New Drug for Cancer Treatment Could Bolster Immune System

Arizona based Translational Genomics Research Institute (TGen), a non-profit organization dedicated to conducting groundbreaking medical research, together with Scottsdale Healthcare, a primary clinical research facility housed in the Virginia G. Piper Cancer Center in Scottsdale and Mayo Clinic, one of only 39 U.S. medical centres that have been named as a National Cancer Institute (NCI) Comprehensive Cancer Center, started testing VTX-2334, a novel Toll-Like Receptor 8 (TLR8) agonists for the treatment of cancer, respiratory and autoimmune diseases in early December 2008. The new drug is developed by VentiRx Pharmaceuticals, Inc., a biopharmaceutical company based in San Diego, and could help cancer patients by stimulating their immune system.

During the initial Phase I trial, a yearlong first-in-humans test, researchers will study the drug's safety and pharmacology of multiple doses of VTX-2337 in patients with late-stage cancer. If successful, a Phase II trial will test the drug's effectiveness on tumours.

Dr. Ramesh Ramanathan, Medical Director of TGen Clincal Research Services at Scottsdale Healthcare, said the new drug appears to be quite promising. ‘VTX-2337 is a new, novel, small molecule aimed at stimulating the immune cells in the blood, lymph nodes, and in and around the tumour. It represents an exciting new class of agents for cancer therapy with good preclinical evidence of activity.’

VentiRx Pharmaceuticals, founded in June 2006 by Michael Kamdar and Robert Hershberg, M.D., Ph.D, is committed to the development of novel medicines for the treatment of cancer, infectious, respiratory, and autoimmune diseases. The medical research team of experienced biotechnology professionals, is excited to be working on this new drug. Michael Kamdar, Executive Vice President and Chief Business Officer at VentiRx : ‘Entering Phase I clinical trials represents a significant milestone for VentiRx and our TLR efforts in that we have rapidly advanced into a clinical development company with a novel molecule that may play an important role and have broad application in the treatment of cancer.’

Role of the immune system
A weakened immune system is often the result of advanced cancer. 'We hope that this new drug will actually help enable the immune system to slow down the growth of tumours, and perhaps even shrink them,' Ramanathan explained.

Toll-like receptors (TLRs) play an important role in stimulating innate and adaptive immunity and TLR ligands have become interesting targets to use as stand-alone immunotherapeutics or vaccine adjuvants for cancer treatment.

VTX-2337 is a small molecule TLR8 agonist that is expected to be used in combination with standard of care for the treatment of patients with cancer. Preclinical evaluation of VTX-2337 suggests that it may play a key role in augmenting the innate arm of the immune system.
There are two broad components of the immune system, the innate arm, and the adaptive arm. Both generally aim to eliminate viruses and bacteria.

• The innate arm senses infectious agents as they infect the body by recognizing structures they have in common, such as lipids, proteins, sugars, and nucleic acids (DNA and RNA). This is an initial rapid response, which is not precise but potent.
• The adaptive arm of the immune system is instructed by the innate arm to devise more specific responses to unique components of the invading pathogens. This is a more precise response and takes longer, especially when an infectious agent is encountered for the first time.

‘VTX-2337 is the first selective TLR8 compound to reach the clinic, and we are hopeful that modulation of the innate immune response will provide a benefit to patients in a number of oncology indications,’ said Dr. Robert Hershberg, Executive Vice President and Chief Medical Officer at VentiRx.

Also read PubMed abstracts:

• Smits EL, Ponsaerts P, Berneman ZN, Van Tendeloo VF. The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. Oncologist 2008 Aug;13(8):859-75. Epub 2008 Aug 13
• Zhang SY, Jouanguy E, Sancho-Shimizu V, von Bernuth H, et al
  Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses.
  Immunol Rev 2007 Dec;220:225-36
• Uematsu S, Akira S
  Toll-like receptors and Type I interferons
  J Biol Chem 2007 May 25;282(21):15319-23. Epub 2007 Mar 29
• Ghosh TK, Mickelson DJ, Fink J, Solberg JC, et al
  Toll-like receptor (TLR) 2-9 agonists-induced cytokines and chemokines: I. Comparison with T cell receptor-induced responses.
  Cell Immunol 2006 Sep;243(1):48-57. Epub 2007 Jan 23
  

Reduction in Breast Density Predicts Potential Benefit of Tamoxifen

Reduction in breast density appears to be a strong indicator of a woman’s response to tamoxifen, an agent used to decrease breast cancer risk. Increased breast density is the leading risk factor for breast cancer, apart from age.

At the CTRC-AACR San Antonio Breast Cancer Symposium, the British researchers said that if their findings are validated in follow-up studies, women at risk for developing breast cancer should have a baseline mammogram before starting use of tamoxifen, and then a follow-up scan a year or two later to monitor breast density.

If there is a reduction, the agent is having an effect; if density is the same, it may not be a beneficial drug for the individual woman, said the study’s lead investigator, Jack Cuzick, Ph.D., head of the Cancer Research UK Centre for Epidemiology, Mathematics and Statistics in London.

“It is important to find a way to predict who will respond to tamoxifen, and changes in breast density may constitute an early indicator of benefit,” said Cuzick. “This is important to know because other preventive options now exist or are being tested.” Cuzick led the International Breast Intervention Study I (IBIS-I), a trial of tamoxifen for breast cancer prevention that involved more than 7,000 participants. Results of the study found the agent reduces the risk of estrogen-positive (ER) breast cancer by 30 to 40 percent among women at high risk. During that study, researchers collected baseline mammograms, as well as mammograms at 18, 36, and 54 months to check for breast cancer development. Based on analysis of these mammograms, Cuzick and his colleagues later found a strong correlation between reduction of breast density in women who use tamoxifen and lowered breast cancer risk.

In this study, the investigators examined a subpopulation of the IBIS-I participants (120 women who developed breast cancer and 943 who didn’t), to see if their mammograms changed over time and if tamoxifen treatment reduced breast density. They also looked at changes in other variables, such as hormone status, body weight and familial factors. They found that only change in mammographic density predicted reduction of risk for ER-positive breast cancer.

For the 46 percent of women in the tamoxifen-treatment group whose breast density was reduced by 10 percent or more, the risk of breast cancer was reduced by 52 percent relative to the control group (women who did not develop breast cancer). Conversely, the 54 percent of women whose density was not reduced by 10 percent only had a non-significant, 8 percent reduction in breast cancer risk. The findings suggest that the impact of tamoxifen on risk reduction is predictable by changes it induces on breast density after 12 to 18 months of treatment, Cuzick said.

For more information:
Cuzick J, Warwick J, Pinney L, Warren R, Cawthorn S, et al. Change in breast density as a biomarker of breast cancer risk reduction; results from IBIS-1. Abstract 61; SABCS, December 10-14, 2008.

Preliminary Study Results Demonstrate that Zoledronic Acid May Have Anti-Tumor Properties

Early evaluations of zoledronic acid, a bisphosphonate used for the treatment of bone metastases in advanced breast cancer, suggest a possible direct anti-tumor effect when combined with neoadjuvant chemotherapy in breast cancer treatment, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium. Bisphosphonates may therefore offer an (neo)adjuvant therapeutic strategy of potential importance.

“Zoledronic acid is primarily targeted to bone and metastasis within the bone marrow microenvironment, but it may also be enhancing the response in the primary breast tumor,” said Robert Coleman, M.D., FRCP, professor of medical oncology at the University of Sheffield in the United Kingdom. Coleman is the lead researcher on the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, which is evaluating the effect of zoledronic acid on breast cancer.

Although the larger AZURE trial is still being evaluated, if the findings in this smaller study are confirmed, the effect could be 'practice changing,' Coleman said. The AZURE trial, a prospective, randomized, open label, clinical trial , enrolled 3,360 women with stage II/III breast cancer to determine whether treatment with zoledronic acid in addition to adjuvant or neoadjuvant chemotherapy would improve disease outcomes. Coleman and colleagues performed a retrospective pathology analysis on 205 patients who received neoadjuvant chemotherapy to determine zoledronic acid’s impact on the primary tumor. Zoledronic acid appeared to reduce tumor size from 30 mm in the chemotherapy alone group to 20.5 mm in the combination group. After adjusting for variables like estrogen receptor status and treatment duration, the difference remained at 42.4 mm in the chemotherapy group and 28.2 mm in the combination group. The pathological complete response rate was 5.8% in the chemotherapy arm and 10.9% in the zoledronic acid group.

The number of patients requiring mastectomy was 77.9% in the chemotherapy group and 65.3% in the combination group. “Zoledronic acid is currently approved for the treatment of bone metastasis and osteoporosis. If the AZURE trial remains positive, then we’ll file for an additional indication,” said Coleman.

For more information

• Winter MC, Thorpe HC, Burkinshaw R, Beevers SJ, Coleman RE, The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response exploratory evidence for direct anti-tumor activity in breast cancer. Abstract 5101; SABCS, December 10-14, 2008.

Patients may benefit from new therapeutic approaches in several platelet disorders

A new combination therapy for previously untreated idiopathic thrombocytopenic purpura (ITP), an investigational oral treatment for chronic ITP, a low-dose platelet transfusion strategy for patients with hypoproliferative thrombocytopenia, and a new therapeutic platelet transfusion approach following high-dose chemotherapy and autologous stem cell transplantation, may benefit patients with various forms of thrombocytopenia.

Thrombocytopenia is a group of bleeding disorders characterized by a low number of platelets in the blood. Failed platelet production, increased splenic sequestration of platelets with normal platelet survival, increased platelet destruction or consumption, dilution of platelets, or a combination of these are the main causes of this condition.

Four studies presented during the during the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA (December 6 - 9) on Saturday, highlighted significant advances in treatment and survival outcomes for patients with various forms of thrombocytopenia.

“We have some very exciting data on novel therapeutic approaches to minimize bleeding episodes in patients with platelet disorders,” explained Kenneth Kaushansky, MD, 2008 President of the American Society of Hematology and Helen M. Ranney Professor and Chair of the Department of Medicine at the University of California, San Diego School of Medicine. “The results of these studies will likely transform the way hematologists treat and manage these conditions, ultimately resulting in improvements in overall patient outcomes such as reducing bruising and unnecessary bleeding that can result if left untreated.”

Types of thrombocytopenia, a blood disorder with 50 to 150 new cases per 1 million people each year, are typically classified by one of three causes: low production of platelets in the bone marrow, increased breakdown of platelets in the bloodstream, or increased breakdown of platelets in the spleen or liver, which can be induced by certain anemias, cancers, infections, or medications. Symptoms can include bruising, nose bleeds, bleeding in the mouth, and rash-like spots on the skin.

If left untreated, thrombocytopenia can become a life-threatening condition when blood platelet counts fall below 5,000 microliters because the risk of serious hemorrhaging or (excessive bleeding) increases. Normal blood platelet counts are typically between 150,000 to 450,000 microliters in adults. Treatment for thrombocytopenia is dependent on the cause and severity of the condition and can include drug therapy, splenectomy (the spleen breaks down blood cells such as platelets), and platelet transfusions.

Rituximab and Dexamethasone vs Dexamethasone Alone in Idiopathic thrombocytopenic purpura

Results from a multicenter phase III study conducted by a team of researchers from Clinica Ematologica DIRM AOUD, Udine, Italy, were presented by Francesco Zaja, MD.

This study is the first trial to prospectively determine that adding the immunotherapy drug rituximab, an anti-CD20 monoclonal antibody, to dexamethasone, a steroid that is a standard therapy for idiopathic thrombocytopenic purpura (ITP), is safe and effective in adult patients with previously untreated ITP, an autoimmune disorder characterized by low platelet counts. Primary ITP, which typically occurs in an otherwise healthy individuals, has an unknown etiology.

After analyzing the data, the researchers concluded that this treatment regimen could be an effective option prior to splenectomy for some patients as well as a possible cure for others.

In this study, patients were randomized to one of two treatment regimens: oral dexamethasone alone (40 mg) given on the first four days of treatment or the same regimen of dexamethasone plus rituximab given as an intravenous infusion (375 mg/m2) once a week for four weeks. Some patients in the dexamethasone-only arm who failed to achieve a sustained response and had platelet counts of less than or equal to 20 x 109/L following 30 days of therapy up to the end of six months received a salvage (rescue) treatment of rituximab plus dexamethasone.

The primary objective of the study was to compare the sustained response (platelet counts greater than or equal to 50 x 109/L from one month to six months from the beginning of therapy) between the two treatment groups. Secondary objectives included overall safety, initial response (platelet count of 50 x 109/L after 30 days of treatment), activity of the salvage therapy (dexamethasone/rituximab) in patients not responding to dexamethasone alone, the identification of clinical and laboratory factors predictive of response, and the pharmacokinetic parameters of rituximab (the level of ritixumab circulating in the blood of patients during the study period) and their potential relation to response.

The researchers examined the results for all enrolled patients, regardless of whether or not they completed the study (intention-to-treat basis, ITT), and on a per-protocol (PP) basis, examining those who had completed the treatment regimen. The ITT group included 52 patients treated with dexamethasone alone and 49 treated with rituximab/dexamethasone. The PP group included 38 patients treated with dexamethasone alone and 26 treated with rituximab/dexamethasone. ITT and PP sustained response rates were 63 percent and 85 percent in the rituximab/dexamethasone combination arm as compared with 36 percent and 39 percent in the dexamethasone-alone arm.

A total of 27 patients who failed to achieve an initial or sustained response in the dexamethasone-alone arm received the salvage treatment. In this group, ITT and PP sustained response rates were 56 percent and 59 percent, respectively.

While were no clinical or laboratory factors predictive of a sustained response identified in the study, the researchers did report a mild increase in the incidence of severe adverse events in the dexamethasone-plus-rituximab arm (2 percent in dexamethasone arm versus 6 percent in dexamethasone-plus-rituximab arm).

For more infromation, read:
Francesco Zaja, Michele Baccarani, Patrizio Mazza, Nicola Vianelli, et al. A Prospective Randomized Study Comparing Rituximab and Dexamethasone Vs Dexamethasone Alone in ITP: Results of Final Analysis and Long Term Follow up. (Plenary Session), Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #1

Click here for an educational resource (The ITP Paradox).

Also read Pubmed abstracts:

• Medeot M, Zaja F, Vianelli N, Battista M, et al. Rituximab therapy in adult patients with relapsed or refractory immune thrombocytopenic purpura: long-term follow-up results. Eur J Haematol. 2008 Sep;81(3):165-9. Epub 2008 May 27.
• Toffoletti E, Zaja F, Chiarvesio A, Michelutti A, et al. No evidences for B-cell clonality by spectratyping analysis in patients with idiopathic thrombocytopenic purpura undergoing rituximab therapy. Haematologica. 2008 May;93(5):795-6.
• Stasi R, Cooper N, Del Poeta G, Stipa E, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood. 2008 Aug 15;112(4):1147-50. Epub 2008 Mar 28.

Effects of Prophylactic Platelet Dose on Transfusion Outcomes (PLADO Trial)

Patients with hypoproliferative thrombocytopenia can be safely and effectively transfused with a low dose of platelets, a strategy that can reduce costs and help prevent shortages in the blood supply. This is the conclusion of Sherrill J. Slichter, MD and her team of researchers at Puget Sound Blood Center for the National Heart, Lung, and Blood Institute Transfusion Medicine/Hemostasis Clinical Trials Network, Seattle, WA, analyzing the data of the first large-scale clinical trial comparing the effects of different platelet-transfusion dosing regimens on hemostatic outcomes.

A total of 1,272 patients with hypoproliferative thrombocytopenia, which is caused by failure of the marrow to produce platelets, who were expected to be hospitalized with platelet counts of less than or equal to 10,000 microliters for more than five days were enrolled in the study and received at least one platelet transfusion. Patients were randomized to receive one of three platelet-transfusion dosing regimens: a low dose (1.1 x 1011 platelets/m2), a medium dose (2.2 x 1011 platelets/m2), or a high dose (4.4 x 1011 platelets/m2). An acceptable dose of platelets could be within 25 percent (lower or higher) of the target dose.

Participating patients were stratified into four groups based on the cause of thrombocytopenia: those who had received chemotherapy for a hematologic malignancy (313 patients), chemotherapy for a solid tumor (seven patients), autologous stem cell transplant (429 patients), or an allogeneic stem cell transplant (523 patients). Patients were prophylactically transfused on days when platelet counts were less than or equal to 10,000 microliters.

The primary endpoint of the study was the percentage of patients with Grade 2 or higher bleeding, calculated using the WHO Bleeding Scale. Grade 2 bleeding is clinically significant bleeding that does not require a red blood cell transfusion. Grade 2 or higher bleeding occurred in 71 percent of patients in the low-dose arm, 69 percent in the medium-dose arm, and 70 percent in the high-dose arm. Grade 3 or higher bleeding, which generally does require treatment by red blood cell transfusion, was seen in 12 percent of patients in the low-dose arm, 9 percent in the medium-dose arm, and 10 percent in the high-dose arm. Grade 4 bleeding, the most serious, was seen in 3 percent, 2 percent, and 2 percent of patients in the low-dose, medium-dose, and high-dose arms, respectively. The median number of red blood cell transfusions (usually given for anemia) was four in each treatment arm. Treatment dose did not affect the frequency of any bleeding grade in any of the four patient groups.

For more information, please read:
Sherrill J. Slichter, MD, Richard M. Kaufman, MD, Susan F Assmann, PhD, Mark E. Brecher, MD, BC. Effects of Prophylactic Platelet (Plt) Dose on Transfusion (Tx) Outcomes (PLADO Trial) Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #285

Also read PubMed abstracts:

• Slichter SJ, Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program. 2007;2007:172-8.
• Slichter SJ, Platelet transfusion therapy. Hematol Oncol Clin North Am. 2007 Aug;21(4):697-729, vii.

Therapeutic platelet transfusion without prophylactic transfusion may significantly reduces platelet transfusion needs.

This study is the first worldwide randomized trial showing that one-quarter to one-third of all platelet transfusions were given unnecessarily in the past and can be reduced in the future without any harm to patients following high-dose chemotherapy and autologous stem cell transplantation, according to Dr. Wandt. MD, at the Klinikum Nuremberg Nord, Nuremberg, Germany.

In this multicenter, randomized trial, the researchers found that the development of major bleeding following high-dose chemotherapy and autologous stem cell transplant can be prevented through an experimental therapeutic strategy in which patients receive platelet transfusions only if they have experienced clinically relevant bleeding. The experimental strategy in this trial was compared with a traditional preventive transfusion strategy in which patients received a transfusion if platelet counts were less than or equal to 10/nL. The researchers concluded that the experimental strategy was both cost effective and safe in this patient population.

A total of 171 patients who had recently received high-dose chemotherapy or autologous stem cell transplant for the treatment of various hematologic cancers, including multiple myeloma, non-Hodgkin lymphoma, Hodgkin disease, and acute leukemia, were randomized to one of two treatment arms: a traditional arm that received preventive platelet transfusions or an experimental arm that was treated only if the patient had experienced signs of clinically relevant bleeding. The primary objective of the study was the reduction of platelet transfusions by 15 to 25 percent. Secondary objectives included safety, duration of leukopenia and thrombocytopenia, and the number of red blood cell transfusions.

Platelet transfusions were significantly reduced by 27 percent in the experimental arm as compared with the traditional arm. In the experimental arm, 46 percent of patients did not need any platelet transfusions, compared with 22 percent of patients in the traditional arm. Using clinically relevant bleeding as the trigger for platelet transfusions rather than using platelet counts of less than or equal to 10/nL as the trigger resulted in more minor hemorrhages occurring in the experimental arm as compared with the traditional arm (28.7 percent versus 9.5 percent); however, no life-threatening or fatal bleeding was reported. The duration of leukopenia and the need for red blood cell transfusions were the same in both arms.

For more information, please read:

Hannes Wandt, MD, Knut Wendelin, MD, Kerstin Schaefer-Eckart, MD, Markus Thalheimer, MD. A Therapeutic Platelet Transfusion Strategy without Routine Prophylactic Transfusion Is Feasible and Safe and Reduces Platelet Transfusion Numbers Significantly: Preliminary Analysis of a Randomized Study in Patients after High Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation. Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #286.

Also read PubMed abstracts:

Wandt H, Schaefer-Eckart K, Frank M. et al. A therapeutic platelet transfusion strategy is safe and feasible in patients after autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 2006 Feb;37(4):387-92.

Oral Eltrombopag for the treatment of chronic Idiopathic Thrombocytopenic Purpura (ITP)

This double-blind, multicenter, phase III study found that long-term therapy with eltrombopag, a thrombopoietin-receptor agonist, compared with placebo treatment significantly increased platelet counts, decreased bleeding symptoms, allowed for a reduction of baseline ITP therapy, and reduced the use of rescue medications in previously treated patients with chronic ITP. In chronic ITP, low blood platelet counts persist unless treated and can last for an indefinite amount of time.

In this study Gregory Cheng, MD and his team of researchers at the Chinese University of Hong Kong, Hong Kong, China, stratified 197 patients with platelet counts less than 30,000 microliters by splenectomy status, use of baseline ITP medication, and platelets of less than or equal to 15,000 microliters. Patients were randomized to receive either eltrombopag at a starting dose of 50 mg once daily (135 patients) or placebo once daily (62 patients).

Depending on individual platelet response, the dose of eltrombopag could be titrated within a range from 25 mg once daily to a maximum dose of 75 mg once daily. The primary endpoint of the study was the odds of achieving platelet counts between 50,000 and 400,000 microliters in patients receiving eltrombopag as compared with placebo. To measure the drug’s safety, bleeding symptoms were prospectively evaluated using the WHO Bleeding Scale.

Patients who received eltrombopag were eight times more likely to achieve platelet counts of 50,000 to 400,000 microliters during the six-month treatment period as compared with those in the placebo arm. While baseline median platelet counts were 16,000 microliters in both groups, platelet counts never exceeded 30,000 microliters in the placebo group. This is in contrast to median platelet counts rising to 36,000 microliters in the eltrombopag group after one week of treatment and ranging from 52,000 to 91,000 microliters for the remainder of the study. Median platelet counts returned to baseline levels two weeks after stopping eltrombopag.

Significantly fewer patients treated with eltrombopag experienced any bleeding or clinically significant bleeding throughout the study as compared with those in the placebo arm. Additionally, more patients in the eltrombopag arm were able to stop or reduce other ITP medication and required less rescue therapy compared with those in the placebo group. Overall incidence of adverse events was similar in both treatment groups and was mostly mild to moderate.

More information, please read:
Gregory Cheng, Mansoor N Saleh, James B Bussel, Claus Marcher. Oral Eltrombopag for the Long-Term Treatment of Patients with Chronic Idiopathic Thrombocytopenic Purpura: Results of a Phase III, Double- Blind, Placebo-Controlled Study (RAISE). Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #400

Also read PubMed abstracts:

• Stasi R. Evangelista ML, Amadori S. Novel thrombopoietic agents: a review of their use in idiopathic thrombocytopenic purpura. Drugs. 2008;68(7):901-12
• Lawson, A. Eltrombopag in thrombocytopenia. N Engl J Med. Mar 6;358(10):1072; author reply 1072-3
• Newland A. Emerging strategies to treat chronic immune thrombocytopenic purpura. Eur J Haematol Suppl. 2008 Feb;(69):27-33.

Also read NEJM article (full article):
McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M. Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C. N Engl J Med. 2007 Nov 29;357(22):2227-36. Clieck here for the PubMed abstract. Author reply.

Combining targeted therapy drugs may treat previously resistant tumors

Blocking two cell signaling pathways leads to dramatic shrinkage of K-Ras-mutated tumors in animal model. This is the conclusion of a team of cancer researchers from several Boston academic medical centers. The team believes that their findings offer a potential treatment for a group of tumors that have resisted previous approaches of treatment with selected targeted therapies.

In their report published in the december issue of Nature Medicine, investigators from Dana-Farber Cancer Institute, a principal teaching affiliate of the Harvard Medical School, Massachusetts General Hospital (MGH) Cancer Center, the original and largest teaching hospital of Harvard Medical School and Beth Israel Deaconess Medical Center (BIDMC) Cancer Center, a patient care, teaching and research affiliate of Harvard Medical School, report that combining two different kinase inhibitors, drugs that interfere with specific cell-growth pathways, led to significant tumor shrinkage in mice with lung cancer driven by mutations in the K-Ras gene.

K-ras, which is part of the ras family of oncogenes which also includes H-ras and N-ras, is involved in the development of a variety of human malignancies. The K-ras oncogene resides on chromosome 12p12, and encodes a 21-kD protein (p21ras) involved in the G-protein signal transduction pathway, modulating cellular proliferation and differentiation. The ras pathway is important in the transmission of growth-promoting signals from the cell surface receptors and affect the production and regulation of key proteins. Mutations of the K-Ras gene occur long before the formation of the actual cancer.

Controversial
So far, researchers believe that the clinical significance of K-ras mutations is somewhat controversial. But a number of studies have shown lower median survival times in patients with mutation-positive tumors in gastrointestinal malignancies. As it turns out, K-ras mutations are one of the most common genetic abnormalities in colon, pancreatic cancers and bile duct carcinomas, detectable in greater than 75% of tumors. These cancers are extremely resistant to treatment.

In gynecological malignancies and endometrial carcinomas, K-ras mutations are noted in up to a third of cases. Studies have shown that in postmenopausal women with endometrial carcinomas, K-ras mutations appear to be an independent risk factor for adverse prognosis. Researchers believe that that the presence of K-ras mutations in endometrial hyperplasia specimens may identify a group of patients with a high probability for progression.

K-ras mutations are also associated with nearly 30% of non-small-cell lung cancer, the leading cause of cancer deaths in the United Sates. In limited stage adenocarcinomas, usually is seen peripherally in the lungs, the presence of K-ras mutation is independently associated with more aggressive disease and decreased patient survival.

"Finding a way to effectively treat K-Ras-mutated cancers would be a huge advance in solid tumor oncology, since these mutations are common in several incurable cancers," explained Jeffrey Engelman, MD, PhD, of the MGH Cancer Center, one of the report's co-lead authors. "Cancers with K-Ras mutations have been resistant to all targeted therapies to date, and it is exciting to learn that a combination of PI3K and MEK inhibitors, two families of drugs currently in clinical development, may be highly effective in these cancers."

The current study began with a focus on the PI3K signaling pathway, which is key to cell survival and known to control cellular motility and adhesion. PI3K mutations have caused tumor development in laboratory studies, but their role had not yet been studied in an animal model. The research team developed a transgenic mouse in which administration of the drug doxycycline induces the expression of cancer-associated PI3K mutations, leading to development of lung tumors.

Treatment of those animals with an investigational PI3K inhibitor did lead to rapid tumor regression. Since previous studies suggested that PI3K inhibition might also block K-Ras-induced tumor development, the investigators also tested the PI3K inhibitor in mice with K-Ras-stimulated tumors.

That treatment was ineffective, but since K-Ras also activates the MEK/ERK signaling pathway, the researchers treated the animals with an investigational MEK inhibitor and with a combination of both drugs. Treatment with the MEK inhibitor alone caused only a modest reduction in tumor size, but combined treatment with both agents caused the K-Ras-stimulated lung tumors to virtually disappear.

"For several years we have known that K-Ras activates two major pathways — the PI3K pathway and the MEK/MAPK pathway — and that these pathways have many redundant functions in tumor growth and survival," notes Lewis Cantley, PhD, of the BIDMC Cancer Center, one of the study's co-corresponding authors. Contley continues: "Inhibitors of both of these pathways are now in clinical trials, and in this paper we show that, while either agent alone has a minor effect on K-Ras-driven tumors in mice, combining inhibitors of both pathways eradicates these tumors with minimal toxicity."

Kwok-Kin Wong, MD, PhD, of Dana-Farber, also a co-corresponding author, adds, "The results of our study are truly remarkable and provide a strong and compelling scientific rationale to test this combination therapy in human phase 1 and 2 trials. This work would not have been possible without the highly productive collaboration between our laboratories at Mass. General, Beth Israel Deaconess and Dana-Farber."

Wong is an assistant professor of medicine at Harvard Medical School, where Engelman is also an assistant professor in medicine and Cantley is the Castle Professor of Medicine.

The researchers are hoping to advance towards clinical trials by testing combination therapy against other models of K-Ras-mutated cancer, including those that involve additional mutations in other tumor-associated genes, and to investigate whether K-Ras-associated tumors will become resistant to combination therapy, a problem that has plagued other targeted cancer therapies.

Also read PubMed abstracts:

• Engelman JA, Chen L , Tan X, Crosby K et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Na. Med 2008 Dec;14(12):1351-1356. Epub 2008 Nov 30.
• Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008 Sep 18;27(41):5486-96.
• Yuan TL, Cantley LC . PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008 Sep 18;27(41):5497-510.

What is the practical impact of quality cancer research?

How does biomedical and clinical research impact daily practice in cancer care? This question has been asked with increasing frequency over the last decade. Results of a study published earlier this year in the British Journal of Cancer, give the answer. The results shows how research in the United Kingdom is helping to deliver significant clinical improvements for cancer patients in the United Kingdom and around the world.

To date, there are 43 oncology guidelines and associated Health Technology Assessments (HTA) published (up to October 2006) in the United Kingdom. Each guideline and associate HTA has a clear evidence base in the form of references, many of which are papers in peer-reviewed journals. Researchers analyzed these guidelines for cancer care from the National Institute of Health and Clinical Excellence (NICE) and the Scottish Medicines Consortium (SMC), and found that papers from UK-based cancer researchers are cited nearly three times more often than would be expected.

These guidelines form the basis of the clinical care given to cancer patients and are devised from an evidence base which includes peer-reviewed research.

In contrast to held idea that the pharmaceutical industry is the biggest sponsor of biomedical research, the study reveals that Cancer Research UK supported over one-third of the clinical trials which were cited as evidence in these guidelines. The number of studies is more than the pharmaceutical industry as a whole, or the UK government. This outcome seems to confirm that altough the private sector will have an important role in identifying and implementing research priorities in cancer research and offer substantial and welcome funding, it does not set the overall research priority end execution. The main reason is that industry by its very nature is partisan and concerned only with commercially viable areas. On the other hand, government agencies, charitable organizations and universities have wider concerns for all cancer research.

Lead author Professor Richard Sullivan, who conducted this study when he was director of clinical programs at Cancer Research UK, and is now at the London School of Economics and the European Cancer Research Managers Foundation, said: "Our study demonstrates the real practical impact of research funding in the UK and shows that cancer research in the UK is punching above its weight.”

International impact
Previous studies have shown a strong sociological tendency for clinical guidelines to focus on domestic research rather than the best international research. The impact of UK research in this study was compared with a standard set by previous studies measuring how far individual countries are expected to deviate from the international standard.

Professor Sullivan continued: "Even taking into account the fact that UK clinical guidelines are inevitably going to be skewed in favor of UK-based research because of the make-up of our healthcare services, we still found that the impact of UK cancer research on clinical practice was disproportionately higher than would be expected - which is a credit to the exceptionally strong research base that we have in this country. We also found indirect evidence that UK cancer research has as impact internationally - particularly in Western Europe."

In numbers
Cancer research conducted in the UK contributes to approximately 6.5 per cent of the world's oncology research output, but almost 20 per cent of cancer research emanating from the UK contributed to the 43 NICE clinical guidelines which were devised before 2006.

The research team analyzed just over 3000 references which were cited across almost 800 research papers over a period of 25 years. The peak years of guideline references were between 1999 and 2001. They looked at the geographical breakdown of the research as well as the type of research conducted and the impact factors of the journals it appeared in. The researchers noted that studies from universities, hospitals and institutes based in Oxford, Cambridge, Edinburgh and Glasgow were the most frequently cited.

Professor Sullivan noted: "This is an interesting finding...[and] this may be because SMC guidelines tend to pay close attention to research coming out of Scotland - but it was still a significant contribution from the two cities."

Kate Law, director of clinical trials at Cancer Research UK, said: "This research highlights the importance of clinical trials carried out in this country and it's great to see that studies funded by Cancer Research UK played a major contribution towards these guidelines. This demonstrates that our research has a significant impact on the clinical management of cancer patients. NICE is seen to be a world leader in the development of quality, evidence based guidelines for cancer care, so it's crucial that the Government and NHS work together to ensure that these guidelines are being uniformly implemented across the country so that all cancer patients can benefit from them."

Although the impact of studies conducted in the United Kingdom is considerable, British researchers in general are concerned about the increased bureaucracy. One researcher noted that patients with cancer are dying because bureaucracy is stifling research. In general, it takes now takes five times longer than in the early 1990s to get a breast or bowel cancer drug into trials.

Professor Sullivan agreed that: "We absolutely agree that research should be carried out in a proper regulatory framework, but because of complex, contradictory, and opaque regulations patients aren’t being protected, they are being failed." The result is a 'culture of fear' in which many now playing it ultra-safe and avoiding sensitive but potentially important areas of research.

Researchers find it incredibly frustrating the added burden of bureaucratic rules slow down the development of new drugs. They agree that this kind of delay is undoubtedly costing lives. They also feel that the added (European) regulations do not provide greater patient safety.

Even though the increase in guidelines may be a concern, most researchers feel that the NICE recommendations are truly based on systematic reviews of the best available evidence. And even when minimal evidence is available, recommendations are based on the opinion of what constitutes good practice.

Also read:
Lewison G, Sullivan, R. The impact of cancer research: how publications influence UK cancer clinical guidelines, British Journal of Cancer (2008) 98, 1944–1950. Click here for the PubMed abstract.

Relative risk similarly increased for low and high dose of bevacizumab

Vascular complications, including venous thromboembolism (VTE) are one of the leading causes of morbidity and mortality in patients with cancer. A variety of antineoplastic agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have received for clinical use while others have entered clinical trials.

Given the well-known interplay between the blood clotting system, angiogenesis, and tumor growth, researchers observed a variety of vascular complications, including venous or arterial thromboembolism and hemorrhage, as relevant toxicities with the use of angiogenesis inhibitors. Concerns were especially alarming with bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in venous thromboembolism is controversial.

Bloomberg and HealthDay News both reported on a meta-analysis recently published in the Journal of American Medical Association (JAMA).

To assess the overall risk of venous thromboembolism associated with the use of bevacizumab, Dr Nalluri and his team of researchers from the Division of Medical Oncology, Department of Medicine, Stony Brook University, Stony Brook, New York, NY 11794, systematic reviewed and analyzed a number of randomized controlled trials.Eligible studies included prospective randomized controlled trials in which standard antineoplastic therapy was used with and without bevacizumab for which data on venous thromboembolism were available.

Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies.

The researchers found 15 randomized controlled trials and identified a total of 7956 patients with a variety of advanced solid tumors. Among those patients receiving bevacizumab, the summary incidences of all-grade and high-grade venous thromboembolism were 11.9% (95% CI, 6.8%-19.9%) and 6.3% (95% CI, 4.8%-8.3%), respectively.

Patients treated with bevacizumab had a significantly increased risk of venous thromboembolism with a relative risk of 1.33 (95% CI, 1.13-1.56; P < .001) compared with controls. The risk was significantly increased for both all-grade and high-grade venous thromboembolism. In addition, the relative risk was similarly increased for bevacizumab at 2.5 mg/kg per week (low dose; RR, 1.31 [95% CI, 1.08-1.60]; P = .007) and 5 mg/kg per week (high dose; RR, 1.31 [95% CI, 1.02-1.68]; P = .04).

The authors of the meta-analysis concluded that the use of bevacizumab in cancer patients was associated with an increased risk of developing venous thromboembolism.

In an unrelated study published in American Journal of Hematology, Dr Francesca Elice and her team of researchers from Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy, concluded that careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs, including bevacizumab, is warranted and that further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy.

PubMed abstracts:

• Nalluri SR., Chu D., Keresztes R., Zhu X., Wu S., Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 2008 Nov 19;300(19):2277-85.
• Elice F, Jacoub J, Rickles FR Hemostatic complications of angiogenesis inhibitors in cancer patients. Am J Hematol 2008 Nov;83(11):862-70.

50th Annual Meeting of the American Society of Hematology Will Feature Breakthrough Research in Blood Diseases

The American Society of Hematology (ASH), the world’s largest professional association of hematologists concerned with the causes and treatment of blood disorders, expects more than 20,000 attendees at the 50th ASH Annual Meeting from December 6-9, 2008, at the Moscone Center in San Francisco, CA. The meeting will showcase the latest research and treatments for blood disorders. In honor of the Society’s golden anniversary, there will also be several special programs including a unique video project featuring influential figures in hematology.

“It is my distinct honor to serve as President during this celebratory year in the Society’s history. The ASH annual meeting continues to be the premier forum for physicians and researchers from around the world to hear the most up-to-date developments in hematology, and this year will be no exception,” said Kenneth Kaushansky, MD, 2008 ASH President, and Helen M. Ranney Professor and Chair of the Department of Medicine at the University of California, San Diego School of Medicine. “In addition to presenting research that affects hematologists in every area of the discipline, this year’s meeting underscores 50 years of unprecedented growth and advancement in the field.”

Highlights of the meeting include special symposia, education programs, special interest seminars, and scientific sessions. As part of the 50th anniversary celebration, the meeting will also feature historical displays showcasing major scientific discoveries and clinical advances in the specialty. Several world-renowned scientists will share their life stories and speak about groundbreaking medical discoveries during the Pioneers in Hematology sessions.

The Special Symposium on the Basic Science of Hemostasis and Thrombosis will provide an opportunity for communication among scientists in the field and focus on the most important basic science contributions from 2008 to each of the three major areas of the field: thrombosis, blood coagulation and fibrinolysis, and platelet biology. In September, the Surgeon General’s Call to Action to Prevent and Reduce Deep-Vein Thrombosis and Pulmonary Embolism encouraged public awareness of this blood condition that affects nearly 1 million Americans each year. The symposium will take place on Tuesday, December 9, from 7:30 – 9:00 a.m. PST.

This year’s Practice Forum, 'The Patient, the Hematologist, and the Unexpected,' will focus on two areas of unexpected results encountered commonly enough to raise the interest of the hematology community. Additionally, this session will look at the public policy environment that will shape the practice of hematology and the Society as it enters its 51st year. This event will take place Saturday, December 6, from 6:00 – 7:30 p.m.

Another highlight of the meeting is the Presidential Symposium, which will focus on hematopoietic stem cells (HSCs). These cells are known for their role in the cure of a variety of diseases as well as for providing an understanding of stem cell development in all mammalian biology. During the symposium on Tuesday, December 9, from 9:45 – 11:45 a.m., three eminent investigators who have made significant contributions to our understanding of HSC biology will discuss the properties of these cells and their role in the human body.

Neal S. Young, MD, of the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), will discuss the pathophysiology of bone marrow failure and how clinical observations of patients with this disease have provided insights into the biology of autoimmunity, viral pathogenesis, and cancer at this year’s E. Donnall Thomas Lecture on Monday, December 8, from 9:30 – 10:30 a.m. Bob Löwenberg, MD, PhD, of the Erasmus University Medical Center in Rotterdam, The Netherlands, will give the Ham-Wasserman Lecture on Saturday, December 6, from 12:30 – 1:30 p.m. Dr. Löwenberg’s lecture will focus on the numerous genetic abnormalities found in acute myeloid leukemia patients and ways to use this information to develop individualized therapies. Both the E. Donnall Thomas Lecture and the Ham-Wasserman Lecture represent areas of medicine that have evolved immensely over the last 50 years.

Honoring Commitment
The Honorable Speaker of the House Nancy Pelosi (D-CA) will receive ASH’s Award for Public Service for her long-time support and leadership on health care issues such as increasing funding for the National Institutes of Health (NIH) and advocating for stem cell research. After assuming the office of Speaker in January 2007, Speaker Pelosi made passage of the Stem Cell Research Enhancement Act one of the cornerstones of the “First 100 Hours” agenda of the 110th Congress. Speaker Pelosi was also instrumental in guiding legislation through Congress to prevent scheduled cuts in Medicare reimbursement for physicians.

Susan Shurin, MD, Deputy Director of the NHLBI (a part of the National Institutes of Health) will be honored with ASH’s Outstanding Service Award. In her role as Deputy Director, Dr. Shurin has worked closely with ASH on many activities of importance to hematology, including restructuring and enhancing NHLBI’s sickle cell disease research program. Dr. Shurin has been a tireless advocate of ensuring NHLBI is at the forefront of innovative technologies and cutting-edge research that will help patients with serious blood diseases such as hemophilia, leukemia, lymphoma, and deep-vein-thrombosis (DVT). She has also been a long-standing and dedicated member of the Society with extensive service on numerous committees and as a faculty member for the ASH Clinical Research Training Institute, an education and mentoring program for promising hematologists early in their careers.

“Both Speaker Pelosi and Dr. Shurin have provided outstanding leadership to strengthen and support programs critical to the work carried out by researchers and practitioners in the hematology community,” said Kaushansky and Helen M. Ranney Professor and Chair of the Department of Medicine at the University of California, San Diego School of Medicine. “It is my honor and pleasure to recognize these two distinguished individuals for their achievements.”

The awards will be announced on Sunday, December 7, at 1:30 p.m. PST following the joint ASH and European Hematology Association Policy Forum.

International Collaboration
This year’s plenary policy forum, '50 Years of Progress in Hematology,' which is co-sponsored by ASH and the European Hematology Association, will feature Nobel Prize winner Peter Agre, MD, who will discuss how his research on water channels in red blood cells, as well as the research of others that originated in hematology, grew to have profound and catalytic influences on numerous areas of science.

Cryoablation of Early Invasive Ductal Breast Cancer With MRI Confirmation Shows Promising Clinical Benefits

Early clinical experience using a Visica® Treatment System to ablate malignant tumors and a margin of surrounding tissue, confirm the effectiveness of ultrasound guided cryoablation, a minimally invasive non-surgical procedure that uses extreme cold to destroy tumors, to completely eradicate small, unifocal Invasive Ductal Breast Cancer (IDC).

Initial data from this multi-center study confirming the data was presented today during the 94th Scientific Assembly and Annual Meeting (November 30 – December 5, 2008) of the Radiological Society of North America (RSNA).

"We are very encouraged that our preliminary results demonstrate that in selected early IDC breast cancers, cryoablation with MRI confirmation may offer the same therapeutic benefit as lumpectomy with less morbidity, improved cosmesis and less cost,” said Garry Levine, M.D. Director of Breast Imaging at Hoag Breast Care Center in Newport Beach, CA.

The study was designed to evaluate the ability of breast contrast-enhanced MRI (CEMRI) to assess the effectiveness of ultrasound guided cryoablation for the local treatment of small, unifocal IDC. Patients with newly diagnosed IDC underwent an ‘early’ pre-ablation CEMRI to establish its MR enhancement pattern. Ultrasound-guided cryoablation was then performed using a Visica Treatment System, developed by Sanarus Medical (Pleasanton, CA), to ablate the malignant tumor and a margin of surrounding tissue.

A 'delayed' CEMRI was performed approximately four weeks post-ablation followed by a standard surgical lumpectomy. The early and delayed CEMRI findings were correlated with the surgical histopathology. In all 15 cases, the post-ablation MRI's showed no suspicious contrast enhancement remaining at the targeted tumor site and histopathology confirmed complete tumor kill within the intended ablation zone. In three cases histopathology confirmed residual DCIS and/or small satellite lesions outside the cryoablation zone.

"Lack of residual suspicious enhancement on post-cryoablation CEMRI appears to correlate with complete tumor kill within the targeted ablation zone. We believe the novel MR findings termed 'black hole', which correlates with an area of coagulation necrosis at the cryoablation site and a surrounding uniform thin rim enhancement, and 'cryohalo' which corresponds to a zone of inflammation at the cryoablation margin, serve as markers for successful ablation, giving us a noninvasive and reproducible method to verify clinical results," explained Dr. Levine.

The study conducted by Dr. Levine and Steven Poplack, MD, Co-Director of Breast Imaging at Dartmouth Hitchcock Medical Center is similar to the National Cancer Institute (NCI) funded clinical trial recently initiated by the American College of Surgeons Oncology Group (ACOSOG).
The ACOSOG study, (A Phase II Trial Exploring the Success of Cryoablation Therapy in the Treatment of Invasive Breast Carcinoma), will also evaluate cryoablation as well as the ability of MRI to evaluate post-cryoablation efficacy.

Click here to read the abstract (New Findings on Contrast-enhanced Magnetic Resonance Imaging (CEMRI), the 'Black Hole' and 'Cryohalo' are Markers for the Efficacy of Ultrasound (US)-guided Cryoablation of Small (less than or equal to 15mm) Unifocal Invasive Ductal Breast Cancer).

Also see:

• Warren RM, Bobrow LG, Earl HM, Can breast MRI help in the management of women with breast cancer treated by neoadjuvant chemotherapy? British Journal of Cancer (2004) 90, 1349–1360
• Sotome K, Yamamoto Y, Hirano A, The role of contrast enhanced MRI in the diagnosis of non-mass image-forming lesions on breast ultrasonography. Breast Cancer 2007;14(4):371-80.

Modifications in Assay Design Increase Detectable Frequency of Tumorigenic Cells

How common is the tumorigenic potential or tumor promoting property in human cancers? For many years, cancer researchers have tried to answer the fundamental question whether all tumor cells are equally likely to cause new cancers.

A generally supported idea is that only a tiny subset of highly prolific cancer cells, dubbed cancer stem cells and estimated to be as few as one in a million, are capable in promoting tumors growth. The fact that these cells are distinguishable from other cancer cells is an important property that scientists would theoretically be able to exploit in designing new, targeted, therapies. Research on diverse cancers, including melanoma, seems to support the hypnotists that only rare human cancer cells form tumors when transplanted into non-obese diabetic/severe combined immunodeficiency mice.

But when a team of researchers from the Howard Hughes Medical Institute, Life Science Institute, Department of Internal Medicine, and the Center for Stem Cell Biology, at the University of Michigan, Ann Arbor, MI, looked at 50 different molecular markers found on the surface of the melanoma cells, they could not find differences between the tumor-causing cells and those that did not spawn tumors. Therefore, they concluded that scientists may have underestimated the frequency of tumorigenic human cancer cells, the extent of which is so far uncertain.

In the 4 December 2008 issue of Nature, the international weekly science journal, the researchers show that by modifying the design of an assay (including the use of more highly immunocompromised non-obese diabetic/severe combined immunodeficiency interleukin-2 receptor gamma-chain-null mice), as many as 25%, or one in four, of the melanoma cells were able to reproduce. Furthermore, in single-cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumors. The authors therefore concluded that modifications to xenotransplantation assays increase the detectable frequency of tumorigenic cells and that they are common in some human cancers.

The researchers acknowledge that it is possible that cancer stem cells are simply more common in certain cancers. They expect that in some cancers, a cancer stem cell model will be more prevalent that in other cancers. The evidence for cancer stem cells in certain cancers is particularly convincing. But, as was reported in the same issue of Nature, researchers who report cancer stem cells in solid tumors should be wary about these results, and should repeat their experiments using techniques that could help transplanted human cells survive in mice. Otherwise, the reserachers conclude, it’s unclear whether they have detected a rare subset of cells that can propagate tumors – or simply a rare subset of human cells that can establish themselves in mice.

Click here for the PubMed abstract. Elsa Quintana, Mark Shackleton, Michael S. Sabel, et al., Efficient tumour formation by single human melanoma cells. Nature 2008 Dec 4;456(7222):593-8.

New Radiotherapy Technology may Improve Outcomes

A 60-year-old prostate cancer patient in Montpeller, has become the first person in France to be treated with a new, fast and precise, form of intensity modulated radiotherapy (IMRT). Each of his treatments at the Centre Régional de Lutte Contre le Cancer (CRLC),Val D'Aurelle in Montpeller, France, took just 75 seconds, several times faster than conventional IMRT treatments.

Dr. Pascal Fenoglietto, the hospital's chief medical physicist for scientific projects, presented the case to his peers at the annual meeting of the Société Française de Radiothérapie Oncologique (French Society of Radiation Oncologists, SFRO, November 12- 14), in the Palais des Congrés de Paris, in Paris, France.

"Compared to conventional IMRT technology [this treatment] was three times quicker," explained Dr. Fenoglietto. "We are now able to use the time we save on treatment delivery to take more images and increase the quality of our care."

The new IMRT technology called RapidArc was developed by Varian Medical Systems, Inc. (Palo Alto, California), a leading manufacturer of medical devices and software for treating cancer with radiotherapy, radiosurgery, proton therapy, and brachytherapy.

With the new, faster, image-guided IMRT, physicians can target radiation beams at a tumor while making just one continuous rotation around the patient. Conventional IMRT treatments are slower and more difficult for radiotherapy radiographers because they target tumors using a complex sequence of fixed beams from multiple angles. The result is that physicians can now better adjust the dose more closely to the size, shape, and location of the tumor which helps them to kill cancer cells more effectively but to spare more healthy tissue with reduced complications and better outcomes. "We now have the opportunity to improve outcomes while offering more patients greater access to advanced care," Dr. Fenoglietto said.

So far, more than 700 patients have been treated with IMRT at the comprehensive cancer center in Montpeller, since its introduction in 2001. According to radiation oncologist Dr. Carmen Llacer Moscardo, "Pelvic cases can take between 12 and 14 minutes to treat with IMRT but we can now do them in less than two minutes with one arc or, if clinically relevant, about three minutes with two arcs around the patient with this new technology. If we do this, there is less possibility for the patient to move and we reduce the chance of internal motion playing a part, as there tends to be a lot of motion in the pelvic region. Also, fast treatments reduce the possibility of inaccuracy and increase patient comfort."

New Mammography Technology Effective in Detecting Breast Cancer

Positron emission mammography or PEM, a new technique for imaging the breast, is not affected by either breast density or a woman’s hormonal status, two factors that limit the effectiveness of standard mammography and MRI at detecting cancer, according to a study presented during the 94th Scientific Assembly and Annual Meeting (November 30 – December 5, 2008) of the Radiological Society of North America (RSNA) on Tuesday.

“The ability of positron emission mammography or PEM to detect cancer does not appear to be adversely affected by breast density, hormone replacement therapy or menopausal status,” explained the lead researcher Kathy Schilling, M.D., director of breast imaging and intervention at the Center for Breast Care at Boca Raton Community Hospital in Florida. “The sensitivity of PEM is equal to or better than breast MRI, and PEM has fewer false-positive results.”

The ability of x-ray mammography, a standard screening tool for breast cancer, to detect lesions is reduced when performed on dense breasts, where tissue is less fatty and more glandular. Breast MRI is effective at detecting cancer in dense breasts and is increasingly being used to screen women at high risk for breast cancer. However, MRI has a high incidence of false-positive test results that indicate cancer is present when it is not. Researchers believe these false positives are due in part to hormonal changes that occur during a woman’s menstrual cycle.

“Unless the MRI is performed on day seven through 14 of a woman’s cycle, reading MRI images is extremely difficult,” Dr. Schilling said. “This is a significant problem with breast MRI.” Because hormones do not have the same effect on PEM results, Dr. Schilling believes the imaging technique could play a significant role both in preoperatively evaluating breast cancer patients and in screening high-risk patients.

In the study, 208 patients with breast cancer underwent PEM, an application of high-resolution breast positron emission tomography (PET) in which a small amount of radioactive material is injected into the body to measure metabolic activity and determine the presence of disease. The researchers used a PET unit specially developed for the breast and small body parts to perform the PEM exam.

Of 189 malignant lesions imaged, PEM detected 176 for an overall sensitivity rate of 93 percent. Fifteen percent were ductal carcinoma in situ (DCIS), a noninvasive cancer confined to the ducts of the breast; 85 percent were invasive cancer.

PEM successfully detected cancer in 100 percent of fatty breasts, 93 percent of dense breasts, 85 percent of extremely dense breasts, 93 percent of women both with and without a history of hormone replacement therapy, 90 percent of pre-menopausal women and 94 percent of post-menopausal women.

According to Dr. Schilling, PEM is well tolerated by patients, who sit upright during the exam and are not alone or closely confined as they would be during an MRI exam. While breast MRI exams produce more than 2,000 images to be interpreted, PEM produces just 48 images that can be correlated with a woman’s mammogram.

“PEM is easier to use, easier to interpret and easier on the patients than MRI,” Dr. Shilling said. “It is also ideal for those patients whose MRI is difficult to interpret due to hormonal influences, women with implants, patients with metal in their bodies, or patients who suffer from claustrophobia. It is exciting that we now have a functional imaging approach with high sensitivity that complements our current anatomic imaging modalities,” she added.

Positron Emission Mammography at a Glance

• Positron emission mammography (PEM) is an effective tool for detecting breast cancer.
• Dense breast tissue and hormonal status can hinder other breast imaging techniques.
• PEM shows high sensitivity and is not limited by these factors.
• PEM, also known as high-resolution breast PET, has fewer false-positive results than breast MRI.
  

Click here to read the abstract (Effect of Breast Density, Menopausal Status, and Hormone Use in High Resolution Positron Emission Mammography).

Bone Marrow-Derived Stem Cells May Offer Novel Therapeutic Option for Skin Disorder

Stem cells derived from bone marrow may serve as a novel therapeutic option to treat a disease called epidermolysis bullosa (EB), a disorder characterized by extraordinarily fragile skin, according to a study pre-published online in Blood, the official journal of the American Society of Hematology.

Epidermolysis bullosa is a disorder characterized by extraordinarily fragile skin and blistering on touch, akin to third degree burns. While the disease is often lethal in the neonatal period, more severe forms of the disease, such as recessive dystrophic EB (referred to as RDEB), can lead to years of painful blistering and mutilating scarring. The condition is caused by significantly reduced collagen type 7 protein (col7) production, a key component of the anchoring fibrils that connect the cutaneous membranes to the dermis of the skin and mucosal tissues in the gastrointestinal tract. A lack of these fibrils means the dermal-epidermal connection is very sensitive, and any action, which can include simple functions such as walking or eating, and the touch of clothing, creates friction between the skin layers that creates blisters and painful sores.

Children with RDEB, who are often referred to as so called butterfly children because their skin is said to be as sensitive as butterfly wings, develop painful skin and mucosal blistering, mutilating scarring, alopecia (hair loss), and other erosions shortly after birth. As a result of the extreme fragility of the skin and the chronic trauma of friction, RDEB patients often develop squamous cell carcinomas (a form of skin cancer). There is currently no cure for the disease, and palliative care includes complex bandaging, surgical removal of damaged tissue, and nutritional support.

"We have been looking into stem cells as viable treatment options for correction of conditions such as epidermolysis bullosa, because they can produce extracellular matrix proteins," explained Jakub Tolar, M.D., Ph.D., of the University of Minnesota and lead author of the study. "In this condition, the skin, the largest organ in the body, can significantly benefit from a renewable source of healthy cells that can help improve the connection between the dermis and epidermis and strengthen the skin against everyday stresses."

In this study, researchers worked with a mouse model of RDEB-infused bone marrow cells to determine if they would increase production of the col7 protein and formation of anchoring fibrils, and improve survival in the mouse recipients. The research team used bone marrow cells enriched for hematopoietic (stem cells that can develop into most blood cell types) and progenitor cells to increase the concentration of cells with the capacity to produce col7. The team tested these cells against non-enriched stem cells to determine their benefit to the treated mice.

Results of the study found that when injected into mice with RDEB, these specially selected marrow-derived stem cells diminished the disease process. They traveled to the diseased skin areas, increased protein and anchoring fibrils, prevented blister formation and extended survival. In contrast to other marrow cells, the selected cells extended the median survival time versus untreated or non-enriched marrow-treated recipients (10.0 versus 5.6 versus 6.0 days, respectively). Three of the 20 mice treated with the enriched cells benefited enough from the treatment to survive longer than the treatment period (untreated RDEB mice usually die within two weeks). Importantly, each survivor demonstrated marked improvement of new blister formation (blisters develop consistently in the areas of trauma, including footpads due to walking or in the oral cavity due to eating) with some evidence of old blisters healing.

"Our data provide the first evidence that a selected population of marrow cells can connect the epidermis and dermis in a mouse model of the disease and offer a potentially valuable approach for treatment of human RDEB and other extracellular matrix disorders. These results provide proof of principle of bone marrow transfer to repair the basement membrane defect in RDEB, and they warrant a clinical trial to assess the safety and efficacy of treatment of human RDEB by means of hematopoietic cell transplantation," said Dr. Tolar.

Research suggests that the systemic infusion of wild-type bone marrow cells could provide benefit to other human disorders of the extracellular matrix. Efforts are underway to identify the requirements of bone marrow-derived stem cells capable of efficiently homing to wounded skin and producing an array of extracellular matrix proteins. As the principal advantage of systemic therapy is its potential to target not only the skin but also the mucosa of the mouth and gastrointestinal tract, the clinical testing of efficacy of human bone marrow for the treatment of human RDEB is underway to determine whether it is of more substantial benefit than local protein, gene, or cellular therapies currently being investigated by other researchers.

An estimated 50 in 1 million live births are diagnosed with EB. The disorder occurs in every racial and ethnic group throughout the world and affects both sexes.

CT Colonography Offers One-Stop Screening for Cancer and Osteoporosis

New research reveals that computed tomography (CT) colonography, also known as virtual colonoscopy, has the potential to screen for two diseases at once—colorectal cancer and osteoporosis, both of which commonly affect adults over age 50. The results of this study were presented on Tuesday at the 94th Scientific Assembly and Annual Meeting (November 30 – December 5, 2008) of the Radiological Society of North America (RSNA).

"With CT colonography, in addition to screening for colorectal cancer, we were able to identify patients with osteoporosis," explained lead author Rizwan Aslam, M.B.Ch.B., assistant clinical professor of radiology at the University of California San Francisco.

CT colonography, an imaging study performed to detect pre-cancerous polyps in the large intestine, begins with an abdominal CT scan, which creates cross-sectional images of all structures in the abdomen including the spine. Computer software then arranges the CT images to create an interior or "fly-through" view of the colon.

Using the same CT images, another software application can create three-dimensional images of the spine, allowing bone mineral density to be measured. Low bone mineral density is usually associated with osteoporosis, a disease in which bones become fragile and more likely to break.
In the study conducted at the San Francisco Veterans Administration Hospital, the researchers evaluated the results of 35 patients who underwent CT colonography and bone mineral density testing with dual-energy x-ray absorptiometry (DEXA), a standard bone density screening tool. Patients included 30 males and five females ranging in age from 54 to 79.

The results of the study showed excellent agreement between the DEXA bone mineral density scores and the data generated through the CT colonography study.

"The bone density measurements obtained from CT colonography were comparable to the DEXA results," Dr. Aslam said. "Both tests identified osteoporotic bones."

Most physicians recommend that adults undergo CT colonography or conventional colonoscopy every seven to 10 years beginning at age 50.

"CT colonography isn’t a replacement for DEXA testing, but it could be a way to screen more people for osteoporosis," Dr. Aslam said. "When an individual undergoes CT colonography, we can also obtain a bone density measurement with no additional radiation and at minimal cost."

According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases, 10 million Americans over age 50 have osteoporosis. Approximately 34 million Americans are at risk due to low bone mass. Detecting osteoporosis early provides for early intervention and treatment.

Virtual colonoscopy at a Glance

• CT colonography may be used to screen for both colorectal cancer and osteoporosis.
• Bone mineral density measurements obtained with CT colonography were in agreement with dual-energy x-ray absorptiometry (DEXA) scores.
• Approximately 10 million Americans have osteoporosis, and 34 million are at risk for the disease..

Click here for the abstract (Assessment of Bone Mineral Density on CT Colonography)

Breast Cancer Treatment Offers Better Outcome to Women with Implants

Women with early-stage breast cancer who have undergone breast augmentation may be treated successfully with a partial-breast radiation treatment called brachytherapy, according to a study presented at the 94th Scientific Assembly and Annual Meeting (November 30 – December 5, 2008) of the Radiological Society of North America (RSNA) on Monday. Patients treated with brachytherapy have better cosmetic outcomes and avoid the risk of the implant hardening, compared to patients who undergo whole-breast radiation therapy.

"We are seeing an increasing number of breast cancer patients with augmentation,” explained Robert R. Kuske Jr., M.D., clinical professor at the University of Arizona Health Sciences Center (AHSC) and radiation oncologist at Arizona Oncology Services (AOS) in Scottsdale, Arizona. “By nature, these women are concerned about their appearance and we need to have options for them."

According to the American Society of Plastic Surgeons, breast augmentation is the most popular cosmetic surgery in the U.S. with 347,500 procedures performed in 2007. This represents an increase of 64 percent since 2000. Approximately one in eight women who undergo breast augmentation will develop breast cancer at some point in their lives.

The most common breast cancer treatment for patients with breast implants is skin-sparing mastectomy and implant exchange. Whole-breast radiation therapy after lumpectomy is an option, but carries a substantial risk during the healing process of scar tissue wrapping around the implant, causing it to become rock-hard and extremely painful. This condition, known as capsular contracture, also distorts the appearance of the breast.

Dr. Kuske set out to determine if partial-breast radiation with brachytherapy might offer a better outcome for women with implants wishing to avoid mastectomy.

Breast brachytherapy is a radiation treatment that can be given in higher doses to a small, targeted area of the breast after lumpectomy. Radioactive “seeds” are guided into place through small plastic tubes, or catheters, with the aid of imaging and a computer. The seeds emit high doses of radiation in short bursts.

Scar tissue is minimal, the implant remains unaffected and treatment time is shortened from 6.5 weeks with whole-breast radiation therapy to five days with brachytherapy.

For the study, 65 women who were diagnosed with small, early stage malignant tumors were treated with brachytherapy after a lumpectomy. The women received two doses per day, separated by six hours, over a five-day period. Follow-up was six months to five years. None of the patients experienced tumor recurrence during the follow-up period. Cosmetic outcome was determined to be good to excellent in 100 percent of patients with 95 percent judged excellent. Implant hardening was not observed in any of the patients.

"Compared to traditional treatments, brachytherapy offers an excellent alternative for these women," Dr. Kuske said. "It offers very high rates of tumor control with fewer side effects and is easier on their lifestyle."

Brachytherapy at a Glance

• Can successfully treat early-stage breast cancer in women with implants and preserve the breast's appearance.
• Substantially reduces the risk of implant hardening.
• Approximately one in eight women who undergo breast augmentation will develop breast cancer during her lifetime.

Click here to read the abstract (Breast Brachytherapy Improves Cosmetic Outcome and Reduces the Risk of Capsular Contracture in Breast Conservation Therapy for Women with Breast Cancer in the Presence of Augmentation Mammoplasty)

New Imaging Technology Targets Hard-to-Detect Breast Cancers

Breast-specific gamma imaging (BSGI) is effective in the detection of cancers generally not found on mammograms or by clinical exam, according to a study presented at the 94th Scientific Assembly and Annual Meeting (November 30 - December 5, 2008) of the Radiological Society of North America (RSNA) in Chicago on Wednesday.

"Breast-specific gamma imaging can help us to identify invasive lobular carcinoma, one of the most difficult to detect breast cancers," explained lead author Rachel F. Brem, M.D., professor of radiology and director of the Breast Imaging and Interventional Center at The George Washington University Medical Center in Washington, D.C. "It also can help us detect additional lesions of all types of breast cancer in women whose mammograms show only one suspicious lesion."


According to the American Cancer Society, breast cancer affects more women than any other non-skin cancer and accounts for more than 40,000 deaths annually in the U.S. Most experts agree that the best way to decrease breast cancer mortality is through early detection using mammography and clinical breast exam. However, some cancers are difficult to detect with mammography and clinical exam, particularly in the earliest stage when treatment is most effective.

While mammography findings are characterized by the difference in appearance between normal and suspicious breast tissue, breast-specific gamma imaging findings are based on how cancerous cells function.

"It is this physiological approach to breast cancer diagnosis that allows for improved cancer detection," Dr. Brem explained.

Breast-specific gamma imaging is an emerging technology using a high-resolution gamma camera that allows for imaging with very mild compression of the breast along with an injection of a low-dose nuclear material called a radiotracer, which is absorbed by the cells. Because cancerous cells have a higher rate of metabolic activity, the tracer is taken up by these cells at a higher level than in normal cells.

Dr. Brem and colleagues reviewed the records of 159 women with at least one suspicious or cancerous lesion found by mammography or physical exam, who had undergone breast-specific gamma imaging to determine if additional lesions were present.

The results showed an additional suspicious lesion missed by mammography and physical exam in 46 (29 percent) of the women. In 14 (36 percent) of the 39 women who underwent biopsy, the newly discovered lesions were cancerous.

"The data suggest that this new tool allows for the diagnosis of more and earlier breast cancers," Dr. Brem said.

Dr. Brem pointed out that breast-specific gamma imaging is not meant to replace mammography, but to be used as an adjunct to mammography. "It is an excellent tool for locating difficult-to-detect cancers and for screening high-risk women who have normal mammograms and physical examination," she said.

Breast-specific gamma imaging at a Glance:

• An effective method of detecting hard-to-find breast cancers
• Can identify cancer not visible on mammograms and not found by clinical examination
• The technology is based on the metabolic activity of cancer cells
  

Click here for the abstract (Breast Specific Gamma Imaging in Women with One Suspicious or Cancerous Breast Lesion)