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Day: 03/16/2022
Melanoma Treatment
Historic Progress. New Options. More Hope.
While melanoma is one of the most dangerous forms of skin cancer, promising new treatment options are improving quality of life and increasing survival rates for patients with advanced melanoma.
If you’ve been diagnosed, your treatment choices depend on the stage of the disease, the location of the tumor and your overall health. Options include:
Ask your doctor to clearly explain the options that might work best for you, including details about the benefits and risks.
Surgical removal of the melanoma
Treating early melanoma
Stage 0 “in situ” and stage I
Tumors discovered at an early stage are confined to the upper layers of the skin and have no evidence of spread. These melanomas are treated by excisional surgery. Usually, this is the only treatment required. The first step was a biopsy, where the physician removed part or all of the lesion and sent it to a lab for analysis, where the melanoma was diagnosed and staged. For the excisional surgery, the surgeon removes more tissue from the site.
Melanoma in situ (stage 0) is localized to the outermost layer of skin (the epidermis). Stage I melanoma has invaded the second layer of skin (the dermis). In both stage 0 and stage I melanoma cases, the physician uses a scalpel to remove any remaining tumor plus a “safety margin” of surrounding normal tissue. The margin of normal skin removed depends on the thickness and location of the tumor. After surgery the margins are checked to make sure they are cancer-free. If the margins are cancer-free, no further surgery is necessary.
Surgeons may, under certain circumstances, recommend removal of melanoma by Mohs surgery. The procedure is done in stages over a few days to remove all of the cancer cells in layers while sparing healthy tissue and leaving the smallest possible scar. One layer at a time is removed and examined until the margins are cancer-free. New advances in this technique make it easier for the surgeon to spot melanoma cells in the margins.
If a melanoma measures 0.8 mm or more in thickness or has other traits such as ulceration that make it more likely to spread to the lymph nodes, a sentinel lymph node biopsy (SLNB) may be performed at the same time as the surgery to remove the primary tumor.
Treating intermediate, high-risk melanomas
Stage II
Since the risk of spreading to local lymph nodes is higher in stage II melanomas, a sentinel lymph node biopsy is often recommended in addition to surgery to remove the original tumor. If melanoma is found in the sentinel node, your physician may examine the rest of the nodes in this lymphatic basin and remove any that contain cancer cells.
After surgery, additional treatment may be recommended, including immunotherapy or radiation to decrease the chance that the melanoma will come back.
What is a sentinel lymph node biopsy? Learn more.
Treating advanced melanomas
Stage III and stage IV
Advanced melanomas are those that have spread beyond the original tumor, most often reaching the lymph nodes and/or distant organs and becoming more difficult to treat.
In recent years, new immunotherapies and targeted therapies have achieved positive results in many patients with stage III and stage IV melanoma.
Patients with stage III melanoma now have options for supplemental or “adjuvant” treatment – medicines that enhance the effectiveness of surgery, with the goal of preventing or delaying relapse and extending survival, ideally achieving a cure.
After surgery to remove the tumor and in many cases the lymph nodes, stage IV patients have up to six frontline treatment options that have had considerable success. In many cases, if the first treatment proves ineffective or stops working, other therapies are available. These therapies work by shrinking tumors and halting or slowing disease progression to help extend life by months to years and perhaps even leading to a cure.
Immunotherapy
Revolutionary treatment options
Pioneering breakthroughs in immunotherapy — the use of medicines to stimulate a patient’s immune system to destroy cancer cells — have led to significant progress in treating patients with advanced melanoma.
Immunotherapies boost the body’s ability to fight melanoma and other cancers by using synthetic versions of natural immune system proteins, or by enabling the release of cells that attack tumors. These therapies are effective when used alone or in combinations.
Checkpoint blockade therapy
To assure that T cells attack only bacteria and disease and not the body itself, the immune system uses checkpoints, molecules that suppress T cells. T cells are the white blood cells that help protect the body from infection. Checkpoints help keep T cells from attacking normal cells in the body.
Checkpoint blockade immunotherapies are given intravenously to melanoma patients to stop checkpoint molecules from inhibiting T cells. This enables the immune system to release waves of T cells to attack and kill cancer cells.
The following checkpoint blockade therapies are being used for patients with advanced melanoma:
Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) blocker
TREATMENT OVERVIEW
Approved by the FDA in 2011 for patients with stage IV melanoma, ipilimumab was the first checkpoint blockade therapy that helped shrink many tumors markedly and extend life for patients with advanced melanoma. Since then, newer immunotherapy drugs have proven even more effective as single therapies (monotherapies), some with less serious side effects.
APPROVED MEDICATION
HOW IT WORKS
Ipilimumab targets CTLA-4, a protein on the T cell that functions as a “brake” to regulate immune system activation. Blocking CTLA-4 allows T cells to attack and destroy tumors.
While ipilimumab is no longer the frontline choice for treating stage IV melanoma, it is often paired with another checkpoint blockade drug, nivolumab, as a combination frontline therapy for stage IV patients, or can be administered if anti-PD-1 treatment has failed.
PD-1 blockers
TREATMENT OVERVIEW
In 2014, the FDA approved two additional checkpoint blockade drugs for use in patients with melanoma that has spread beyond the lymph nodes or for melanomas that cannot be removed by surgery (stage IV).
APPROVED MEDICATIONS
Pembrolizumab (Keytruda®)
Nivolumab (Opdivo®)
HOW THEY WORK
PD-1 (programmed death-1), a protein receptor on T cells that binds to a complementary protein called PD-L1 on the surface of other cells, helps keep the immune system in check. Both drugs block PD-1 to release the brakes on T cells and allow them to attach melanoma cells.
These drugs can be used alone (monotherapies), or nivolumab can be used in combination with ipilimumab. They can be used as the first treatment option, before other medicines have been tried, and as a second option when other treatments have failed or stopped working.
In 2017, the FDA approved nivolumab for therapy after tumor removal (known as adjuvant therapy) in stage III patients who have melanoma in the lymph nodes.
In February 2019, the FDA also approved the checkpoint blockade therapy pembrolizumab for the adjuvant treatment of stage III melanoma that has metastasized to the lymph nodes after tumor removal. The approval was based on phase 3 research demonstrating that pembrolizumab significantly prolonged recurrence-free survival (RFS) in patients with resected, high-risk stage III melanoma. Depending on the patient, either nivolumab or pembrolizumab can now be considered the frontline option for adjuvant treatment of stage III melanoma in patients who do not have a defective BRAF gene. (In those who do have defective BRAF, the combination targeted therapy dabrafenib-trametinib (Tafinlar®-Mekinist®) can also be considered a frontline option.)
In December 2021, the FDA expanded the approval of pembrolizumab to the adjuvant treatment of stage IIB and IIC melanoma, which have the same high risk for recurrence or death as stage III melanomas. The approval was based on phase 3 research demonstrating that pembrolizumab reduced the risk of disease recurrence or death by 35 percent compared to placebo in patients with surgically removed stage IIB or IIC melanoma. This approval essentially doubles the number of melanoma patients now eligible for adjuvant immunotherapy.
Combination immunotherapy
Unprecedented results by pairing therapies
TREATMENT OVERVIEW
In 2016, the FDA approved the combination of nivolumab and ipilimumab as a frontline therapy for patients with metastatic or inoperable melanoma.
APPROVED MEDICATIONS
Nivolumab-Ipilimumab (Opdivo® – Yervoy®)
HOW IT WORKS
By pairing two successful checkpoint blockade therapies, researchers have created another treatment option that has proven even more effective in shrinking tumors and prolonging life than either drug therapy used on its own, though adverse reactions with the combination medicine are also stronger than with either medicine alone.
*Learn more about combination immunotherapy and targeted therapy.
Oncolytic virus therapy
TREATMENT OVERVIEW
In 2015, the FDA approved the oncolytic virus therapy talimogene laherparepvec (Imlygic®), also known as T-VEC, to treat the skin and lymph nodes of patients with advanced melanomas that cannot be surgically removed.
APPROVED MEDICATIONS
Talimogene laherparepvec, or T-VEC (Imlygic®)
HOW IT WORKS
This new class of immunotherapy, injected directly into tumors, uses a lab-altered virus, known as an oncolytic virus, that is specifically programmed to infect and kill cancer cells exclusively. At the same time, an immune-boosting protein in the virus accelerates the body’s immune response to the tumors. The medicine’s most immediate effect is to shrink the size of injected tumors, but the secondary goal is for the drug to work systemically, attacking the cancer throughout the body.
Similar viruses are now being studied, with the goal of producing more options for melanoma patients whose diseases have spread or returned.
Adoptive cell transfer
HOW IT WORKS
This experimental new avenue uses white blood cells called tumor-infiltrating lymphocytes (TILs) to attack melanoma. The treatment is currently being explored in clinical trials on patients with advanced melanomas that have not responded to other treatments. Most often, the lymphocytes found to be attacking the melanoma are extracted from the patient, cultured in massive numbers in a lab and then returned to the patient.
Early immunotherapies
TREATMENT OVERVIEW
Older forms of immunotherapy once used in high-risk stage II, III and IV melanoma patients have since been replaced as frontline treatments by newer, more effective treatment options.
APPROVED MEDICATIONS
Interferon alfa-2b
Interleukin-2
Pegylated Interferon alfa-2b
HOW THEY WORK
These early forms of immunotherapy worked by boosting the immune system’s ability to fight disease. They are less used today because of the superior results of the newer therapies.
Targeted therapies
Personalized cancer treatment
The development of revolutionary targeted therapies marked the beginning of a new era of personalized medicine for melanoma patients, allowing tumors to be treated with minimal damage to healthy cells.
Targeted therapies use drugs and other agents to attack melanoma by inhibiting the action of defective genes and molecules – including BRAF and MEK – that play a role in accelerating the growth and spread of melanoma cells. When successful, these treatments halt or slow the progression of the disease and help patients live longer.
In the past decade there has been notable success using BRAF- and MEK-targeted therapies to treat advanced melanoma.
What is BRAF?
BRAF is known as a “switch gene.” It produces a protein that normally regulates skin cells, allowing them to multiply only when needed. But genetic changes (mutations) to BRAF can keep it switched on abnormally, driving out-of-control tumor growth.
About half of all melanoma patients have the BRAF mutation. Targeted therapies have had significant success in improving outcomes for patients with advanced melanoma who have the BRAF mutation.
BRAF inhibitors
TREATMENT OVERVIEW
In 2011, vermurafenib became the first targeted therapy approved for advanced melanoma patients. For varying amounts of time, it shut off the BRAF gene’s production of the BRAF protein.
APPROVED MEDICATIONS
Vemurafenib (Zelboraf®)
Dabrafenib (Tafinlar®)
Encorafenib (Braftovi®)
HOW THEY WORK
These targeted drugs interrupt and deactivate the tumor growth pathway driven by the genetic change in BRAF, delaying the progression of the disease, shrinking tumors and extending the life of patients.
If testing confirms that a patient has advanced melanoma, the lab will generally perform a BRAF mutation test to determine whether the tumor has the defective gene. These results show whether therapies targeting BRAF can be used in treatment.
What is MEK?
MEK is an enzyme that works together with BRAF to regulate cell growth. Drugs that inhibit MEK can also help treat melanomas that arise because of mutations in the BRAF gene.
MEK inhibitors
TREATMENT OVERVIEW
BRAF-targeted therapies are often remarkably effective for a period of time, but in most patients, the melanoma eventually develops a resistance to treatment and begins to grow again. Medications targeting MEK were developed to address this resistance and halt the advancement of the disease.
APPROVED MEDICATIONS
Trametinib (Mekinist®)
Cobimetinib (Cotellic®)
Binimetinib (Mektovi®)
HOW THEY WORK
To delay melanoma treatment resistance and increase survival, researchers developed targeted drugs that inhibit MEK.
Combination targeted therapies
Better health outcomes by pairing therapies
TREATMENT OVERVIEW
A melanoma patient with defective BRAF who goes on targeted therapy will almost always be treated with drugs that inhibit both BRAF and MEK, because pairing these targeted drugs has been found to work better than the BRAF therapies alone. Patients treated with combination therapies have faster, more dramatic and sustained tumor shrinkage, slower disease progression and live longer on average, while also experiencing fewer serious side effects. The combos work so effectively that the use of the single-drug targeted therapies has been virtually eliminated.
APPROVED MEDICATIONS
Dabrafenib-Trametinib (Tafinlar®-Mekinist®)
Encorafenib-Binimetinib (Braftovi®-Mektovi®)
Cobimetinib-Vemurafenib (Cotellic®-Zelboraf®)
HOW THEY WORK
The principle behind combination therapy is that even when the BRAF inhibitor meets with resistance, the MEK inhibitor can be effective in slowing or stopping disease progression.
*Learn more about the combination immunotherapy and targeted therapy: Atezolizumab-Cobimetinib-Vemurafenib (Tecentriq®-Cotellic®-Zelboraf®).
Chemotherapy
TREATMENT OVERVIEW
Since immunotherapies and targeted therapies produce vastly superior results, chemotherapy is no longer a frontline therapy. It is most often used if targeted therapies and/or checkpoint blockade therapies fail. It may sometimes be used in conjunction with these other therapies.
APPROVED MEDICATIONS
Dacarbazine (DTIC)
Temozolomide
HOW IT WORKS
Chemotherapy is a systemic approach to stopping tumor growth using certain medicines that either kill cancer cells or stop them from multiplying. It has never been proven to extend life for melanoma patients as a single therapy, however, and can have serious side effects.
Radiation therapy
TREATMENT OVERVIEW
Radiation is rarely used to treat a primary melanoma tumor, but may be used to treat melanomas that have spread to the brain or other distant sites to shrink tumors and decrease pain, improve comfort and mobility. It can also be used on the surgical site after surgery to help assure that all tumor cells have been killed, and is being studied in combination with treatments such as checkpoint blockade therapies to enhance outcomes.
HOW IT WORKS
Radiation is a localized treatment that directs high-energy X-ray beams to penetrate and destroy the tumors or keep them from growing. Radiation is most often used for:
- Melanomas at high risk of recurrence: Radiation can be used after surgery to lower the chance of recurrence after removal of certain types of melanomas.
- Melanomas that have returned: If the melanoma has come back on the skin or lymph nodes, in certain cases, doctors may treat with radiation to reduce or eliminate the tumor and potentially prevent spread to distant sites.
- Melanomas that have spread: Radiation may be used to help make checkpoint blockade therapies or targeted therapies work more effectively.
Clinical trials
If you have been diagnosed with advanced melanoma, you may be eligible to participate in a clinical trial – a carefully controlled research study using new or experimental treatments.
Before making a decision, it’s important to discuss the possibilities, risks and benefits of clinical trials with your doctor. For more information about clinical trials that are being conducted now, along with results of recent trials, visit the Find Studies page on the U.S. National Institutes of Health website.
On the horizon
While more melanoma treatment options exist today than ever before, there are even more new approaches currently being explored. Building on today’s strong forward momentum in understanding and treating melanoma, researchers are hard at work refining the therapeutic combinations and strategies to improve outcomes. Someday, advanced melanoma may be transformed from a deadly disease to a chronic, manageable or even curable condition.
Mohs: The Gold Standard
Mohs surgery is on the rise, for good reasons: It has the lowest recurrence rates, highest cure rates and best cosmetic results of any skin cancer treatment. A physician member of The Skin Cancer Foundation explains why Mohs has it all.
Lifesaving new medications for people with advanced melanoma, called targeted therapies and immunotherapies, have grabbed the biggest skin cancer headlines in the past few years, and that’s good news. But for people with the more common nonmelanoma skin cancers, basal cell and squamous cell carcinoma (BCC and SCC), an older technique has also been drawing more attention and favor than ever. I recently led the task force to establish consensus guidelines on the treatment of BCC and SCC, which were published this year. They demonstrate that Mohs surgery is the treatment of choice for many BCCs and SCCS, and the single most precise and effective method for eliminating these cancers.1-3
Did you know your chance of developing a nonmelanoma skin cancer in your lifetime is about one in five? More than 5.3 million cases of BCC and SCC are diagnosed in the U.S. each year. Exposure to ultraviolet (UV) light, either from the sun or from indoor tanning, is the greatest risk factor for developing these skin cancers, so it’s not surprising that approximately 80 percent of these cancers occur on the head and neck, where exposure is greatest. Unfortunately, since these are the most conspicuous skin cancers, they are also the most cosmetically challenging, capable of becoming disfiguring and sometimes dangerous if not caught at an early stage.
That’s why I want you to know just what Mohs surgery is, how it works, and what it can do to leave you cancer-free while looking the best you can after surgery.
How Mohs surgery works
Sometimes known as Mohs micrographic surgery, the technique was invented in the 1930s by Dr. Frederic Mohs at the University of Wisconsin, but it didn’t develop into a mainstream treatment until practitioners such as NYU dermatologist Perry Robins, MD, refined the technique and spread the word about it in the 1970s and 1980s. The use of Mohs surgery has especially been growing in the past 15 years, above all for skin cancers in the head and neck region.2-5
The most obvious difference between Mohs surgery and routine excisional surgery is that Mohs is done in stages while you wait for lab results, which are obtained immediately on site, rather than the tissue sample being sent to a lab for results days later.
A surgeon specially trained in Mohs surgery, pathology and reconstructive surgery first may draw some marks around the lesion with ink to guide the treatment, then injects a local anesthesia. Using a scalpel, the doctor removes the thinnest possible layer of visible cancerous tissue. (Sometimes doctors gauge this by feel as well as by sight.) A nurse or assistant bandages your wound and shows you to a waiting area.
The surgeon then color-codes the tissue with ink to map exactly where it was removed from the body. Next, a technician processes the tumor in the on-site laboratory by freezing the tissue so that it can be readily cut into paper-thin sections (like a stack of dimes) and placed on slides. The tissue on the slides is then stained and the Mohs surgeon examines these slides under a microscope. If the doctor finds any remaining cancer cells, the areas are pinpointed on the map, and you’re called back into the operating room. The doctor numbs those areas again before precisely removing another layer of tissue from each of the locations where cancer cells remain.
Mohs Surgery
The Most Effective Technique for Treating Common Skin Cancers
Mohs surgery is considered the most effective technique for treating many basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), the two most common types of skin cancer. Sometimes called Mohs micrographic surgery, the procedure is done in stages, including lab work, while the patient waits. This allows the removal of all cancerous cells for the highest cure rate while sparing healthy tissue and leaving the smallest possible scar.
It began as a technique called chemosurgery, developed by Frederic E. Mohs, MD, in the late 1930s, but was not widely known. In the mid 1960s, Perry Robins, MD, studied the procedure with Dr. Mohs, and recognized that it had great potential for the field of dermatology. He brought the technique to NYU, where he established the first fellowship training program to teach dermatologists this skin cancer surgery. Dr. Robins helped advance the procedure into what is now called Mohs surgery and went on to teach and promote it around the world.
- IN PARTNERSHIP WITH
THE ADVANTAGE OF MOHS
CURE RATE
for a skin cancer that has not been treated before
Who performs the procedure?
Mohs surgery is performed by doctors who are specially trained to fulfill three roles:
- as the surgeon who removes the cancerous tissue
- as the pathologist who analyzes the lab specimens
- as the surgeon who closes or reconstructs the wound
Advantages of Mohs surgery
Efficient, cost-effective treatment
- Single-visit outpatient surgery
- Local anesthesia
- Lab work done on-site
Precise results
- Physician examines 100% of tumor margins
- Spares healthy tissue
- Leaves the smallest scar possible
The highest cure rate
- Up to 99% for a skin cancer that has not been treated before
- Up to 94% for a skin cancer that has recurred after previous treatment
What happens during Mohs surgery
The procedure is done in stages, all in one visit, while the patient waits between each stage. After removing a layer of tissue, the surgeon examines it under a microscope in an on-site lab. If any cancer cells remain, the surgeon knows the exact area where they are and removes another layer of tissue from that precise location, while sparing as much healthy tissue as possible. The doctor repeats this process until no cancer cells remain.
Step 1: Examination and prep
Depending on the location of your skin cancer, you may be able to wear your street clothes, or you may need to put on a hospital gown. The Mohs surgeon examines the spot where you had your biopsy and may mark it with a pen for reference. The doctor positions you for best access, which may mean sitting up or lying down. A surgical drape is placed over the area. If your skin cancer is on your face, that may mean you can’t see what’s happening, but the doctor talks you through it. The surgeon then injects a local anesthesia, which numbs the area completely. You stay awake throughout the procedure.
Step 2: Top layer removal
Using a scalpel, the surgeon removes a thin layer of visible cancerous tissue. Some skin cancers may be “the tip of the iceberg,” meaning they have roots or extensions that aren’t visible from the surface. The lab analysis, which comes next, will determine that. Your wound is bandaged temporarily and you can relax while the lab work begins.
Step 3: Lab analysis
The surgeon cuts the tissue into sections, color codes them with dyes and draws a map of the surgical site. In the lab, a technician freezes the divided tissue, then cuts very thin horizontal slices like a layer cake. The slices are placed on microscope slides, stained and covered. This meticulous process takes time.
Step 4: Microscopic examination
Using a microscope, the surgeon examines all the edges and underside of the tissue on the slides and, if any cancer cells remain, marks their location on the map. The physician then lets you know whether you need another layer of tissue removed.
Step 5: Second layer removal
Back in the operating room, the surgeon injects more anesthesia if needed and removes another layer of skin, precisely where the cancer cells remain, based on the map. Then, while you wait, the lab work begins again. This entire process is repeated as many times as needed until there are no more cancer cells.
Step 6: Wound repair
Once the site is clear of all cancer cells, the wound may be left open to heal or the surgeon may close it with stitches. This depends on its size and location. In some cases, a wound may need reconstruction with a skin flap, where neighboring tissue is moved into the wound, or possibly a skin graft. In some cases, your Mohs surgeon may coordinate the repair of your wound with another specialist such as a plastic surgeon, oculoplastic surgeon or hand surgeon. In most instances, however, the Mohs surgeon will repair the wound immediately after obtaining clear margins.
Step 7: Finishing up
If more than one or two rounds are needed, the entire process can take up to several hours, so be prepared for that. It’s worth it, though, because this precise technique has the highest cure rate of any treatment method and can save the greatest amount of healthy tissue, leaving the smallest scar possible. Carefully follow your doctor’s instructions for wound care, scar care and follow-up to achieve the best outcome.
Is Mohs right for me?
Mohs surgery is the gold standard for treating many basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), including those in cosmetically and functionally important areas around the eyes, nose, lips, ears, scalp, fingers, toes or genitals. Mohs is also recommended for BCCs or SCCs that are large, aggressive or growing rapidly, that have indistinct edges, or have recurred after previous treatment. Some surgeons are also successfully using Mohs surgery on certain cases of melanoma.
More body fat linked to lower bone density, especially in men
High levels of body fat are associated with a lower bone mineral density, with the association more pronounced in men compared with women, according to study data published in The Journal of Clinical Endocrinology & Metabolism.
“While higher BMI is generally associated with higher bone density, our study demonstrates that lean and fat mass affect bone density differently and that obesity is not a guarantee against osteoporosis,” Rajesh K. Jain, MD, assistant professor in the section of endocrinology, diabetes and metabolism and director of the endocrinology fellowship program at the University of Chicago Medicine, told Healio. “Patients with obesity should still undergo recommended bone density screening, especially if they have other risk factors, such as older age, previous fracture, family history or steroid use.”
Jain and colleagues analyzed data from 10,814 adults aged 20 to 59 years who participated in the National Health and Nutrition Examination Survey from 2011 to 2018 and underwent a total body DXA scan. T-scores were calculated to determine total body BMD. Lean mass index and fat mass index were calculated to assess the effects of body composition on BMD.
After adjusting for age, sex, race and ethnicity, height, smoking status, lean mass index and fat mass index, every 1 kg/m2 of lean mass index was associated with a 0.19 higher total body BMD T-score (P < .001). Conversely, each 1 kg/m2 increase in fat mass index was associated with a 0.1 decrease in BMD T-score (P < .001).
The association between fat mass index and BMD T-score differed for men and women. Women had a BMD T-score decrease of 0.08 points for every 1 kg/m2 increase in fat mass index, whereas men had a 0.13 lower BMD T-score with every 1 kg/m2 increase in fat mass index (P for interaction < .001). The association between fat mass index and BMD T-score did not differ by age group. For lean mass index, Mexican American adults had a lower BMD T-score increase of 0.16 for each 1 kg/m2 increase compared with a 0.21 BMD T-score increase for each 1 kg/m2 for white adults (P for interaction = .004). There were no other differences observed between race and ethnicity groups.
“Unfortunately, body composition is not a routine clinical measurement, so we rarely know what a patient’s body fat or body lean mass is,” Jain said. “Factors that correlate with high body fat and low lean mass are often associated with osteoporosis or fractures, and their presence should prompt clinicians to consider osteoporosis screening. This includes, for example, the presence of diabetes or poor performance on physical activity measures, such as grip strength.”
Jain said future research should examine the effects that weight loss may have on BMD.
“In general, weight loss has been associated with bone loss and fractures, but this study suggests the type of weight loss — lean vs. fat mass — may be important in determining if or how much bone loss occurs,” Jain said.
For more information:
Rajesh K. Jain, MD, can be reached at rjain2@medicine.bsd.uchicago.edu.
PERSPECTIVE
Mone Zaidi, MD, PhD, MBA, MACP, FRCP
Over the past two decades, we have worked on the idea that pituitary hormones have diverse functions beyond the unitary actions that appear traditionally in endocrine textbooks. We found, for the first time, that thyroid-stimulating hormone and follicle-stimulating hormone have direct actions on bone. The implication of these studies was that low TSH and high follicle-stimulating hormone levels in hyperthyroidism and after menopause likely contribute to the bone loss hitherto attributed solely to high thyroid hormone and low estrogen levels, respectively (Abe E, et al. Cell. 2003;doi:10.1016/s0092-8674(03)00771-2).
Correlative studies in cohorts across the globe have shown strong associations between serum TSH or follicle-stimulating hormone, markers of bone remodeling, bone mineral density and fracture risk, independently of thyroxine or estrogen. Focusing on the effects of follicle-stimulating hormone, we developed a targeted follicle-stimulating hormone blocking antibody that prevented bone loss in mouse models (Zhu LL, et al. Proc Natl Acad Sci U S A. 2012;doi:10.1073/pnas.1212806109). Intriguingly, the follicle-stimulating hormone blocking antibody also reduced body fat and converted white adipose tissue to thermogenic beige adipose tissue (Liu X, et al, Nature. 2017;doi:10.1038/nmeth.4436) and, in a separate study, prevented cognitive decline and Alzheimer-like neuropathology in mouse models (Xiong, et al, Nature, 2022; in press).
Our humanized monoclonal follicle-stimulating hormone blocking antibody replicates these actions and has shown promise in preclinical studies toward first-in-human clinical trials in the very near future. Our admittedly ambitious premise is to treat osteoporosis, obesity and neurodegeneration with a single drug.
Mone Zaidi, MD, PhD, MBA, MACP, FRCP
Professor of Medicine and Pharmacological Sciences
Director, Center for Translational Medicine and Pharmacology
Director, Mount Sinai Bone Program
Icahn Sinai School of Medicine at Mount Sinai
Higher saturated bone marrow lipid levels increase fracture risk for older adults
Older adults with higher levels of saturated bone marrow lipids have a higher risk for fractures, whereas those with more unsaturated marrow lipids have a lower fracture risk, according to study findings.
“It has been established that greater bone marrow adiposity is associated with aging and osteoporosis,” Gina N. Woods, MD, associate professor of medicine at University of California, San Diego, told Healio. “The aim of this study was to evaluate whether the type of fat within bone marrow, not just the total amount, influences bone. The take-home message is that saturated and unsaturated marrow lipids have distinct and opposing effects on skeletal health in older adults.”
Woods and colleagues analyzed data from the AGES-Reykjavik study, a longitudinal observational study of community-dwelling older adults. Participants underwent quantitative CT scans of the spine and hip at baseline, and DXA scans of the hip, anteroposterior spine and lateral spine at baseline and during follow-up visits. MRI scans were conducted to measure bone marrow lipids. Incident fractures were identified between baseline and Dec. 31, 2012, using data from the Reykjavik study fracture registry. Fractures occurring from January 2013 to March 15, 2019, were obtained from hospital records. Participants had sex steroid and bone biomarkers measured through serum collections at baseline.
The findings were published in The Journal of Bone and Mineral Research.
There were 465 older adults included in the study cohort, including 243 men (mean age, 82.6 years) and 222 women (mean age, 80.7 years). Men had an areal bone mineral density reduction of 0.3 mg/cm2 per year, and 18.9% had at least one fracture during 4.7 years of follow-up. The annual areal BMD reduction among women was 3.5 mg/cm2, and 23.9% reported a fracture during a mean follow-up of 5.5 years.
Saturated lipid content lowers BMD
In adjusted analyses, each standard deviation increase in vertebral marrow saturated lipid content was associated with a 23.6% reduction in lower spine trabecular bone density and a 26.8% reduction in lower spine compressive strength index. There was also a 13% reduction in trabecular BMD and a 1.2% reduction in cortical BMD at the total hip, and a 23.5% reduction in trabecular BMD and a 1% reduction in cortical BMD at the femoral neck with each standard deviation increase in vertebral marrow saturated lipid content.
Each standard deviation increase in vertebral marrow unsaturated lipid content was associated with a 17.5% increase in trabecular spine BMD, a 26.2% increase in spine compressive strength, an 11.5% increase in total hip trabecular BMD and a 22% increase in femoral neck trabecular BMD.
Saturated and unsaturated lipid content were not associated with changes in any bone parameters for the full cohort. For women, each standard deviation increase in saturated lipid content was linked to a 3.82 mg2/cm4 reduction of spine compressive strength index each year, and each standard deviation increase in unsaturated lipid content increased the loss of femoral neck trabecular BMD by 1.39 mg/cm3 each year.
Increased fracture risk with higher saturated lipids
Each standard deviation increase in saturated lipid content increased the odds for a prevalent vertebral fracture (OR = 1.46; 95% CI, 1.11-1.92) and incident radiographic vertebral fracture (OR = 1.55; 95% CI, 1.03-2.34). Each standard deviation increase in unsaturated lipid content decreased the likelihood for incident radiographic vertebral fracture (OR = 0.58; 95% CI, 0.38-0.89).
“We did not find marrow lipid composition to be significantly associated with bone loss, although we did find associations with prevalent and incident fractures,” Woods said. “These findings suggest that marrow lipid composition may influence fracture risk through a mechanism that is independent of bone density.”
There were no associations observed between saturated lipid content and bone biomarkers.
Each standard deviation increase in unsaturated lipid content was associated with a 6.87% reduction in procollagen type 1 N-terminal propeptide (P1NP) and a 6.97% reduction in C-terminal telopeptide of type 1 collagen (CTX).
Woods said more research is needed on the factors regulating marrow lipid accumulation and lipid composition, as well as whether marrow lipid interventions can affect bone health.
New clinical trial will test three mRNA vaccine candidates for HIV
The National Institute of Allergy and Infectious Diseases announced Monday that it has initiated a phase 1 clinical trial of three experimental messenger RNA HIV vaccines.
The study will be conducted by NIAID-funded HIV Vaccine Trials Network (HVTN), which is based at the Fred Hutchinson Cancer Research Center in Seattle.
Anthony S. Fauci
“Finding an HIV vaccine has proven to be a daunting scientific challenge,” NIAID Director Anthony S. Fauci, MD, said in a press release. “With the success of safe and highly effective COVID-19 vaccines, we have an exciting opportunity to learn whether mRNA technology can achieve similar results against HIV infection.”
An mRNA vaccine works by delivering a piece of genetic material that teaches the immune system to recognize a target pathogen and mount a response, the NIH noted. The technology was used to create the first two licensed COVID-19 vaccines made by Pfizer-BioNTech and Moderna.
The new trial, HVTN 302, will assess whether three experimental HIV vaccines — currently named BG505 MD39.3 mRNA, BG505 MD39.3 gp151 mRNA and BG505 MD39.3 gp151 CD4KO mRNA — are safe and can induce immune responses.
The vaccines are designed to present the spike protein found on the surface of HIV. None can cause HIV infection.
HVTN 302 will be led by Jesse Clark, MD, an HIV researcher at the University of California, Los Angeles, and Sharon Riddler, MD, associate chief of clinical research at the University of Pittsburgh. It will enroll adults aged 18 to 55 years in 11 U.S. cities — Birmingham, Alabama; Boston; Los Angeles; New York; Philadelphia; Pittsburgh; Rochester, New York; and Seattle.
The researchers will randomly assign participants to one of six groups, each receiving three doses of one of the experimental vaccines. The first three groups, each made up of 18 participants, will receive intramuscular injections of 100 µg of their assigned candidate at their first visit and again at 2 months, followed by a third dose at 6 months.
Researchers will evaluate participants 2 weeks after their first dose to ensure that safety criteria are met. If so, the remaining three groups will be vaccinated with 250 µg of the assigned vaccine at the same time intervals.
The trial is expected to be completed by July 2023.
PERSPECTIVE
Paul A. Volberding
The amazing success of mRNA vaccines in COVID-19 makes it obvious and imperative to apply this technology to other viral infections that have been historic challenges to effective immunization development to date.
Certainly, HIV is high on this list.
The ability to tailor the immunogen so readily with the mRNA approach could allow the improved response we have waited for so long. This will be an interesting process to follow. Clearly, this is an understatement.
Paul A. Volberding, MD
Chief Medical Editor,Infectious Disease News
Professor emeritus of medicine
University of California, San Francisco
Studies confirm COVID-19 vaccination during pregnancy benefits newborns
Findings have shown that COVID-19 mRNA vaccines are safe and effective during pregnancy, and evidence also suggests that the benefits of maternal vaccination extend to newborns.
However, despite the track record of the vaccines and the negative health outcomes associated COVID-19 during pregnancy, vaccine uptake among pregnant women has remained lower compared with that of the general population.
A recent analysis showed that pregnant women are motivated to get vaccinated if health care workers explain how immunization benefits their baby. We spoke with experts about the safety of COVID-19 vaccines during pregnancy and the studies showing how maternal vaccination can protect infants.
‘Primum non nocere’
In a study published this year, Goldshtein and colleagues found that rates of preterm birth, all-cause neonatal hospitalization, post-neonatal hospitalization, congenital anomalies and infant mortality were similar between newborns who were and were not exposed to the Pfizer-BioNTech vaccine in utero.
Mary Jane Minkin
“The two important tenets of medicine are ‘primum non nocere’ and ‘secundum bene facere’ — first do no harm; second, do good,” Mary Jane Minkin, MD, clinical professor in the department of obstetrics, gynecology and reproductive sciences at the Yale School of Medicine, told Healio. “[This study] clearly outlines no harm … and there are also other studies out there confirming this.”
One such study found that babies exposed to the vaccine during their mothers’ pregnancy did not hinder fetal brain development.
‘Secundum bene facere’
Multiple studies have shown that newborns may benefit from maternal vaccination, fulfilling the “do good” principle to which Minkin alluded.
In one study, Yang and colleagues evaluated levels of anti-spike immunoglobin G (IgG) antibodies in pregnant women who had received at least one dose of either the Moderna, Pfizer-BioNTech or Johnson & Johnson vaccines. Their data showed that being fully vaccinated at any time during pregnancy was associated with the presence of maternal antibodies.
Conti and colleagues studied a contrasting cohort — mothers with COVID-19 — and found that infants had antibodies in their saliva, “which may partly explain why newborns are resistant to SARS-CoV-2 infection,” they said. They also found that antibodies can be transferred via breast milk to newborns.
Despite this seeming benefit of infection, Yang and colleagues discovered that vaccination during the third trimester yielded maternal and umbilical antibody titers comparable to those observed in women with previous SARS-CoV-2 infection. Additionally, they found that receiving a booster shot during the third trimester was associated with an even greater concentration of antibodies than natural infection.
Another study conducted by Kugelman and colleagues supported these findings, specifically regarding the Pfizer-BioNTech vaccine administered during the second trimester. Though both mothers and their babies in this study had humoral responses, newborns had a 2.6-times higher level of antibodies compared with their mothers.
This transfer of antibodies is crucial for protecting the youngest children, Minkin emphasized.
“Newborns are basically immunocompromised; they cannot make antibodies when they are born,” said Minkin, who is also a Healio Women’s Health & OB/GYN Peer Perspective Board Member. “No trials on immunization to kids are going to look at newborns under 6 months old, so getting this vulnerable group antibodies is key.”
Looking past the newborn stage, Shook and colleagues found that 57% of infants aged 6 months whose mothers had been vaccinated during pregnancy had retained antibodies, compared with 8% of those whose mothers were infected with SARS-CoV-2 during pregnancy. Though this study was small, “these findings provide further incentive for pregnant individuals to pursue COVID-19 vaccination,” the researchers wrote.
Importance of vaccination
As data continue to support the benefits of maternal COVID-19 vaccination for newborns, doctors must continue to advocate for vaccination of pregnant women, according to experts.
Sarah Stock
“There is now good evidence that vaccination is the safest and most effective way for pregnant women to protect themselves and their babies against COVID-19 infection,” Sarah Stock, MD, PhD, a reader in maternal and fetal health and an honorary consultant and subspecialist in maternal and fetal medicine at the University of Edinburgh Usher Institute, told Healio. “If you are at any stage in pregnancy or hoping to become pregnant, I would strongly encourage you to get vaccinated.”
Given these data and the increased risk for pregnancy complications associated with COVID-19, Minkin said it is best for pregnant women to get vaccinated than risk infection.
“All these [studies] demonstrate that maternal vaccination is safer for the mother, but also safer for her newborn, so why not get the vaccination?” she said. “We often don’t get the opportunity to take a win-win situation.”
References:
- Conti MG, et al. JAMA Netw Open. 2021;doi:10.1001/jamanetworkopen.2021.32563.
- Fuss TL, et al. Womens Health Issues. 2021;doi:10.1016/j.whi.2021.09.004.
- Goldshtein I, et al. JAMA Pediatr. 2022;doi:10.1001/jamapediatrics.2022.0001.
- Kugelman N, et al. JAMA Pediatr. 2022;doi:10.1001/jamapediatrics.2021.5683.
- Shook LL, et al. JAMA. 2022;doi:10.1001/jama.2022.1206.
- Yang YJ, et al. Obstet Gynecol. 2022;doi:10.1097/AOG.0000000000004693.
Link between high cholesterol and heart disease ‘inconsistent,’ new study finds
New research from RCSI University of Medicine and Health Sciences has revealed that the link between ‘bad’ cholesterol (LDL-C) and poor health outcomes, such as heart attack and stroke, may not be as strong as previously thought.
Published in JAMA Internal Medicine, the research questions the efficacy of statins when prescribed with the aim of lowering LDL-C and therefore reducing the risk of cardiovascular disease (CVD).
Previous research has suggested that using statins to lower LDL-C positively affects health outcomes, and this is reflected in the various iterations of expert guidelines for the prevention of CVD. Statins are now commonly prescribed by doctors, with one third of Irish adults over the age of 50 taking statins, according to previous research.
The new findings contradict this theory, finding that this relationship was not as strong as previously thought. Instead, the research demonstrates that lowering LDL-C using statins had an inconsistent and inconclusive impact on CVD outcomes such as myocardial infarction (MI), stoke, and all-cause mortality.
In addition, it indicates that the overall benefit of taking statins may be small and will vary depending on an individual’s personal risk factors.
The lead author on the paper is Dr Paula Byrne from the HRB Centre for Primary Care Research based in RCSI’s Department of General Practice. Commenting on the findings, Dr Byrne said: “The message has long been that lowering your cholesterol will reduce your risk of heart disease, and that statins help to achieve this. However, our research indicates that, in reality, the benefits of taking statins are varied and can be quite modest.”
The researchers go on to suggest that this updated information should be communicated to patients through informed clinical decision-making and updated clinical guidelines and policy.
This important discovery was a collaboration with Professor Susan M Smith, also of RCSI and with researchers from the University of New Mexico, USA, (Dr Robert DuBroff), the Institute for Scientific Freedom in Denmark (Dr Maryanne Demasi), Bond University in Australia (Dr Mark Jones) and independent researcher Dr Kirsty O’Brien.
Statin therapy underused for treating severe hypercholesterolemia
The number of adults with severe hypercholesterolemia prescribed general and high-intensity statins in a Kentucky health system falls below recommended guidelines, according to a study published in The American Journal of Cardiology.
Wael Eid
“Individuals with severe hypercholesterolemia have a fivefold higher long-term risk for coronary heart disease and atherosclerotic cardiovascular disease compared with individuals with average LDL-C levels,” Wael Eid, MD, an endocrinologist and lipid specialist at St. Elizabeth Physicians Regional Diabetes Center in Covington, Kentucky, the University of Kentucky College of Medicine in Lexington, the University of South Dakota Sanford School of Medicine in Sioux Falls and Alexandria University in Egypt, told Healio. “There are distinct rigorous guidelines to support aggressive treatment for severe hypercholesterolemia with high-intensity statins and other lipid-lowering therapies, if needed. However, there is a general feeling that these guidelines are not yet fully implemented. The value of this study was to assess the extent of use of these guidelines in the population we serve, to identify potential areas of gaps in care, and to be able to identify these individual patients and optimize their treatment.”
Eid and colleagues conducted a cross-sectional study of every patient who had LDL cholesterol measured in the St. Elizabeth Health Care system from 2009 to April 2020. Severe hypercholesterolemia was defined as having LDL cholesterol levels of at least 190 mg/dL. Those with severe hypercholesterolemia were placed in one group (n = 19,695) while those without severe hypercholesterolemia were placed into a second group (n = 245,525).
The severe hypercholesterolemia group had a higher prevalence of hypertension and higher mean blood pressure, systolic BP, diastolic BP and cholesterol values than those with nonsevere hypercholesterolemia.
Most patients with no comorbidities in the severe hypercholesterolemia group were treated by primary care providers (43.2% to 45.7%) — who mostly prescribed low- or moderate-intensity statin therapy — whereas 3.4% to 4.4% were treated by an endocrinologist and 2.5% to 3.3% by a cardiologist.
In the severe hypercholesterolemia group, 77% were prescribed general statins and 27% high-intensity statin therapy. Of the severe hypercholesterolemia group, 83% had persistently elevated LDL cholesterol levels, and 22% of these were prescribed a high-intensity statin.
Patients with comorbidities were more likely to be prescribed statins, regardless of hypercholesterolemia severity. Adults with severe hypercholesterolemia aged 40 to 75 years (74% to 76.3%) and those older than 75 years (65.6% to 73.6%) were more likely to receive a statin prescription than those younger than 40 years (50% to 58.3%).
“There was evidence of treatment paradox where those with highest risk for CVD are not treated as aggressively as they should,” Eid said. “Less than one-third of patients with severe hypercholesterolemia are treated by high-intensity statins. Younger patients with severe hypercholesterolemia are being less aggressively treated than those who are middle-aged, even though both have high risk for CVD. Most of these patients are being cared for at primary care offices rather than specialty medicine, and that is where most of the efforts in optimizing care should be targeted.”
Eid said support is needed from quality improvement and clinical utilization departments to have initiatives for optimizing risk for patients with severe hypercholesterolemia. He added that greater awareness of severe hypercholesterolemia in primary care practices and identifying barriers for statin therapy optimization are other important issues to address.
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