydlo R, Tsimirika K, Karkantaris C, Politou M, Voskaridou E, Rahemtulla A, Dimopoulos MA, Zervas K.

[1] 1Department of Hematology, 251 General Airforce Hospital, Athens, Greece [2] 2Department of Hematology, Faculty of Medicine Imperial College London, Hammersmith Hospital, London, UK

Man inspired by stricken friend

Friends often go the extra mile for each other.

Rick Myerburg, of O'Hara, is about to go 1,755 miles for his friend.

Myerburg, 60, plans to travel that distance over 25 days in August and September on his 27-speed carbon fiber bicycle, riding through 10 states along the Mississippi River from Minneapolis, Minn. to New Orleans, La. He hopes to raise $100,000 to benefit the Leukemia & Lymphoma Society in the name of his friend, Mark Unatin, 61, of Upper St. Clair, who is stricken with myeloma, a cancer of the bone marrow and blood.

It will be the longest ride he has ever attempted. But when Myerburg thinks of his friend and the radiation, chemotherapy and transplants he has endured to fight cancer, it doesn't seem so daunting.

"If Mark can go through this, I can climb a hill," Myerburg said.

Myerburg is one of about 16 people booked for the complete "Great Mississippi Ride" organized by New Hampshire-based America by Bicycle for Aug. 13 to Sept. 7. The riders will leave Minneapolis on Aug. 14, pedaling between 37 and 101 miles a day. Two rest days are worked into the schedule.

Myerburg and Unatin, both grandfathers, have known each other for more than 22 years, with their roots together going back to Allderdice High School. They became friends at the River Club, where they used to work out together when Unatin was able.

Unatin, an attorney, was first diagnosed with multiple myeloma in December 2001. He was in remission for about three years after a stem cell transplant in August 2002, but relapsed in April. He is now taking chemotherapy twice a week and radiation daily.

"The life span for somebody with multiple myeloma is about three to five years. I've had this disease for longer than that. I'm just happy to be here," Unatin said. "If I had this disease 10 years ago, I would have been dead by now."

Unatin said he owes his life to new discoveries in the fight against cancer. He's taking a chemotherapy that didn't exist a year ago.

"These things don't just happen," he said. "You can't take it for granted."

Myerburg, who owned the Adeles women's specialty store in Squirrel Hill for 20 years and now works for Cuccaro Plumbing in his retirement, said he's been bike riding seriously for about three years. He exercises regularly, and tries to ride two to three hours every day.

Myerburg said the biking has improved his health, and he's ready for the upcoming journey.

"I'm definitely better fit at 60 than I was at 50," he said.

Unatin said he doubts he could have handled the ride Myerburg is about to embark on, even when he was healthy. The longest he ever rode was 22 miles at Ohiopyle.

"I know that he's pushing himself to do 1,700 miles. Ricky does a lot of bike riding, but he's never done anything like this. He's pushing himself for my sake and the sake of this fundraiser," Unatin said. "It is a tremendous mental and physical effort for which I am very grateful."

Unatin said he's thinking of meeting his friend at the end of his ride in New Orleans. He plans to be in touch with him every day by e-mail.

"I hope that people realize the effort that he's making and try to match it with just a little contribution to the Leukemia & Lymphoma Society," Unatin said.

2-Methoxyestradiol at low dose induces differentiation of myeloma cells

Previous studies showed that 2-methoxyestradiol (2ME2) could suppress the proliferation of myeloma cells and induce their apoptosis. In the present study, we found that treatments with low-concentration of 2ME2 resulted in some maturing morphological changes of myeloma cells. Flow cytometric analysis showed that the expression of CD49e on the myeloma cells surface was significantly increased by 2ME2. Moreover, 2ME2 increased the secretion of light chain protein remarkably. Furthermore, the expressions of transcription factor XBP-1 mRNA and protein were also up-regulated. These results demonstrated that 2ME2 at low-concentration could induce differentiation of the myeloma cells, which would provide a new, safe strategy for myeloma therapy.

Department of Hematology, Changzheng Hospital, Shanghai, China

PMID: 16038732 [PubMed - in process]

Leukemia & Lymphoma Society - Stohlman Scholar Awards

The Leukemia & Lymphoma Society Honors Five Scientists for Outstanding Work in Blood Cancer Research

WHITE PLAINS, NY - The Leukemia & Lymphoma Society has selected five researchers to receive its prestigious Stohlman Scholar Award, recognizing outstanding contributions to the advancement of blood cancer research.

The Stohlman Award is given to Society Scholars who are in the fifth year of their research scholarship. Society Scholars are highly qualified investigators who have demonstrated their ability to conduct original research bearing on leukemia, lymphoma or myeloma. These Scholars hold faculty-level or equivalent positions at major research institutions. This year's Stohlman Scholars include the following individuals:

• Katherine Borden, Ph.D., associate professor, Institute for Research in Immunology and Cancer, Universite de Montreal
  Dr. Borden's work has led to the discovery of a novel molecular mechanism for oncogenic transformation and to the discovery of a novel treatment strategy for leukemias and other
  cancers. Currently, her work is focusing on the protein eIF4E's function in normal cells and how it is disrupted in a subset of acute myeloid leukemias. In studying this, Dr. Borden's team has helped identify a molecular inhibitor of eIF4E -- ribavirin -- which impedes transformation activity in laboratory and animal models. She is currently pursuing the possibility of using ribavirin in clinical trials to treat acute myeloid leukemias.
• Genhong Cheng, Ph.D., associate professor, Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles
  Dr. Cheng's research is aimed at understanding the process of immune responses in host defense against bacterial and viral infections, as well as tumor challenges. Defects in any steps in this process can increase a host's susceptibility to pathogen infections, whereas overreactive immune responses can also lead to many inflammatory diseases and metabolic syndromes. The goal of Dr. Cheng's work is to develop novel strategies to enhance the ability of the immune system to defend pathogen infections and tumor challenges, and also to prevent or inhibit inflammatory and metabolic diseases.
• Glenn Dranoff, M.D., associate professor, Harvard Medical School, leader, Dana-Farber/Harvard Cancer Center Program in Cancer Immunology
  Dr. Dranoff's research focuses on understanding the molecular and cellular mechanisms underlying the stimulation of anti-tumor immunity, and on the development of cancer vaccines for diverse hematologic and solid malignancies.
• David Pellman, M.D., associate professor of pediatrics, Harvard Medical School, and Ted Williams Senior Investigator, Dana-Farber Cancer Institute, Boston
  The focus of Dr. Pellman's research is identifying how aberrations in chromosomal stability affect the development of cancer. Dr. Pellman is investigating how the structural elements of the cell, the cytoskeleton, impact chromosomal stability and how, in turn, altering chromosomal stability can effect the physiology of tumor cells.
• Tomasz Skorski, M.D., Ph.D., associate professor, Center for Biotechnology and Department of Biology, Temple University, Philadelphia
  The focus of Dr. Skorski's research is to understand the mechanisms of DNA repair and genetic instability in leukemias expressing fusion tyrosine kinases such as BCR/ABL. Dr. Skorski is investigating how leukemia cells repair DNA lesions caused by reactive oxygen species or cytotoxic treatment and why the repair is unfaithful. These phenomena contribute to drug resistance and malignant progression of the disease.

"The work of these outstanding scholars has been supported by the Society because of our expectation that it will be translated into improved treatments and cures for patients with hematological cancers," said Marshall Lichtman, M.D., the Society's Executive Vice President of Research & Medical Programs.

The Stohlman Scholar Award is given in memory of Frederick Stohlman Jr., M.D., a major figure in stem cell physiology and blood cell cancer research.

About The Leukemia & Lymphoma Society
The Leukemia & Lymphoma Society, headquartered in White Plains, NY, with 66 chapters in the United States and Canada, is the world's largest voluntary health organization dedicated to funding blood cancer research and providing education and patient services. The Society's mission: Cure leukemia, lymphoma, Hodgkin's disease and myeloma, and improve the quality of life of patients and their families.

Since its founding in 1949, the Society has invested more than $424 million in research specifically targeting leukemia, lymphoma and myeloma. Last year alone, the Society made more than 2.5 million contacts with patients, caregivers and healthcare professionals.

For more information about blood cancer, visit www.LLS.org.

The role of markers of bone remodeling in multiple myeloma

Osteolytic bone disease is a frequent complication of multiple myeloma, resulting in skeletal complications that are a significant cause of morbidity and mortality. A characteristic feature of myeloma bone disease is that the lesions rarely heal and bone scans are often negative in myeloma patients who have extensive lytic lesions, offering very little in the follow-up of bone disease. X-rays are also of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone turnover, such as N- and C-terminal cross-linking telopeptide of type I collagen (NTX, CTX/ICTP, respectively), and newer ones such as the tartrate resistant acid phosphatase isoform 5b, provide information on bone dynamics that in turn may reflect disease activity in bone. Several studies have shown bone markers to be elevated in myeloma patients and reflect the extent of bone disease, while in some of them bone resorption markers correlate with survival. These markers may also be helpful in identifying those patients likely to respond to bisphosphonate treatment, and monitoring the effectiveness of bisphosphonate therapy in the management of myeloma bone disease. This review attempts to summarize the existing data for the role of markers of bone remodeling in assessing the extent of bone destruction in myeloma and monitoring bone turnover during specific anti-myeloma treatment. We also discuss some novel markers that may be of particular interest in the near future.

Terpos E, Politou M, Rahemtulla A.

Department of Hematology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, W12 0NN London, UK. e.terpos@imperial.ac.uk