Key molecular regulator of uterine fibroids

Uterine leiomyomas, also called uterine fibroids, are benign tumors that originate from the smooth muscle of the uterus. Fibroids are the most common non-cancerous tumor of the female genital tract, affecting 80% of all women during their lifetime. More than half of women develop fibroids during their reproductive years, often complicating pregnancy. Fibroids are a major source of heavy uterine bleeding, pain, and reduced fertility, resulting in reduced quality of life and significant stress for many women. 

Treatments for fibroids consist of surgery, including hysterectomy or myomectomy, hormonal modulators, such as gonadotropin-releasing hormone agonists, and uterine arterial embolization (UAE), which blocks the blood supply to the tumor. The only true cure is surgical resection, with hormonal approaches and UAE estimated to shrink tumors by 30-40%. Bleeding and pain can also be significantly reduced by these treatments. However, results vary, and many women do not derive benefit from available procedures. Progress in designing new treatments has been slow, largely because we have a poor understanding of the biology of fibroids.

A new study recently identified a molecule that is expressed at abnormally high levels in fibroids. The molecule, H19, belongs to a class of molecules called long noncoding RNAs. H19 was found at increased levels in fibroid tissues from 30 women, including 20 premenopausal, compared with normal uterine myometrium tissues from the same women. High expression of H19 caused fibroid cells to double in number faster, whereas getting rid of H19 actually slowed down growth. Importantly, H19 also drove expression of molecular profiles that have previously been linked to fibroid development and growth. Thus, H19 may function upstream as a key regulator of fibroids. Estrogen and progesterone are thought to influence fibroid growth. This new study showed that combined exposure to estrogen and progesterone increased H19 expression and other fibroid-promoting genes. When H19 was eliminated, the effects of estrogen and progesterone were abolished. 

Although these results are preliminary, they are exciting for several reasons. We know so little about fibroids, and options for women who suffer from this debilitating chronic medical condition are limited. Fibroids receive little attention from the research community. The few studies that have been published in recent years are mostly preclinical in animal models and do not generally include patient samples. This new study used matched human fibroid and normal myometrium tissue from the same patients. This study also explored molecular mechanisms and biology, demonstrating cause and effect and not purely correlative findings.

Further studies are urgently needed to confirm the role of H19 and to identify other major mechanisms promoting fibroids. Identification of key regulators of fibroid development and growth moves us one step closer to understanding this disease and improving therapeutic options for women.

Reference: Cao T et al. Oncogene 2019 May 15

Simple health and wellness tips: screening and education

“No one is without knowledge except he who asks no questions.” ~ Ancient Proverb

You play an incredibly powerful role in dictating the course of your health. As discussed in the last post, 80% of chronic illnesses can be prevented through the lifestyle choices you make each day. But making informed decisions requires deliberate self-awareness and honesty. In addition to paying attention to diet and exercise, you can build self-awareness through active health screening and education. A major key to being proactive about your health is understanding your unique medical profile.

Know your body and your health risks. Routine medical, dental, and visual screenings help create a baseline profile of what’s normal for you. They may also help catch problems at early stages, when they are often easier to treat. Recommended evaluations may monitor blood pressure, cholesterol, glucose, body mass index, colorectal, breast, cervical, and/or prostate health (1). These tests are not just for primary prevention; they can help you follow ongoing concerns, so you can control progression of existing conditions. Staying up to date on immunizations, and practicing protective skin care are also important strategies for preventing serious medical problems. How frequently you decide to visit your doctor depends on your underlying health status and personal needs.

Medical visits should not be restricted to physician visits. Dental appointments are also important for your overall health. Gum disease, or periodontal disease, is diagnosed in more than 3 million people each year in the US (2). This bacterial infection is associated with poor dental care, resulting in swollen, red gums, loose teeth, and increased oral sensitivity. There is an increased risk of gum disease if you smoke or have diabetes, so dental care is especially important in these cases. Perhaps surprisingly, periodontal disease is not just an issue for your mouth. It increases your risk of developing serious systemic problems, including rheumatoid arthritis and heart disease (3). This occurs because the bacteria that cause gum disease can move through your blood, affecting blood vessels in the heart and creating harmful blood clots.

Outside of scheduled appointments, self-examination and an ongoing awareness of your physical and emotional wellness are critical. Recommended monthly self-exams include breast, testicular, and skin checks. Any sudden or persistent changes, such as lumps, pain, color, swelling, or rashes, can help identify problems early, increasing the probability of treating and curing an illness. As an example, if a woman feels a lump in her breast, she should act immediately and see a doctor. If a cancer is diagnosed and restricted to the breast, her chance of surviving 5 years is almost 99% based on statistics for women in the US (4). However, the 5-year survival from cancer that has spread from the breast to distant organs falls to 27%. These statistics vary patient to patient but emphasize the importance of early detection. Detecting the cancer before it spreads makes a significant difference in survival.

Despite the tremendous benefits of healthy lifestyle choices, our genetics are intimately tied to our risk profile of developing medical conditions. Therefore, to truly know your health risks, you must know your family history. It’s particularly important to keep a record of medical problems among first-degree relatives, meaning your parents, siblings, and children, since you share substantial genetic overlap. The National Institutes of Health actually recommends keeping a medical record for three generations of your family (5). The idea is to be aware of medical patterns in your family, including diseases for which you may have increased risk. It does not mean that you are going to develop the disease, but it does suggest that you should be proactive about taking steps to reduce your risk.

Understand your personal health record. A personal health record is a comprehensive set of your health information that you maintain and control. Everything about your health should be kept in this record. It may be a paper data set, electronic, or a combination. The information should be as complete as possible, including past and current illnesses, allergies, medications, health evaluations, surgeries, and family medical history. Ask your healthcare providers for records, such as images and reports, so you have them accessible when you want them. Having this record readily available is important for your peace of mind and that of your family. Simply creating the record is not enough; take steps to clearly understand everything in your record, including the side effect profiles of your medications, and how your medications interact with one another. Another advantage of having a personal health record is that you do not have to be dependent on your healthcare team for information. If you need information for work, travel, or a new doctor, you will have it available. If there’s an emergency, a family member can consult your record when contacting the hospital. Here is additional information to help you develop your personal health record.

Ask lots of questions, and know where to look for information. Our knowledge is only as deep as the quality and honesty of our questions. Ask openly about risk factors, prevention strategies, health and fitness, medications, and lifestyle changes. Even if your healthcare practitioner does not know the answer, he or she should be able to guide you to an appropriate source. If you feel that your questions are not being answered, or that you are being rushed, find a provider who will support your health enough to address your questions. If you have concerns about identifying credible written sources, ask your physician for advice. Scholarly databases, such as the National Library of Medicine, Medline Plus, and PubMed, are good places to start. Check out this site for great tips about credible sources of health information. When you read health articles online, pay attention to the affiliations, credentials and conflicts of interests of the website and author, as these may bias their advice. Medical research evolves rapidly, so check the date on your article to make sure you are reading the most recent information. It’s also useful to read articles with referenced sources, so you can go back and check the original articles. Checking multiple sites or articles for consistency of information, and consulting with your physician for advice are important steps towards ensuring that you can trust the information you are reading.

In our next post, we’ll cover simple strategies for integrating greater levels of balance and wellness into our lives.

Five ways to improve your health writing skills

Health writing is a broad field, filled with a number of smaller niches. You may be focused on fitness, nutrition, women’s health, or cancer, just to name a few. Whatever your specific interest or specialty is, getting started as a writer can be intimidating. Here are a few simple strategies that can help improve your writing.

Read content from other health writers. Writing styles differ according to author, niche, and audience. Read a variety of content from health writers. Identify articles written for the same types of audiences you want to target. Note the structure and tone of the writing. Break the article down by paragraph, and decide what purpose each paragraph fills in the article. Effective nonfiction writing is usually centered on key messages, as explained here. Identify the main teaching points in the article you are reading. What is the overall take-home message? How does the author organize these objectives and messages to create a clear, concise story? Take note of research that is cited to understand the types and numbers of sources you may need as supporting evidence to write a piece of similar length or style. The tone and voice will vary more than structure when you start comparing articles; that’s what makes each author unique. Still, there are some patterns to notice. For example, if a piece is written for a patient, how does the writer maintain a positive, helpful message, even when discussing a serious condition? What reading level does the piece appear to target, and how does that affect word choice? If a piece is written primarily for healthcare professionals or researchers, how does the author make the article interesting and engaging, rather than purely academic? Annotate each article as you go through this exercise. You’ll begin spotting patterns in health writing articles that are targeted to similar audiences. You can apply these general patterns in structure and voice to your own outlines as you build your health writing practice.

Keep up with news from your niche. This is critical. Health research moves at a ridiculously rapid pace. Understand what constitutes a credible source in your field, and read these sources regularly. For example, if your focus is oncology, read abstracts from the top-tier oncology journals on PubMed each week to identify new articles. You can set up automatic alerts based on keyword searches. Follow blogs from the major oncology associations and reputable oncology news websites daily. Many of these sources offer e-mail newsletters that can automatically be sent to you. Also, mine abstract databases from major annual oncology conferences to stay in touch with breaking news. Health writers must stay up-to-date, or their content risks becoming obsolete and irrelevant, and possibly filled with errors if something new has been learned.

Write regularly and listen to feedback. Write as many different types of content targeted to your primary audience as you can. As long as you practice consistently, you will improve. Seek feedback from clients, colleagues, mentors, and writing groups. Feedback is most effective when it highlights your strengths and weaknesses, so you know exactly what’s working, and what needs to be improved. Don’t be afraid to try new types of deliverables. There are so many possibilities in health writing; articles, blogs, book chapters, abstracts, news summaries, and medical needs assessments are just a few examples. Research and read other writers’ work. Then, try writing something new, and ask for feedback; it’s the only way to learn and become a strong health writer capable of writing diverse types of content.

Join classes and professional organizations. Formal courses, online writing programs, and professional organizations often provide resources to help improve health writing skills. Identify health writing groups or classes online or in your area, and see if they offer feedback, specialized teaching, books, or certifications that will help you grow as a writer. In addition to medical and science writing associations, there are freelance health writers who offer online courses. Check out this link for additional advice.

Write for your audience. Health writers are educators. Your content is designed to teach an audience something new about a specific health topic. Keeping your reader in mind as you write will automatically focus your attention and improve your writing. Imagine your audience as you write. What concerns do they have? As you practice writing for the same general audience a few times, you’ll learn how to address their major needs and anxieties. Targeting your writing to help your audience is one of the most effective ways to improve the tone, clarity, and quality of your health writing.

These are just a handful of easy tips to help you on your way to becoming a strong, impactful health writer. It’s a continuous process, and regardless of how senior a writer is, there is always something new to learn. Be kind to yourself, and approach writing with a growth mindset, so that you are open to learning and evolving even when new challenges present themselves.

Organizing nonfiction writing around learning objectives

As nonfiction writers, we strive to educate our readers. Our goal is to communicate interesting ideas clearly and concisely. Sometimes the early stages of nonfiction writing are overwhelming. Sifting through all of our research, and trying to convey our ideas in a meaningful way can be challenging. One strategy to help organize your writing in the early stages is to create a set of learning objectives. Try to limit these to 3-4 per chapter or article. For smaller pieces, such as blog posts, 1-2 learning objectives is sufficient. Objectives should capture the main points that you intend for the reader to learn from your writing. It’s most useful to create these before you develop an outline or first draft. These objectives will provide you with a structural framework, around which you can build your entire work of nonfiction. 

One common system used for developing educational learning objectives is Bloom’s taxonomy (1). Using this system, you can create goals based on whether you want to increase a reader’s knowledge or comprehension of an area or their abilities to apply, analyze, evaluate, or synthesize something new based on what they learn from you. Helpful sites that explain in greater detail how Bloom’s is used for curriculum development are found here and here.

Knowledge-based objectives are the most straightforward to create. These focus on what you want your reader to remember. Think of objectives that use verbs, such as recognize, list, or recall. Let’s look at an example. If you are writing an article about breast cancer therapy for medical students, one of your objectives may be for your readers to be able to list the names of drugs used to treat specific types of breast cancer. Having this first learning objective in mind will help you know what kind of research to do, and what content to include as you build your outline and first draft. If your objective is to improve a reader’s comprehension or understanding of a topic, structure your writing around objectives that help the reader explain, compare, or summarize. Using the same example of an article about cancer therapy, you may include an objective for a reader to be able to explain how chemotherapy affects cancer cells. Deeper learning goals equip a reader with the abilities to critique or design specific endpoints. Sticking with the example of a breast cancer therapy article, your deeper objectives may be for readers to be able to apply facts about cancer therapy to predict how normal cells will be affected, or to be able to design an individualized treatment plan for a patient. Having these goals in mind before doing your research will ensure that you include enough information for readers to make evidence-based predictions and conclusions.

Once you have a set of objectives for your article or chapter, you can further develop each to build a detailed outline. The best part of creating learning objectives is the clarity you will gain regarding the goals and purpose of your article. Clarifying exactly what you want to communicate to your readers is a critical early step for keeping your writing focused and organized. Ultimately, taking the time upfront to develop clear goals will help your writing flow and enrich your reader’s learning experience.

(1) Bloom, B. S. (1956). “Taxonomy of Educational Objectives, Handbook I: The Cognitive Domain.” New York: David McKay Co Inc.

Combining endocrine therapies for metastatic breast cancer

Breast cancer remains the most commonly diagnosed cancer among women worldwide and is a leading cause of cancer-related death (1). In 2018, more than two million new cases were diagnosed, and more than 600,000 deaths were attributed to breast cancer. Breast cancers that have metastasized, or spread to other organs, often benefit from treatment with a cocktail of drugs. Strategic selection of drugs is based on molecular analysis of a tumor biopsy.

Approximately 70% of breast cancers express the estrogen receptor (ER) and are amenable to therapies that block estrogen or ER activity (2). These therapies are often classified within a larger category of drugs called endocrine or hormone therapies. There are many types of endocrine therapies, each with different mechanisms of inhibiting hormone action. Aromatase inhibitors (AIs), such as anastrozole, block estrogen synthesis, whereas selective ER down-regulators, such as fulvestrant, bind and reduce levels of the ER. Because of their different mechanisms of action, drugs from different endocrine therapy classes may be combined to exert increased inhibitory effects on ER-positive breast cancer. This type of combination approach was used in the S0226 phase 3 trial (NCT00075764). In this trial, postmenopausal women with previously untreated metastatic breast cancer were treated with the combination of anastrozole plus fulvestrant and compared with patients who received anastrozole alone. The combination treatment was previously reported to increase progression-free survival compared with the single agent (15 vs 13.5 months) (3).

Updated outcomes of the S0226 trial were recently reported at a median follow-up of seven years (4). About 45% of patients in the single-drug arm had crossed over to the combination treatment by the time of follow-up evaluation. Among 694 patients included in the updated report, progression-free survival remained significantly higher for the group treated with the combination. In addition, median overall survival was significantly higher for those receiving the combination treatment vs anastrozole alone (49.8 vs 42.0 months). Importantly, the differences in overall survival appeared to be dependent on whether patients had previously been treated with another endocrine agent, the selective ER modulator tamoxifen. Among those who did not have a history of tamoxifen treatment, median overall survival was significantly different with the combination vs anastrozole alone (52.2 vs 40.3 months). However, if patients had previously received tamoxifen, median overall survival did not significantly differ between the combination and anastrozole-alone groups (48.2 vs 43.5 months). The authors of the updated report noted the importance of considering differences in patient populations when interpreting and comparing results across studies. Previous trials that failed to show significant differences between single-agent AIs and cocktails of AIs with fulvestrant included patients previously treated with endocrine agents. Response rates and survival outcomes may be lower in some patients in this subgroup due to underlying endocrine resistance resulting from prior exposure to other endocrine agents. In addition, any time more than one drug is used, there are increased concerns about safety and side effects. However, high-grade (≥3) side effects were similar between the two treatment groups, suggesting that safety and toxicity were not compromised by the combination treatment.

Overall, the updated results from this phase 3 trial support the efficacy of combining the AI, anastrozole, with fulvestrant as a first-line option for patients with postmenopausal ER-positive metastatic breast cancer. This treatment combination has the potential to improve survival outcomes in patients who have not previously been treated with endocrine therapy.

References: (1) Bray et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. (2) Waks and Winer. Breast Cancer Treatment: A Review. JAMA. 2019 Jan 22;321(3):288-300. (3) Mehta et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. (4) Mehta et al. Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer. N Engl J Med. 2019 Mar 28;380(13):1226-1234.

Heading towards a better preclinical model of uterine leiomyoma

Uterine leiomyomas, which are also called uterine fibroids, are non-cancerous tumors arising from the smooth muscle of the uterine myometrium wall. The lifetime incidence of fibroids is estimated to exceed 70%, making these the most frequently diagnosed benign tumor of the female genital tract. Fibroids represent a major cause of heavy uterine bleeding, pain, and reduced fertility.

The biology of fibroid development is poorly understood, although its growth is largely thought to be estrogen-dependent. Currently, the only reliable curative medical option is hysterectomy. Other treatment options, such as uterine arterial embolization and hormonal therapy, can alleviate symptoms and reduce tumor size, but typically do not resolve the condition.

A major challenge with studying fibroids is the lack of physiologically relevant models in the lab. Evaluation of myoma tumor tissue ex vivo is complicated by eventual overgrowth of tumor-associated fibroblasts. Two recent papers published in Endocrine Related Cancer and Journal of Biological Methods report a method for developing patient-derived uterine leiomyoma xenografts (1,2). The investigators used tissue from the most common genetic subtype of uterine leiomyoma, the MED12-mutant subtype. After the tumor was surgically removed from the patient, the tissue was digested and cultured for 1-3 days. Cells were mixed with collagen and grafted into the subrenal capsule of ovariectomized mice. PDX uterine leiomyoma growth was documented in mice supplemented with both estrogen and progesterone. Removal of estrogen and progesterone resulted in a rapid reduction of tumor size of about 60%. Limitations of the model include differences in the hormonal and microenvironment of the kidney vs uterus.

Development of models that more closely mimic human uterine fibroids will allow us to gain increased knowledge about the biology and molecular mechanisms driving the development and growth of these tumors. These models may also be suitable for evaluating new treatment approaches for this common and debilitating condition.

(1) Serna VA, Wu X, Qiang W, Thomas J, Blumenfeld ML, Kurita T. Cellular kinetics of MED12-mutant uterine leiomyoma growth and regression in vivo. Endocr Relat Cancer. 2018 Jul;25(7):747-759.

(2) Serna VA, Kurita T. Patient-derived xenograft model for uterine leiomyoma by sub-renal capsule grafting. J Biol Methods. 2018;5(2).

Head-to-head comparison of the safety and efficacy of once-weekly exenatide versus once-daily liraglutide for the treatment of type 2 diabetes

Example of a scientific summary written for a physician audience

Achieving optimal glycemic control is an important clinical objective during the management of type 2 diabetes. There are many types of anti-hyperglycemic drugs currently available. Glucagon-like peptide-1 (GLP-1) receptor agonists are a relatively new class of injectable anti-hyperglycemic agents. Exenatide was the first GLP-1 receptor agonist to be approved as a once-weekly formulation. Exenatide is a synthetic version of exendin-4, a peptide agonist of the GLP-1 receptor. Another GLP-1 receptor agonist, liraglutide, is an analogue of human GLP-1. Liraglutide is approved for once-daily use in patients with type 2 diabetes. Multiple head-to-head comparisons have shown improved glycemic control after administration of once-weekly exenatide or once-daily liraglutide compared with oral anti-hyperglycemic agents or twice-daily exenatide.1-5

DURATION-6 was the first study to directly compare the efficacy and safety of once-weekly exenatide to once-daily liraglutide in patients with type 2 diabetes.6 A 26-week, randomized, open-label, parallel-group investigation was performed at 105 sites in 19 countries. Participants were adults with type 2 diabetes and suboptimal glycemic control despite lifestyle changes and treatment with oral anti-hyperglycemic agents. Patients were randomly assigned by a computer-based method to receive daily injections of liraglutide (titrated up to 1.8 mg) or weekly injections of exenatide (2 mg). An intention-to-treat analysis was performed on 911 patients enrolled in the trial. There were 450 patients in the liraglutide group and 461 patients in the exenatide group. The primary endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to the end of the trial.

Both treatments were associated with significant reductions in HbA1c. Liraglutide reduced HbA1c levels by 1.48%, whereas exenatide reduced HbA1c levels by 1.28%. Exenatide was initially hypothesized to be non-inferior to liraglutide. However, based on relative changes in HbA1c, exenatide did not meet the predefined criterion of non-inferiority to liraglutide. Body weight and fasting serum glucose levels were also significantly decreased in both groups. Patients treated with liraglutide showed more significant changes in body weight and fasting glucose compared with those in the exenatide group. Both groups showed similar levels of improvement in blood pressure, markers of cardiovascular health, and patient-reported health outcomes.

Nausea, vomiting, and diarrhea were the most common adverse effects of both treatments and were generally mild to moderate. These gastrointestinal events occurred more frequently at the beginning of the trial and were more common in the liraglutide group. Fifteen patients in the liraglutide group withdrew from the trial during the first month due to adverse gastrointestinal effects. By contrast, none of the patients in the exenatide group experienced gastrointestinal complications that required treatment discontinuation during the first four weeks. The most common adverse event in the exenatide group was the development of injection-site nodules. Major hypoglycemic events were not observed. However, minor hypoglycemic events occurred in a similar number of patients in each group. Minor hypoglycemia was more common in patients who received concomitant treatment with oral anti-hyperglycemic agents.

This head-to-head comparison of two long-acting GLP-1 receptor agonists demonstrated that both treatment regimens offer clinical benefit. Once-weekly exenatide and once-daily liraglutide effectively reduced HbA1c and fasting blood glucose levels in patients with inadequately controlled type 2 diabetes. Glycemic control and weight loss were significantly greater in the liraglutide group. However, gastrointestinal side effects were also more common in patients treated with liraglutide. The relative risks and benefits should be carefully considered for each patient when deciding between a once-weekly formulation of exenatide and a once-daily injection of liraglutide.

References:

1. Bergenstal RM, Wysham C, MacConell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 2010; 376: 431–39.

2. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008; 372: 1240–50.

3. Blevins T, Pullman J, Malloy J, et al. DURATION-5: Exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab 2011; 96: 1301–10.

4. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374: 39–47.

5. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009; 373: 473–81.

6. Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 2013; 381: 117-24.