Nursing study examines obesity in relation to breast cancer related lymphedema

Each year, about 1.38 million women worldwide are diagnosed with breast cancer. Advances in treatment have facilitated a 90% five-year survival rate among those treated. Given the increased rate and length of survival following breast cancer, more and more survivors are facing life-time risk of developing late effects of cancer treatment that negatively impact long-term survival. In particular, Breast cancer-related lymphedema is one of the most distressing and feared late effects.

Lymphedema, characterized by the abnormal swelling of one or more limbs, is most often the result of an obstruction or disruption of the lymphatic system over the course of the cancer treatment. Lymphedema usually manifests after a latent period of one to five, or even twenty years, after treatment. Consequently, lymphedema remains a major health problem affecting many breast cancer survivors and exerting a tremendous negative impact on survivors' quality of life. Although at present, no surgery or medication can cure lymphedema, this condition can be managed with early and appropriate treatment.

"Obesity is an established risk factor not only for breast-cancer related lymphedema but also for breast cancer occurrence, recurrence, and fatality," says Mei R. Fu, PhD, RN, ACNS-BC, FAAN, associate professor of Chronic Disease Management at the New York University College of Nursing (NYUCN). "Accordingly, we believe obesity is a significant, but modifiable risk factor for lymphedema."

However, Dr. Fu notes existing research has produced conflicting findings. For example, some studies suggest that obesity is a risk factor when defined as having a body mass index (BMI) of 30 kg/m2 or more, while others posit the risk is posed with as low of a BMI as 25 kg/m2.

Such discrepancies are in part due to study limitations, such as retrospective assessments, small sample sizes, and self-reports. To bridge the gap, a team of NYUCN researchers, led by Dr. Fu conducted a study, "Patterns of Obesity and Lymph Fluid Level during the First Year of Breast Cancer Treatment: A Prospective Study," designed to prospectively investigate patterns of obesity as it relates to lymphedema. The team's findings were published in the Journal of Personalized Medicine.

"We determined the best way to quantify the relationship between obesity and lymphedema, was to first examine obesity as it relates to lymph fluid level," said Dr. Fu. 'Patterns of Obesity and Lymph Fluid Level during the First Year of Breast Cancer Treatment: A Prospective Study,' followed 140 women through their first year of cancer treatment, measuring their lymph fluid levels -- known as L-Dex values -- and weight before their surgeries, four to eight weeks and a year post-op.

General instructions were given to participants on maintaining pre-surgery weight. Among the 140 participants, 136 completed the study. More than 60% of the participants were obese (30.8%) or overweight (32.4%), while only two participants were underweight and about 35% measured at normal weight. This pattern of obesity and overweight was consistent at four to eight weeks and twelve months post-surgery. At twelve months post-surgery, the majority of the women (72.1%) maintained pre-surgery weight and 15.4% had lost more than 5% of their weight; 12.5% of the women experienced more than a 5% increase in weight. L-Dex values consistent with lymphedema were particularly prevalent in patients with a BMI greater than 30 kg/m2, this trend was observed throughout the study.

Obesity and overweight remain among women at the time of cancer diagnosis and the patterns of obesity and overweight continue during the first year of treatment.

"General instructions on having nutrition-balanced and portion-appropriate diet and physical activities daily or weekly can be effective to maintain pre-surgery weight," says Dr. Fu. "Such general instructions may create less burden and stress to women when facing the diagnosis and treatment of breast cancer."

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New York University.

New study links neuropilin 2 deficiency to inflammation-induced edema and lymphedema

Unexpected massive, persistent fluid accumulation and fewer lymphatic capillaries lead to formulation of new hypothesis, according to a new report in The American Journal of Pathology

Fluid accumulation and swelling (edema) may result from the malfunctioning of regulatory processes controlling vessel permeability in the body. Edema frequently occurs in chronic inflammatory diseases including psoriasis and eczema. Capillaries in the lymphatic system usually drain the excess fluid but their dysfunction can lead to another serious condition: lymphedema. A new study published in The American Journal of Pathology found that deficiency in neuropilin 2 (Nrp2) receptors in vascular endothelial cells results in excessive and prolonged fluid build-up after inflammation. This discovery may guide investigators toward new pharmacological therapies for edema and lymphedema.

The newest research for lead investigator Diane R. Bielenberg, PhD, began with a twist. Bielenberg, an Assistant Professor in the Department of Surgery, Harvard Medical School and Vascular Biology Program, Boston Children's Hospital (Boston), described how previous studies that inhibited vascular endothelial growth factor receptors (VEGFRs, the co-receptors of Nrp2) have shown reduced blood vessel permeability following inflammation. "Therefore, we expected to see less permeability after inflammation in neuropilin 2 (Nrp2) knockout mice," Bielenberg explained. To her team's surprise, the Nrp2 knockout mice showed massively increased and prolonged edema following inflammation. Investigation into this finding led Bielenberg's laboratory to formulate a novel hypothesis -- that endogenous Semaphorin 3F (Sema3F) protein acting through Nrp2 inhibits vascular permeability and edema. Additional experiments and data support this new hypothesis.

The investigators measured ear swelling in mice after topically introducing an inflammation-causing substance. Fluid retention was 2.5-fold higher in the Nrp2-deficient mice than controls. The swelling in control mice began to recede within two days of inflammation and returned to near-normal levels by four days. In contrast, the swelling in the Nrp2-deficient mice remained significantly elevated over control levels for more than 10 days.

The researchers also found that in Nrp2-mutant mice the lack of a superficial lymphatic capillary plexus causes impaired drainage of fluid. Co-investigators Patrick Mucka, MS, and Nicholas Levonyak, MS, of the Vascular Biology Program at Boston Children's Hospital, explain that the prolonged lymphedema seen in Nrp2 knockout mice may be caused by architectural defects resulting from improper lymphatic vessel sprouting during development.

Interestingly, the enhanced leakage in the Nrp2-deficient mice was associated with the loss of endogenous Sema3F activity. Sema3F competes with VEGFA for binding to Nrp2 and is therefore termed an inhibitory ligand of Nrp2. This competitive inhibition, in turn, prevents vascular permeability. Addition of exogenous Sema3F protein therefore inhibits edema. Dr. Bielenberg encourages the pursuit of future studies on the role of the Sema3F/Nrp2 axis in chronic inflammation or lymphedema. Although these studies were performed in mice, mutations in the human NRP2 gene have been found in patients with primary lymphedema. This gene conservation suggests a high likelihood that humans and mice share a similar molecular mechanism behind this process, an encouraging indication for the translation of these findings.

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Elsevier

Researchers study patients' genetic and susceptibility risk factors for lymphedema

Each year, about 1.38 million women worldwide are diagnosed with breast cancer. Advances in diagnosis and treatment have facilitated a 90-percent, five-year survival rate, among those treated. However, with the increased rate and length of survival following breast cancer, patients face a lifetime risk of developing lymphedema, one of the most distressing and feared late onset breast cancer-related effects.

Lymphedema is an abnormal accumulation of lymph fluid in the ipsilateral body area, or upper limb. This remains an ongoing major health problem affecting more than 40 percent of 3.1 million breast cancer survivors in the U.S. Lymphedema following breast cancer surgery is typically considered to be primarily due to the mechanical injury from surgery. However, recent research has found that inflammation-infection and higher body mass index are also main predictors of lymphedema.

Researchers from New York University Rory Meyers College of Nursing (NYU Meyers), led by Dr. Mei R. Fu, PhD, RN, FAAN, conducted a study, "Precision assessment of heterogeneity of lymphedema phenotype, genotypes and risk prediction," to address this phenomenon and prospectively examine phenotype of arm lymphedema by limb volume and lymphedema symptoms in relation to inflammatory genes in women treated for breast cancer.

The study, published in The Breast, is the first of its kind in exploring associations between genetic susceptibility targeting identified phenotypic risk factors of inflammation and heterogeneous phenotypes of lymphedema.

"It remains puzzling that up to 23% of survivors who only had lumpectomy with sentinel lymph node biopsy of 1 or 2 lymph nodes removed have developed lymphedema, while some survivors who had mastectomy with more than 10 lymph nodes removed have not," said Dr. Fu. "There is a critical need to understand heterogeneity of lymphedema phenotype in relation to assessment of lymphedema phenotype and related biological mechanism."

The study consisted of 136 women with a mean age of 52 with a first time diagnosis of breast cancer (Stage I-III), and were scheduled for surgical treatment of lumpectomy or mastectomy.
The researchers measured data at 4-8 weeks post-surgery and 12 months post-surgery to monitor development of lymphedema during this period. They used lymphedema phenotyping to measure more symptoms than the typical method of observing swelling and limb volume. The symptom phenotyping was important in indicating early stage lymphedema where limb volume cannot be assessed yet.

The researchers found that using symptom phenotyping, prior to surgery, only one participant had more than 8 symptoms and only 18 had 1-7 symptoms. At 4-8 weeks post-surgery all participants had at least one symptom, 53% had 1-7 symptoms, and 46% had more than 8 symptoms, whereas only 16% had arm lymphedema defined by limb volume increase. At 12 months post-surgery 26.5% had more than 8 symptoms and 63% reported 1-7 symptoms, whereas only 22.8% had arm lymphedema as defined by limb volume.

Additionally, prior to surgery, identification of symptom phenotypes was not feasible, as 86% of participants were symptom-free. However, at 4-8 weeks post-surgery 58.1% of participants were classified as the phenotype of impaired limb mobility, with 86% discomfort, and 55.9% fluid accumulation. At 12 months 55.2% of participants were classified as the phenotype of impaired limb mobility with 38.2% pain/discomfort, and 44.1% fluid accumulation.

This data found significant associations between genotypes related to several lymphatic and inflammatory genes and symptom phenotypes of impaired limb mobility, fluid accumulation, and pain/discomfort. The data further provides support for heterogeneity of lymphedema phenotypes, especially phenotype of symptom clusters based on biological mechanisms.

Dr. Fu notes that the sample size and only 12-month period of observation does put limitations on the study.

The evidence from the study supports that interventions to promote lymph fluid flow and optimize body mass index have demonstrated positive effects for phenotype of fluid accumulation. Additionally, this study underscores the need for further research and exploration to advance understanding.

"Precision assessment of heterogeneity of lymphedema phenotype and understanding the biological mechanism of each phenotype through exploration of inherited genetic susceptibility is a logical step for finding a cure for this chronic condition," said Dr. Fu. "Our research team has laid the foundation for, and shown the importance of, further studies on this topic. We hope it will help us gain a better understanding of lymphedema that will eventually lead to a cure."

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New York University

Retinoic acid may significantly prevent lymphedema development, experimental model suggests

A study conducted at the Keck School of Medicine of the University of Southern California (USC) showed that 9-cis retinoic acid (alitretinoin) could significantly prevent postsurgical lymphedema. Furthermore, the experiments were conducted with updated, easily reproducible mouse models that more accurately simulated lymphedema development in humans. The National Institutes of Health-funded study was published in the Annals of Surgery.

Lymphedema occurs when damaged lymph nodes are unable to drain properly, causing swelling and tissue buildup. Lymphedema affects 140 million individuals globally, including 5 million people in the United States whose lymphedema is related to cancer-related lymphadenectomy. As surgical developments continue to increase cancer survival rates, the prevalence of lymphedema is expected to rise. And with no known cure for post-surgical lymphedema, lymph node dysfunction can negatively impact long-term quality of life.

"Physically, lymphedema is both uncomfortable and inconvenient," said Alex Wong, MD, assistant professor of surgery at Keck School of Medicine and one of the co-corresponding authors of the study. "Some patients express frustration at things we take for granted, like getting dressed. And for many of them, the swollen and deformed extremity is an unwelcome reminder of the cancer they fought or are still fighting."

To examine the effect of alitretinoin, the research team induced lymphedema by making a small incision in the hind legs of mice rather than the base of the tail, as previous studies had done. This updated model better simulated lymph node dysfunction in humans in that rodent tails are not subject to the effects of gravity to the same extent as human arms and legs. And more simply, humans do not have a tail.

"Developing a more effective model for lymphedema research is as much of an achievement from our research as illustrating the potential benefits of retinoic acid," said Young-Kwon Hong, PhD, associate professor of surgery at Keck School of Medicine and co-corresponding author of the study. Hong previously illustrated the potential benefits of alitretinoin on preventing lymphedema in petri-dish models before developing the mouse model.

After the hind paw incisions were repaired, the mice were divided into two groups. One group received daily injections of 9-cis retinoic acid, while the other received a vehicle solution as a control. The mice treated with the retinoic acid experienced less postsurgical edema and significantly less paw lymphedema compared to the control group. Moreover, the mice treated with the retinoic acid had much faster lymphatic drainage and increased lymphatic vessel density.

"Lymphatic drainage and maintenance of the integrity of the lymphatic vessels are two key factors in preventing lymphedema," Hong said. "9-cis retinoic acid's ability to accomplish both makes it a promising treatment option."

Alitretinoin is already approved by the Food and Drug Administration for the treatment of skin lesions in acquired immune deficiency syndrome-related Kaposi's sarcoma and eczema. If further studies prove fruitful, Wong hopes to establish a clinical trial for alitretinoin as a preventive measure against lymphedema.

"Our immediate next step is to experiment with timing," Wong said. "Currently, physicians watch and wait for lymphedema, but our study suggests that treatment at the time of surgery may be a more effective course."

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Keck Medicine of USC.

Psychological Intervention Lowers Survivors’ Fear of Cancer Recurrence

"The number of people surviving cancer is higher than ever before, but many survivors fear that the cancer will return even long after they have finished treatment. The hope is that the positive results of this fear-reducing intervention will pave the way for making it more widely available to patients," said Don S. Dizon, MD, FACP, ASCO Expert.

CHICAGO -- About 50% of all cancer survivors and 70% of young breast cancer survivors report moderate to high fear of recurrence. The fear can be so distressing that it negatively affects medical follow-up behavior, mood, relationships, work, goal setting, and quality of life. Yet, interventions to alleviate this fear are lacking.

In a phase II randomized clinical trial, a psychological intervention called Conquer Fear substantially lowered fear of recurrence immediately after the intervention, and three and six months later. General anxiety, cancer-specific distress, and quality of life were better in the psychological intervention group immediately after therapy.

The study will be featured in a press briefing today and presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.

"The reduction in fear of recurrence in the psychological intervention group was large enough to improve survivors' psychological and emotional wellbeing," said lead study author Jane Beith, MD, PhD, a Medical Oncologist at the University of Sydney in Australia, who developed the Conquer Fear intervention with colleagues, including psycho-oncologist Phyllis Butow, BA(Hons)Dip Ed, MClinPsych, MPH, PhD. "The majority of participants were young women with breast cancer, but we expect the intervention may be appropriate for other patients who have moderate to high fear of recurrence."

About the Intervention
The Conquer Fear psychology intervention is based on a novel theoretical framework developed by the authors (the intervention was developed for research and is not yet used in clinical practice). Trained study therapists delivered the intervention in five 60- to 90-minute individual, face-to-face sessions over 10 weeks. Conquer Fear focuses on:

• accepting the inherent uncertainty of whether the cancer would come back
• teaching strategies to control worry
• giving survivors more control over where they place their attention
• helping them focus on what they want to get out of life
• choosing a sensible level of cancer screening and sticking to it

About the Study
Researchers randomly assigned 222 survivors of stage I-III breast cancer, colorectal cancer, or melanoma who reported high fear of recurrence to either the Conquer Fear intervention or relaxation training (control group). All survivors had completed cancer treatment two months to five years before enrolling in this study and were cancer free at the time.

Survivors in the control group received five 60-minute, individual, face-to-face relaxation sessions. The sessions were delivered over 10 weeks by trained study therapists and incorporated muscle relaxation, meditative relaxation, and visualization and quick relaxation techniques. Both groups received instructions for home-based practice.

To measure change in fear of cancer recurrence, researchers used total scores from a validated 42-item questionnaire called Fear of Cancer Recurrence Inventory or FCRI. The scores range from 0 to 168, with higher scores indicating worse fear of recurrence. Survivors completed the questionnaire at enrollment, immediately after the intervention, and three and six months later.

Key Findings
The average FCRI score at baseline was 82.7 in the intervention arm and 85.7 in the control arm. The primary outcome of the study, total fear-of-cancer-recurrence score, was reduced significantly more in the intervention group (by 18.1 points on average) than in the control group (by 7.6 points on average), immediately after the intervention. This represents a standardized effect size of 0.44, within the range considered clinically important.

FCRI scores continued to decrease over time, with significant difference between groups at 6 months, decreasing by 27.2 points on average in the intervention group and 17.8 points on average in the control group.

The researchers also explored other patient outcomes, including cancer-specific distress (how much someone is plagued with thoughts about cancer), general distress (anxiety, depression, and stress), and quality of life (covers independent living, physical pain, mental health, happiness, coping, relationships, and self-worth). The psychological intervention had a greater positive effect on these outcomes than relaxation training.

Next Steps
The authors note that while Conquer Fear is effective in a face-to-face format, it is a time- and resource-intensive intervention. Other formats, such as delivery via internet, in a group, or by phone, may be possible. A stepped care approach could also be considered, with only those with severe fear of recurrence receiving face-to-face intervention.

"In this study, the interventions were delivered by experienced psycho-oncologists. It is possible that community psychologists or other professionals who have basic training in cognitive therapy could deliver the interventions, given appropriate training and supervision," said Dr. Beith.

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American Society of Clinical Oncology.

Less can be more when removing lymph nodes during breast cancer surgery

A conservative approach to removing lymph nodes is associated with less harm for breast cancer patients and often yields the same results as more radical procedures, researchers at UT Southwestern Medical Center have found.

In the Oct. 2 edition of the Journal of the American Medical Association, lead author Dr. Roshni Rao, associate professor of surgery at UT Southwestern, and other investigators from the Harold C. Simmons Cancer Center reviewed studies on patient outcomes of women who had received various forms of surgical treatment, ranging from removal of one lymph node to prevent the spread of breast cancer to removing the entire network of lymph nodes spanning the armpits.

Until recently, clinical practice guidelines advised complete axillary node dissection -- removal of all 20-30 axillary nodes -- if a woman's sentinel node biopsy was positive. The sentinel node is generally the first node to which cancer cells will spread from a primary tumor. A positive sentinel lymph node biopsy indicates the tumor has metastasized and can be used to determine the stage of the cancer. Axillary lymph nodes are distributed at the edge of the chest muscles and into the armpits and lower neck.

For women with no suspicious axillary nodes who undergo breast-conserving therapy, there is little evidence of benefit in doing a complete axillary node dissection compared with sentinel node biopsy alone, the reviewers reported. Breast conserving therapy is defined as partial mastectomy followed by whole breast radiation.

"In the past, axillary nodal status was a critical factor considered in therapy decisions," said Dr. Rao, a breast cancer surgeon. "With the validation of sentinel lymph node biopsy, the same staging information can be obtained with less morbidity and risk to the patient. And now that decisions regarding chemotherapy are often guided by molecular tumor profiling in an era of personalized medicine, there are other avenues to explore beyond aggressive surgeries."

To assess the effect of the guidelines, Dr. Rao and her colleagues reviewed the risks and benefits of sentinel node biopsy as compared with complete axillary node dissection in previous published research. They also compared these procedures with nonsurgical interventions (i.e., additional radiation) in women with breast cancer who do not have palpable lymph nodes or ultrasound evidence that their cancer has spread to the axillary nodes.

They also reviewed the rate of recurrence of axillary node metastases, mortality, morbidity, and complications associated with each intervention, using online medical databases. In all, more than 1,000 results were examined from 17 studies to write the JAMA review.

Avoiding axillary surgery if possible is important, Dr. Rao said, because it can cause shoulder and arm symptoms including lymphedema, severe pain or numbness, and reduced range of motion, and it generally involves longer stays in the hospital, as opposed to sentinel node surgery.

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UT Southwestern Medical Center

New solution in detecting breast-cancer related lymphedema

Viewed as one of the most feared outcomes of breast cancer treatment, doctors struggle detecting and diagnosing breast-cancer related Lymphedema -- a condition affecting the lymphatic system and causing psychosocial distress and physical challenges for patients.

Now, a team of researchers led by Mei R. Fu, PhD, RN, ACNS-BC, associate professor of Chronic Disease Management at the New York University College of Nursing (NYUCN), offers supporting evidence for using Bioelectrical Impedance Analysis (BIA) ratios to assess Lymphedema. The study, "L-DEX Ratio in Detecting Breast Cancer-Related Lymphedema: Reliability, Sensitivity, and Specificity," published in Lymphology, argues because the low frequency electronic current cannot travel through cell membranes, it provides a direct measure of lymph fluid outside the cells. This allows for a more accurate assessment of lymphedema using a Lymphedema Index named L-Dex ratio.

"To lessen breast cancer survivors' worry about lymphedema development, the BIA may have a role in clinical practice by adding confidence in the detection of arm lymphedema among breast cancer survivors," says Dr. Fu, "even when pre-surgical BIA baseline measures are not available."

The objective of the study was to examine the reliability, sensitivity, and specificity of cross-sectional assessment of BIA in detecting lymphedema in a large metropolitan clinical setting.

Measuring lymphedema is challenging because most methods cannot distinguish bone and soft tissues from extracellular fluid. BIA is time-efficient, easy to operate and easy to interpret, making it ideal for clinical practice. Dr. Fu's research collected data from 250 women, including healthy female adults, breast cancer survivors with lymphedema, and those at risk for lymphedema, demonstrating that survivors with lymphedema had significantly higher L-Dex ratios, which shows the possibility of using BIA to discriminate between those cohorts of women.

"Our study also demonstrated that using a more sensitive L-Dex cutoff point, this allowed for BIA to catch 34% of the usually missed lymphedema cases," said Dr. Fu. "This allows for earlier treatment, which naturally leads to better outcomes for at-risk patients."

The American Cancer society estimates that in 2013 approximately 232,340 new cases of breast cancer are detected, adding to the already 2.9 million breast cancer survivors, all with a at a lifetime risk of Lymphedema.

"Giving that all the women who are treated for breast cancer are at a life-time risk for lymphedema, using assessment methods that can accurately identify true lymphedema cases among at-risk breast cancer survivors is of the ultimate importance for clinical practice," added Dr. Fu.

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New York University

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Genetic Markers Associated To the Growth of Lymphedema in Breast Cancer Survivors

A new UC San Francisco study has found a clear association between certain genes and the development of lymphedema, a painful and chronic condition that often occurs after breast cancer surgery and some other cancer treatments.
The researchers also learned that the risks of developing lymphedema increased significantly for women who had more advanced breast cancer at the time of diagnosis, more lymph nodes removed or a significantly higher body mass index.
The study is the first to evaluate genetic predictors of lymphedema in a large group of women using a type of technology, bioimpedance spectroscopy, to measure increases in fluid in the arm. Bioimpedance spectroscopy is a noninvasive procedure that allows one to measure body composition including an increase in fluid in an arm or a leg.
The study, which involved some 400 women who were tracked over four to five years, will be published online on April 16 in PLOS ONE.
“The genetic markers found in our study make perfect sense,” said senior author Bradley Aouizerat, PhD, a professor at the UCSF School of Nursing in the department of physiological nursing. “These genes are ‘turned on’ later in the development of our lymph system and blood vessels. They appear to play a role in the ability of our lymphatic system to function on an ongoing basis. It is possible in some individuals who have changes in these genes, that lymphedema could develop after an injury like breast cancer surgery because these genes do not function properly.”

Lymphedema is a swelling or buildup of fluid in the lymphatic tissues, typically in the arms and fingers but also commonly in the patient’s legs and trunk. It can occur after treatment for any form of cancer that affects lymph node drainage. The exact prevalence is unknown, and the onset of the condition can greatly vary, but as many as 56 percent of women who undergo breast cancer surgery develop lymphedema within two years, according to the National Cancer Institute. More than a half-million breast cancer survivors in the United States are estimated to be afflicted with the condition.
Lymphedema can be debilitating, causing scarring, discomfort, disfigurement, difficulty in exercising, walking or other daily activities. Some patients are unable to wear their usual clothing or jewelry because of the increased weight and size of their affected limbs. There’s no cure for the condition – treatment generally centers on controlling pain and reducing swelling.

Genomic Determinants of Lymphedema

To date, much of the research on lymphedema focused on identifying which women were at greater risk for the development of the condition, and relied only on patient self-reporting or on data from their medical charts.
In the new study, the authors hypothesized that genomic determinants were behind some of the variations in the occurrence of lymphedema as well as the time of onset of the condition.
The study involved 410 women who were at least six months post-treatment for breast cancer surgery on one breast, and either had lymphedema in their upper extremity or did not have the condition.
The women were assessed at the Clinical Research Center at the UCSF Medical Center at Mt. Zion, one of eight clinical sites in the Bay Area managed by UCSF’s Clinical and Translational Science Institute.
As part of the research, the women underwent spectroscopy measurements of their arms, and genomic DNA was extracted. Genotyping was performed blinded to the women’s lymphedema status.
The researchers found that women with lymphedema had:

• More advanced breast cancer at the time of diagnosis;
• A higher number of positive lymph nodes;
• Were more likely to have a significantly higher body mass index.
• The authors also found associations between lymphedema and four genes known to play a role in the development of lymphedema.

“These findings suggest that complex interactions may exist between a variety of patient characteristics and genetic markers that place some women at higher risk for the development of lymphedema,’’ said lead author Christine Miaskowski, RN, PhD, a professor at the UCSF School of Nursing in the department of physiological nursing. “Our hope is that once our findings are confirmed in a future study, we will be able to identify women at higher risk for lymphedema prior to breast cancer surgery, and initiate measures to prevent the development of this devastating condition.”
The study was funded by grants from the National Cancer Institute (CA107091 and CA118658) and the American Cancer Society.

Researchers Advocate Exercise for Breast Cancer Survivors, Lymphedema Patients

Lymphedema, a chronic swelling condition common in breast cancer survivors, affects three million people in the U.S. In the past, most people believed that exercise might induce or worsen lymphedema. After reviewing the literature, University of Missouri researchers say the benefits of exercise outweigh the risks for breast cancer survivors and patients with lymphedema. Jane Armer, professor in the Sinclair School of Nursing, says patients at risk for lymphedema can exercise if they closely monitor their activities.

"Exercise can be beneficial and not harmful for breast cancer survivors," Armer said. "Each individual should balance the pros and cons of the activity she chooses, but keep in mind that being sedentary has risks and being active is beneficial in many ways, including possibly reducing the risk of cancer recurrence."

Lymphedema can occur any time after cancer treatment and is usually caused by the removal or radiation of lymph nodes as part of the treatment process. Armer found that patients who exercise had no greater risk for developing lymphedema than those who do not exercise. In addition, patients with lymphedema did not worsen their condition by exercising. She says future research is needed to determine whether exercise prevents the condition.

"Breast cancer survivors do not need to restrict their activity as we once thought," Armer said. "If patients want to be active, they should carefully condition their bodies by increasing repetitions of resistance exercises under proper supervision."

In another new literature review, Armer and her colleagues examined published literature pertaining to the surgical treatment of lymphedema. They found that in most studies surgery did not eliminate the need for traditional compression garments in patients with lymphedema.

"Many people think surgery will correct the underlying lymphatic problem, but that is not correct," Armer said. "There are several surgical techniques that may reduce the swelling associated with lymphedema. In most cases, it is recommended that patients undergo traditional therapy using specialized massage and compression garments and bandages to reduce fluid and swelling before considering surgery."

The literature reviews were the first two in a series of thirteen reviews to be published in conjunction with the American Lymphedema Framework Project (ALFP). Established in 2008, the ALFP aims to increase awareness of lymphedema, improve patient care and enhance training for professionals caring for persons at risk or with cancer-related lymphedema. The ALFP has two main goals: maintain up-to-date best practices supported with evidence-based lymphedema treatment guidelines for health practitioners, and create a minimum data set of all available lymphedema research and clinical data.

The first article, "Exercise in patients with lymphedema: A systematic review of the contemporary literature," was published in the Journal of Cancer Survivorship. The second, "The surgical treatment of lymphedema: A systematic review of the contemporary literature," was published in Annals of Surgical Oncology.

Liver Cells, Insulin-Producing Cells, Thymus Can Be Developed in Lymph Nodes, Team Discovers

Lymph nodes can provide a suitable home for a variety of cells and tissues from other organs, suggesting that a cell-based alternative to whole organ transplantation might one day be feasible, according to researchers at the University of Pittsburgh School of Medicine and the McGowan Institute for Regenerative Medicine. In a report recently published online in Nature Biotechnology, the research team showed for the first time that liver cells, thymus tissue and insulin-producing pancreatic islet cells, in an animal model, can thrive in lymph nodes despite being displaced from their natural sites.

Hepatitis virus infection, alcoholic cirrhosis and other diseases can cause so much damage that liver transplantation is the only way to save the patient, noted senior investigator Eric Lagasse, Pharm. D., Ph.D., associate professor, Department of Pathology, Pitt School of Medicine. Children with DiGeorge syndrome lack functional thymus glands to produce essential immune cells, and diabetes can be cured with a pancreas transplant.

"However, the scarcity of donor organs means many people will not survive the wait for transplantation," said Dr. Lagasse, whose lab is at the McGowan Institute. "Cell therapies are being explored, but introducing cells into tissue already ravaged by disease decreases the likelihood of successful engraftment and restoration of function."

In the study, his team tested the possibility of using lymph nodes, which are abundant throughout the body and have a rich blood supply, as a new home for cells from other organs in what is called an "ectopic" transplant.

They injected healthy liver cells from a genetically-identical donor animal into lymph nodes of mice at various locations. The result was an enlarged, liver-like node that functioned akin to the liver; in fact, a single hepatized lymph node rescued mice that were in danger of dying from a lethal metabolic liver disease. Likewise, thymus tissue transplanted into the lymph node of mice that lacked the organ generated functional immune systems, and pancreatic islet cell transplants restored normal blood sugar control in diabetic animals.

"Our goal is not necessarily to replace the entire liver, for example, but to provide sufficient cell mass to stabilize liver function and sustain the patient's life," Dr. Lagasse said. "That could buy time until a donor organ can be transplanted. Perhaps, in some cases, ectopic cell transplantation in the lymph node might allow the diseased organ to recover."

Best Ways To Manage Lymphedema: Exercise And Complete Decongestive Therapy

Nearly 40 percent of breast cancer survivors suffer from lymphedema, a chronic condition that causes body limbs to swell from fluid buildup, as a result of lymph node removal and radiation therapy. A cure for lymphedema does not exist, so individuals with the condition must find ways to manage the symptoms throughout their lifetimes. Now, a team of researchers and clinicians working with a University of Missouri lymphedema expert has found that full-body exercise and complete decongestive therapy (CDT) are the best ways for patients to minimize their symptoms and maintain their quality of life.

"There's a sense of empowerment - of autonomy - that comes from meeting the challenge of living with lymphedema," said Jane Armer, an MU nursing professor. "Some breast cancer survivors say that they've become a new person after cancer because they met a challenge, and they like the stronger person they've become. The challenge of lymphedema is similar. It's something that is pervasive in every part of life. It takes problem solving and persistence to manage the condition without letting it interfere with their goals."

Armer and her colleagues reviewed published research about lymphedema self-management in order to determine which practices were most effective in managing the condition. The researchers found that full-body exercise, such as weight lifting and stretching, was likely to be effective in minimizing lymphedema symptoms. In addition, the researchers concluded that complete decongestive therapy (CDT), a comprehensive treatment approach that incorporates skin care, exercise, manual lymphatic drainage and bandaging of swollen limbs, also helps patients effectively manage the condition.

"Previous research suggests that, the earlier the interventions, the better the outcomes," Armer said. "If patients can learn how to successfully manage the condition early on, then they can continue those processes throughout their lives, and their outcomes will be better than those of individuals who resist participating in self-care."

New Guideline Offers Evidence-Based Testimonials On Function Of Sentinel Lymph Node Biopsy For Melanoma Staging In The U.S.A.

The American Society of Clinical Oncology (ASCO) and the Society for Surgical Oncology (SSO) have issued their first evidence-based clinical practice guideline on the use of sentinel lymph node biopsy (SLNB) to stage patients with newly diagnosed melanoma. Although SLNB has proven to be an important tool for determining prognosis and selecting treatment for many patients with melanoma, recent studies suggest that the procedure is inconsistently used. The new guideline recommendations, based on a review of all available evidence, are intended to clarify which patients should receive the procedure.

SLNB is a minimally invasive surgical technique that enables doctors to determine whether cancer has spread, a key factor in determining the appropriate surgical and drug treatments, and establishing a patient's eligibility for clinical trials. In the procedure, the "sentinel" lymph node - the node close to the tumor, to which cancer cells are most likely to spread - is removed and examined under a microscope for evidence of cancer. If cancer is found, additional surrounding lymph nodes are removed to accurately assess, or "stage," the disease and prevent further cancer spread. In most cases, however, no cancer is detected in the sentinel node and no additional lymph nodes need to be removed, allowing patients to avoid further pain, discomfort, expense, and possible side effects from a more extensive operation.

"When used for the right patients at the right time, sentinel lymph node biopsy is one of our best tools for personalizing melanoma treatment, and for sparing patients from unnecessary procedures or therapies," explained Sandra L. Wong, MD, lead author and Co-chair of the guideline panel and Assistant Professor of Surgery at the University of Michigan. "But we know this procedure is used inconsistently in the United States. We hope this guideline will provide the clarity physicians need to make the most of the procedure and further improve care for patients with melanoma."

The new clinical practice guideline was developed by a multidisciplinary panel of 14 clinical and methodological experts convened by ASCO and SSO. The panel reviewed literature published between January 1990 and August 2011, analyzing 73 studies that included more than 25,000 patients.

The guideline recommendations state the following:

SLNB is recommended for all patients with melanoma tumors of intermediate thickness (between 1 and 4 mm): Studies have shown that the technique is useful for identifying small nearby metastases in these patients, who account for about one-third of all melanoma cases. SLNB detects cancer in the sentinel node in about 18 to 26 percent of these patients, according to the guideline authors.

Evidence is insufficient to recommend routine SLNB for patients with thin melanoma tumors (less than 1 mm): Thin melanomas are the most common form of melanoma, and can usually be cured through surgical removal of the primary tumor. While SNLB is not necessary in most cases, the guideline recommendations note that it may be considered in select patients with thin melanomas who have certain high-risk factors, such as an ulcerated tumor or rapidly dividing cancer cells.

SLNB for patients with thick melanoma tumors (greater than 4 mm) may be recommended: Thick melanomas are more uncommon than the above two types, but are considered more likely to spread elsewhere in the body. While there are few studies focusing on the use of SLNB in patients with thick melanomas, use of SLN biopsy in this population may be recommended for staging purposes and to facilitate regional disease control.

Completion lymph node dissection is recommended for all patients with a positive SLNB: Complete removal of the remaining lymph nodes has been shown to prevent or limit further cancer spread in these patients. While it is not yet known whether this approach improves survival, the authors note that an ongoing study, the Multicenter Selective Lymphadenectomy Trial II, is expected to help resolve that question.

The guideline concludes that doctors should discuss SLNB as part of a comprehensive treatment planning process with their patients with melanoma. This discussion should address the risks and benefits of the procedure, and patients' individual values and preferences, so patients can make fully informed decisions.

"Our rapidly growing understanding of the biology of melanoma is driving development of more effective treatments with fewer side effects for patients," said Gary H. Lyman, MD, MPH, guideline Co-chair and Professor of Medicine and Director of Comparative Effectiveness and Outcomes Research at Duke University School of Medicine and the Duke Cancer Institute. "But to take advantage of this progress, we need to know the true extent of the disease from the start. This guideline will help ensure that sentinel lymph node biopsy is used appropriately whenever it can provide that vital information while avoiding unnecessary procedures in patients who are unlikely to benefit."

More information on the new guideline can be found at: http://www.asco.org/guidelines/snbmelanoma, and at http://www.surgonc.org--policy/practice-management/clinical-guidelines/clinical- guidelines---melanoma.aspx. A patient-oriented view of the guideline, "What to Know: ASCO/SSO Guideline on Use of Sentinel Lymph Node Biopsy for Melanoma Staging," can be found on ASCO's award-winning patient information website, http://www.cancer.net.

Lymphedema Patients Need Personalized Care

Millions of American cancer survivors experience chronic discomfort as a result of lymphedema, a common side effect of surgery and radiation therapy in which affected areas swell due to protein-rich fluid buildup. After reviewing published literature on lymphedema treatments, a University of Missouri researcher says emphasizing patients' quality of life rather than focusing solely on reducing swelling is critical to effectively managing the condition.

Jane Armer, professor in the MU Sinclair School of Nursing and director of nursing research at Ellis Fischel Cancer Center, said many insurance providers and health care professionals assess whether lymphedema patients need treatment based solely on how swollen their limbs are. However, several studies have shown that the volume of fluid doesn't necessarily correspond with patients' discomfort.

"Practitioners need to treat the swelling while considering patients' distress. We don't want to burden them with unnecessary or ineffective treatments," Armer said. "Health care providers should focus on managing symptoms and choose carefully among various treatments to provide individualized care plans that comfort patients, which may require modifying existing protocols."

In their literature review, Armer and her colleagues found that Complete Decongestive Therapy (CDT), a comprehensive approach for treating lymphedema involving skin care, exercise, manual lymphatic drainage and compression of the swollen limbs, may be the best form of specialized lymphedema management.

"Patients have different medical needs and come from culturally diverse backgrounds. They have different goals, support systems, pain levels and treatment tolerances. All these factors influence patients' responses to care, which affects their well-being," said Marcia Beck, a review co-author and an MU graduate who now works at Truman Medical Centers in Kansas City, Mo.

"Caring for lymphedema patients should be flexible and adjusted to maintain patients' quality of life," said Ausanee Wanchai, another co-author who received her doctorate at MU and now teaches at Boromarajonani College of Nursing in Buddhachinnaraj, Thailand.

In a separate literature review, the researchers found that Intermittent Pneumatic Compression (IPC) therapy, in which sequential inflatable devices surrounding swollen limbs are used to increase lymphatic circulation, is beneficial as an adjunct therapy for chronic lymphedema patients who have limited or no access to medical care; patients can use the compression devices in their homes.

Armer said further research is needed to demonstrate the usefulness of various lymphedema treatments, such as CDT and IPC. The literature reviews were the third and fourth in a series of 12 to be published in conjunction with the American Lymphedema Framework Project (ALFP). As director of the ALFP, Armer works alongside clinical experts and investigators to increase awareness of lymphedema and related disorders. The ALFP was founded in 2008 and is headquartered at the MU Center for Lymphedema Research, Practice and Health Policy. Its steering committee and staff currently are partnering with the International Lymphedema Framework (ILF) in producing an updated edition of the ILF Best Practice Document from 2006.

The article, "Palliative Care for Cancer-Related Lymphedema: A Systematic Review," recently was published in the Journal of Palliative Medicine. Armer's co-authors also included researchers from MU and the University of Texas. The other review, "Intermittent Pneumatic Compression Therapy: A Systematic Review," was published in the journal Lymphology earlier this year. Researchers from the NorthShore University HealthSystem, Walter Reed Military Medicine Center and University of Texas contributed to the review.

Lymfactin™ Discovered To Considerably Gain Growth Of Lymphatic Vessels In Animal Study

Laurantis Pharma, a privately held biotechnology company based in Finland, announced that LymfactinTM, adenoviral VEGF-C growth factor therapy, was successful in rebuilding lymphatic vessels in pre-clinical animal models. The use of VEGF-C growth therapy to regenerate lymphatic vessels over time may be used to assist lymph node transfer surgery as a technique to treat secondary lymphedema.

The results were presented at the 23rd International Congress of Lymphology in Malmö, Sweden by Kari Alitalo, MD, PhD, Academy Professor, Molecular Cancer Biology Program Biomedicum Helsinki, University of Helsinki, and Anne Saaristo, MD, PhD, Consultant Plastic Surgeon, Turku University Central Hospital, Turku, Finland. The researchers were able to demonstrate VEGF-C's ability to induce the spontaneous growth of lymphatic vessels during the first two weeks of treatment, which then stabilized and matured over the course of the next six months.

The ability of VEGF-C to regulate the growth of lymphatic vessels presents an advantage for the use of lymph node transfer as a way of treating lymphedema. Currently lymph node transfer is being tested as a way to rebuild the lymphatic vascular anatomy but no treatment currently helps to assist the spontaneous growth of lymphatic vessels.

"Breast cancer patients have an urgent need for better treatments for lymphedma," said Dr. Saaristo. "With Lymfactin, we see the potential to increase the impact of the operation and reduce the amount of lymphoid tissue that needs to be removed from other parts of the body. Ideally Lymfactin will result in more durable lymph node transplants, reducing the need for painful pressure bandages."

Lymphedema

Lymphedema, localized swelling due to fluid accumulation, is caused by the disruption in the flow of lymphatic fluid, usually associated with the removal of lymph nodes as treatment for breast cancer. About 20 to 30 percent of patients who have had lymph nodes removed as a part of treatment for breast cancer will develop chronic lymphedema. Currently, there is no cure for the condition, and treatments are limited in their ability to reduce swelling and reduce the risk of infection.

ViroPharma Declares Culmination Of Registration In Phase 2 Study Evaluating Subcutaneous Delivery Of Cinryze™ (C1 Esterase Inhibitor [Human])

ViroPharma Incorporated (Nasdaq: VPHM) announced that it has completed enrollment in its Phase 2 study evaluating subcutaneous delivery of Cinryze™ (C1esterase inhibitor [human]). This multi-center, open-label, multi-dose Phase 2 study is designed to evaluate the safety, pharmacokinetics and pharmacodynamics of subcutaneous versus intravenous administration of Cinryze in adolescent and adult subjects with hereditary angioedema (HAE). The company expects to have preliminary data from this study by the end of this year, which will help inform the next steps of development for this mode of administration.

"The rapid enrollment into this study is indicative of the interest in, and also the potential for, prophylaxis with a subcutaneous form of Cinryze," commented Judy Johnson, ViroPharma's vice president of clinical pharmacology and nonclinical development. "We look forward to completing this important study which will inform our path forward, including the Phase 3 study design. We are excited by the potential of a subcutaneous option for patients who choose prevention of their HAE attacks."

Cinryze was approved by the U.S. Food and Drug Administration in October 2008 for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE.

Clinical Study Design

This is a multi-center, open-label multiple dose study in 24 adolescent and adult HAE patients in the US. All eligible subjects have been randomized into one of two treatment groups: Patients received Cinryze via IV infusion two times per week for two weeks. Then, following a 14-day washout period, subjects received Cinryze via subcutaneous administration at one of two dose levels (either 1000U or 2000U) two times per week for two weeks. Safety and PK/PD assessments are being evaluated throughout each treatment period.

About Cinryze™ (C1 esterase inhibitor [human])

Cinryze is a highly purified, pasteurized and nanofiltered plasma-derived C1 esterase inhibitor product that has been approved by FDA for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE. C1 inhibitor therapy has been used acutely for more than 35 years in Europe to treat patients with C1 inhibitor deficiency. Cinryze is not currently approved in the European Union or any of its member states.

The most common adverse reactions observed have been upper respiratory infection, sinusitis, rash and headache. No drug-related serious adverse events (SAEs) have been observed in clinical trials. Severe hypersensitivity reactions may occur. Thrombotic events have occurred in patients receiving high dose off-label C1 inhibitor therapy well above the approved treatment dosage regimen. Monitor patients with known risk factors for thrombotic events. With any blood or plasma derived product, there may be a risk of transmission of infectious agents, e.g. viruses and, theoretically, the CJD agent. The risk has been reduced by screening plasma donors for prior exposure to certain virus infections and by manufacturing steps to reduce the risk of viral transmission including pasteurization and nanofiltration.

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Cinryze is for intravenous use only. A dose of 1000 Units of Cinryze can be administered every 3 or 4 days for routine prophylaxis against angioedema attacks in HAE patients. Cinryze is administered at an injection rate of 1 mL per minute.

About Hereditary Angioedema (HAE)

HAE is a rare, severely debilitating, life-threatening genetic disorder caused by a deficiency of C1 inhibitor, a human plasma protein. This condition is the result of a defect in the gene controlling the synthesis of C1 inhibitor. C1 inhibitor maintains the natural regulation of the contact, complement, and fibrinolytic systems, that when left unregulated, can initiate or perpetuate an attack by consuming the already low levels of endogenous C1 inhibitor in HAE patients. Patients with C1 inhibitor deficiency experience recurrent, unpredictable, debilitating, and potentially life threatening attacks of inflammation affecting the larynx, abdomen, face, extremities and urogenital tract. Patients with HAE experience approximately 20 to 100 days of incapacitation per year. There are estimated to be at least 6,000 people with HAE in the United States.

Forward Looking Statements

Certain statements in this press release contain forward-looking statements that involve a number of risks and uncertainties. Forward-looking statements provide our current expectations or forecasts of future events, including the therapeutic indication and use, safety, efficacy, tolerability and potential of Cinryze and our focus, goals, strategy, research and development programs, and ability to develop pharmaceutical products, commercialize pharmaceutical products, and execute on our plans including clinical development activities with Cinryze related to subcutaneous administration. There can be no assurance that that our phase 2 clinical program with Cinryze utilizing subcutaneous administration will yield positive results or support further development of Cinryze for subcutaneous administration. The FDA or EMA may view the data regarding subcutaneous administration of Cinryze as insufficient or inconclusive, request additional data, require additional clinical studies, delay any decision past the time frames anticipated by us, limit any approved indications, or deny the approval of Cinryze for subcutaneous administration. These factors, and other factors, including, but not limited to those described in our annual report on Form 10-K for the year ended December 31, 2009 filed with the Securities and Exchange Commission, could cause future results to differ materially from the expectations expressed in this press release. The forward-looking statements contained in this press release are made as of the date hereof and may become outdated over time. ViroPharma does not assume any responsibility for updating any forward-looking statements. These forward looking statements should not be relied upon as representing our assessments as of any date subsequent to the date of this press release.

Source: ViroPharma Incorporated.

Research Laid Out At ASCO By Foremost Physicians And Investigators From The John Theurer Cancer Center

The John Theurer Cancer Center at Hackensack University Medical Center has announced that its physicians and researchers will present 16 abstracts on treatment and diagnostic progress in many different areas of oncology during the Annual Meeting of American Society of Clinical Oncology (ASCO) in Chicago, IL from June 4-8.

"At the John Theurer Cancer Center, we're dedicated to providing extraordinary cancer care to our patients, which includes conducting high-quality cancer research and cutting-edge clinical trials," said Andrew L. Pecora, M.D., F.A.C.P., C.P.E., Chairman and Executive Administrative Director, the John Theurer Cancer Center. "We're pleased to add to an important body of research at this premier oncology conference."

Abstracts from the John Theurer Cancer Center research that are scheduled to be presented include:

* Phase I study of combined vorinostat (V), lenalidomide (L), and dexamethasone (D) in patients (pts) with relapsed or refractory multiple myeloma (MM). (8031) (Poster Discussion Session) - Friday, June 4 from 2:00 p.m. - 6:00 p.m. in E450a
* Phase II study of denileukindiftitox with CHOP chemotherapy in newly-diagnosed PTCL: CONCEPT trial. (8045) (Poster Discussion Session) - Friday, June 4 from 2:00 p.m. - 6:00 p.m. in E450a
* Response of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) with nongerminal center B-cell phenotype to lenalidomide (L) alone or in combination with rituximab (R). (8038) (Poster Discussion Session) - Friday, June 4 from 2:00 p.m. - 6:00 p.m. in E450a
* The association between the Mantle Cell Lymphoma International Prognostic Index (MIPI) and survival in patients treated with rituximab-HCVAD (RHCVAD) alternating with rituximab-methotrexate-AraC (R-MTX-AraC). (8092) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Effect of front-line therapy with either high-dose therapy and autologous stem cell rescue (HDT/ASCR) or dose-intensive therapy (R-Hypercvad) on outcome in mantle cell lymphoma (MCL). (8067) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Impact of high-risk classification by FISH on overall survival in myeloma: An Eastern Cooperative Oncology Group (ECOG) study E4A03. (10546) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Interim results of phase II trial of pegylated liposomal doxorubicin (PLD) followed by bexarotene in advanced cutaneous T-cell lymphoma (CTCL). (8053) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Neurotoxic and peripheral neuropathic effects in preclinical and clinical studies of carfilzomib (CFZ), a novel proteasome inhibitor (PI). (8135) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Rituximab, fludarabine, mitoxantrone, and dexamethasone (R-FND) for patients with relapsed indolent B-cell lymphoma (RIL). (8078) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Treatment patterns and outcome among patients with multiple myeloma relapsing and or refractory to bortezomib and immunomodulatory drugs: A multicenter International Myeloma Working Group study. (8125) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Update on vantage program to assess combined vorinostat (V) and bortezomib (B) in patients (pts) with relapsed and/or refractory (RR) multiple myeloma (MM). (8133) (General Poster Session) - Saturday, June 5 from 8:00 am - 12:00 p.m. in S Hall A2
* Effect of early chemotherapy intensification with BEACOPP in high-risk, interim-PET positive, advanced-stage Hodgkin lymphoma on overall treatment outcome of ABVD. (8006) (Oral Abstract Session) - Saturday, June 5 from 1:00 p.m. - 4:00 p.m. in E354a
* Elotuzumab in combination with bortezomib in patients with relapsed/refractory multiple myeloma: A phase I study. (8003) (Clinical Science Symposium) Saturday, June 5 from 4:30 p.m. - 6:00 p.m. in E354a
* Phase Ib study of oral panobinostat (LBH589) plus intravenous bortezomib in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM). (8001) (Clinical Science Symposium) Saturday, June 5 from 4:30 p.m. - 6:00 p.m. in E354a
* Results of an ongoing open-label, phase II study of carfilzomib in patients with relapsed and/or refractory multiple myeloma (R/R MM). (8000) (Clinical Science Symposium) Saturday, June 5 from 4:30 p.m. - 6:00 p.m. in E354a

Source:
Amy Leahing
John Theurer Cancer Center

Update On Lymphoma Drug Trial: Potential Breakthrough For T- Cell Lymphoma Patients With Drug That Mimics A Vitamin

Final results of a pivotal Phase 2 clinical trial of pralatrexate (PDX) for patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) were reported by the study's principal investigator, Dr. Owen A. O'Connor of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and NewYork-Presbyterian Hospital/Columbia. T-cell lymphoma (PTCL) is a biologically diverse group of blood cancers that account for as many as 15 percent of non-Hodgkin's lymphoma (NHL) cases in the United States.

Data from the PROPEL (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma) trial show that pralatrexate, a drug that partially works by mimicking the vitamin folic acid, has an estimated median duration of response of 287 days, or 9.4 months. As previously reported, 29 of 109 evaluable patients, or 27 percent, showed a complete or partial response.

"Until now, these patients could only expect to survive several weeks. This study shows that it may be possible to extend this to many months - a result that is nothing short of spectacular and may likely represent a breakthrough in the development of new drugs for T-cell lymphoma," said Dr. O'Connor, director of the Lymphoid Development and Malignancy Program and chief of the Lymphoma Service at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center, and associate professor of medicine at Columbia University College of Physicians and Surgeons. "Based on these promising data, pralatrexate has the potential to play a clinically meaningful role in the treatment of patients with relapsed or refractory PTCL."

Pralatrexate, designed to look like the natural vitamin folic acid, disrupts DNA synthesis in tumor cells. The drug is designed to selectively accumulate in tumor cells, after which it then induces programmed cell death, or apoptosis, in the cancer cell.

There are currently no pharmaceutical agents approved for use in the treatment of either first-line or relapsed or refractory PTCL, and overall five-year survival is approximately 25 percent after first-line therapy. In addition to those PTCL patients who do not respond to first-line treatment, a significant number of first-line multi-agent chemotherapy responders relapse or become refractory after treatment.

The PROPEL trial is organized by Allos Therapeutics Inc., the maker of the drug. The company expects to submit a New Drug Application to the U.S. Food and Drug Administration for marketing approval of pralatrexate sometime in the first half of 2009. The results of the trial will be submitted for presentation at an upcoming scientific meeting and for publication in a peer-reviewed journal.

Pralatrexate was developed by a team of researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) and the Southern Research Institute, including Dr. O'Connor, while at MSKCC. Dr. O'Connor and his colleagues identified the unique activity of pralatrexate in patients with lymphoma. Dr. O'Connor has continued to study pralatrexate at NewYork-Presbyterian/Columbia, now focusing on determining how the drug works in T-cell lymphoma, and on how best to combine it with other drugs to improve the treatment of patient with hematologic cancers.

The critical PROPEL (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma) trial - an international, multicenter, open-label, single-arm study - enrolled a total of 115 patients with relapsed or refractory PTCL, 109 of whom are considered evaluable for response according to the trial protocol. It is believed that PROPEL is the largest prospectively designed single-agent trial conducted to date for this patient population.

To be eligible for the trial, patients' disease must have progressed after at least one prior treatment. Patients were considered evaluable if they received at least one dose of pralatrexate and their diagnosis of PTCL was confirmed by independent pathology review. Patients received 30 mg/m2 of pralatrexate intravenously once every week for six weeks followed by one week of rest per cycle of treatment. Patients also received vitamin B12 and folic acid supplementation. The primary endpoint of the trial is objective response rate, as assessed by central, independent oncology review using International Workshop Criteria (IWC). Duration of response is the key secondary endpoint.

Of the 29 patients who achieved a response according to central independent oncology review, 7 patients had a complete response (CR), 2 patients had a complete response unconfirmed (CRu) and 20 patients had a partial response (PR). According to the PROPEL investigators, 42 of 109 evaluable patients, or 39 percent, achieved a response. Of these, 15 patients had a CR, 4 patients had a CRu and 23 patients had a PR. PROPEL patients received a median of three prior systemic treatment regimens (range of 1 to 12), including 18 patients, or 16 percent, who had previously undergone an autologous stem cell transplant. In the trial, 66 percent of the patients who responded did so after cycle one of therapy. Patients will continue to be followed for long-term survival.

Peripheral T-Cell Lymphoma

According to the American Cancer Society, approximately 66,000 patients are expected to be diagnosed with non-Hodgkin's lymphoma in the United States in 2009. Annual prevalence is estimated to be approximately 9,500 patients. In addition to the 30 percent to 50 percent of PTCL patients that do not respond to first-line treatment, a significant number of first-line, multi-agent chemotherapy responders relapse or become refractory after treatment.

NewYork-Presbyterian Hospital

NewYork-Presbyterian Hospital, based in New York City, is the nation's largest not-for-profit, non-sectarian hospital, with 2,242 beds. The Hospital has nearly 2 million inpatient and outpatient visits in a year, including more than 230,000 visits to its emergency departments - more than any other area hospital. NewYork-Presbyterian provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine at five major centers: NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian Hospital/Columbia University Medical Center, Morgan Stanley Children's Hospital of NewYork-Presbyterian, NewYork-Presbyterian Hospital/The Allen Pavilion and NewYork-Presbyterian Hospital/Westchester Division. One of the largest and most comprehensive health care institutions in the world, the Hospital is committed to excellence in patient care, research, education and community service. It ranks sixth in U.S.News & World Report's guide to "America's Best Hospitals," ranks first on New York magazine's "Best Hospitals" survey, has the greatest number of physicians listed in New York magazine's "Best Doctors" issue, and is included among Solucient's top 15 major teaching hospitals. The Hospital's mortality rates are among the lowest for heart attack and heart failure in the country, according to a 2007 U.S. Department of Health and Human Services (HHS) report card. The Hospital has academic affiliations with two of the nation's leading medical colleges: Weill Cornell Medical College and Columbia University College of Physicians and Surgeons. For more information, visit www.nyp.org.

Columbia University Medical Center

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The Medical Center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is now among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States.

Source: NewYork-Presbyterian Hospital

A Century-Old Puzzle Comes Together, Scientists ID Potential Protein Trigger In Lung Disease Sarcoidosis

Lung researchers at Johns Hopkins have identified a possible protein trigger responsible for sarcoidosis, a potentially fatal inflammatory disease marked by tiny clumps of inflammatory cells that each year leave deep, grainy scars on the lungs, lymph nodes, skin and almost all major organs in hundreds of thousands of Americans.

The disorder, whose cause has been a persistent mystery for nearly a century, strikes mostly young adults and disproportionately affects African Americans.

The link between sarcoidosis and overproduction of the suspected protein trigger, called serum amyloid A, was revealed after a six-year investigation encompassing more than two dozen laboratory experiments, including some on diseased lung tissue samples from 86 patients in the Baltimore area.

"The increase in production of serum amyloid A explains for the first time how inflammation can persist in the lungs without being triggered by an active infection," says study senior investigator and pulmonologist David Moller, M.D., a professor at the Johns Hopkins University School of Medicine. Moller is also director of the sarcoidosis clinic at The Johns Hopkins Hospital.

Study lead investigator Edward Chen, M.D., says the new findings also clear the path for developing drug treatments or vaccines that can block serum amyloid A from binding to cell receptors and kicking off inflammation.

In the short term, however, Moller says his team has plans to use the study results to create diagnostic tests that could better predict which people with the disease are likely to heal on their own or are more likely to suffer persistent inflammation, which can lead to scarring, difficulty breathing, and heart failure that can only be fixed by lung transplantation.

In a report published in February in the American Journal of Respiratory and Critical Care Medicine, the Johns Hopkins scientists described their research on what was behind the microscopic clusters of inflamed tissue and white blood cells, or granulomas, which are a defining feature of sarcoidosis.

Such lung lesions are not unique to sarcoidosis and can be triggered by infections, such as in tuberculosis, which is often confused with sarcoidosis. But unlike tuberculosis, sarcoidosis is not an infectious disease, does not yield to antibiotics, and is not limited to any particular organ, occurring as well in the eyes, skin, brain, heart and liver.

Of particular interest to researchers was the role played by so-called amyloids, a set of proteins known to cause other persistent inflammatory conditions, such as amyloidosis. Indeed, a different kind of amyloid has been tied to plaques in the brain tissue of people with Alzheimer's disease.

Key among the researchers' findings in sarcoidosis patients was that serum amyloid A stood out because it was heavily concentrated within the granulomas in diseased and scarred lung tissue. Researchers found the protein a hundred to a thousand times more widespread in sarcoidosis tissue samples than in samples from people with tuberculosis, another granuloma-forming lung disease. Similarly elevated amyloid levels were seen in comparison tests with tissue samples from people with lung cancer and Crohn's disease.

Further tests in patients' lung cell cultures showed that adding serum amyloid A spiked production of at least a half-dozen key inflammatory chemicals known to be involved in damaging tissue.

In another series of experiments in mice, the team discovered that granuloma formation in the lungs sped up when the mice were given injections of synthetic serum amyloid A. Mice had previously been injected with specially coated plastic beads designed to trigger sarcoidosis-like lesions. Adding the synthetic protein led to the same biochemical reactions in the mice as observed in humans, suggesting to the researchers that serum amyloid A played a key role in triggering sarcoidosis.

To better understand how serum amyloid A might be driving granuloma formation, the team used special antibodies to block various cell surface receptor sites where the protein would bind to the white blood cells and spur inflammation. Tests in human lung cells showed that blocking one particular receptor, toll-like receptor-2 (TLR2), inhibited the sustained inflammatory reaction typically associated with sarcoidosis. But when left to bind on its own, without an antibody blocking TLR2, the open receptor could attach to serum amyloid A, and raised production of inflammatory chemicals would ensue.

"Not only have we shown that serum amyloid A is a key protein trigger in sarcoidosis, but we also have evidence that the resulting inflammation is dependent on binding the protein at toll-like receptor-2, which opens up a host of possibilities that drugs blocking this binding site could prove an effective treatment for this disease," says Chen, an assistant professor at Johns Hopkins.

Funding support for the report and research was provided by the National Institutes of Health, the American Thoracic Society, the Foundation for Sarcoidosis Research, the Life and Breath Foundation, and the Hospital for the Consumptives of Maryland (Eudowood.)

Source: Johns Hopkins Medicine

Tumors Hide Out From The Immune System By Mimicking Lymph Nodes

A new mechanism explaining how tumors escape the body's natural immune surveillance has recently been discovered at EPFL (Ecole Polytechnique Fédérale de Lausanne) in Switzerland. The study shows how tumors can create a tolerant microenviroment and avoid attack by the immune system by mimicking key features of lymph nodes. The discovery, published in Science and in Science Express, online March 25, 2010, underscores the role of the lymphatic system in cancer and may open up new possibilities for cancer treatment.

"The tumor tricks the body into thinking it is healthy tissue," says lead author Melody Swartz, head of the Laboratory of Lymphatic and Cancer Bioengineering (LLCB) and EPFL professor. Swartz and her team set out to understand how immune tolerance is induced by tumors, allowing them to progress and spread. The researchers from EPFL concentrated their efforts on a certain protein that is normally present in healthy lymph nodes to attract T cells and program them to perform vital immune functions. They found that some tumors can secrete this protein to transform the outer layer of the tumor into lymphoid-like tissue. This outer layer then attracts and effectively re-programs the T cells to recognize the tumor as friend not foe, resulting in a tumor that goes undetected by the immune system.

Since most tumors progress only if they have escaped the immune system, this new understanding of one mechanism by which the tumor can bypasses or hides from immune defenses is an important step towards future cancer therapies. "The finding that tumors can attract naïve and regulatory T cells and educate them has important implications for tumor immunotherapy," says Jacqui Shields, from LLCB. The study also opens up potential novel areas of research focusing on the relationship between lymphatic systems and cancer research. According to Shields, the concept that tumors mimic lymphoid tissue to alter the host's immune response represents a new understanding of tumors' interactions with the lymphatic system.

The laboratory is affiliated with the EPFL's Institute of Bioengineering and the Swiss Institute for Experimental Cancer Research.

Source: Ecole Polytechnique Federale de Lausanne (EPFL)

Shire Presents Positive Data For Patients With Type 1 Gaucher Disease Who Switched To VPRIV(TM)

Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, presented positive data from a Phase III clinical trial (TKT-034) designed to evaluate the safety of switching to VPRIV (velaglucerase alfa for injection), from imiglucerase, as well as an interim analysis of safety data from an ongoing multicenter open-label treatment protocol (HGT-GCB-058) implemented to provide VPRIV to patients affected by the continuing shortage of imiglucerase. A post-hoc analysis of Phase I/II data on therapeutic goal attainment was also presented at the 2010 American College of Medical Genetics Annual Clinical Genetics Meeting in Albuquerque, New Mexico. These data add to the growing body of clinical evidence which support the use of VPRIV in patients both transitioning from imiglucerase or who are treatment naive.

Adult and pediatric patients with Type 1 Gaucher disease were switched from imiglucerase (15-60 U/kg every other week) to the same number of units of VPRIV in the Phase III switch study (40 patients) and the ongoing US treatment protocol (>150 patients). In study TKT-034, no patients developed IgG antibodies to VPRIV, including 3 patients who tested positive for anti-imiglucerase antibodies at screening. In addition, hemoglobin concentration, platelet counts, and liver and spleen volumes remained stable over the course of the one year study, demonstrating safety and maintenance of efficacy over this time frame. One patient in the Phase III trial discontinued due to a serious hypersensitivity reaction and the most common side effects reported in the two studies were infusion-related reactions.

"Results from the Phase III study provide important information regarding the safety and sustained efficacy of VPRIV for patients with Type 1 Gaucher disease who were previously on imiglucerase and should help inform treatment decisions during and after the imiglucerase supply shortage," said Dr. Gregory Grabowski, Director of the Division of Human Genetics, Cincinnati Children's Hospital Medical Center and Principal Investigator of the 034 study. "These data confirm what many physicians have experienced."

A post hoc analysis from a third study, TKT-025EXT, designed to examine attainment of long-term therapeutic goals in 8 patients with Type 1 Gaucher disease treated with velaglucerase alfa, was also presented at the meeting. The initial dose of 60 U/kg was lowered to 30 U/kg after patients achieved at least 2 of 4 predefined therapeutic goals following 1 year of treatment. Clinically meaningful achievement of long-term therapeutic goals for hemoglobin concentration, platelet counts, and liver and spleen volumes was observed within 4 years of initiation of treatment.

Shire also reported important findings that suggested substantial antigenic differences when antibody response to treatment with VPRIV and imiglucerase were compared. Among the 99 patients who enrolled in the Phase III studies the seroconversion rate was 1% (1 of 82) against VPRIV versus 23% (4 of 17) against imiglucerase.

Velaglucerase alfa is manufactured in Shire's facility in Cambridge MA, which was inspected and approved by the FDA for the commercial production of VPRIV.

Study Results and Design for TKT-034, HGT-GBC-058 and TKT-025EXT

TKT-034

In this global, open-label, multicenter study, patients were enrolled in the US (11 sites), Europe (3 sites) and Israel (1 site), and of the 41 patients enrolled, 40 received study drug. One patient discontinued due to a serious hypersensitivity reaction and one patient discontinued at week 31 due to a perceived lack of improvement. At the time of discontinuation, this patient's clinical parameters were stable and consistent with those of the entire group of patients in the study.

Hemoglobin concentration, platelet counts, and spleen and liver volume were sustained at therapeutic levels through one year of treatment with VPRIV, as demonstrated by pre-specified efficacy criteria for clinically significant change:

-- Hemoglobin concentration: the mean change from baseline was -0.1 g/dL, with a 90 percent confidence interval of -0.3 to 0.1 g/dL, within the predefined efficacy criterion of plus or minus 1 g/dL.

-- Platelet counts: the percent change from baseline was +7.0%, with a 90 percent confidence interval of 0.5 to 13.5%, within the predefined efficacy criterion of plus or minus 20%.

-- Spleen volume: the percent change from baseline was -5.6%, with a 90 percent confidence interval of -10.8 to -0.4% within the predefined efficacy criterion of plus or minus 15%.

-- Liver volume: the percent change from baseline was -0.0%, with a 90 percent confidence interval of -2.6 to 2.6% within the predefined efficacy criterion of plus or minus 15%.

Study design

The primary objective of TKT-034 was to evaluate the safety of VPRIV in patients with Type 1 Gaucher disease who transitioned from imiglucerase to VPRIV. The secondary objectives were to evaluate changes from baseline in hemoglobin concentration, platelet counts, and spleen and liver volumes by Magnetic Resource Imaging (MRI) after every other week dosing of VPRIV.


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Patients over the age of two years and receiving imiglucerase at a dose between 15 and 60 U/kg every other week for at least 30 months with no dose change in the last 6 months were eligible, provided they had demonstrated stable hemoglobin concentration and platelet counts. Patients were infused in one hour with the same number of units of VPRIV as their prior imiglucerase dose.

HGT-GCB-058

This ongoing multicenter, open-label treatment protocol was initiated at the request of the Food and Drug Administration (FDA) to provide VPRIV to patients who otherwise have limited or no access to imiglucerase due to a continuing supply shortage.

Between September 1, 2009 and January 31, 2010, more than 150 patients in the US enrolled into HGT-GCB-058 and received at least one infusion of VPRIV. Of these, 3 were treatment naive and the rest were previously treated with imiglucerase. Following the administration of the first three infusions of VPRIV at the clinical site, patients who experienced no treatment-related serious adverse events or infusion-related adverse events were eligible to transition to home therapy at the discretion of the investigator. Patients were required to return to the clinic site quarterly for observation.

An interim safety analysis of the more than 150 patients on the treatment protocol was conducted. Among those patients previously treated with imiglucerase, a total of 18% experienced a treatment emergent adverse event that was possibly or probably related to the study drug. The most commonly observed treatment emergent adverse events among switch patients included at least one infusion-related reaction, nasopharyngitis, nausea, fatigue, headache, dizziness and influenza. Approximately 1% of patients experienced a severe adverse event that was considered to be possibly or probably related to the study drug.

TKT-025EXT: Study Results and Design of Therapeutic Goal Analysis

This post-hoc analysis of data from the Phase I/II and extension trial of velaglucerase alfa showed that clinically meaningful long-term therapeutic goals were achieved within 4 years of initiation of velaglucerase alfa treatment.

The efficacy parameters were evaluated against the therapeutic goals described by Pastores et al (Seminars in Hematology, 2004) aand included absolute and percent changes in hemoglobin levels, platelet counts, and spleen and liver volumes as measured by MRI. Evaluation in this study was limited to those patients who were exposed to velaglucerase alfa for a minimum of 48 months and for whom a complete clinical data set corresponding to the study endoints was available at baseline and annually through 48 months (8 patients, 4 male, 4 female). Patients were evaluated for the achievement of each individual therapeutic goal. The percentage of patients achieving each specific goal over time was determined. In addition the percentage of patients with a complete response (achieved all 4 therapeutic goals) over time was also evaluated.

At baseline, no patient was at goal for all 4 clinical parameters: 4 of 8 patients were at goal for hemoglobin concentration, 0 of 8 for platelet count, 4 of 8 for liver volume, and 0 of 8 for spleen volume. After 1 year of treatment, all patients achieved at least 2 therapeutic goals, and all patients maintained clinical parameters for goals that were already at the recommended targets when treatment began. All 8 patients were eligible for and began step-wise dose reduction to velaglucerase alfa 30 U/kg EOW starting between 12 and 18 months. By year 4 of treatment, all patients met goals for all 4 clinical parameters; therefore, 100% achievement was observed for each of the 4 long-term, therapeutic goals.

More about VPRIV

VPRIV (velaglucerase alfa for injection) was approved by the US FDA as a long-term enzyme replacement therapy for adult and pediatric patients with Type 1 Gaucher disease on February 26, 2010. A marketing application for VPRIV has also been granted accelerated assessment by the European Medicines Agency in the European Union (EU). Shire expects to launch VPRIV in the EU by the end of 2010 and in other countries beginning in 2011.

VPRIV is for patients who are treatment naive as well as patients who have been treated with imiglucerase. The most serious adverse reactions seen with VPRIV were hypersensitivity reactions. Infusion-related reactions were the most commonly observed adverse reactions in patients treated with VPRIV in clinical studies. The most commonly observed symptoms of infusion-related reactions were: headache, dizziness, low or high blood pressure, nausea, tiredness and weakness, and fever. Generally the infusion-related reactions were mild and, in treatment-naive patients, onset occurred mostly during the first 6 months of treatment and tended to occur less frequently with time. Adverse reactions more commonly seen in pediatric patients compared to those observed in adult patients (>10% difference) include rash, upper respiratory tract infection, prolonged activated partial thromboplastin time, and fever.

As with all therapeutic proteins, there is a potential for immunogenicity. In the clinical studies 1 of 54 treatment-naive patients treated with VPRIV developed IgG class antibodies. It is unknown if the presence of IgG antibodies to VPRIV is associated with a higher risk of infusion reactions.

SHIRE PLC

Shire's strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit hyperactivity disorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire's in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.

"SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995

Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, the Company's results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company's Specialty Pharmaceutical and Human Genetic Therapies products, as well as the ability to secure and integrate new products for commercialization and/or development; government regulation of the Company's products; the Company's ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company's products; the Company's ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company's ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company's filings with the Securities and Exchange Commission.

Source: Shire plc