OBG Management caught up with Drs. Jan Shifren and Genevieve Neal-Perry while they were attending the annual meeting of The North American Menopause Society (NAMS), held October 12-15, 2022, in Atlanta, Georgia. Dr. Shifren presented on the “Ins and Outs of Hormone Therapy,” while Dr. Neal-Perry focused on “Menopause Physiology.” 

Evaluating symptomatic patients for appropriate hormone therapy

OBG Management: In your presentation to the group at the NAMS meeting, you described a 51-year-old patient with the principal symptoms of frequent hot flashes and night sweats, sleep disruption, fatigue, irritability, vaginal dryness, and dyspareunia. As she reported already trying several lifestyle modification approaches, what are your questions for her to determine whether hormone therapy (HT), systemic or low-dose vaginal, is advisable?

Jan Shifren, MD: As with every patient, you need to begin with a thorough history and confirm her physical exam is up to date. If there are concerns related to genitourinary symptoms of menopause (GSM), then a pelvic exam is indicated. This patient is a healthy menopausal woman with bothersome hot flashes, night sweats, and vaginal dryness. Sleep disruption from night sweats is likely the cause of her fatigue and irritability, and her dyspareunia due to atrophic vulvovaginal changes. The principal indication for systemic HT is bothersome vasomotor symptoms (VMS), and a healthy woman who is under age 60 or within 10 years of the onset of menopause is generally a very good candidate for hormones. For this healthy 51-year-old with bothersome VMS unresponsive to lifestyle modification, the benefits of HT should outweigh potential risks. As low-dose vaginal estrogen therapy is minimally absorbed and very safe, this would be recommended instead of systemic HT if her only menopause symptoms were vaginal dryness and dyspareunia.

HT types and formulations

OBG Management: For this patient, low-dose vaginal estrogen is appropriate. In general, how do you decide on recommendations for combination therapy or estrogen only, and what formulations and dosages do you recommend?

Dr. Shifren: Any woman with a uterus needs to take a progestogen together with estrogen to protect her uterus from estrogen-induced endometrial overgrowth. With low dose vaginal estrogen therapy, however, concurrent progestogen is not needed.

Continue to: Estrogen options...

Many of our patients like the idea that they are using “natural” HT. I inform them that bioidentical is a marketing term rather than a medical term, but if their goal is to take the same hormones that their ovaries made when they were younger, they should use FDA-approved formulations of estradiol and progesterone for their menopausal HT symptoms. I do not recommend compounded bioidentical HT due to concerns regarding product quality and safety. The combination of FDA-approved estradiol patches and oral micronized progesterone provides a high quality, carefully regulated bioidentical HT regimen. For women greatly preferring an oral estrogen, oral estradiol with micronized progesterone is an option.

In addition to patient preference for natural HT, the reasons that I encourage women to consider the estradiol transdermal patch for their menopausal HT include:

1. no increased risk of venous thromboembolic events when physiologically dosed menopausal estradiol therapy is provided by a skin patch (observational data).¹ With oral estrogens, even when dosed for menopause, VTE risk increases, as coagulation factors increase due to the first-pass hepatic effect. This does not occur with non-oral menopausal estrogens.
2. no increased risk of gallbladder disease, which occurs with oral estrogen therapy (observational data)²
3. possibly lower risk of stroke when low-dose menopausal HT is provided via skin patch (observational data)³
4. convenience—the patches are changed once or twice weekly
5. wide range of doses available, which optimizes identifying the lowest effective dose and decreasing the dose over time.

Progestogen options. Progestogens may be given daily or cyclically. Use of daily progestogen typically results in amenorrhea, which is preferred by most women. Cyclic use of a progestogen for 12-14 days each month results in a monthly withdrawal bleed, which is a good option for a woman experiencing bothersome breakthrough bleeding with daily progestogen. Use of a progestogen-releasing IUD is an off-label alternative for endometrial protection with menopausal HT. As discussed earlier, as many women prefer bioidentical HT, one of our preferred regimens is to provide transdermal estradiol with FDA-approved oral micronized progesterone. There are several patches that combine estradiol with a progestogen, but there is not a lot of dosing flexibility and product choice. There also is an approved product available that combines oral estradiol and micronized progesterone in one tablet.

Scheduling follow-up

OBG Management: Now that you have started the opening case patient on HT, how often are you going to monitor her for treatment?

Dr. Shifren: Women will not experience maximum efficacy for hot flash relief from their estrogen therapy for 3 months, so I typically see a patient back at 3 to 4 months to assess side effects and symptom control. I encourage women to reach out sooner if they are having a bothersome side effect. Once she is doing well on an HT regimen, we assess risks and benefits of ongoing treatment annually. The goal is to be certain she is on the lowest dose of estrogen that treats her symptoms, and we slowly decrease the estrogen dose over time.

Breast cancer risk

OBG Management: In your presentation, you mentioned that the risk of breast cancer does not increase appreciably with short-term use of HT. Is it possible to define short term?

Dr. Shifren: In the Women’s Health Initiative (WHI), a large double-blind, randomized, placebo-controlled trial of menopausal HT, there was a slight increase in breast cancer risk after approximately 4 to 5 years of use in women using estrogen with progestogen.⁴ I share with patients that this increased risk is about the same as that of obesity or drinking more than 1 alcoholic beverage daily. As an increased risk of breast cancer does not occur for several years, a woman may be able to take hormones for bothersome symptoms, feel well, and slowly come off without incurring significant breast cancer risk. In the WHI, there was no increase in breast cancer risk in women without a uterus randomized to estrogen alone.

Regarding cardiovascular risk, in the WHI, an increased risk of cardiovascular events generally was not seen in healthy women younger than age 60 and within 10 years of the onset of menopause.⁵ Benefits of HT may not outweigh risks for women with significant underlying cardiovascular risk factors, even if they are younger and close to menopause onset.

Continue to: The importance of shared decision making...

Dr. Shifren: As with any important health care decision, women should be involved in an individualized discussion of risks and benefits, with shared decision making about whether HT is the right choice. Women also should be involved in ongoing decisions regarding HT formulation, dose, and duration of use.

A nonhormonal option for hot flashes

OBG Management: How many women experience VMS around the time of menopause?

Dr. Genevieve Neal-Perry, MD, PhD: About 60% to 70% of individuals will experience hot flashes around the time of the menopause.⁶ Of those, about 40% are what we would call moderate to severe hot flashes—which are typically the most disruptive in terms of quality of life.⁷ The window of time in which they are likely to have them, at typically their most intense timeframe, is 2 years before the final menstrual period and the year after.⁷ In terms of the average duration, however, it’s about 7 years, which is a lot longer than what we previously thought.⁸ Moreover, there are disparities in that women of color, particularly African American women, can have them as long as 10 years.⁸
 

OBG Management: Can you explain why the VMS occur, and specifically around the time of menopause?

Dr. Neal-Perry: For many years we did not understand the basic biology of hot flashes. When you think about it, it’s completely amazing—when half of our population experiences hot flashes, and we don’t understand why, and we don’t have therapy that specifically targets hot flashes.

What we now know from work completed by Naomi Rance, in particular, is that a specific region of the brain, the hypothalamus, exhibited changes in number of neurons that seemed to be increased in size in menopausal people and smaller in size in people who were not menopausal.⁹ That started the journey to understanding the biology, and eventual mechanism, of hot flashes. It took about 10-15 years before we really began to understand why.

What we know now is that estrogen, a hormone that is made by the ovaries, activates and inactivates neurons located in the hypothalamus, a brain region that controls our thermoregulation—the way your body perceives temperature. The hypothalamus controls your response to temperature, either you experience chills or you dissipate heat by vasodilating (hot flush) and sweating.

The thermoregulatory region of the hypothalamus houses cells that receive messages from KNDy neurons, neurons also located in the hypothalamus that express kisspeptin, neurokinin, and dynorphin. Importantly, KNDy neurons express estrogen receptors. (The way that I like to think about estrogen and estrogen receptors is that estrogen is like the ball and the receptor is like the catcher’s mitt.) When estrogen interacts with this receptor, it keeps KNDy neurons quiet. But the increased variability and loss of estrogen that occurs around the time of menopause “disinhibits” KNDy neurons—meaning that they are no longer being reined in by estrogen. In response to decreased estrogen regulation, KNDy neurons become hypertrophied with neurotransmitters and more active. Specifically, KNDy neurons release neurokinin, a neuropeptide that self-stimulates KNDy neurons and activates neurons in the thermoregulatory zone of the brain—it’s a speed-forward feed-backward mechanism. The thermoregulatory neurons interpret this signal as “I feel hot,” and the body begins a series of functions to cool things down.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Continue to: Treatments that act on the thermoregulatory region

Dr. Neal-Perry: I have described what happens in the brain around the time of menopause, and what triggers those hot flashes.

Estrogen. The reason that estrogen worked to treat the hot flashes is because estrogen inhibits and calms the neurons that become hyperactive during the menopause.

Fezolinetant. Fezolinetant is unique because it specifically targets the hormone receptor that triggers hot flashes, the neurokinin receptor. Fezolinetant is a nonhormone therapy that not only reduces the activity of KNDy neurons but also blocks the effects of neurons in the thermoregulatory zone, thereby reducing the sensation of the hot flashes. We are in such a special time in medical history for individuals who experience hot flashes because now we understand the basic biology of hot flashes, and we can generate targeted therapy to manage hot flashes—that is for both individuals who identify as women and individuals who identify as men, because both experience hot flashes.
 

OBG Management: Is there a particular threshold of hot flash symptoms that is considered important to treat, or is treatment based on essentially the bother to patients?

Dr. Neal-Perry: Treatment is solely based on if it bothers the patient. But we do know that people who have lots of bothersome hot flashes have a higher risk for heart disease and may have sleep disruption, reduced cognitive function, and poorer quality of life. Sleep dysfunction can impact the ability to think and function and can put those affected at increased risk for accidents.

For people who are having these symptoms that are disruptive to their life, you do want to treat them. You might say, “Well, we’ve had estrogen, why not use estrogen,” right? Well estrogen works very well, but there are lots of people who can’t use estrogen—individuals who have breast cancer, blood clotting disorders, significant heart disease, or diabetes. Then there are just some people who don’t feel comfortable using estrogen.

We have had a huge gap in care for individuals who experience hot flashes and who are ineligible for menopausal HT. While there are other nonhormonal options, they often have side effects like sexual dysfunction, hypersomnolence, or insomnia. Some people choose not to use these nonhormonal treatments because the side effects are worse for them than to trying to manage the hot flashes. The introduction to a nonhormonal therapy that is effective and does not have lots of side effects is exciting and will be welcomed by many who have not found relief.
 

OBG Management: Is fezolinetant available now for patients?

Dr. Neal-Perry: It is not available yet. Hopefully, it will be approved within the next year. Astellas recently completed a double blind randomized cross over design phase 3 study that found fezolinetant is highly effective for the management of hot flashes and that it has a low side effect profile.¹⁰ Fezolinetant’s most common side effect was COVID-19, a reflection of the fact that the trial was done during the COVID pandemic. The other most common side effect was headache. Everything else was minimal.

Other drugs in the same class as fezolinetant have been under development for the management of hot flashes; however, they encountered liver function challenges, and studies were stopped. Fezolinetant did not cause liver dysfunction.

Hot flash modifiers

OBG Management: Referring to that neuropathway, are there physiologic differences among women who do and do not experience hot flashes, and are there particular mechanisms that may protect patients against being bothered by hot flashes?

Dr. Neal-Perry: Well, there are some things that we can control, and there are things that we cannot control (like our genetic background). Some of the processes that are important for estrogen receptor function and estrogen metabolism, as well as some other receptor systems, can work differently. When estrogen metabolism is slightly different, it could result in reduced estrogen receptor activity and more hot flashes. Then there are some receptor polymorphisms that can increase or reduce the risk for hot flashes—the genetic piece.¹¹

There are things that can modify your risk for hot flashes and the duration of hot flashes. Individuals who are obese or smoke may experience more hot flashes. Women of color, especially African American women, tend to have hot flashes occur earlier in their reproductive life and last for a longer duration; hot flashes may occur up to 2 years before menopause, last for more than 10 years, and be more disruptive. By contrast, Asian women tend to report fewer and less disruptive hot flashes.⁸
 

OBG Management: If fezolinetant were to be FDA approved, will there be particular patients that it will most appropriate for, since it is an estrogen alternative?

Dr. Neal-Perry: Yes, there may be different patients who might benefit from fezolinetant. This will depend on what the situation is—patients who have breast cancer, poorly controlled diabetes, or heart disease, and those patients who prefer not to use estrogen will benefit from fezolinetant, as we are going to look for other treatment options for those individuals. It will be important for medical providers to listen to their patients and understand the medical background of that individual to really define what is the best next step for the management of their hot flashes.

This is an exciting time for individuals affected by menopausal hot flashes; to understand the biology of hot flashes gives us real opportunities to bridge gaps around how to manage them. Individuals who experience hot flashes will know that they don’t have to suffer, that there are other options that are safe, that can help meet their needs and put them in a better place. ●

Multiethnic differences in the menopause experience

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Excerpted from the presentation, “Do you see me? Culturally responsive care in menopause,” by Makeba Williams, MD, NCMP, at The North American Menopause Society meeting in Atlanta, Georgia, October 12-15, 2022.

Dr. Williams is Vice Chair of Professional Development and Wellness, Associate Professor, Washington University School of Medicine

The Study of Women’s Health Across the Nation (SWAN) challenged the notion that there is a universal menopausal experience.¹ Up until that time, we had been using this universal experience that is based largely on the experiences of White women and applying that data to the experiences of women of color. Other research has shown that African American women have poorer quality of life and health status, and that they receive less treatment for a number of conditions.^2,3

In a recent review of more than 20 years of literature, we found only 17 articles that met the inclusion criteria, reflecting the invisibility of African American women and other ethnic and racial minorities in the menopause literature and research. Key findings included that African American women^1,4:

• experience an earlier age of onset of menopause
• have higher rates of premature menopause and early menopause, which is a risk factor for cardiovascular disease
• experience a longer time of the menopausal transition, with variability in the average age of menopause onset
• overall report lower rates of vaginal symptoms
• are less likely to report sleep disturbances than White women or Hispanic women, but more likely to report these symptoms than Asian women
• experience a higher prevalence, frequency, and severity of vasomotor symptoms (VMS), and were more bothered by those symptoms

− 48.4 years in the Healthy Women’s Study

− 50.9 years in the Penn Ovarian Aging Study

− 51.4 years in SWAN

• reported lower educational attainment, experiencing more socioeconomic disadvantage and exposure to more adverse life effects
• receive less treatment for VMS, hypertension, and depression, and are less likely to be prescribed statin drugs
• experience more discrimination
• use cigarettes and tobacco more, but are less likely to use alcohol and less likely to have physical activity.

Cultural influences on menopause

Im and colleagues have published many studies looking at cultural influences on African American, Hispanic, and Asian American women, and comparing them to White women.⁵ Notable differences were found regarding education level, family income, employment, number of children, and greater perceived health (which is associated with fewer menopausal symptoms). They identified 5 qualitative ideas:

1. Positive acceptance. Minority women, or racial and ethnic women, perceived the transition to menopause more positively, and generally took on a posture of acceptance, reporting feeling liberated from many of the challenges associated with the reproductive period. In addition, many associated a greater sense of maturity and respect within their communities with the natural aging process.
2. Optimism. Ethnic women tended to embrace menopause, using humor and laughter to express emotions during stressful life changes. This runs counter to many of the perspectives reported by White women, who often viewed the menopausal transition and aging negatively, as we equate aging with the loss of youthfulness in the United States.
3. Unique, not universal. Most of the ethnic minority women thought that there was something unique about their menopausal experiences, and that they were influenced by immigration transition, financial situations, etc. Many White woman perceived that the menopausal experience was shared among all women.
4. Closed, not open. There were differences in how we talk about symptoms, or whether or not we talk about them at all. Ethnic women tended to be silent about their symptoms. By contrast, White women tended to be more open and talkative and communicative about their symptoms.
5. Minimizing, not controlling. No symptom management was the strategy of choice for most women. Minority women tended to manage their symptoms by tolerating and normalizing them. Only those women with the most serious symptoms sought out medication for temporary relief. Some expressed a tendency to downplay their symptoms because many of them had more important things that they were dealing with in their lives.

What is an individual social identity?

An individual social identity reflects the many groups to which one belongs. It is how one shows up, and yet it is much more than how they physically show up. When you pass your eye on patients, you are only seeing the tip of the iceberg. The full social identity of a patient resides below the surface. Social identity is complex, on a continuum, and can change depending on time and place. How we prioritize our social identities may change, depending on the context and the situation.

Our intersecting social identities give rise to our cultural identity, and it is through the prism of intersectionality that we can understand the ways in which our social identities converge to give rise to disparities in health care in midlife and menopausal women. Holding space for cultural identity, we can impact how our patients are perceiving their menopause, how they are moving through decision making about taking care of themselves in menopause. And we can provide more responsive care to their cultural identities, and hopefully at the end of the day we reduce some of these disparities that we are seeing in our menopausal patients and also are reducing our unconscious bias in our patient interactions.

Culturally responsive care

There are several components to home in on when we are trying to provide culturally responsive care to patients.

1. A commitment to being culturally curious. We have to accept what the literature is sharing with us, that there is not a universal menopausal experience. We have for far too long applied this universal experience of menopause that has largely been based on White women to different racial and ethnic populations.
2. Recognizing. I appreciate that my identity as a Black woman may be very different from other Black women in the room, or whatever their social identity. I am not expected to understand all of the others’ experiences, and I don’t expect that for you either.
3. Acknowledge unconscious implicit biases. Acknowledge the groups to which you have a strong implicit bias, and allow it to drive you to reduce barriers to engaging with patients.
4. Connecting with the individual patient. It is through a process of individuating that we learn from our patients’ unique characteristics, rather than relying on assumptions and stereotypes. We have a window of opportunity to see our patient and move beyond thinking of them in terms of racial and ethnic stereotypes or particular social groups. It is through this process of individualizing that we can seek answers to key questions.

The ultimate goal is to understand our individual patients’ perceptions, outlook on menopause, and contextual factors in their lives that influence the menopause journey.

CASE ENCOUNTER

I quickly look at the patient-filled form before I knock on the exam door, and I see that the patient has checked off that she has hot flashes, night sweats, and I make a mental note, she’s menopausal. I already have a preliminary plan to give this patient hormone therapy. I open the door, and I see that she’s Black. I know, based upon the data from SWAN and others, that her menopause means longer duration, more severe vasomotor symptoms. I have already teed up a prescription to go to the pharmacy.

The problem is, I have not even talked to her. She may actually nod her head, saying that she is going to go to the pharmacy, but she may never pick up that prescription. She likely leaves my office feeling unheard; her needs are unmet. I move onto the next patient. I feel good, but in actuality, I didn’t hear her. I have provided her bias and stereotyped care. I missed an opportunity to truly engage this patient and her care, and my good intentions of following the literature about her experience in menopause have contributed quite likely to her increased morbidity and mortality, her increased cardiovascular disease risk, all because I have not held space for her cultural identity.

References

1. Harlow SD, Burnett-Bowie SM, Greendale GA, et al. Disparities in reproductive aging and midlife health between Black and White women: the Study of Women’s Health Across the Nation (SWAN). Women’s Midlife Health. 2022;8:3. doi: 10.1186/s40695-022-00073-y.
2. Chlebowski RT, Aragaki AK, Anderson GL, et al. Forty-year trends in menopausal hormone therapy use and breast cancer incidence among postmenopausal black and white women. Cancer. 2020;126:2956-2964. doi: 10.1002/ cncr.32846.
3. Weng HH, McBride CM, Bosworth HB, et al. Racial differences in physician recommendation of hormone replacement therapy. Prev Med. 2001;33:668673. doi: 10.1006/pmed.2001.0943.
4. Williams M, Richard-Davis G, Williams PL, et al. A review of African American women’s experiences in menopause. Menopause. 2022;29:1331-1337. doi: 10.1097/GME.0000000000002060.
5. Im EO. Ethnic differences in symptoms experienced during the menopausal transition. Health Care Women Int. 2009;30:339-355. doi: 10.1080/07399330802695002.

OBG Management caught up with Drs. Jan Shifren and Genevieve Neal-Perry while they were attending the annual meeting of The North American Menopause Society (NAMS), held October 12-15, 2022, in Atlanta, Georgia. Dr. Shifren presented on the “Ins and Outs of Hormone Therapy,” while Dr. Neal-Perry focused on “Menopause Physiology.” 

Evaluating symptomatic patients for appropriate hormone therapy

OBG Management: In your presentation to the group at the NAMS meeting, you described a 51-year-old patient with the principal symptoms of frequent hot flashes and night sweats, sleep disruption, fatigue, irritability, vaginal dryness, and dyspareunia. As she reported already trying several lifestyle modification approaches, what are your questions for her to determine whether hormone therapy (HT), systemic or low-dose vaginal, is advisable?

Jan Shifren, MD: As with every patient, you need to begin with a thorough history and confirm her physical exam is up to date. If there are concerns related to genitourinary symptoms of menopause (GSM), then a pelvic exam is indicated. This patient is a healthy menopausal woman with bothersome hot flashes, night sweats, and vaginal dryness. Sleep disruption from night sweats is likely the cause of her fatigue and irritability, and her dyspareunia due to atrophic vulvovaginal changes. The principal indication for systemic HT is bothersome vasomotor symptoms (VMS), and a healthy woman who is under age 60 or within 10 years of the onset of menopause is generally a very good candidate for hormones. For this healthy 51-year-old with bothersome VMS unresponsive to lifestyle modification, the benefits of HT should outweigh potential risks. As low-dose vaginal estrogen therapy is minimally absorbed and very safe, this would be recommended instead of systemic HT if her only menopause symptoms were vaginal dryness and dyspareunia.

HT types and formulations

OBG Management: For this patient, low-dose vaginal estrogen is appropriate. In general, how do you decide on recommendations for combination therapy or estrogen only, and what formulations and dosages do you recommend?

Dr. Shifren: Any woman with a uterus needs to take a progestogen together with estrogen to protect her uterus from estrogen-induced endometrial overgrowth. With low dose vaginal estrogen therapy, however, concurrent progestogen is not needed.

Continue to: Estrogen options...

Many of our patients like the idea that they are using “natural” HT. I inform them that bioidentical is a marketing term rather than a medical term, but if their goal is to take the same hormones that their ovaries made when they were younger, they should use FDA-approved formulations of estradiol and progesterone for their menopausal HT symptoms. I do not recommend compounded bioidentical HT due to concerns regarding product quality and safety. The combination of FDA-approved estradiol patches and oral micronized progesterone provides a high quality, carefully regulated bioidentical HT regimen. For women greatly preferring an oral estrogen, oral estradiol with micronized progesterone is an option.

In addition to patient preference for natural HT, the reasons that I encourage women to consider the estradiol transdermal patch for their menopausal HT include:

1. no increased risk of venous thromboembolic events when physiologically dosed menopausal estradiol therapy is provided by a skin patch (observational data).¹ With oral estrogens, even when dosed for menopause, VTE risk increases, as coagulation factors increase due to the first-pass hepatic effect. This does not occur with non-oral menopausal estrogens.
2. no increased risk of gallbladder disease, which occurs with oral estrogen therapy (observational data)²
3. possibly lower risk of stroke when low-dose menopausal HT is provided via skin patch (observational data)³
4. convenience—the patches are changed once or twice weekly
5. wide range of doses available, which optimizes identifying the lowest effective dose and decreasing the dose over time.

Progestogen options. Progestogens may be given daily or cyclically. Use of daily progestogen typically results in amenorrhea, which is preferred by most women. Cyclic use of a progestogen for 12-14 days each month results in a monthly withdrawal bleed, which is a good option for a woman experiencing bothersome breakthrough bleeding with daily progestogen. Use of a progestogen-releasing IUD is an off-label alternative for endometrial protection with menopausal HT. As discussed earlier, as many women prefer bioidentical HT, one of our preferred regimens is to provide transdermal estradiol with FDA-approved oral micronized progesterone. There are several patches that combine estradiol with a progestogen, but there is not a lot of dosing flexibility and product choice. There also is an approved product available that combines oral estradiol and micronized progesterone in one tablet.

Scheduling follow-up

OBG Management: Now that you have started the opening case patient on HT, how often are you going to monitor her for treatment?

Dr. Shifren: Women will not experience maximum efficacy for hot flash relief from their estrogen therapy for 3 months, so I typically see a patient back at 3 to 4 months to assess side effects and symptom control. I encourage women to reach out sooner if they are having a bothersome side effect. Once she is doing well on an HT regimen, we assess risks and benefits of ongoing treatment annually. The goal is to be certain she is on the lowest dose of estrogen that treats her symptoms, and we slowly decrease the estrogen dose over time.

Breast cancer risk

OBG Management: In your presentation, you mentioned that the risk of breast cancer does not increase appreciably with short-term use of HT. Is it possible to define short term?

Dr. Shifren: In the Women’s Health Initiative (WHI), a large double-blind, randomized, placebo-controlled trial of menopausal HT, there was a slight increase in breast cancer risk after approximately 4 to 5 years of use in women using estrogen with progestogen.⁴ I share with patients that this increased risk is about the same as that of obesity or drinking more than 1 alcoholic beverage daily. As an increased risk of breast cancer does not occur for several years, a woman may be able to take hormones for bothersome symptoms, feel well, and slowly come off without incurring significant breast cancer risk. In the WHI, there was no increase in breast cancer risk in women without a uterus randomized to estrogen alone.

Regarding cardiovascular risk, in the WHI, an increased risk of cardiovascular events generally was not seen in healthy women younger than age 60 and within 10 years of the onset of menopause.⁵ Benefits of HT may not outweigh risks for women with significant underlying cardiovascular risk factors, even if they are younger and close to menopause onset.

Continue to: The importance of shared decision making...

Dr. Shifren: As with any important health care decision, women should be involved in an individualized discussion of risks and benefits, with shared decision making about whether HT is the right choice. Women also should be involved in ongoing decisions regarding HT formulation, dose, and duration of use.

A nonhormonal option for hot flashes

OBG Management: How many women experience VMS around the time of menopause?

Dr. Genevieve Neal-Perry, MD, PhD: About 60% to 70% of individuals will experience hot flashes around the time of the menopause.⁶ Of those, about 40% are what we would call moderate to severe hot flashes—which are typically the most disruptive in terms of quality of life.⁷ The window of time in which they are likely to have them, at typically their most intense timeframe, is 2 years before the final menstrual period and the year after.⁷ In terms of the average duration, however, it’s about 7 years, which is a lot longer than what we previously thought.⁸ Moreover, there are disparities in that women of color, particularly African American women, can have them as long as 10 years.⁸
 

OBG Management: Can you explain why the VMS occur, and specifically around the time of menopause?

Dr. Neal-Perry: For many years we did not understand the basic biology of hot flashes. When you think about it, it’s completely amazing—when half of our population experiences hot flashes, and we don’t understand why, and we don’t have therapy that specifically targets hot flashes.

What we now know from work completed by Naomi Rance, in particular, is that a specific region of the brain, the hypothalamus, exhibited changes in number of neurons that seemed to be increased in size in menopausal people and smaller in size in people who were not menopausal.⁹ That started the journey to understanding the biology, and eventual mechanism, of hot flashes. It took about 10-15 years before we really began to understand why.

What we know now is that estrogen, a hormone that is made by the ovaries, activates and inactivates neurons located in the hypothalamus, a brain region that controls our thermoregulation—the way your body perceives temperature. The hypothalamus controls your response to temperature, either you experience chills or you dissipate heat by vasodilating (hot flush) and sweating.

The thermoregulatory region of the hypothalamus houses cells that receive messages from KNDy neurons, neurons also located in the hypothalamus that express kisspeptin, neurokinin, and dynorphin. Importantly, KNDy neurons express estrogen receptors. (The way that I like to think about estrogen and estrogen receptors is that estrogen is like the ball and the receptor is like the catcher’s mitt.) When estrogen interacts with this receptor, it keeps KNDy neurons quiet. But the increased variability and loss of estrogen that occurs around the time of menopause “disinhibits” KNDy neurons—meaning that they are no longer being reined in by estrogen. In response to decreased estrogen regulation, KNDy neurons become hypertrophied with neurotransmitters and more active. Specifically, KNDy neurons release neurokinin, a neuropeptide that self-stimulates KNDy neurons and activates neurons in the thermoregulatory zone of the brain—it’s a speed-forward feed-backward mechanism. The thermoregulatory neurons interpret this signal as “I feel hot,” and the body begins a series of functions to cool things down.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Continue to: Treatments that act on the thermoregulatory region

Dr. Neal-Perry: I have described what happens in the brain around the time of menopause, and what triggers those hot flashes.

Estrogen. The reason that estrogen worked to treat the hot flashes is because estrogen inhibits and calms the neurons that become hyperactive during the menopause.

Fezolinetant. Fezolinetant is unique because it specifically targets the hormone receptor that triggers hot flashes, the neurokinin receptor. Fezolinetant is a nonhormone therapy that not only reduces the activity of KNDy neurons but also blocks the effects of neurons in the thermoregulatory zone, thereby reducing the sensation of the hot flashes. We are in such a special time in medical history for individuals who experience hot flashes because now we understand the basic biology of hot flashes, and we can generate targeted therapy to manage hot flashes—that is for both individuals who identify as women and individuals who identify as men, because both experience hot flashes.
 

OBG Management: Is there a particular threshold of hot flash symptoms that is considered important to treat, or is treatment based on essentially the bother to patients?

Dr. Neal-Perry: Treatment is solely based on if it bothers the patient. But we do know that people who have lots of bothersome hot flashes have a higher risk for heart disease and may have sleep disruption, reduced cognitive function, and poorer quality of life. Sleep dysfunction can impact the ability to think and function and can put those affected at increased risk for accidents.

For people who are having these symptoms that are disruptive to their life, you do want to treat them. You might say, “Well, we’ve had estrogen, why not use estrogen,” right? Well estrogen works very well, but there are lots of people who can’t use estrogen—individuals who have breast cancer, blood clotting disorders, significant heart disease, or diabetes. Then there are just some people who don’t feel comfortable using estrogen.

We have had a huge gap in care for individuals who experience hot flashes and who are ineligible for menopausal HT. While there are other nonhormonal options, they often have side effects like sexual dysfunction, hypersomnolence, or insomnia. Some people choose not to use these nonhormonal treatments because the side effects are worse for them than to trying to manage the hot flashes. The introduction to a nonhormonal therapy that is effective and does not have lots of side effects is exciting and will be welcomed by many who have not found relief.
 

OBG Management: Is fezolinetant available now for patients?

Dr. Neal-Perry: It is not available yet. Hopefully, it will be approved within the next year. Astellas recently completed a double blind randomized cross over design phase 3 study that found fezolinetant is highly effective for the management of hot flashes and that it has a low side effect profile.¹⁰ Fezolinetant’s most common side effect was COVID-19, a reflection of the fact that the trial was done during the COVID pandemic. The other most common side effect was headache. Everything else was minimal.

Other drugs in the same class as fezolinetant have been under development for the management of hot flashes; however, they encountered liver function challenges, and studies were stopped. Fezolinetant did not cause liver dysfunction.

Hot flash modifiers

OBG Management: Referring to that neuropathway, are there physiologic differences among women who do and do not experience hot flashes, and are there particular mechanisms that may protect patients against being bothered by hot flashes?

Dr. Neal-Perry: Well, there are some things that we can control, and there are things that we cannot control (like our genetic background). Some of the processes that are important for estrogen receptor function and estrogen metabolism, as well as some other receptor systems, can work differently. When estrogen metabolism is slightly different, it could result in reduced estrogen receptor activity and more hot flashes. Then there are some receptor polymorphisms that can increase or reduce the risk for hot flashes—the genetic piece.¹¹

There are things that can modify your risk for hot flashes and the duration of hot flashes. Individuals who are obese or smoke may experience more hot flashes. Women of color, especially African American women, tend to have hot flashes occur earlier in their reproductive life and last for a longer duration; hot flashes may occur up to 2 years before menopause, last for more than 10 years, and be more disruptive. By contrast, Asian women tend to report fewer and less disruptive hot flashes.⁸
 

OBG Management: If fezolinetant were to be FDA approved, will there be particular patients that it will most appropriate for, since it is an estrogen alternative?

Dr. Neal-Perry: Yes, there may be different patients who might benefit from fezolinetant. This will depend on what the situation is—patients who have breast cancer, poorly controlled diabetes, or heart disease, and those patients who prefer not to use estrogen will benefit from fezolinetant, as we are going to look for other treatment options for those individuals. It will be important for medical providers to listen to their patients and understand the medical background of that individual to really define what is the best next step for the management of their hot flashes.

This is an exciting time for individuals affected by menopausal hot flashes; to understand the biology of hot flashes gives us real opportunities to bridge gaps around how to manage them. Individuals who experience hot flashes will know that they don’t have to suffer, that there are other options that are safe, that can help meet their needs and put them in a better place. ●

Multiethnic differences in the menopause experience

---

Excerpted from the presentation, “Do you see me? Culturally responsive care in menopause,” by Makeba Williams, MD, NCMP, at The North American Menopause Society meeting in Atlanta, Georgia, October 12-15, 2022.

Dr. Williams is Vice Chair of Professional Development and Wellness, Associate Professor, Washington University School of Medicine

The Study of Women’s Health Across the Nation (SWAN) challenged the notion that there is a universal menopausal experience.¹ Up until that time, we had been using this universal experience that is based largely on the experiences of White women and applying that data to the experiences of women of color. Other research has shown that African American women have poorer quality of life and health status, and that they receive less treatment for a number of conditions.^2,3

In a recent review of more than 20 years of literature, we found only 17 articles that met the inclusion criteria, reflecting the invisibility of African American women and other ethnic and racial minorities in the menopause literature and research. Key findings included that African American women^1,4:

• experience an earlier age of onset of menopause
• have higher rates of premature menopause and early menopause, which is a risk factor for cardiovascular disease
• experience a longer time of the menopausal transition, with variability in the average age of menopause onset
• overall report lower rates of vaginal symptoms
• are less likely to report sleep disturbances than White women or Hispanic women, but more likely to report these symptoms than Asian women
• experience a higher prevalence, frequency, and severity of vasomotor symptoms (VMS), and were more bothered by those symptoms

− 48.4 years in the Healthy Women’s Study

− 50.9 years in the Penn Ovarian Aging Study

− 51.4 years in SWAN

• reported lower educational attainment, experiencing more socioeconomic disadvantage and exposure to more adverse life effects
• receive less treatment for VMS, hypertension, and depression, and are less likely to be prescribed statin drugs
• experience more discrimination
• use cigarettes and tobacco more, but are less likely to use alcohol and less likely to have physical activity.

Cultural influences on menopause

Im and colleagues have published many studies looking at cultural influences on African American, Hispanic, and Asian American women, and comparing them to White women.⁵ Notable differences were found regarding education level, family income, employment, number of children, and greater perceived health (which is associated with fewer menopausal symptoms). They identified 5 qualitative ideas:

1. Positive acceptance. Minority women, or racial and ethnic women, perceived the transition to menopause more positively, and generally took on a posture of acceptance, reporting feeling liberated from many of the challenges associated with the reproductive period. In addition, many associated a greater sense of maturity and respect within their communities with the natural aging process.
2. Optimism. Ethnic women tended to embrace menopause, using humor and laughter to express emotions during stressful life changes. This runs counter to many of the perspectives reported by White women, who often viewed the menopausal transition and aging negatively, as we equate aging with the loss of youthfulness in the United States.
3. Unique, not universal. Most of the ethnic minority women thought that there was something unique about their menopausal experiences, and that they were influenced by immigration transition, financial situations, etc. Many White woman perceived that the menopausal experience was shared among all women.
4. Closed, not open. There were differences in how we talk about symptoms, or whether or not we talk about them at all. Ethnic women tended to be silent about their symptoms. By contrast, White women tended to be more open and talkative and communicative about their symptoms.
5. Minimizing, not controlling. No symptom management was the strategy of choice for most women. Minority women tended to manage their symptoms by tolerating and normalizing them. Only those women with the most serious symptoms sought out medication for temporary relief. Some expressed a tendency to downplay their symptoms because many of them had more important things that they were dealing with in their lives.

What is an individual social identity?

An individual social identity reflects the many groups to which one belongs. It is how one shows up, and yet it is much more than how they physically show up. When you pass your eye on patients, you are only seeing the tip of the iceberg. The full social identity of a patient resides below the surface. Social identity is complex, on a continuum, and can change depending on time and place. How we prioritize our social identities may change, depending on the context and the situation.

Our intersecting social identities give rise to our cultural identity, and it is through the prism of intersectionality that we can understand the ways in which our social identities converge to give rise to disparities in health care in midlife and menopausal women. Holding space for cultural identity, we can impact how our patients are perceiving their menopause, how they are moving through decision making about taking care of themselves in menopause. And we can provide more responsive care to their cultural identities, and hopefully at the end of the day we reduce some of these disparities that we are seeing in our menopausal patients and also are reducing our unconscious bias in our patient interactions.

Culturally responsive care

There are several components to home in on when we are trying to provide culturally responsive care to patients.

1. A commitment to being culturally curious. We have to accept what the literature is sharing with us, that there is not a universal menopausal experience. We have for far too long applied this universal experience of menopause that has largely been based on White women to different racial and ethnic populations.
2. Recognizing. I appreciate that my identity as a Black woman may be very different from other Black women in the room, or whatever their social identity. I am not expected to understand all of the others’ experiences, and I don’t expect that for you either.
3. Acknowledge unconscious implicit biases. Acknowledge the groups to which you have a strong implicit bias, and allow it to drive you to reduce barriers to engaging with patients.
4. Connecting with the individual patient. It is through a process of individuating that we learn from our patients’ unique characteristics, rather than relying on assumptions and stereotypes. We have a window of opportunity to see our patient and move beyond thinking of them in terms of racial and ethnic stereotypes or particular social groups. It is through this process of individualizing that we can seek answers to key questions.

The ultimate goal is to understand our individual patients’ perceptions, outlook on menopause, and contextual factors in their lives that influence the menopause journey.

CASE ENCOUNTER

I quickly look at the patient-filled form before I knock on the exam door, and I see that the patient has checked off that she has hot flashes, night sweats, and I make a mental note, she’s menopausal. I already have a preliminary plan to give this patient hormone therapy. I open the door, and I see that she’s Black. I know, based upon the data from SWAN and others, that her menopause means longer duration, more severe vasomotor symptoms. I have already teed up a prescription to go to the pharmacy.

The problem is, I have not even talked to her. She may actually nod her head, saying that she is going to go to the pharmacy, but she may never pick up that prescription. She likely leaves my office feeling unheard; her needs are unmet. I move onto the next patient. I feel good, but in actuality, I didn’t hear her. I have provided her bias and stereotyped care. I missed an opportunity to truly engage this patient and her care, and my good intentions of following the literature about her experience in menopause have contributed quite likely to her increased morbidity and mortality, her increased cardiovascular disease risk, all because I have not held space for her cultural identity.

References

1. Harlow SD, Burnett-Bowie SM, Greendale GA, et al. Disparities in reproductive aging and midlife health between Black and White women: the Study of Women’s Health Across the Nation (SWAN). Women’s Midlife Health. 2022;8:3. doi: 10.1186/s40695-022-00073-y.
2. Chlebowski RT, Aragaki AK, Anderson GL, et al. Forty-year trends in menopausal hormone therapy use and breast cancer incidence among postmenopausal black and white women. Cancer. 2020;126:2956-2964. doi: 10.1002/ cncr.32846.
3. Weng HH, McBride CM, Bosworth HB, et al. Racial differences in physician recommendation of hormone replacement therapy. Prev Med. 2001;33:668673. doi: 10.1006/pmed.2001.0943.
4. Williams M, Richard-Davis G, Williams PL, et al. A review of African American women’s experiences in menopause. Menopause. 2022;29:1331-1337. doi: 10.1097/GME.0000000000002060.
5. Im EO. Ethnic differences in symptoms experienced during the menopausal transition. Health Care Women Int. 2009;30:339-355. doi: 10.1080/07399330802695002.

OBG Management caught up with Drs. Jan Shifren and Genevieve Neal-Perry while they were attending the annual meeting of The North American Menopause Society (NAMS), held October 12-15, 2022, in Atlanta, Georgia. Dr. Shifren presented on the “Ins and Outs of Hormone Therapy,” while Dr. Neal-Perry focused on “Menopause Physiology.” 

Evaluating symptomatic patients for appropriate hormone therapy

OBG Management: In your presentation to the group at the NAMS meeting, you described a 51-year-old patient with the principal symptoms of frequent hot flashes and night sweats, sleep disruption, fatigue, irritability, vaginal dryness, and dyspareunia. As she reported already trying several lifestyle modification approaches, what are your questions for her to determine whether hormone therapy (HT), systemic or low-dose vaginal, is advisable?

Jan Shifren, MD: As with every patient, you need to begin with a thorough history and confirm her physical exam is up to date. If there are concerns related to genitourinary symptoms of menopause (GSM), then a pelvic exam is indicated. This patient is a healthy menopausal woman with bothersome hot flashes, night sweats, and vaginal dryness. Sleep disruption from night sweats is likely the cause of her fatigue and irritability, and her dyspareunia due to atrophic vulvovaginal changes. The principal indication for systemic HT is bothersome vasomotor symptoms (VMS), and a healthy woman who is under age 60 or within 10 years of the onset of menopause is generally a very good candidate for hormones. For this healthy 51-year-old with bothersome VMS unresponsive to lifestyle modification, the benefits of HT should outweigh potential risks. As low-dose vaginal estrogen therapy is minimally absorbed and very safe, this would be recommended instead of systemic HT if her only menopause symptoms were vaginal dryness and dyspareunia.

HT types and formulations

OBG Management: For this patient, low-dose vaginal estrogen is appropriate. In general, how do you decide on recommendations for combination therapy or estrogen only, and what formulations and dosages do you recommend?

Dr. Shifren: Any woman with a uterus needs to take a progestogen together with estrogen to protect her uterus from estrogen-induced endometrial overgrowth. With low dose vaginal estrogen therapy, however, concurrent progestogen is not needed.

Continue to: Estrogen options...

Many of our patients like the idea that they are using “natural” HT. I inform them that bioidentical is a marketing term rather than a medical term, but if their goal is to take the same hormones that their ovaries made when they were younger, they should use FDA-approved formulations of estradiol and progesterone for their menopausal HT symptoms. I do not recommend compounded bioidentical HT due to concerns regarding product quality and safety. The combination of FDA-approved estradiol patches and oral micronized progesterone provides a high quality, carefully regulated bioidentical HT regimen. For women greatly preferring an oral estrogen, oral estradiol with micronized progesterone is an option.

In addition to patient preference for natural HT, the reasons that I encourage women to consider the estradiol transdermal patch for their menopausal HT include:

1. no increased risk of venous thromboembolic events when physiologically dosed menopausal estradiol therapy is provided by a skin patch (observational data).¹ With oral estrogens, even when dosed for menopause, VTE risk increases, as coagulation factors increase due to the first-pass hepatic effect. This does not occur with non-oral menopausal estrogens.
2. no increased risk of gallbladder disease, which occurs with oral estrogen therapy (observational data)²
3. possibly lower risk of stroke when low-dose menopausal HT is provided via skin patch (observational data)³
4. convenience—the patches are changed once or twice weekly
5. wide range of doses available, which optimizes identifying the lowest effective dose and decreasing the dose over time.

Progestogen options. Progestogens may be given daily or cyclically. Use of daily progestogen typically results in amenorrhea, which is preferred by most women. Cyclic use of a progestogen for 12-14 days each month results in a monthly withdrawal bleed, which is a good option for a woman experiencing bothersome breakthrough bleeding with daily progestogen. Use of a progestogen-releasing IUD is an off-label alternative for endometrial protection with menopausal HT. As discussed earlier, as many women prefer bioidentical HT, one of our preferred regimens is to provide transdermal estradiol with FDA-approved oral micronized progesterone. There are several patches that combine estradiol with a progestogen, but there is not a lot of dosing flexibility and product choice. There also is an approved product available that combines oral estradiol and micronized progesterone in one tablet.

Scheduling follow-up

OBG Management: Now that you have started the opening case patient on HT, how often are you going to monitor her for treatment?

Dr. Shifren: Women will not experience maximum efficacy for hot flash relief from their estrogen therapy for 3 months, so I typically see a patient back at 3 to 4 months to assess side effects and symptom control. I encourage women to reach out sooner if they are having a bothersome side effect. Once she is doing well on an HT regimen, we assess risks and benefits of ongoing treatment annually. The goal is to be certain she is on the lowest dose of estrogen that treats her symptoms, and we slowly decrease the estrogen dose over time.

Breast cancer risk

OBG Management: In your presentation, you mentioned that the risk of breast cancer does not increase appreciably with short-term use of HT. Is it possible to define short term?

Dr. Shifren: In the Women’s Health Initiative (WHI), a large double-blind, randomized, placebo-controlled trial of menopausal HT, there was a slight increase in breast cancer risk after approximately 4 to 5 years of use in women using estrogen with progestogen.⁴ I share with patients that this increased risk is about the same as that of obesity or drinking more than 1 alcoholic beverage daily. As an increased risk of breast cancer does not occur for several years, a woman may be able to take hormones for bothersome symptoms, feel well, and slowly come off without incurring significant breast cancer risk. In the WHI, there was no increase in breast cancer risk in women without a uterus randomized to estrogen alone.

Regarding cardiovascular risk, in the WHI, an increased risk of cardiovascular events generally was not seen in healthy women younger than age 60 and within 10 years of the onset of menopause.⁵ Benefits of HT may not outweigh risks for women with significant underlying cardiovascular risk factors, even if they are younger and close to menopause onset.

Continue to: The importance of shared decision making...

Dr. Shifren: As with any important health care decision, women should be involved in an individualized discussion of risks and benefits, with shared decision making about whether HT is the right choice. Women also should be involved in ongoing decisions regarding HT formulation, dose, and duration of use.

A nonhormonal option for hot flashes

OBG Management: How many women experience VMS around the time of menopause?

Dr. Genevieve Neal-Perry, MD, PhD: About 60% to 70% of individuals will experience hot flashes around the time of the menopause.⁶ Of those, about 40% are what we would call moderate to severe hot flashes—which are typically the most disruptive in terms of quality of life.⁷ The window of time in which they are likely to have them, at typically their most intense timeframe, is 2 years before the final menstrual period and the year after.⁷ In terms of the average duration, however, it’s about 7 years, which is a lot longer than what we previously thought.⁸ Moreover, there are disparities in that women of color, particularly African American women, can have them as long as 10 years.⁸
 

OBG Management: Can you explain why the VMS occur, and specifically around the time of menopause?

Dr. Neal-Perry: For many years we did not understand the basic biology of hot flashes. When you think about it, it’s completely amazing—when half of our population experiences hot flashes, and we don’t understand why, and we don’t have therapy that specifically targets hot flashes.

What we now know from work completed by Naomi Rance, in particular, is that a specific region of the brain, the hypothalamus, exhibited changes in number of neurons that seemed to be increased in size in menopausal people and smaller in size in people who were not menopausal.⁹ That started the journey to understanding the biology, and eventual mechanism, of hot flashes. It took about 10-15 years before we really began to understand why.

What we know now is that estrogen, a hormone that is made by the ovaries, activates and inactivates neurons located in the hypothalamus, a brain region that controls our thermoregulation—the way your body perceives temperature. The hypothalamus controls your response to temperature, either you experience chills or you dissipate heat by vasodilating (hot flush) and sweating.

The thermoregulatory region of the hypothalamus houses cells that receive messages from KNDy neurons, neurons also located in the hypothalamus that express kisspeptin, neurokinin, and dynorphin. Importantly, KNDy neurons express estrogen receptors. (The way that I like to think about estrogen and estrogen receptors is that estrogen is like the ball and the receptor is like the catcher’s mitt.) When estrogen interacts with this receptor, it keeps KNDy neurons quiet. But the increased variability and loss of estrogen that occurs around the time of menopause “disinhibits” KNDy neurons—meaning that they are no longer being reined in by estrogen. In response to decreased estrogen regulation, KNDy neurons become hypertrophied with neurotransmitters and more active. Specifically, KNDy neurons release neurokinin, a neuropeptide that self-stimulates KNDy neurons and activates neurons in the thermoregulatory zone of the brain—it’s a speed-forward feed-backward mechanism. The thermoregulatory neurons interpret this signal as “I feel hot,” and the body begins a series of functions to cool things down.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Continue to: Treatments that act on the thermoregulatory region

Dr. Neal-Perry: I have described what happens in the brain around the time of menopause, and what triggers those hot flashes.

Estrogen. The reason that estrogen worked to treat the hot flashes is because estrogen inhibits and calms the neurons that become hyperactive during the menopause.

Fezolinetant. Fezolinetant is unique because it specifically targets the hormone receptor that triggers hot flashes, the neurokinin receptor. Fezolinetant is a nonhormone therapy that not only reduces the activity of KNDy neurons but also blocks the effects of neurons in the thermoregulatory zone, thereby reducing the sensation of the hot flashes. We are in such a special time in medical history for individuals who experience hot flashes because now we understand the basic biology of hot flashes, and we can generate targeted therapy to manage hot flashes—that is for both individuals who identify as women and individuals who identify as men, because both experience hot flashes.
 

OBG Management: Is there a particular threshold of hot flash symptoms that is considered important to treat, or is treatment based on essentially the bother to patients?

Dr. Neal-Perry: Treatment is solely based on if it bothers the patient. But we do know that people who have lots of bothersome hot flashes have a higher risk for heart disease and may have sleep disruption, reduced cognitive function, and poorer quality of life. Sleep dysfunction can impact the ability to think and function and can put those affected at increased risk for accidents.

For people who are having these symptoms that are disruptive to their life, you do want to treat them. You might say, “Well, we’ve had estrogen, why not use estrogen,” right? Well estrogen works very well, but there are lots of people who can’t use estrogen—individuals who have breast cancer, blood clotting disorders, significant heart disease, or diabetes. Then there are just some people who don’t feel comfortable using estrogen.

We have had a huge gap in care for individuals who experience hot flashes and who are ineligible for menopausal HT. While there are other nonhormonal options, they often have side effects like sexual dysfunction, hypersomnolence, or insomnia. Some people choose not to use these nonhormonal treatments because the side effects are worse for them than to trying to manage the hot flashes. The introduction to a nonhormonal therapy that is effective and does not have lots of side effects is exciting and will be welcomed by many who have not found relief.
 

OBG Management: Is fezolinetant available now for patients?

Dr. Neal-Perry: It is not available yet. Hopefully, it will be approved within the next year. Astellas recently completed a double blind randomized cross over design phase 3 study that found fezolinetant is highly effective for the management of hot flashes and that it has a low side effect profile.¹⁰ Fezolinetant’s most common side effect was COVID-19, a reflection of the fact that the trial was done during the COVID pandemic. The other most common side effect was headache. Everything else was minimal.

Other drugs in the same class as fezolinetant have been under development for the management of hot flashes; however, they encountered liver function challenges, and studies were stopped. Fezolinetant did not cause liver dysfunction.

Hot flash modifiers

OBG Management: Referring to that neuropathway, are there physiologic differences among women who do and do not experience hot flashes, and are there particular mechanisms that may protect patients against being bothered by hot flashes?

Dr. Neal-Perry: Well, there are some things that we can control, and there are things that we cannot control (like our genetic background). Some of the processes that are important for estrogen receptor function and estrogen metabolism, as well as some other receptor systems, can work differently. When estrogen metabolism is slightly different, it could result in reduced estrogen receptor activity and more hot flashes. Then there are some receptor polymorphisms that can increase or reduce the risk for hot flashes—the genetic piece.¹¹

There are things that can modify your risk for hot flashes and the duration of hot flashes. Individuals who are obese or smoke may experience more hot flashes. Women of color, especially African American women, tend to have hot flashes occur earlier in their reproductive life and last for a longer duration; hot flashes may occur up to 2 years before menopause, last for more than 10 years, and be more disruptive. By contrast, Asian women tend to report fewer and less disruptive hot flashes.⁸
 

OBG Management: If fezolinetant were to be FDA approved, will there be particular patients that it will most appropriate for, since it is an estrogen alternative?

Dr. Neal-Perry: Yes, there may be different patients who might benefit from fezolinetant. This will depend on what the situation is—patients who have breast cancer, poorly controlled diabetes, or heart disease, and those patients who prefer not to use estrogen will benefit from fezolinetant, as we are going to look for other treatment options for those individuals. It will be important for medical providers to listen to their patients and understand the medical background of that individual to really define what is the best next step for the management of their hot flashes.

This is an exciting time for individuals affected by menopausal hot flashes; to understand the biology of hot flashes gives us real opportunities to bridge gaps around how to manage them. Individuals who experience hot flashes will know that they don’t have to suffer, that there are other options that are safe, that can help meet their needs and put them in a better place. ●

Multiethnic differences in the menopause experience

---

Excerpted from the presentation, “Do you see me? Culturally responsive care in menopause,” by Makeba Williams, MD, NCMP, at The North American Menopause Society meeting in Atlanta, Georgia, October 12-15, 2022.

Dr. Williams is Vice Chair of Professional Development and Wellness, Associate Professor, Washington University School of Medicine

The Study of Women’s Health Across the Nation (SWAN) challenged the notion that there is a universal menopausal experience.¹ Up until that time, we had been using this universal experience that is based largely on the experiences of White women and applying that data to the experiences of women of color. Other research has shown that African American women have poorer quality of life and health status, and that they receive less treatment for a number of conditions.^2,3

In a recent review of more than 20 years of literature, we found only 17 articles that met the inclusion criteria, reflecting the invisibility of African American women and other ethnic and racial minorities in the menopause literature and research. Key findings included that African American women^1,4:

• experience an earlier age of onset of menopause
• have higher rates of premature menopause and early menopause, which is a risk factor for cardiovascular disease
• experience a longer time of the menopausal transition, with variability in the average age of menopause onset
• overall report lower rates of vaginal symptoms
• are less likely to report sleep disturbances than White women or Hispanic women, but more likely to report these symptoms than Asian women
• experience a higher prevalence, frequency, and severity of vasomotor symptoms (VMS), and were more bothered by those symptoms

− 48.4 years in the Healthy Women’s Study

− 50.9 years in the Penn Ovarian Aging Study

− 51.4 years in SWAN

• reported lower educational attainment, experiencing more socioeconomic disadvantage and exposure to more adverse life effects
• receive less treatment for VMS, hypertension, and depression, and are less likely to be prescribed statin drugs
• experience more discrimination
• use cigarettes and tobacco more, but are less likely to use alcohol and less likely to have physical activity.

Cultural influences on menopause

Im and colleagues have published many studies looking at cultural influences on African American, Hispanic, and Asian American women, and comparing them to White women.⁵ Notable differences were found regarding education level, family income, employment, number of children, and greater perceived health (which is associated with fewer menopausal symptoms). They identified 5 qualitative ideas:

1. Positive acceptance. Minority women, or racial and ethnic women, perceived the transition to menopause more positively, and generally took on a posture of acceptance, reporting feeling liberated from many of the challenges associated with the reproductive period. In addition, many associated a greater sense of maturity and respect within their communities with the natural aging process.
2. Optimism. Ethnic women tended to embrace menopause, using humor and laughter to express emotions during stressful life changes. This runs counter to many of the perspectives reported by White women, who often viewed the menopausal transition and aging negatively, as we equate aging with the loss of youthfulness in the United States.
3. Unique, not universal. Most of the ethnic minority women thought that there was something unique about their menopausal experiences, and that they were influenced by immigration transition, financial situations, etc. Many White woman perceived that the menopausal experience was shared among all women.
4. Closed, not open. There were differences in how we talk about symptoms, or whether or not we talk about them at all. Ethnic women tended to be silent about their symptoms. By contrast, White women tended to be more open and talkative and communicative about their symptoms.
5. Minimizing, not controlling. No symptom management was the strategy of choice for most women. Minority women tended to manage their symptoms by tolerating and normalizing them. Only those women with the most serious symptoms sought out medication for temporary relief. Some expressed a tendency to downplay their symptoms because many of them had more important things that they were dealing with in their lives.

What is an individual social identity?

An individual social identity reflects the many groups to which one belongs. It is how one shows up, and yet it is much more than how they physically show up. When you pass your eye on patients, you are only seeing the tip of the iceberg. The full social identity of a patient resides below the surface. Social identity is complex, on a continuum, and can change depending on time and place. How we prioritize our social identities may change, depending on the context and the situation.

Our intersecting social identities give rise to our cultural identity, and it is through the prism of intersectionality that we can understand the ways in which our social identities converge to give rise to disparities in health care in midlife and menopausal women. Holding space for cultural identity, we can impact how our patients are perceiving their menopause, how they are moving through decision making about taking care of themselves in menopause. And we can provide more responsive care to their cultural identities, and hopefully at the end of the day we reduce some of these disparities that we are seeing in our menopausal patients and also are reducing our unconscious bias in our patient interactions.

Culturally responsive care

There are several components to home in on when we are trying to provide culturally responsive care to patients.

1. A commitment to being culturally curious. We have to accept what the literature is sharing with us, that there is not a universal menopausal experience. We have for far too long applied this universal experience of menopause that has largely been based on White women to different racial and ethnic populations.
2. Recognizing. I appreciate that my identity as a Black woman may be very different from other Black women in the room, or whatever their social identity. I am not expected to understand all of the others’ experiences, and I don’t expect that for you either.
3. Acknowledge unconscious implicit biases. Acknowledge the groups to which you have a strong implicit bias, and allow it to drive you to reduce barriers to engaging with patients.
4. Connecting with the individual patient. It is through a process of individuating that we learn from our patients’ unique characteristics, rather than relying on assumptions and stereotypes. We have a window of opportunity to see our patient and move beyond thinking of them in terms of racial and ethnic stereotypes or particular social groups. It is through this process of individualizing that we can seek answers to key questions.

The ultimate goal is to understand our individual patients’ perceptions, outlook on menopause, and contextual factors in their lives that influence the menopause journey.

CASE ENCOUNTER

I quickly look at the patient-filled form before I knock on the exam door, and I see that the patient has checked off that she has hot flashes, night sweats, and I make a mental note, she’s menopausal. I already have a preliminary plan to give this patient hormone therapy. I open the door, and I see that she’s Black. I know, based upon the data from SWAN and others, that her menopause means longer duration, more severe vasomotor symptoms. I have already teed up a prescription to go to the pharmacy.

The problem is, I have not even talked to her. She may actually nod her head, saying that she is going to go to the pharmacy, but she may never pick up that prescription. She likely leaves my office feeling unheard; her needs are unmet. I move onto the next patient. I feel good, but in actuality, I didn’t hear her. I have provided her bias and stereotyped care. I missed an opportunity to truly engage this patient and her care, and my good intentions of following the literature about her experience in menopause have contributed quite likely to her increased morbidity and mortality, her increased cardiovascular disease risk, all because I have not held space for her cultural identity.

References

1. Harlow SD, Burnett-Bowie SM, Greendale GA, et al. Disparities in reproductive aging and midlife health between Black and White women: the Study of Women’s Health Across the Nation (SWAN). Women’s Midlife Health. 2022;8:3. doi: 10.1186/s40695-022-00073-y.
2. Chlebowski RT, Aragaki AK, Anderson GL, et al. Forty-year trends in menopausal hormone therapy use and breast cancer incidence among postmenopausal black and white women. Cancer. 2020;126:2956-2964. doi: 10.1002/ cncr.32846.
3. Weng HH, McBride CM, Bosworth HB, et al. Racial differences in physician recommendation of hormone replacement therapy. Prev Med. 2001;33:668673. doi: 10.1006/pmed.2001.0943.
4. Williams M, Richard-Davis G, Williams PL, et al. A review of African American women’s experiences in menopause. Menopause. 2022;29:1331-1337. doi: 10.1097/GME.0000000000002060.
5. Im EO. Ethnic differences in symptoms experienced during the menopausal transition. Health Care Women Int. 2009;30:339-355. doi: 10.1080/07399330802695002.

Medical professionals are well aware that civil liability (malpractice) may incur when a patient is harmed because of carelessness (negligence). Recent criminal charges against physicians and a nurse, however, have called medical professionals’ attention to the fact that they also may face criminal charges for inappropriate practice.

We cite 2 cases in which criminal liability resulted from bad medical practice. In both instances, there was considerable concern among medical professionals that criminal charges for making a mistake would make it difficult to practice without fear of criminal charges. One concern is that criminal charges could drive good people out of the profession or make them too cautious.¹

We look more closely at those 2 cases in which criminal liability was imposed. These cases are outliers. Relatively few criminal cases against medical professionals are based on the quality of care. (There are, however, more criminal charges related to fraudulent billing and other insurance fraud, kickbacks, Medicare and Medicaid abuse, and the like.²) At the same time, the criminal law does not stop at the front door of a clinic or hospital.³ When medical professionals engage in seriously inappropriate health care conduct that directly harms someone, criminal liability may result.⁴

Anatomy of a crime

Crimes generally require a specific mental state (mens rea) and an act (actus reus). The law specifies the mental state required for conviction. It can range from premeditation—once commonly called “malice aforethought”—to negligence. The mens rea requirement is an essential element of the crime—as we will see in the discussion of the prescription drug cases. A few offenses do not require even negligence, but overwhelmingly, crimes require something more than simple negligence.⁵

The act requirement is generally obvious, such as firing a gun, driving while intoxicated, or recklessly giving inappropriate medication to a patient. It may include “attempts,” crimes where an act was not completed. For example, attempted murder or conspiracy to commit do not require a completed offense, only intent plus overt acts toward carrying out the crime. Similarly, the wrongful act usually has to produce some harm, but again there are exceptions (attempts). To obtain a conviction, the prosecution must prove all of the elements of the crime, including the required mens rea, beyond a reasonable doubt.⁶

With this general background, we turn to the first case, in which the charge was a form of homicide. Please note that the following case description was derived from news descriptions of the case, because juries do not publish opinions concerning their conclusions and court documents are unavailable. The public reports therefore may contain factual gaps and errors.

CASE 1 Patient dies after nurse administers wrong drug

RaDonda Vaught, a 38-year-old experienced registered nurse employed at Vanderbilt University Medical Center (VUMC) in the intensive care unit (ICU), was providing care for a 76-year-old patient who was admitted to VUMC’s ICU in December 2017 in association with a brain injury. The brain injury involved a fall with resultant subdural hematoma. In preparation for a positron emission tomography (PET) scan to assess the patient’s injury, the physician team prescribed the sedative Versed (midazolam) because of the patient’s claustrophobia. During the course of treatment, Ms. Vaught inadvertently administered the wrong drug, a fatal dose of the muscle relaxant vecuronium, to the patient, which resulted in the patient being unable to breathe. Apparently, Ms. Vaught had been unable to find the midazolam and disengaged a safeguard, proceeding into override mode, and thus vecuronium was dispensed. By the time the error was noticed, the patient was already in cardiac arrest with resultant brain damage (partial brain death). The patient died soon thereafter.

How this medication error occurred

The medication error occurred when Ms. Vaught overrode a computer in the medical system when she could not find the “Versed” entry and typed in “VE,” which was the abbreviation for vecuronium. The prosecutors in the case stated that she failed to distinguish that vecuronium is dispensed as a powder and Versed as a liquid formula. The vecuronium has a red cap, which warns that it is a paralyzing agent. Ms. Vaught ignored these red flags, according to the prosecutors. Furthermore, the lawsuit filing documented her discussion that she was “distracted with something” at the time and admitted to overriding the medication warning.

Continue to: The charges in this case...

The charges revolved around “criminally negligent homicide and gross neglect of an impaired adult,” the most notable charge being criminally negligent homicide. Potential consequences were up to an 8 years’ prison sentence.⁷

Furthermore, the Tennessee Board of Nursing revoked Ms. Vaught’s license in July 2021.⁸ The Board also reportedly fined her $3,000.⁹

The criminal proceedings were filed in Davidson County Criminal Court, with Judge Jennifer Smith presiding. Ms. Vaught repeatedly manifested remorse for the event. The patient’s family, including her son Michael and her daughters-in-law, provided tearful testimonies at the hearing. Ms. Vaught repeatedly cried during the testimonies. The nurse did not provide an apology, according to one daughter-in-law. The news media reported that the family did not want jail time for Ms. Vaught.⁷ Nurses across the country were “jolted,” as expressed by the news media.¹⁰

Why the controversy?

The entire issue of medical errors continues to be discussed among both the medical and the legal professions. To have a nursing personnel held to the level of criminal liability is unusual.

It was clear that Ms. Vaught took responsibility for her actions, and neither the prosecutors nor defendant attorneys sensed any evidence of malice on her part. On the other hand, there was enough evidence and concern for District Attorney Glenn Funk to proceed with prosecution-related action. Ms. Vaught was facing years in prison if convicted.

WHAT’S THE VERDICT?

In March 2022, the jury convicted Ms. Vaught of criminally negligent homicide—but not of reckless homicide, a more serious offense.

Judge Smith granted a judicial diversion, that is, the conviction would be expunged from the record if Ms. Vaught completed a 3-year probation. Judge Smith noted the “credible remorse expressed by Nurse Vaught” and went on to state, “this is a terrible, terrible, mistake and there have been consequences to the defendant.” In the courtroom, Ms. Vaught apologized to the patient’s family and conveyed that she will “forever be haunted by her role in the (patient’s) passing.”

Overall, this served as an opportunity for health care workers to address oftentimes poor working conditions, which have been exacerbated by the COVID-19 pandemic.

The Davidson County District Attorney’s office conveyed that this was one case of a careless nurse and not a reflection of the nursing profession. The prosecutors were in accord with a probation verdict. The family felt that their mother, the patient, would not want to see the nurse serve a jail sentence: “Mom was a very forgiving person.”

The patient’s cause of death was listed as “intracerebral hemorrhage and cardiac arrest.” One year later, a new death certificate was issued and noted vecuronium intoxication as the cause of death.

Continue to: The health care institution’s involvement...

The health care institution’s involvement

Approximately 1 year after an apparent anonymous tip was made to health care officials, an unscheduled state and federal investigation, with the threat of possible sanctions, occurred at the VUMC. This was predicated on the criminal indictment related to Ms. Vaught. In the end, her nursing license was revoked, as noted earlier. The family earlier reached an out-of-court settlement with the hospital and there were a number of problems identified at the university medical center.¹¹

Legal principles in the case

Most criminal cases are state cases. Crimes are defined in state statutes, and the trial takes place in state courts. Thus, crimes are defined a little differently from state to state. Ms. Vaught, for example, was tried in Tennessee under the laws of that state.

Homicide involves the killing of a human being. It may not be a crime. For example, there is “justifiable homicide,” such as self-defense. At the other extreme is first-degree murder, an intentional and planned killing. In this case, Ms. Vaught was charged with criminally negligent homicide, which is usually the least serious of criminal homicides but is still a felony. (Some states have misdemeanor manslaughter, which was not an issue in this case.) In some states, criminally negligent homicide is sometimes referred to as involuntary manslaughter. The mens rea for involuntary manslaughter is generally recklessness or “criminal negligence.” This crime goes by various names depending on the state, but involuntary manslaughter and criminally negligent homicide are common names.

Ordinary negligence versus criminal negligence. Criminal negligence is usually considered a more serious mistake than ordinary negligence. This is where there is a difference between civil malpractice negligence and criminal negligence. Criminal negligence is somewhat more careless than ordinary negligence. To use a driving example, if Dr. A was driving home from the hospital, missed seeing a red light, and killed Joe Pedestrian, it could be ordinary negligence. If, however, Dr. B was texting or drinking while driving, causing Dr. B to be distracted and miss seeing the red light, killing a pedestrian, it could be criminal negligence and result in the conviction for the homicide. Of course, in either case there could be civil liability for causing the death.

Applying these legal principles to the reported facts in Ms. Vaught’s case, it appears there was more than simple negligence. That is, the nurse was more than careless. Using “VE” for the wrong drug might have been negligent. In addition, however, she disengaged a safeguard meant to prevent wrongful use of the drug, failed to notice that the drug was a powder instead of a liquid, and ignored the red cap warning that the drug was a paralyzing agent. It becomes apparent why the jury could have found aggravated or criminal negligence.

It is worth emphasizing that in this case, the criminal charges were unusual. For years, studies have suggested that many deaths result from medical errors. The Institute of Medicine famously said that the number of deaths from medical errors was equivalent to that of a 747 airplane crashing every day.^12,13 These events result in a relatively small number of malpractice actions but an infinitesimally small number of homicide charges. Among other things, prosecutors are reluctant to pursue such cases regarding acts carried out as part of clinical duties unless there is strong evidence, and grand juries may be reluctant to indict medical professionals.¹⁴

Nonetheless, medical professionals ultimately can be criminally responsible for deaths resulting from intentional, or criminally negligent, careless practice. Such liability should not dissuade nurses or others from medical practice any more than the much more common homicide charges that can occur from driving an automobile carelessly that results in someone’s death. A fundamental purpose of the criminal law is to disincentivize unnecessarily harmful (deadly) conduct, whether it is distracted driving or distracted nursing.

Continue to: The drug-prescribing crimes...

The drug-prescribing crimes

The US Supreme Court considered a much different kind of criminal medical practice in 2 (consolidated) cases in its 2021–2022 Term. Physicians in 2 states were each tried and convicted of federal charges of illegally dispensing or distributing (prescribing) controlled substances.¹⁵ A federal statute makes it a felony for a physician, or others, “except as authorized” to “knowingly or intentionally distribute, or dispense a controlled substance.”¹⁶ Federal regulations clarify the statute. The regulation provides that a prescription is authorized only if a doctor issues it “for a legitimate medical purpose . . . acting in the usual course of professional practice.”¹⁷

CASE 2 Physicians charged with overprescribing controlled substances

In these 2 drug-prescribing cases, the physicians had grossly overprescribed the opioids. One reportedly wrote prescriptions in 2 states in exchange for payments in cash or, infrequently, firearms, approximating the cost of the prescriptions to street drugs. The other had a clinic that, over about 4 years, issued 300,000 prescriptions for controlled substances and was a significant source for some kinds of fentanyl.¹⁸

WHAT’S THE VERDICT?

In each trial, the juries found the defendant guilty of improper distribution of controlled substances. Although the charges were not homicides, the sentencing judges were much more severe than the court had been in the nursing case discussed above. One physician received a prison term of 20 years, the other, a 25-year term. These undoubtedly reflect both the outrageous conduct and the likely great harm the defendants did.

The Supreme Court heard the cases

The Supreme Court reversed these physicians’ convictions. The Court held that the lower courts had not correctly described for the juries the mens rea required for a conviction under these charges. The Supreme Court held that to be convicted of these offenses, the government had to prove “beyond a reasonable doubt that the defendant [physician] knew that he or she was acting in an unauthorized manner.”¹⁹ Both can be retried and probably will be unless they reach a plea agreement with the federal government. Nonetheless, the Court established a very high standard. Carelessness is not enough, but rather “knowingly” acting in an unauthorized way is required. Although these physicians were prosecuted under federal law, other physicians have been prosecuted under state laws limiting the distribution of controlled substances.²⁰

Some physicians have expressed concern that the Supreme Court, in these cases, made the practice of medicine more dangerous for physicians (the threat of criminal sanctions) and patients (making it more difficult to obtain pain control, for example).^21,22 That view may be overly pessimistic for 2 reasons. First, the Court actually made it more difficult to convict physicians of writing excessive prescriptions. It did so by setting a higher mens rea standard than lower courts were using, that is, the physician had to “knowingly” act in an unauthorized way. Because “knowingly” can be implied by the circumstances, taking guns or cash would be evidence that the physician knowingly misprescribed.

More fundamentally, the actions of these physicians appear to be well outside even a generous legitimate level of controlled substance prescription. These convictions should not be misunderstood as a way of federal courts to crack down on pain medications. However, the original convictions are a warning to the small handful who grossly overprescribe controlled substances.

Lessons about criminal law and the practice of medicine

Medical professionals’ strong reaction to criminal charges is understandable. Criminal charges can result in jail time (the physicians involved in the controlled substance case were sentenced to 20 years or more) and hefty fines; bring social and professional disapprobation; may lead to license discipline; and are terribly disruptive even for those found not guilty. To make matters worse, malpractice insurance ordinarily does not cover criminal charges, so any fines and the cost of defense are likely out of pocket for those charged—and that can be very expensive. Therefore, the strong reaction to the cases we have described is understandable.

At the same time, the probability of criminal charges against medical personnel for their medical treatment is very low compared with, for example, fraudulent billing, their driving habits, or tax avoidance. Criminal charges are much more likely to arise from insurance fraud, Medicare or Medicaid dishonesty, kickbacks, false statements, and similar corruption crimes rather than inadequate practice. In the cases we examined here, there is an enhanced or aggravated negligence in one case and grossly inappropriate prescribing in the others (which the Supreme Court held must be “knowingly” wrong).

Finally, there is an irony. Medical professionals worried about practice-related criminal charges should be thankful for the malpractice system. Civil malpractice is, as a practical matter, an alternative for patients who believe they were mistreated or harmed by physicians or other providers. They have the option of finding a private attorney to file a civil complaint. In the absence of that system, they would be much more likely to take their grievance and complaint to the prosecutor to seek answers and retribution. Criminal law and civil liability are each a way of allowing someone harmed by another to seek redress. Both are intended to deter harmful conduct and provide some individual and social retribution for such behavior. The civil system, of course, also provides the potential for compensation to those injured. An injured patient without the possibility of a civil suit sometimes would turn to the criminal system for satisfaction. This way, the malpractice system is a better alternative to criminal charges. ●

Medical professionals are well aware that civil liability (malpractice) may incur when a patient is harmed because of carelessness (negligence). Recent criminal charges against physicians and a nurse, however, have called medical professionals’ attention to the fact that they also may face criminal charges for inappropriate practice.

We cite 2 cases in which criminal liability resulted from bad medical practice. In both instances, there was considerable concern among medical professionals that criminal charges for making a mistake would make it difficult to practice without fear of criminal charges. One concern is that criminal charges could drive good people out of the profession or make them too cautious.¹

We look more closely at those 2 cases in which criminal liability was imposed. These cases are outliers. Relatively few criminal cases against medical professionals are based on the quality of care. (There are, however, more criminal charges related to fraudulent billing and other insurance fraud, kickbacks, Medicare and Medicaid abuse, and the like.²) At the same time, the criminal law does not stop at the front door of a clinic or hospital.³ When medical professionals engage in seriously inappropriate health care conduct that directly harms someone, criminal liability may result.⁴

Anatomy of a crime

Crimes generally require a specific mental state (mens rea) and an act (actus reus). The law specifies the mental state required for conviction. It can range from premeditation—once commonly called “malice aforethought”—to negligence. The mens rea requirement is an essential element of the crime—as we will see in the discussion of the prescription drug cases. A few offenses do not require even negligence, but overwhelmingly, crimes require something more than simple negligence.⁵

The act requirement is generally obvious, such as firing a gun, driving while intoxicated, or recklessly giving inappropriate medication to a patient. It may include “attempts,” crimes where an act was not completed. For example, attempted murder or conspiracy to commit do not require a completed offense, only intent plus overt acts toward carrying out the crime. Similarly, the wrongful act usually has to produce some harm, but again there are exceptions (attempts). To obtain a conviction, the prosecution must prove all of the elements of the crime, including the required mens rea, beyond a reasonable doubt.⁶

With this general background, we turn to the first case, in which the charge was a form of homicide. Please note that the following case description was derived from news descriptions of the case, because juries do not publish opinions concerning their conclusions and court documents are unavailable. The public reports therefore may contain factual gaps and errors.

CASE 1 Patient dies after nurse administers wrong drug

RaDonda Vaught, a 38-year-old experienced registered nurse employed at Vanderbilt University Medical Center (VUMC) in the intensive care unit (ICU), was providing care for a 76-year-old patient who was admitted to VUMC’s ICU in December 2017 in association with a brain injury. The brain injury involved a fall with resultant subdural hematoma. In preparation for a positron emission tomography (PET) scan to assess the patient’s injury, the physician team prescribed the sedative Versed (midazolam) because of the patient’s claustrophobia. During the course of treatment, Ms. Vaught inadvertently administered the wrong drug, a fatal dose of the muscle relaxant vecuronium, to the patient, which resulted in the patient being unable to breathe. Apparently, Ms. Vaught had been unable to find the midazolam and disengaged a safeguard, proceeding into override mode, and thus vecuronium was dispensed. By the time the error was noticed, the patient was already in cardiac arrest with resultant brain damage (partial brain death). The patient died soon thereafter.

How this medication error occurred

The medication error occurred when Ms. Vaught overrode a computer in the medical system when she could not find the “Versed” entry and typed in “VE,” which was the abbreviation for vecuronium. The prosecutors in the case stated that she failed to distinguish that vecuronium is dispensed as a powder and Versed as a liquid formula. The vecuronium has a red cap, which warns that it is a paralyzing agent. Ms. Vaught ignored these red flags, according to the prosecutors. Furthermore, the lawsuit filing documented her discussion that she was “distracted with something” at the time and admitted to overriding the medication warning.

Continue to: The charges in this case...

The charges revolved around “criminally negligent homicide and gross neglect of an impaired adult,” the most notable charge being criminally negligent homicide. Potential consequences were up to an 8 years’ prison sentence.⁷

Furthermore, the Tennessee Board of Nursing revoked Ms. Vaught’s license in July 2021.⁸ The Board also reportedly fined her $3,000.⁹

The criminal proceedings were filed in Davidson County Criminal Court, with Judge Jennifer Smith presiding. Ms. Vaught repeatedly manifested remorse for the event. The patient’s family, including her son Michael and her daughters-in-law, provided tearful testimonies at the hearing. Ms. Vaught repeatedly cried during the testimonies. The nurse did not provide an apology, according to one daughter-in-law. The news media reported that the family did not want jail time for Ms. Vaught.⁷ Nurses across the country were “jolted,” as expressed by the news media.¹⁰

Why the controversy?

The entire issue of medical errors continues to be discussed among both the medical and the legal professions. To have a nursing personnel held to the level of criminal liability is unusual.

It was clear that Ms. Vaught took responsibility for her actions, and neither the prosecutors nor defendant attorneys sensed any evidence of malice on her part. On the other hand, there was enough evidence and concern for District Attorney Glenn Funk to proceed with prosecution-related action. Ms. Vaught was facing years in prison if convicted.

WHAT’S THE VERDICT?

In March 2022, the jury convicted Ms. Vaught of criminally negligent homicide—but not of reckless homicide, a more serious offense.

Judge Smith granted a judicial diversion, that is, the conviction would be expunged from the record if Ms. Vaught completed a 3-year probation. Judge Smith noted the “credible remorse expressed by Nurse Vaught” and went on to state, “this is a terrible, terrible, mistake and there have been consequences to the defendant.” In the courtroom, Ms. Vaught apologized to the patient’s family and conveyed that she will “forever be haunted by her role in the (patient’s) passing.”

Overall, this served as an opportunity for health care workers to address oftentimes poor working conditions, which have been exacerbated by the COVID-19 pandemic.

The Davidson County District Attorney’s office conveyed that this was one case of a careless nurse and not a reflection of the nursing profession. The prosecutors were in accord with a probation verdict. The family felt that their mother, the patient, would not want to see the nurse serve a jail sentence: “Mom was a very forgiving person.”

The patient’s cause of death was listed as “intracerebral hemorrhage and cardiac arrest.” One year later, a new death certificate was issued and noted vecuronium intoxication as the cause of death.

Continue to: The health care institution’s involvement...

The health care institution’s involvement

Approximately 1 year after an apparent anonymous tip was made to health care officials, an unscheduled state and federal investigation, with the threat of possible sanctions, occurred at the VUMC. This was predicated on the criminal indictment related to Ms. Vaught. In the end, her nursing license was revoked, as noted earlier. The family earlier reached an out-of-court settlement with the hospital and there were a number of problems identified at the university medical center.¹¹

Legal principles in the case

Most criminal cases are state cases. Crimes are defined in state statutes, and the trial takes place in state courts. Thus, crimes are defined a little differently from state to state. Ms. Vaught, for example, was tried in Tennessee under the laws of that state.

Homicide involves the killing of a human being. It may not be a crime. For example, there is “justifiable homicide,” such as self-defense. At the other extreme is first-degree murder, an intentional and planned killing. In this case, Ms. Vaught was charged with criminally negligent homicide, which is usually the least serious of criminal homicides but is still a felony. (Some states have misdemeanor manslaughter, which was not an issue in this case.) In some states, criminally negligent homicide is sometimes referred to as involuntary manslaughter. The mens rea for involuntary manslaughter is generally recklessness or “criminal negligence.” This crime goes by various names depending on the state, but involuntary manslaughter and criminally negligent homicide are common names.

Ordinary negligence versus criminal negligence. Criminal negligence is usually considered a more serious mistake than ordinary negligence. This is where there is a difference between civil malpractice negligence and criminal negligence. Criminal negligence is somewhat more careless than ordinary negligence. To use a driving example, if Dr. A was driving home from the hospital, missed seeing a red light, and killed Joe Pedestrian, it could be ordinary negligence. If, however, Dr. B was texting or drinking while driving, causing Dr. B to be distracted and miss seeing the red light, killing a pedestrian, it could be criminal negligence and result in the conviction for the homicide. Of course, in either case there could be civil liability for causing the death.

Applying these legal principles to the reported facts in Ms. Vaught’s case, it appears there was more than simple negligence. That is, the nurse was more than careless. Using “VE” for the wrong drug might have been negligent. In addition, however, she disengaged a safeguard meant to prevent wrongful use of the drug, failed to notice that the drug was a powder instead of a liquid, and ignored the red cap warning that the drug was a paralyzing agent. It becomes apparent why the jury could have found aggravated or criminal negligence.

It is worth emphasizing that in this case, the criminal charges were unusual. For years, studies have suggested that many deaths result from medical errors. The Institute of Medicine famously said that the number of deaths from medical errors was equivalent to that of a 747 airplane crashing every day.^12,13 These events result in a relatively small number of malpractice actions but an infinitesimally small number of homicide charges. Among other things, prosecutors are reluctant to pursue such cases regarding acts carried out as part of clinical duties unless there is strong evidence, and grand juries may be reluctant to indict medical professionals.¹⁴

Nonetheless, medical professionals ultimately can be criminally responsible for deaths resulting from intentional, or criminally negligent, careless practice. Such liability should not dissuade nurses or others from medical practice any more than the much more common homicide charges that can occur from driving an automobile carelessly that results in someone’s death. A fundamental purpose of the criminal law is to disincentivize unnecessarily harmful (deadly) conduct, whether it is distracted driving or distracted nursing.

Continue to: The drug-prescribing crimes...

The drug-prescribing crimes

The US Supreme Court considered a much different kind of criminal medical practice in 2 (consolidated) cases in its 2021–2022 Term. Physicians in 2 states were each tried and convicted of federal charges of illegally dispensing or distributing (prescribing) controlled substances.¹⁵ A federal statute makes it a felony for a physician, or others, “except as authorized” to “knowingly or intentionally distribute, or dispense a controlled substance.”¹⁶ Federal regulations clarify the statute. The regulation provides that a prescription is authorized only if a doctor issues it “for a legitimate medical purpose . . . acting in the usual course of professional practice.”¹⁷

CASE 2 Physicians charged with overprescribing controlled substances

In these 2 drug-prescribing cases, the physicians had grossly overprescribed the opioids. One reportedly wrote prescriptions in 2 states in exchange for payments in cash or, infrequently, firearms, approximating the cost of the prescriptions to street drugs. The other had a clinic that, over about 4 years, issued 300,000 prescriptions for controlled substances and was a significant source for some kinds of fentanyl.¹⁸

WHAT’S THE VERDICT?

In each trial, the juries found the defendant guilty of improper distribution of controlled substances. Although the charges were not homicides, the sentencing judges were much more severe than the court had been in the nursing case discussed above. One physician received a prison term of 20 years, the other, a 25-year term. These undoubtedly reflect both the outrageous conduct and the likely great harm the defendants did.

The Supreme Court heard the cases

The Supreme Court reversed these physicians’ convictions. The Court held that the lower courts had not correctly described for the juries the mens rea required for a conviction under these charges. The Supreme Court held that to be convicted of these offenses, the government had to prove “beyond a reasonable doubt that the defendant [physician] knew that he or she was acting in an unauthorized manner.”¹⁹ Both can be retried and probably will be unless they reach a plea agreement with the federal government. Nonetheless, the Court established a very high standard. Carelessness is not enough, but rather “knowingly” acting in an unauthorized way is required. Although these physicians were prosecuted under federal law, other physicians have been prosecuted under state laws limiting the distribution of controlled substances.²⁰

Some physicians have expressed concern that the Supreme Court, in these cases, made the practice of medicine more dangerous for physicians (the threat of criminal sanctions) and patients (making it more difficult to obtain pain control, for example).^21,22 That view may be overly pessimistic for 2 reasons. First, the Court actually made it more difficult to convict physicians of writing excessive prescriptions. It did so by setting a higher mens rea standard than lower courts were using, that is, the physician had to “knowingly” act in an unauthorized way. Because “knowingly” can be implied by the circumstances, taking guns or cash would be evidence that the physician knowingly misprescribed.

More fundamentally, the actions of these physicians appear to be well outside even a generous legitimate level of controlled substance prescription. These convictions should not be misunderstood as a way of federal courts to crack down on pain medications. However, the original convictions are a warning to the small handful who grossly overprescribe controlled substances.

Lessons about criminal law and the practice of medicine

Medical professionals’ strong reaction to criminal charges is understandable. Criminal charges can result in jail time (the physicians involved in the controlled substance case were sentenced to 20 years or more) and hefty fines; bring social and professional disapprobation; may lead to license discipline; and are terribly disruptive even for those found not guilty. To make matters worse, malpractice insurance ordinarily does not cover criminal charges, so any fines and the cost of defense are likely out of pocket for those charged—and that can be very expensive. Therefore, the strong reaction to the cases we have described is understandable.

At the same time, the probability of criminal charges against medical personnel for their medical treatment is very low compared with, for example, fraudulent billing, their driving habits, or tax avoidance. Criminal charges are much more likely to arise from insurance fraud, Medicare or Medicaid dishonesty, kickbacks, false statements, and similar corruption crimes rather than inadequate practice. In the cases we examined here, there is an enhanced or aggravated negligence in one case and grossly inappropriate prescribing in the others (which the Supreme Court held must be “knowingly” wrong).

Finally, there is an irony. Medical professionals worried about practice-related criminal charges should be thankful for the malpractice system. Civil malpractice is, as a practical matter, an alternative for patients who believe they were mistreated or harmed by physicians or other providers. They have the option of finding a private attorney to file a civil complaint. In the absence of that system, they would be much more likely to take their grievance and complaint to the prosecutor to seek answers and retribution. Criminal law and civil liability are each a way of allowing someone harmed by another to seek redress. Both are intended to deter harmful conduct and provide some individual and social retribution for such behavior. The civil system, of course, also provides the potential for compensation to those injured. An injured patient without the possibility of a civil suit sometimes would turn to the criminal system for satisfaction. This way, the malpractice system is a better alternative to criminal charges. ●

Medical professionals are well aware that civil liability (malpractice) may incur when a patient is harmed because of carelessness (negligence). Recent criminal charges against physicians and a nurse, however, have called medical professionals’ attention to the fact that they also may face criminal charges for inappropriate practice.

We cite 2 cases in which criminal liability resulted from bad medical practice. In both instances, there was considerable concern among medical professionals that criminal charges for making a mistake would make it difficult to practice without fear of criminal charges. One concern is that criminal charges could drive good people out of the profession or make them too cautious.¹

We look more closely at those 2 cases in which criminal liability was imposed. These cases are outliers. Relatively few criminal cases against medical professionals are based on the quality of care. (There are, however, more criminal charges related to fraudulent billing and other insurance fraud, kickbacks, Medicare and Medicaid abuse, and the like.²) At the same time, the criminal law does not stop at the front door of a clinic or hospital.³ When medical professionals engage in seriously inappropriate health care conduct that directly harms someone, criminal liability may result.⁴

Anatomy of a crime

Crimes generally require a specific mental state (mens rea) and an act (actus reus). The law specifies the mental state required for conviction. It can range from premeditation—once commonly called “malice aforethought”—to negligence. The mens rea requirement is an essential element of the crime—as we will see in the discussion of the prescription drug cases. A few offenses do not require even negligence, but overwhelmingly, crimes require something more than simple negligence.⁵

The act requirement is generally obvious, such as firing a gun, driving while intoxicated, or recklessly giving inappropriate medication to a patient. It may include “attempts,” crimes where an act was not completed. For example, attempted murder or conspiracy to commit do not require a completed offense, only intent plus overt acts toward carrying out the crime. Similarly, the wrongful act usually has to produce some harm, but again there are exceptions (attempts). To obtain a conviction, the prosecution must prove all of the elements of the crime, including the required mens rea, beyond a reasonable doubt.⁶

With this general background, we turn to the first case, in which the charge was a form of homicide. Please note that the following case description was derived from news descriptions of the case, because juries do not publish opinions concerning their conclusions and court documents are unavailable. The public reports therefore may contain factual gaps and errors.

CASE 1 Patient dies after nurse administers wrong drug

RaDonda Vaught, a 38-year-old experienced registered nurse employed at Vanderbilt University Medical Center (VUMC) in the intensive care unit (ICU), was providing care for a 76-year-old patient who was admitted to VUMC’s ICU in December 2017 in association with a brain injury. The brain injury involved a fall with resultant subdural hematoma. In preparation for a positron emission tomography (PET) scan to assess the patient’s injury, the physician team prescribed the sedative Versed (midazolam) because of the patient’s claustrophobia. During the course of treatment, Ms. Vaught inadvertently administered the wrong drug, a fatal dose of the muscle relaxant vecuronium, to the patient, which resulted in the patient being unable to breathe. Apparently, Ms. Vaught had been unable to find the midazolam and disengaged a safeguard, proceeding into override mode, and thus vecuronium was dispensed. By the time the error was noticed, the patient was already in cardiac arrest with resultant brain damage (partial brain death). The patient died soon thereafter.

How this medication error occurred

The medication error occurred when Ms. Vaught overrode a computer in the medical system when she could not find the “Versed” entry and typed in “VE,” which was the abbreviation for vecuronium. The prosecutors in the case stated that she failed to distinguish that vecuronium is dispensed as a powder and Versed as a liquid formula. The vecuronium has a red cap, which warns that it is a paralyzing agent. Ms. Vaught ignored these red flags, according to the prosecutors. Furthermore, the lawsuit filing documented her discussion that she was “distracted with something” at the time and admitted to overriding the medication warning.

Continue to: The charges in this case...

The charges revolved around “criminally negligent homicide and gross neglect of an impaired adult,” the most notable charge being criminally negligent homicide. Potential consequences were up to an 8 years’ prison sentence.⁷

Furthermore, the Tennessee Board of Nursing revoked Ms. Vaught’s license in July 2021.⁸ The Board also reportedly fined her $3,000.⁹

The criminal proceedings were filed in Davidson County Criminal Court, with Judge Jennifer Smith presiding. Ms. Vaught repeatedly manifested remorse for the event. The patient’s family, including her son Michael and her daughters-in-law, provided tearful testimonies at the hearing. Ms. Vaught repeatedly cried during the testimonies. The nurse did not provide an apology, according to one daughter-in-law. The news media reported that the family did not want jail time for Ms. Vaught.⁷ Nurses across the country were “jolted,” as expressed by the news media.¹⁰

Why the controversy?

The entire issue of medical errors continues to be discussed among both the medical and the legal professions. To have a nursing personnel held to the level of criminal liability is unusual.

It was clear that Ms. Vaught took responsibility for her actions, and neither the prosecutors nor defendant attorneys sensed any evidence of malice on her part. On the other hand, there was enough evidence and concern for District Attorney Glenn Funk to proceed with prosecution-related action. Ms. Vaught was facing years in prison if convicted.

WHAT’S THE VERDICT?

In March 2022, the jury convicted Ms. Vaught of criminally negligent homicide—but not of reckless homicide, a more serious offense.

Judge Smith granted a judicial diversion, that is, the conviction would be expunged from the record if Ms. Vaught completed a 3-year probation. Judge Smith noted the “credible remorse expressed by Nurse Vaught” and went on to state, “this is a terrible, terrible, mistake and there have been consequences to the defendant.” In the courtroom, Ms. Vaught apologized to the patient’s family and conveyed that she will “forever be haunted by her role in the (patient’s) passing.”

Overall, this served as an opportunity for health care workers to address oftentimes poor working conditions, which have been exacerbated by the COVID-19 pandemic.

The Davidson County District Attorney’s office conveyed that this was one case of a careless nurse and not a reflection of the nursing profession. The prosecutors were in accord with a probation verdict. The family felt that their mother, the patient, would not want to see the nurse serve a jail sentence: “Mom was a very forgiving person.”

The patient’s cause of death was listed as “intracerebral hemorrhage and cardiac arrest.” One year later, a new death certificate was issued and noted vecuronium intoxication as the cause of death.

Continue to: The health care institution’s involvement...

The health care institution’s involvement

Approximately 1 year after an apparent anonymous tip was made to health care officials, an unscheduled state and federal investigation, with the threat of possible sanctions, occurred at the VUMC. This was predicated on the criminal indictment related to Ms. Vaught. In the end, her nursing license was revoked, as noted earlier. The family earlier reached an out-of-court settlement with the hospital and there were a number of problems identified at the university medical center.¹¹

Legal principles in the case

Most criminal cases are state cases. Crimes are defined in state statutes, and the trial takes place in state courts. Thus, crimes are defined a little differently from state to state. Ms. Vaught, for example, was tried in Tennessee under the laws of that state.

Homicide involves the killing of a human being. It may not be a crime. For example, there is “justifiable homicide,” such as self-defense. At the other extreme is first-degree murder, an intentional and planned killing. In this case, Ms. Vaught was charged with criminally negligent homicide, which is usually the least serious of criminal homicides but is still a felony. (Some states have misdemeanor manslaughter, which was not an issue in this case.) In some states, criminally negligent homicide is sometimes referred to as involuntary manslaughter. The mens rea for involuntary manslaughter is generally recklessness or “criminal negligence.” This crime goes by various names depending on the state, but involuntary manslaughter and criminally negligent homicide are common names.

Ordinary negligence versus criminal negligence. Criminal negligence is usually considered a more serious mistake than ordinary negligence. This is where there is a difference between civil malpractice negligence and criminal negligence. Criminal negligence is somewhat more careless than ordinary negligence. To use a driving example, if Dr. A was driving home from the hospital, missed seeing a red light, and killed Joe Pedestrian, it could be ordinary negligence. If, however, Dr. B was texting or drinking while driving, causing Dr. B to be distracted and miss seeing the red light, killing a pedestrian, it could be criminal negligence and result in the conviction for the homicide. Of course, in either case there could be civil liability for causing the death.

Applying these legal principles to the reported facts in Ms. Vaught’s case, it appears there was more than simple negligence. That is, the nurse was more than careless. Using “VE” for the wrong drug might have been negligent. In addition, however, she disengaged a safeguard meant to prevent wrongful use of the drug, failed to notice that the drug was a powder instead of a liquid, and ignored the red cap warning that the drug was a paralyzing agent. It becomes apparent why the jury could have found aggravated or criminal negligence.

It is worth emphasizing that in this case, the criminal charges were unusual. For years, studies have suggested that many deaths result from medical errors. The Institute of Medicine famously said that the number of deaths from medical errors was equivalent to that of a 747 airplane crashing every day.^12,13 These events result in a relatively small number of malpractice actions but an infinitesimally small number of homicide charges. Among other things, prosecutors are reluctant to pursue such cases regarding acts carried out as part of clinical duties unless there is strong evidence, and grand juries may be reluctant to indict medical professionals.¹⁴

Nonetheless, medical professionals ultimately can be criminally responsible for deaths resulting from intentional, or criminally negligent, careless practice. Such liability should not dissuade nurses or others from medical practice any more than the much more common homicide charges that can occur from driving an automobile carelessly that results in someone’s death. A fundamental purpose of the criminal law is to disincentivize unnecessarily harmful (deadly) conduct, whether it is distracted driving or distracted nursing.

Continue to: The drug-prescribing crimes...

The drug-prescribing crimes

The US Supreme Court considered a much different kind of criminal medical practice in 2 (consolidated) cases in its 2021–2022 Term. Physicians in 2 states were each tried and convicted of federal charges of illegally dispensing or distributing (prescribing) controlled substances.¹⁵ A federal statute makes it a felony for a physician, or others, “except as authorized” to “knowingly or intentionally distribute, or dispense a controlled substance.”¹⁶ Federal regulations clarify the statute. The regulation provides that a prescription is authorized only if a doctor issues it “for a legitimate medical purpose . . . acting in the usual course of professional practice.”¹⁷

CASE 2 Physicians charged with overprescribing controlled substances

In these 2 drug-prescribing cases, the physicians had grossly overprescribed the opioids. One reportedly wrote prescriptions in 2 states in exchange for payments in cash or, infrequently, firearms, approximating the cost of the prescriptions to street drugs. The other had a clinic that, over about 4 years, issued 300,000 prescriptions for controlled substances and was a significant source for some kinds of fentanyl.¹⁸

WHAT’S THE VERDICT?

In each trial, the juries found the defendant guilty of improper distribution of controlled substances. Although the charges were not homicides, the sentencing judges were much more severe than the court had been in the nursing case discussed above. One physician received a prison term of 20 years, the other, a 25-year term. These undoubtedly reflect both the outrageous conduct and the likely great harm the defendants did.

The Supreme Court heard the cases

The Supreme Court reversed these physicians’ convictions. The Court held that the lower courts had not correctly described for the juries the mens rea required for a conviction under these charges. The Supreme Court held that to be convicted of these offenses, the government had to prove “beyond a reasonable doubt that the defendant [physician] knew that he or she was acting in an unauthorized manner.”¹⁹ Both can be retried and probably will be unless they reach a plea agreement with the federal government. Nonetheless, the Court established a very high standard. Carelessness is not enough, but rather “knowingly” acting in an unauthorized way is required. Although these physicians were prosecuted under federal law, other physicians have been prosecuted under state laws limiting the distribution of controlled substances.²⁰

Some physicians have expressed concern that the Supreme Court, in these cases, made the practice of medicine more dangerous for physicians (the threat of criminal sanctions) and patients (making it more difficult to obtain pain control, for example).^21,22 That view may be overly pessimistic for 2 reasons. First, the Court actually made it more difficult to convict physicians of writing excessive prescriptions. It did so by setting a higher mens rea standard than lower courts were using, that is, the physician had to “knowingly” act in an unauthorized way. Because “knowingly” can be implied by the circumstances, taking guns or cash would be evidence that the physician knowingly misprescribed.

More fundamentally, the actions of these physicians appear to be well outside even a generous legitimate level of controlled substance prescription. These convictions should not be misunderstood as a way of federal courts to crack down on pain medications. However, the original convictions are a warning to the small handful who grossly overprescribe controlled substances.

Lessons about criminal law and the practice of medicine

Medical professionals’ strong reaction to criminal charges is understandable. Criminal charges can result in jail time (the physicians involved in the controlled substance case were sentenced to 20 years or more) and hefty fines; bring social and professional disapprobation; may lead to license discipline; and are terribly disruptive even for those found not guilty. To make matters worse, malpractice insurance ordinarily does not cover criminal charges, so any fines and the cost of defense are likely out of pocket for those charged—and that can be very expensive. Therefore, the strong reaction to the cases we have described is understandable.

At the same time, the probability of criminal charges against medical personnel for their medical treatment is very low compared with, for example, fraudulent billing, their driving habits, or tax avoidance. Criminal charges are much more likely to arise from insurance fraud, Medicare or Medicaid dishonesty, kickbacks, false statements, and similar corruption crimes rather than inadequate practice. In the cases we examined here, there is an enhanced or aggravated negligence in one case and grossly inappropriate prescribing in the others (which the Supreme Court held must be “knowingly” wrong).

Finally, there is an irony. Medical professionals worried about practice-related criminal charges should be thankful for the malpractice system. Civil malpractice is, as a practical matter, an alternative for patients who believe they were mistreated or harmed by physicians or other providers. They have the option of finding a private attorney to file a civil complaint. In the absence of that system, they would be much more likely to take their grievance and complaint to the prosecutor to seek answers and retribution. Criminal law and civil liability are each a way of allowing someone harmed by another to seek redress. Both are intended to deter harmful conduct and provide some individual and social retribution for such behavior. The civil system, of course, also provides the potential for compensation to those injured. An injured patient without the possibility of a civil suit sometimes would turn to the criminal system for satisfaction. This way, the malpractice system is a better alternative to criminal charges. ●

Clinicians in the United States are reporting more cases of invasive group A streptococcal infection (iGAS) in children, according to an alert from the Centers for Disease Control and Prevention. These infections are rare but can be deadly, and they can affect adults as well as children.

Health care providers should consider this bacterial infection as a possible cause of severe illness in children and adults, including those with recent or co-occurring viral respiratory infections, the agency advised in a Dec. 22 alert.

In some cases, iGAS manifests as persistent or worsening symptoms after a patient with a known viral infection initially starts to show signs of improvement, according to the agency.

In November, the CDC was notified about a possible increase in cases of pediatric iGAS at a hospital in Colorado. Since then, two surveillance systems – the Infectious Diseases Society of America’s Emerging Infections Network and the CDC’s Active Bacterial Core Surveillance System – have detected potential increases in pediatric iGAS cases in other states.

The uptick has coincided with “increased circulation of respiratory syncytial virus (RSV), influenza viruses, SARS-CoV-2, and other respiratory viruses,” the advisory stated. “While the overall number of cases has remained relatively low and iGAS infections remain rare in children, [the] CDC is investigating these reports.”
 

Not just strep throat

Group A Streptococcus bacteria can cause strep throat and infections in skin and soft tissue. The pathogens also can lead to uncommon but severe diseases, such as sepsis, streptococcal toxic shock syndrome, and necrotizing fasciitis, according to the CDC. The severe illnesses “are associated with high mortality rates and require immediate treatment, including appropriate antibiotic therapy,” the agency said.

Groups at higher risk for iGAS include people aged 65 years or older, American Indian and Alaska Native populations, residents of long-term care facilities, those with wounds or skin disease, people who inject drugs, and people experiencing homelessness.

People with medical conditions such as diabetes, cancer, immunosuppression, and chronic kidney, heart, or respiratory disease also are at increased risk.

Invasive strep A infections initially decreased during the COVID-19 pandemic amid measures to reduce the spread of disease, such as masking and social distancing. But since September, monthly cases have exceeded those in 2020 and 2021. “It is too early to determine whether this rise is beyond what would be expected for pre-COVID” seasonal patterns, the CDC said.
 

Recommendations

Because iGAS can occur after the flu or chickenpox, health care providers should offer influenza and varicella vaccinations to all eligible people who are not up to date with their vaccines.

In addition, clinicians should educate patients about symptoms of iGAS that require urgent medical attention, including necrotizing fasciitis, cellulitis, and toxic shock syndrome.

They also should obtain cultures for suspected cases of iGAS as clinically indicated, follow guidelines for the diagnosis and treatment of strep throat, and be aware of alternative ways to treat strep throat in children amid a shortage of amoxicillin suspension.

Researchers have reported more cases of iGAS in the United Kingdom this year, as well. According to the UK Health Security Agency, 74 deaths, including 16 children, in England have been attributed to iGAS since September.

“We know that this is concerning for parents, but I want to stress that while we are seeing an increase in cases in children, this remains very uncommon,” UKHSA Deputy Director Colin Brown said in a news release. “There are lots of winter bugs circulating that can make your child feel unwell that mostly aren’t cause for alarm. However, make sure you talk to a health professional if your child is getting worse after a bout of scarlet fever, a sore throat, or respiratory infection.”

A fever that doesn’t resolve, dehydration, extreme tiredness, and difficulty breathing are signs to watch out for, Dr. Brown said.

A version of this article first appeared on Medscape.com.

Clinicians in the United States are reporting more cases of invasive group A streptococcal infection (iGAS) in children, according to an alert from the Centers for Disease Control and Prevention. These infections are rare but can be deadly, and they can affect adults as well as children.

Health care providers should consider this bacterial infection as a possible cause of severe illness in children and adults, including those with recent or co-occurring viral respiratory infections, the agency advised in a Dec. 22 alert.

In some cases, iGAS manifests as persistent or worsening symptoms after a patient with a known viral infection initially starts to show signs of improvement, according to the agency.

In November, the CDC was notified about a possible increase in cases of pediatric iGAS at a hospital in Colorado. Since then, two surveillance systems – the Infectious Diseases Society of America’s Emerging Infections Network and the CDC’s Active Bacterial Core Surveillance System – have detected potential increases in pediatric iGAS cases in other states.

The uptick has coincided with “increased circulation of respiratory syncytial virus (RSV), influenza viruses, SARS-CoV-2, and other respiratory viruses,” the advisory stated. “While the overall number of cases has remained relatively low and iGAS infections remain rare in children, [the] CDC is investigating these reports.”
 

Not just strep throat

Group A Streptococcus bacteria can cause strep throat and infections in skin and soft tissue. The pathogens also can lead to uncommon but severe diseases, such as sepsis, streptococcal toxic shock syndrome, and necrotizing fasciitis, according to the CDC. The severe illnesses “are associated with high mortality rates and require immediate treatment, including appropriate antibiotic therapy,” the agency said.

Groups at higher risk for iGAS include people aged 65 years or older, American Indian and Alaska Native populations, residents of long-term care facilities, those with wounds or skin disease, people who inject drugs, and people experiencing homelessness.

People with medical conditions such as diabetes, cancer, immunosuppression, and chronic kidney, heart, or respiratory disease also are at increased risk.

Invasive strep A infections initially decreased during the COVID-19 pandemic amid measures to reduce the spread of disease, such as masking and social distancing. But since September, monthly cases have exceeded those in 2020 and 2021. “It is too early to determine whether this rise is beyond what would be expected for pre-COVID” seasonal patterns, the CDC said.
 

Recommendations

Because iGAS can occur after the flu or chickenpox, health care providers should offer influenza and varicella vaccinations to all eligible people who are not up to date with their vaccines.

In addition, clinicians should educate patients about symptoms of iGAS that require urgent medical attention, including necrotizing fasciitis, cellulitis, and toxic shock syndrome.

They also should obtain cultures for suspected cases of iGAS as clinically indicated, follow guidelines for the diagnosis and treatment of strep throat, and be aware of alternative ways to treat strep throat in children amid a shortage of amoxicillin suspension.

Researchers have reported more cases of iGAS in the United Kingdom this year, as well. According to the UK Health Security Agency, 74 deaths, including 16 children, in England have been attributed to iGAS since September.

“We know that this is concerning for parents, but I want to stress that while we are seeing an increase in cases in children, this remains very uncommon,” UKHSA Deputy Director Colin Brown said in a news release. “There are lots of winter bugs circulating that can make your child feel unwell that mostly aren’t cause for alarm. However, make sure you talk to a health professional if your child is getting worse after a bout of scarlet fever, a sore throat, or respiratory infection.”

A fever that doesn’t resolve, dehydration, extreme tiredness, and difficulty breathing are signs to watch out for, Dr. Brown said.

A version of this article first appeared on Medscape.com.

Clinicians in the United States are reporting more cases of invasive group A streptococcal infection (iGAS) in children, according to an alert from the Centers for Disease Control and Prevention. These infections are rare but can be deadly, and they can affect adults as well as children.

Health care providers should consider this bacterial infection as a possible cause of severe illness in children and adults, including those with recent or co-occurring viral respiratory infections, the agency advised in a Dec. 22 alert.

In some cases, iGAS manifests as persistent or worsening symptoms after a patient with a known viral infection initially starts to show signs of improvement, according to the agency.

In November, the CDC was notified about a possible increase in cases of pediatric iGAS at a hospital in Colorado. Since then, two surveillance systems – the Infectious Diseases Society of America’s Emerging Infections Network and the CDC’s Active Bacterial Core Surveillance System – have detected potential increases in pediatric iGAS cases in other states.

The uptick has coincided with “increased circulation of respiratory syncytial virus (RSV), influenza viruses, SARS-CoV-2, and other respiratory viruses,” the advisory stated. “While the overall number of cases has remained relatively low and iGAS infections remain rare in children, [the] CDC is investigating these reports.”
 

Not just strep throat

Group A Streptococcus bacteria can cause strep throat and infections in skin and soft tissue. The pathogens also can lead to uncommon but severe diseases, such as sepsis, streptococcal toxic shock syndrome, and necrotizing fasciitis, according to the CDC. The severe illnesses “are associated with high mortality rates and require immediate treatment, including appropriate antibiotic therapy,” the agency said.

Groups at higher risk for iGAS include people aged 65 years or older, American Indian and Alaska Native populations, residents of long-term care facilities, those with wounds or skin disease, people who inject drugs, and people experiencing homelessness.

People with medical conditions such as diabetes, cancer, immunosuppression, and chronic kidney, heart, or respiratory disease also are at increased risk.

Invasive strep A infections initially decreased during the COVID-19 pandemic amid measures to reduce the spread of disease, such as masking and social distancing. But since September, monthly cases have exceeded those in 2020 and 2021. “It is too early to determine whether this rise is beyond what would be expected for pre-COVID” seasonal patterns, the CDC said.
 

Recommendations

Because iGAS can occur after the flu or chickenpox, health care providers should offer influenza and varicella vaccinations to all eligible people who are not up to date with their vaccines.

In addition, clinicians should educate patients about symptoms of iGAS that require urgent medical attention, including necrotizing fasciitis, cellulitis, and toxic shock syndrome.

They also should obtain cultures for suspected cases of iGAS as clinically indicated, follow guidelines for the diagnosis and treatment of strep throat, and be aware of alternative ways to treat strep throat in children amid a shortage of amoxicillin suspension.

Researchers have reported more cases of iGAS in the United Kingdom this year, as well. According to the UK Health Security Agency, 74 deaths, including 16 children, in England have been attributed to iGAS since September.

“We know that this is concerning for parents, but I want to stress that while we are seeing an increase in cases in children, this remains very uncommon,” UKHSA Deputy Director Colin Brown said in a news release. “There are lots of winter bugs circulating that can make your child feel unwell that mostly aren’t cause for alarm. However, make sure you talk to a health professional if your child is getting worse after a bout of scarlet fever, a sore throat, or respiratory infection.”

A fever that doesn’t resolve, dehydration, extreme tiredness, and difficulty breathing are signs to watch out for, Dr. Brown said.

A version of this article first appeared on Medscape.com.

A common food dye found in candy, soft drinks, and some cereals, known as Allura Red, can lead to inflammatory bowel diseases, Crohn’s disease, and other health problems, new research shows.

Long-term ingestion of the dye disrupts gut function, causing a series of changes that lead to a higher risk of colitis, according to the research from McMaster University, Hamilton, Ont. The findings were published in Nature Communications.

The dye is also known as FD&C Red 40 and Food Red 17. It adds color and texture and is often used to attract children, according to a press release on Eurekalert.

“This study demonstrates significant harmful effects of Allura Red on gut health and identifies gut serotonin as a critical factor mediating these effects. These findings have important implications in the prevention and management of gut inflammation,” said senior author Waliul Khan, MBBS, PhD, a professor in the McMaster department of pathology and molecular medicine.

“What we have found is striking and alarming, as this common synthetic food dye is a possible dietary trigger for IBDs,” he said. “The literature suggests that the consumption of Allura Red also affects certain allergies, immune disorders, and behavioural problems in children, such as attention deficit hyperactivity disorder.”

The human diet in Western cultures, with its reliance on processed fats, red and processed meat, and low fiber, contributes to IBDs as well, Dr. Khan said.

Food dyes such as Allura Red have been used more and more in recent years. Their effect on gut health hasn’t been studied much.

A version of this article first appeared on WebMD.com.

A common food dye found in candy, soft drinks, and some cereals, known as Allura Red, can lead to inflammatory bowel diseases, Crohn’s disease, and other health problems, new research shows.

Long-term ingestion of the dye disrupts gut function, causing a series of changes that lead to a higher risk of colitis, according to the research from McMaster University, Hamilton, Ont. The findings were published in Nature Communications.

The dye is also known as FD&C Red 40 and Food Red 17. It adds color and texture and is often used to attract children, according to a press release on Eurekalert.

“This study demonstrates significant harmful effects of Allura Red on gut health and identifies gut serotonin as a critical factor mediating these effects. These findings have important implications in the prevention and management of gut inflammation,” said senior author Waliul Khan, MBBS, PhD, a professor in the McMaster department of pathology and molecular medicine.

“What we have found is striking and alarming, as this common synthetic food dye is a possible dietary trigger for IBDs,” he said. “The literature suggests that the consumption of Allura Red also affects certain allergies, immune disorders, and behavioural problems in children, such as attention deficit hyperactivity disorder.”

The human diet in Western cultures, with its reliance on processed fats, red and processed meat, and low fiber, contributes to IBDs as well, Dr. Khan said.

Food dyes such as Allura Red have been used more and more in recent years. Their effect on gut health hasn’t been studied much.

A version of this article first appeared on WebMD.com.

A common food dye found in candy, soft drinks, and some cereals, known as Allura Red, can lead to inflammatory bowel diseases, Crohn’s disease, and other health problems, new research shows.

Long-term ingestion of the dye disrupts gut function, causing a series of changes that lead to a higher risk of colitis, according to the research from McMaster University, Hamilton, Ont. The findings were published in Nature Communications.

The dye is also known as FD&C Red 40 and Food Red 17. It adds color and texture and is often used to attract children, according to a press release on Eurekalert.

“This study demonstrates significant harmful effects of Allura Red on gut health and identifies gut serotonin as a critical factor mediating these effects. These findings have important implications in the prevention and management of gut inflammation,” said senior author Waliul Khan, MBBS, PhD, a professor in the McMaster department of pathology and molecular medicine.

“What we have found is striking and alarming, as this common synthetic food dye is a possible dietary trigger for IBDs,” he said. “The literature suggests that the consumption of Allura Red also affects certain allergies, immune disorders, and behavioural problems in children, such as attention deficit hyperactivity disorder.”

The human diet in Western cultures, with its reliance on processed fats, red and processed meat, and low fiber, contributes to IBDs as well, Dr. Khan said.

Food dyes such as Allura Red have been used more and more in recent years. Their effect on gut health hasn’t been studied much.

A version of this article first appeared on WebMD.com.

Dr Harold Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, reports on studies in HR+/HER2- breast cancer presented at the 2022 San Antonio Breast Cancer Symposium. 

Dr Burstein reports on the phase 2 RIGHT Choice study, which is the first head-to-head comparison of endocrine therapy plus a CDK4/6 inhibitor vs chemotherapy for stage IV breast cancer. The results indicate that frontline therapy using the combination is superior to chemotherapy.  

Dr Burstein next comments on the phase 3 CAPItello-291 trial, which looked at a new AKT inhibitor, capivasertib. The study compared capivasertib plus fulvestrant vs fulvestrant alone and found that the combination provided meaningful improvements in progression-free survival. He then reports on the phase 2 SERENA-2 trial, which compared fulvestrant with camizestrant, an oral selective estrogen receptor degrader, in the second-line setting. The study showed that camizestrant was superior to fulvestrant.  

An update of the phase 3 monarchE trial showed an increasing benefit from adding abemaciclib to endocrine therapy in the adjuvant setting, regardless of the Ki-67 index. 

In closing, Dr Burstein discusses the POSITIVE trial, which indicated that endocrine therapy can be safely interrupted in women whose breast cancer is in remission and who are pursuing pregnancy.  

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Harold Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, reports on studies in HR+/HER2- breast cancer presented at the 2022 San Antonio Breast Cancer Symposium. 

Dr Burstein reports on the phase 2 RIGHT Choice study, which is the first head-to-head comparison of endocrine therapy plus a CDK4/6 inhibitor vs chemotherapy for stage IV breast cancer. The results indicate that frontline therapy using the combination is superior to chemotherapy.  

Dr Burstein next comments on the phase 3 CAPItello-291 trial, which looked at a new AKT inhibitor, capivasertib. The study compared capivasertib plus fulvestrant vs fulvestrant alone and found that the combination provided meaningful improvements in progression-free survival. He then reports on the phase 2 SERENA-2 trial, which compared fulvestrant with camizestrant, an oral selective estrogen receptor degrader, in the second-line setting. The study showed that camizestrant was superior to fulvestrant.  

An update of the phase 3 monarchE trial showed an increasing benefit from adding abemaciclib to endocrine therapy in the adjuvant setting, regardless of the Ki-67 index. 

In closing, Dr Burstein discusses the POSITIVE trial, which indicated that endocrine therapy can be safely interrupted in women whose breast cancer is in remission and who are pursuing pregnancy.  

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Harold Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, reports on studies in HR+/HER2- breast cancer presented at the 2022 San Antonio Breast Cancer Symposium. 

Dr Burstein reports on the phase 2 RIGHT Choice study, which is the first head-to-head comparison of endocrine therapy plus a CDK4/6 inhibitor vs chemotherapy for stage IV breast cancer. The results indicate that frontline therapy using the combination is superior to chemotherapy.  

Dr Burstein next comments on the phase 3 CAPItello-291 trial, which looked at a new AKT inhibitor, capivasertib. The study compared capivasertib plus fulvestrant vs fulvestrant alone and found that the combination provided meaningful improvements in progression-free survival. He then reports on the phase 2 SERENA-2 trial, which compared fulvestrant with camizestrant, an oral selective estrogen receptor degrader, in the second-line setting. The study showed that camizestrant was superior to fulvestrant.  

An update of the phase 3 monarchE trial showed an increasing benefit from adding abemaciclib to endocrine therapy in the adjuvant setting, regardless of the Ki-67 index. 

In closing, Dr Burstein discusses the POSITIVE trial, which indicated that endocrine therapy can be safely interrupted in women whose breast cancer is in remission and who are pursuing pregnancy.  

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Breast cancer treatments have made great strides in recent years with significant reductions in overall mortality. However, the incidence of breast cancer has increased just slightly in recent years after a dip in the early 2000s.

“The good news is that mortality is decreasing, but it still remains high. We still have a long way to go to tackle this problem of breast cancer incidence as well as the number of deaths,” said Angela DeMichele, MD, co-leader of the breast cancer research program at the University of Pennsylvania’s Abramson Cancer Center. She participated in a session on obstacles in breast cancer treatment held in December at the San Antonio Breast Cancer Symposium. She joined other oncologists in outlining key challenges that need to be addressed to improve breast cancer diagnosis and treatment.

They highlighted six obstacles: The need for more prevention/early detection strategies; the underutilization of artificial intelligence; underuse of precision oncology such as targeted therapies; the need for innovation in clinical trials; a widening gap in cancer disparities; and the need to align incentives and funding for research collaboration, training, and retention.

Since 2012, the Food and Drug Administration has approved 20 new therapeutics to treat breast cancer. Nadia Harbeck, MD, PhD, director of the breast center at LMU University Hospital, Munich, said that the development of new therapies has in a way become a victim of its own success. Therapies and survival have improved, making it harder to compare novel therapies to the standard of care and prove a benefit. Treatment guidelines are changing so quickly that clinical trials are sometimes obsolete by the time they are published because of changes to the standard of care. That places a need on more real-world evidence that can be designed to be useful in the clinic, and AI can help here. “We need to convince regulators to act upon cleverly planned real world evidence analysis. You can randomize them, you can use registries, and you should also be able to change labels because of [new] data,” Dr. Harbeck said.

There are many risk factors that drive breast cancer, and it is very heterogeneous, said Christine Ambrosone, PhD, chair of the department of cancer prevention and control at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. She called for identifying patients who are at risk for a poor prognosis, such as patients with hormone receptor–negative breast cancer, high-grade, and triple-negative breast cancer. Otherwise there is a risk of overtreatment of low-risk tumors, which could potentially be identified with new tools in precision oncology such as liquid biopsy tests, also known as multicancer early detection tests. These tests can detect cancers long before they become symptomatic. The first such test was launched this year and many more are in clinical trials.

Regina Barzilay, PhD, professor and expert in the use of artificial intelligence in health at the Massachusetts Institute of Technology, pointed out that machine learning is used in many fields, but hardly at all in breast cancer. It could be applied to data on biomarkers and other factors collected from retrospective analyses and clinical trials. She added that machine learning is often applied to biochemistry and single cell analysis of other tumor types, but rarely in breast cancer. “It is severely underutilized,” Dr. Barzilay said. One challenge is that researchers are not necessarily familiar with the techniques of machine learning and AI. Another issue is that breast cancer data are not easy to share and may not be readily available to AI researchers. “An investment in interchangeable data is crucially important,” she said.

Artificial intelligence could assist in identifying and modeling factors that contribute to cancer risk by teasing apart complicated relationships, such as the association between pregnancy, breastfeeding, and breast cancer risk. Pregnancy reduces the risk of hormone receptor–positive disease, but increases the risk of hormone receptor–negative disease.

Another key challenge is the underuse of “omics” technologies, which measure large scale patterns in biological characteristics such as gene variation or protein expression. That has roots in the history of breast cancer being considered as a separate entity from other solid tumors such as lung or pancreatic cancer. Fabrice André, MD, PhD, an oncologist with Gustave Roussy Cancer Center, France, emphasized that breast cancer shouldn’t be considered an entity when it’s metastatic. Instead, tumors should be defined by molecular characteristics they share. He anticipates a personalized medicine future where academic and industry groups collaborate to create an individualized therapy for patients based on genetic factors.
 

Access to therapies for all patients

Novel and effective therapies can make a difference only if patients have access to them, and a key obstacle to improving breast cancer care is racism and inequities in health care. “We have to acknowledge that there is racism in medicine. I think once we acknowledge that, then we can look at things in our practices that we need to change. We can think very broadly and look at things that perhaps disadvantage one population over another,” said Lori Pierce, MD, a radiation oncologist with the University of Michigan, Ann Arbor.

Dr. Pierce also emphasized the need to recruit more underrepresented groups to participate in clinical trials. For example, of six breast cancer clinical trials – for margetuximab (Margenza), sacituzumab govitecan (Trodelvy), tucatinib (Tukysa), trastuzumab deruxtecan (Enhertu), alpelisib (Piqray), and talazoparib (Talzenna), only a small percentage included Black, Asian, and Hispanic women. For trastuzumab deruxtecan, which is widely recognized as a best-in-class HER2-targeting antibody drug conjugate, 51% were White, 42% Asian, 6% Hispanic, and 3% Black. For sacituzumab govitecan, a blockbuster drug for triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer that disproportionately affects Black women, only 7% of women enrolled in clinical trials were Black. In clinical trials for margetuximab, approved to treat HER2-positive breast cancer, 80% of participants were White, 5% Black, 6% Asian, and 9% Hispanic.

There is a perception that minorities may be unwilling to participate in clinical trials, but that’s not true, according to Patty Spears, a research manager of the Patient Advocates for Research Council at the University of North Carolina. “We know that there are data that clearly show that patients will go on clinical trials at the same rate, whether they’re Black, White, Asian, or whatever. You have to be able to have them in your system and ask them to go on trial,” she said.

Another panelist told a personal anecdote to illustrate the point. Matthew Ellis, MD, PhD, recalled that he spent 13 years at Washington University in St. Louis, serving one of the more segregated cities in the United States. The city hospital closed, and Washington University and the Siteman Cancer Center signed a contract to treat the underserved population that was suddenly without a source of care. “Subsequent to that, we over-accrued relative to the population of African American patients. What that taught me is it’s nothing to do with the lack of willingness of African Americans to participate in clinical trials. Quite the opposite. It’s the question of access to clinical trials, access to great care, and not creating health care systems that segregate patients into places where they’re not getting access,” he said.

Breast cancer treatments have made great strides in recent years with significant reductions in overall mortality. However, the incidence of breast cancer has increased just slightly in recent years after a dip in the early 2000s.

“The good news is that mortality is decreasing, but it still remains high. We still have a long way to go to tackle this problem of breast cancer incidence as well as the number of deaths,” said Angela DeMichele, MD, co-leader of the breast cancer research program at the University of Pennsylvania’s Abramson Cancer Center. She participated in a session on obstacles in breast cancer treatment held in December at the San Antonio Breast Cancer Symposium. She joined other oncologists in outlining key challenges that need to be addressed to improve breast cancer diagnosis and treatment.

They highlighted six obstacles: The need for more prevention/early detection strategies; the underutilization of artificial intelligence; underuse of precision oncology such as targeted therapies; the need for innovation in clinical trials; a widening gap in cancer disparities; and the need to align incentives and funding for research collaboration, training, and retention.

Since 2012, the Food and Drug Administration has approved 20 new therapeutics to treat breast cancer. Nadia Harbeck, MD, PhD, director of the breast center at LMU University Hospital, Munich, said that the development of new therapies has in a way become a victim of its own success. Therapies and survival have improved, making it harder to compare novel therapies to the standard of care and prove a benefit. Treatment guidelines are changing so quickly that clinical trials are sometimes obsolete by the time they are published because of changes to the standard of care. That places a need on more real-world evidence that can be designed to be useful in the clinic, and AI can help here. “We need to convince regulators to act upon cleverly planned real world evidence analysis. You can randomize them, you can use registries, and you should also be able to change labels because of [new] data,” Dr. Harbeck said.

There are many risk factors that drive breast cancer, and it is very heterogeneous, said Christine Ambrosone, PhD, chair of the department of cancer prevention and control at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. She called for identifying patients who are at risk for a poor prognosis, such as patients with hormone receptor–negative breast cancer, high-grade, and triple-negative breast cancer. Otherwise there is a risk of overtreatment of low-risk tumors, which could potentially be identified with new tools in precision oncology such as liquid biopsy tests, also known as multicancer early detection tests. These tests can detect cancers long before they become symptomatic. The first such test was launched this year and many more are in clinical trials.

Regina Barzilay, PhD, professor and expert in the use of artificial intelligence in health at the Massachusetts Institute of Technology, pointed out that machine learning is used in many fields, but hardly at all in breast cancer. It could be applied to data on biomarkers and other factors collected from retrospective analyses and clinical trials. She added that machine learning is often applied to biochemistry and single cell analysis of other tumor types, but rarely in breast cancer. “It is severely underutilized,” Dr. Barzilay said. One challenge is that researchers are not necessarily familiar with the techniques of machine learning and AI. Another issue is that breast cancer data are not easy to share and may not be readily available to AI researchers. “An investment in interchangeable data is crucially important,” she said.

Artificial intelligence could assist in identifying and modeling factors that contribute to cancer risk by teasing apart complicated relationships, such as the association between pregnancy, breastfeeding, and breast cancer risk. Pregnancy reduces the risk of hormone receptor–positive disease, but increases the risk of hormone receptor–negative disease.

Another key challenge is the underuse of “omics” technologies, which measure large scale patterns in biological characteristics such as gene variation or protein expression. That has roots in the history of breast cancer being considered as a separate entity from other solid tumors such as lung or pancreatic cancer. Fabrice André, MD, PhD, an oncologist with Gustave Roussy Cancer Center, France, emphasized that breast cancer shouldn’t be considered an entity when it’s metastatic. Instead, tumors should be defined by molecular characteristics they share. He anticipates a personalized medicine future where academic and industry groups collaborate to create an individualized therapy for patients based on genetic factors.
 

Access to therapies for all patients

Novel and effective therapies can make a difference only if patients have access to them, and a key obstacle to improving breast cancer care is racism and inequities in health care. “We have to acknowledge that there is racism in medicine. I think once we acknowledge that, then we can look at things in our practices that we need to change. We can think very broadly and look at things that perhaps disadvantage one population over another,” said Lori Pierce, MD, a radiation oncologist with the University of Michigan, Ann Arbor.

Dr. Pierce also emphasized the need to recruit more underrepresented groups to participate in clinical trials. For example, of six breast cancer clinical trials – for margetuximab (Margenza), sacituzumab govitecan (Trodelvy), tucatinib (Tukysa), trastuzumab deruxtecan (Enhertu), alpelisib (Piqray), and talazoparib (Talzenna), only a small percentage included Black, Asian, and Hispanic women. For trastuzumab deruxtecan, which is widely recognized as a best-in-class HER2-targeting antibody drug conjugate, 51% were White, 42% Asian, 6% Hispanic, and 3% Black. For sacituzumab govitecan, a blockbuster drug for triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer that disproportionately affects Black women, only 7% of women enrolled in clinical trials were Black. In clinical trials for margetuximab, approved to treat HER2-positive breast cancer, 80% of participants were White, 5% Black, 6% Asian, and 9% Hispanic.

There is a perception that minorities may be unwilling to participate in clinical trials, but that’s not true, according to Patty Spears, a research manager of the Patient Advocates for Research Council at the University of North Carolina. “We know that there are data that clearly show that patients will go on clinical trials at the same rate, whether they’re Black, White, Asian, or whatever. You have to be able to have them in your system and ask them to go on trial,” she said.

Another panelist told a personal anecdote to illustrate the point. Matthew Ellis, MD, PhD, recalled that he spent 13 years at Washington University in St. Louis, serving one of the more segregated cities in the United States. The city hospital closed, and Washington University and the Siteman Cancer Center signed a contract to treat the underserved population that was suddenly without a source of care. “Subsequent to that, we over-accrued relative to the population of African American patients. What that taught me is it’s nothing to do with the lack of willingness of African Americans to participate in clinical trials. Quite the opposite. It’s the question of access to clinical trials, access to great care, and not creating health care systems that segregate patients into places where they’re not getting access,” he said.

Breast cancer treatments have made great strides in recent years with significant reductions in overall mortality. However, the incidence of breast cancer has increased just slightly in recent years after a dip in the early 2000s.

“The good news is that mortality is decreasing, but it still remains high. We still have a long way to go to tackle this problem of breast cancer incidence as well as the number of deaths,” said Angela DeMichele, MD, co-leader of the breast cancer research program at the University of Pennsylvania’s Abramson Cancer Center. She participated in a session on obstacles in breast cancer treatment held in December at the San Antonio Breast Cancer Symposium. She joined other oncologists in outlining key challenges that need to be addressed to improve breast cancer diagnosis and treatment.

They highlighted six obstacles: The need for more prevention/early detection strategies; the underutilization of artificial intelligence; underuse of precision oncology such as targeted therapies; the need for innovation in clinical trials; a widening gap in cancer disparities; and the need to align incentives and funding for research collaboration, training, and retention.

Since 2012, the Food and Drug Administration has approved 20 new therapeutics to treat breast cancer. Nadia Harbeck, MD, PhD, director of the breast center at LMU University Hospital, Munich, said that the development of new therapies has in a way become a victim of its own success. Therapies and survival have improved, making it harder to compare novel therapies to the standard of care and prove a benefit. Treatment guidelines are changing so quickly that clinical trials are sometimes obsolete by the time they are published because of changes to the standard of care. That places a need on more real-world evidence that can be designed to be useful in the clinic, and AI can help here. “We need to convince regulators to act upon cleverly planned real world evidence analysis. You can randomize them, you can use registries, and you should also be able to change labels because of [new] data,” Dr. Harbeck said.

There are many risk factors that drive breast cancer, and it is very heterogeneous, said Christine Ambrosone, PhD, chair of the department of cancer prevention and control at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. She called for identifying patients who are at risk for a poor prognosis, such as patients with hormone receptor–negative breast cancer, high-grade, and triple-negative breast cancer. Otherwise there is a risk of overtreatment of low-risk tumors, which could potentially be identified with new tools in precision oncology such as liquid biopsy tests, also known as multicancer early detection tests. These tests can detect cancers long before they become symptomatic. The first such test was launched this year and many more are in clinical trials.

Regina Barzilay, PhD, professor and expert in the use of artificial intelligence in health at the Massachusetts Institute of Technology, pointed out that machine learning is used in many fields, but hardly at all in breast cancer. It could be applied to data on biomarkers and other factors collected from retrospective analyses and clinical trials. She added that machine learning is often applied to biochemistry and single cell analysis of other tumor types, but rarely in breast cancer. “It is severely underutilized,” Dr. Barzilay said. One challenge is that researchers are not necessarily familiar with the techniques of machine learning and AI. Another issue is that breast cancer data are not easy to share and may not be readily available to AI researchers. “An investment in interchangeable data is crucially important,” she said.

Artificial intelligence could assist in identifying and modeling factors that contribute to cancer risk by teasing apart complicated relationships, such as the association between pregnancy, breastfeeding, and breast cancer risk. Pregnancy reduces the risk of hormone receptor–positive disease, but increases the risk of hormone receptor–negative disease.

Another key challenge is the underuse of “omics” technologies, which measure large scale patterns in biological characteristics such as gene variation or protein expression. That has roots in the history of breast cancer being considered as a separate entity from other solid tumors such as lung or pancreatic cancer. Fabrice André, MD, PhD, an oncologist with Gustave Roussy Cancer Center, France, emphasized that breast cancer shouldn’t be considered an entity when it’s metastatic. Instead, tumors should be defined by molecular characteristics they share. He anticipates a personalized medicine future where academic and industry groups collaborate to create an individualized therapy for patients based on genetic factors.
 

Access to therapies for all patients

Novel and effective therapies can make a difference only if patients have access to them, and a key obstacle to improving breast cancer care is racism and inequities in health care. “We have to acknowledge that there is racism in medicine. I think once we acknowledge that, then we can look at things in our practices that we need to change. We can think very broadly and look at things that perhaps disadvantage one population over another,” said Lori Pierce, MD, a radiation oncologist with the University of Michigan, Ann Arbor.

Dr. Pierce also emphasized the need to recruit more underrepresented groups to participate in clinical trials. For example, of six breast cancer clinical trials – for margetuximab (Margenza), sacituzumab govitecan (Trodelvy), tucatinib (Tukysa), trastuzumab deruxtecan (Enhertu), alpelisib (Piqray), and talazoparib (Talzenna), only a small percentage included Black, Asian, and Hispanic women. For trastuzumab deruxtecan, which is widely recognized as a best-in-class HER2-targeting antibody drug conjugate, 51% were White, 42% Asian, 6% Hispanic, and 3% Black. For sacituzumab govitecan, a blockbuster drug for triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer that disproportionately affects Black women, only 7% of women enrolled in clinical trials were Black. In clinical trials for margetuximab, approved to treat HER2-positive breast cancer, 80% of participants were White, 5% Black, 6% Asian, and 9% Hispanic.

There is a perception that minorities may be unwilling to participate in clinical trials, but that’s not true, according to Patty Spears, a research manager of the Patient Advocates for Research Council at the University of North Carolina. “We know that there are data that clearly show that patients will go on clinical trials at the same rate, whether they’re Black, White, Asian, or whatever. You have to be able to have them in your system and ask them to go on trial,” she said.

Another panelist told a personal anecdote to illustrate the point. Matthew Ellis, MD, PhD, recalled that he spent 13 years at Washington University in St. Louis, serving one of the more segregated cities in the United States. The city hospital closed, and Washington University and the Siteman Cancer Center signed a contract to treat the underserved population that was suddenly without a source of care. “Subsequent to that, we over-accrued relative to the population of African American patients. What that taught me is it’s nothing to do with the lack of willingness of African Americans to participate in clinical trials. Quite the opposite. It’s the question of access to clinical trials, access to great care, and not creating health care systems that segregate patients into places where they’re not getting access,” he said.

Dr Peter Martin, from Weill Cornell Medicine in New York, NY, highlights breakthroughs and developments in mantle cell lymphoma presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition. 

Dr Martin begins with the top-ranked abstract from the meeting, a European trial that looked at ibrutinib as a substitute for autologous stem cell transplantation (ASCT) in younger patients. The results suggest that the era of upfront ASCT may now be over. 

Next, he reports on a trial that investigated the addition of the second-generation BTK inhibitor acalabrutinib to lenalidomide and rituximab. The combination provided excellent clinical responses, indicating that mantle cell lymphoma patients may soon be able to avoid chemotherapy altogether. 

The next trial selected by Dr Martin examined whether the addition of lenalidomide to consolidation rituximab after first-line bendamustine-rituximab would improve survival outcomes. The study reported no additional benefit, at the cost of increased adverse events. 

Dr Martin closes by discussing two trials in the relapsed/refractory setting, one a phase 1 trial of the bispecific antibody glofitamab, the other a phase 1b-2 trial of venetoclax with lenalidomide and rituximab. Both showed encouraging results that point to potential future treatment strategies. 

--

Associate Professor of Medicine, Weill Cornell Medicine, New York, NY 

Peter Martin, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca; ADCT; BeiGene; Bristol Myers Squibb; Epizyme; Genentech; Gilead; Janssen; Takeda 

Dr Peter Martin, from Weill Cornell Medicine in New York, NY, highlights breakthroughs and developments in mantle cell lymphoma presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition. 

Dr Martin begins with the top-ranked abstract from the meeting, a European trial that looked at ibrutinib as a substitute for autologous stem cell transplantation (ASCT) in younger patients. The results suggest that the era of upfront ASCT may now be over. 

Next, he reports on a trial that investigated the addition of the second-generation BTK inhibitor acalabrutinib to lenalidomide and rituximab. The combination provided excellent clinical responses, indicating that mantle cell lymphoma patients may soon be able to avoid chemotherapy altogether. 

The next trial selected by Dr Martin examined whether the addition of lenalidomide to consolidation rituximab after first-line bendamustine-rituximab would improve survival outcomes. The study reported no additional benefit, at the cost of increased adverse events. 

Dr Martin closes by discussing two trials in the relapsed/refractory setting, one a phase 1 trial of the bispecific antibody glofitamab, the other a phase 1b-2 trial of venetoclax with lenalidomide and rituximab. Both showed encouraging results that point to potential future treatment strategies. 

--

Associate Professor of Medicine, Weill Cornell Medicine, New York, NY 

Peter Martin, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca; ADCT; BeiGene; Bristol Myers Squibb; Epizyme; Genentech; Gilead; Janssen; Takeda 

Dr Peter Martin, from Weill Cornell Medicine in New York, NY, highlights breakthroughs and developments in mantle cell lymphoma presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition. 

Dr Martin begins with the top-ranked abstract from the meeting, a European trial that looked at ibrutinib as a substitute for autologous stem cell transplantation (ASCT) in younger patients. The results suggest that the era of upfront ASCT may now be over. 

Next, he reports on a trial that investigated the addition of the second-generation BTK inhibitor acalabrutinib to lenalidomide and rituximab. The combination provided excellent clinical responses, indicating that mantle cell lymphoma patients may soon be able to avoid chemotherapy altogether. 

The next trial selected by Dr Martin examined whether the addition of lenalidomide to consolidation rituximab after first-line bendamustine-rituximab would improve survival outcomes. The study reported no additional benefit, at the cost of increased adverse events. 

Dr Martin closes by discussing two trials in the relapsed/refractory setting, one a phase 1 trial of the bispecific antibody glofitamab, the other a phase 1b-2 trial of venetoclax with lenalidomide and rituximab. Both showed encouraging results that point to potential future treatment strategies. 

--

Associate Professor of Medicine, Weill Cornell Medicine, New York, NY 

Peter Martin, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca; ADCT; BeiGene; Bristol Myers Squibb; Epizyme; Genentech; Gilead; Janssen; Takeda 

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

Test

Test

Test

The U.S. Food and Drug Administration has approved mosunetuzumab-axgb (Lunsumio) for use in patients with relapsed or refractory follicular lymphoma who have received at least two previous systemic therapies.

This product is a first-in-class bispecific antibody that is designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells, according to the manufacturer, Genentech.

Mosunetuzumab-axgb is administered as an intravenous infusion for a fixed duration, which allows for time off therapy, and can be infused in an outpatient setting, the company noted.

The drug was granted an accelerated approval on the basis of response rate data from the phase 2 GO29781 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial, the company noted.

The GO29781 study was carried out in individuals with pretreated follicular lymphoma, including those who were at high risk for disease progression or whose disease was refractory to prior therapies.

A complete response was achieved in 60% of patients (54 of 90).

An objective response rate (a combination of complete and partial responses) was seen in 80% of patients who received the drug, with a majority maintaining responses for at least 18 months.

The median duration of response among those who responded was 22.8 months.

Safety data come from 218 patients with hematologic cancers who received mosunetuzumab-axgb at the recommended dose. The most common adverse event was cytokine release syndrome (39%), which can be severe and life-threatening. The median duration of cytokine release syndrome events was 3 days (range, 1-29 days). Other common adverse events (≥ 20%) included fatigue, rash, pyrexia, and headache.

“This approval is a significant milestone for people with relapsed or refractory follicular lymphoma, who have had limited treatment options until now,” said Elizabeth Budde, MD, PhD, from the City of Hope, Los Angeles, division of lymphoma, and clinical trial investigator.

Dr. Budde presented data on mosunetuzumab-axgb at the 2021 annual meeting of the American Society of Hematology, as reported by this news organization.

She noted that the 60% complete response rate seen with this new drug contrasts with the 14% that has been seen for historical controls.

“We have seen deep and durable responses in heavily pretreated, high-risk relapsed/refractory follicular lymphoma patients with fixed-duration treatment. We also observed a very favorable tolerability profile, with most cytokine release syndrome confined to cycle 1 and low grade, and treatment administration is without mandatory hospitalization,” she commented at the time.

A lymphoma specialist who was not involved in the study told this news organization at the time that he was favorably impressed by the findings.

“To me, the single-agent data looks really outstanding, with a response rate of 80%, a complete response rate of 60%, and a median duration of response of 23 months, and really very acceptable rates of cytokine release syndrome,” commented Brad S. Kahl, MD, from the Siteman Cancer Center and Washington University in St. Louis.

“I think as a single agent – if it does get approval – it will be a really valuable addition to the armamentarium in follicular lymphoma,” he added.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved mosunetuzumab-axgb (Lunsumio) for use in patients with relapsed or refractory follicular lymphoma who have received at least two previous systemic therapies.

This product is a first-in-class bispecific antibody that is designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells, according to the manufacturer, Genentech.

Mosunetuzumab-axgb is administered as an intravenous infusion for a fixed duration, which allows for time off therapy, and can be infused in an outpatient setting, the company noted.

The drug was granted an accelerated approval on the basis of response rate data from the phase 2 GO29781 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial, the company noted.

The GO29781 study was carried out in individuals with pretreated follicular lymphoma, including those who were at high risk for disease progression or whose disease was refractory to prior therapies.

A complete response was achieved in 60% of patients (54 of 90).

An objective response rate (a combination of complete and partial responses) was seen in 80% of patients who received the drug, with a majority maintaining responses for at least 18 months.

The median duration of response among those who responded was 22.8 months.

Safety data come from 218 patients with hematologic cancers who received mosunetuzumab-axgb at the recommended dose. The most common adverse event was cytokine release syndrome (39%), which can be severe and life-threatening. The median duration of cytokine release syndrome events was 3 days (range, 1-29 days). Other common adverse events (≥ 20%) included fatigue, rash, pyrexia, and headache.

“This approval is a significant milestone for people with relapsed or refractory follicular lymphoma, who have had limited treatment options until now,” said Elizabeth Budde, MD, PhD, from the City of Hope, Los Angeles, division of lymphoma, and clinical trial investigator.

Dr. Budde presented data on mosunetuzumab-axgb at the 2021 annual meeting of the American Society of Hematology, as reported by this news organization.

She noted that the 60% complete response rate seen with this new drug contrasts with the 14% that has been seen for historical controls.

“We have seen deep and durable responses in heavily pretreated, high-risk relapsed/refractory follicular lymphoma patients with fixed-duration treatment. We also observed a very favorable tolerability profile, with most cytokine release syndrome confined to cycle 1 and low grade, and treatment administration is without mandatory hospitalization,” she commented at the time.

A lymphoma specialist who was not involved in the study told this news organization at the time that he was favorably impressed by the findings.

“To me, the single-agent data looks really outstanding, with a response rate of 80%, a complete response rate of 60%, and a median duration of response of 23 months, and really very acceptable rates of cytokine release syndrome,” commented Brad S. Kahl, MD, from the Siteman Cancer Center and Washington University in St. Louis.

“I think as a single agent – if it does get approval – it will be a really valuable addition to the armamentarium in follicular lymphoma,” he added.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved mosunetuzumab-axgb (Lunsumio) for use in patients with relapsed or refractory follicular lymphoma who have received at least two previous systemic therapies.

This product is a first-in-class bispecific antibody that is designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells, according to the manufacturer, Genentech.

Mosunetuzumab-axgb is administered as an intravenous infusion for a fixed duration, which allows for time off therapy, and can be infused in an outpatient setting, the company noted.

The drug was granted an accelerated approval on the basis of response rate data from the phase 2 GO29781 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial, the company noted.

The GO29781 study was carried out in individuals with pretreated follicular lymphoma, including those who were at high risk for disease progression or whose disease was refractory to prior therapies.

A complete response was achieved in 60% of patients (54 of 90).

An objective response rate (a combination of complete and partial responses) was seen in 80% of patients who received the drug, with a majority maintaining responses for at least 18 months.

The median duration of response among those who responded was 22.8 months.

Safety data come from 218 patients with hematologic cancers who received mosunetuzumab-axgb at the recommended dose. The most common adverse event was cytokine release syndrome (39%), which can be severe and life-threatening. The median duration of cytokine release syndrome events was 3 days (range, 1-29 days). Other common adverse events (≥ 20%) included fatigue, rash, pyrexia, and headache.

“This approval is a significant milestone for people with relapsed or refractory follicular lymphoma, who have had limited treatment options until now,” said Elizabeth Budde, MD, PhD, from the City of Hope, Los Angeles, division of lymphoma, and clinical trial investigator.

Dr. Budde presented data on mosunetuzumab-axgb at the 2021 annual meeting of the American Society of Hematology, as reported by this news organization.

She noted that the 60% complete response rate seen with this new drug contrasts with the 14% that has been seen for historical controls.

“We have seen deep and durable responses in heavily pretreated, high-risk relapsed/refractory follicular lymphoma patients with fixed-duration treatment. We also observed a very favorable tolerability profile, with most cytokine release syndrome confined to cycle 1 and low grade, and treatment administration is without mandatory hospitalization,” she commented at the time.

A lymphoma specialist who was not involved in the study told this news organization at the time that he was favorably impressed by the findings.

“To me, the single-agent data looks really outstanding, with a response rate of 80%, a complete response rate of 60%, and a median duration of response of 23 months, and really very acceptable rates of cytokine release syndrome,” commented Brad S. Kahl, MD, from the Siteman Cancer Center and Washington University in St. Louis.

“I think as a single agent – if it does get approval – it will be a really valuable addition to the armamentarium in follicular lymphoma,” he added.

A version of this article first appeared on Medscape.com.