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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News Source:
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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News Source:
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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News Source:
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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News Source:
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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News Source:
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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News Source:
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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News Source:
New York University

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